Cannabinoid Es

Contents
Cannabinoid
1.1
1.2
Cannabinoid receptors
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1.1
Cannabinoid receptor type 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1.2
Cannabinoid receptor type 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.1
Cannabis-derived cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.2
Cannabinoids from other plants
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.3
Cannabis plant prole
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.4
Pharmacology
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.5
Separation
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.6
Natural occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2.7
History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Endocannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3.1
Types of endocannabinoid ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3.2
Function
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.4
Synthetic cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.5
Table of natural cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.6
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.7
References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.8
Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.9
External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
1.9.1
Cannabinoid information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
1.9.2
Cannabinoid research organizations
10
1.3
Phytocannabinoids
. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Entourage eect
11
2.1
External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
2.2
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
Synthetic cannabis
12
3.1
Misnomer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
3.2
Ingredients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
3.2.1
Articial cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
3.3
ii
CONTENTS
3.4
Drug testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
3.5
Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
3.5.1
Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
3.5.2
South America . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
3.5.3
Asia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
3.5.4
Australasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
3.5.5
North America . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15
History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
3.6.1
Slang terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
3.7
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16
3.8
External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
3.6
4-HTMPIPO
21
4.1
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
4.2
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
5F-PB-22
22
5.1
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
5.2
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22
A-40174
23
6.1
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
6.2
References
23
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A-41988
24
7.1
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
7.2
References
24
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A-796,260
25
8.1
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
25
8.2
References
25
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A-834,735
26
9.1
See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
9.2
References
26
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10 A-836,339
10.1 References
27
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11 AB-001
27
28
11.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28
11.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28
12 AB-005
12.1 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
29
CONTENTS
iii
12.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
12.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
13 AB-CHMINACA
30
13.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14 AB-FUBINACA
30
31
14.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31
14.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31
15 AB-PINACA
32
15.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
15.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
16 Abnormal cannabidiol
33
16.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33
16.2 References
33
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17 ADB-FUBINACA
35
17.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35
17.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35
18 ADB-PINACA
36
18.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
36
18.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
36
19 ADBICA
37
19.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
37
19.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
37
20 Ajulemic acid
20.1 References
38
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21 AM-087
38
39
21.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39
21.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39
22 AM-1220
40
22.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
40
22.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
40
23 AM-1221
41
23.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41
23.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41
24 AM-1235
42
iv
CONTENTS
24.1 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
24.1.1 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
24.1.2 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
24.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
24.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
42
25 AM-1241
43
25.1 Eects in bone cancer model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
43
25.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
43
25.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
43
26 AM-1248
45
26.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45
26.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
45
27 AM-1714
46
27.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
46
27.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
46
28 AM-2201
47
28.1 Hazards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
28.2 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
47
28.3 Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
28.4 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
28.5 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47
29 AM-2232
48
29.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
48
29.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
48
30 AM-2233
49
30.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
49
30.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
49
31 AM-2389
50
31.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
50
31.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
50
32 AM-4030
51
32.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
51
32.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
51
33 AM-411
33.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
52
52
CONTENTS
33.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
34 AM-630
52
53
34.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
53
34.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
53
35 AM-6545
54
35.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
54
35.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
54
36 AM-679 (cannabinoid)
55
36.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
55
36.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
55
37 AM-694
56
37.1 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56
56
37.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56
37.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56
38 AM-855
57
38.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
39 AM-905
57
58
39.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
40 AM-906
58
59
40.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
59
40.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
59
41 AM-919
60
41.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
60
41.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
60
42 AM-938
61
42.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
61
42.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
61
43 AM404
62
43.1 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
43.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
62
43.3 References
62
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
44 AMG-1
44.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
63
63
vi
CONTENTS
45 AMG-3
64
45.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
46 AMG-36
64
65
46.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
47 AMG-41
65
66
47.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
48 APINACA
66
67
48.1 Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
67
48.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
67
48.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
67
49 AR-231,453
68
49.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
68
49.2 References
68
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
50 Arachidonyl-2'-chloroethylamide
50.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
51 Arachidonylcyclopropylamide
51.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
52 N-Arachidonylglycine
69
69
70
70
71
52.1 Synthesis
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
52.2 Research
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
52.2.1 Eects on the nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
52.2.2 Eects on the immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
52.2.3 Cell migration
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71
52.2.4 Other targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
72
52.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
72
53 AZ-11713908
74
53.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
74
53.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
74
54 BAY 38-7271
54.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
55 BAY 59-3074
55.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56 BML-190
56.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
75
75
76
76
77
77
CONTENTS
vii
57 (C6)-CP 47,497
78
57.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

58 (C9)-CP 47,497
78
79
58.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

59 Canbisol
79
80
59.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
80
59.2 References
80
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
60 Cannabichromene
81
60.1 Medical uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
81
60.2 References
81
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
61 Cannabicyclohexanol
82
61.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
82
61.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
82
62 Cannabicyclol
83
62.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
83
62.2 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
83
63 Cannabidiol
84
63.1 Clinical applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
84
63.1.1 Antimicrobial actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
84
63.1.2 Neurological eects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
84
63.1.3 Psychotropic eect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
84
63.1.4 Dravet syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.2 CBD-enhanced cannabis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.3 Industrial hemp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.4 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.4.1 Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.4.2 Pharmacokinetic interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.4.3 Pharmaceutical preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.5 Isomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
85
63.6 Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
86
63.6.1 Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
86
63.7 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
86
63.8 US patent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
86
63.9 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
87
63.10External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
89
64 Cannabidivarin
64.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
90
90
viii
CONTENTS
64.2 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
90
64.3 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
90
65 Cannabigerol
91
65.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
91
65.2 References
91
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
66 Cannabinoidergic
92
66.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
92
66.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
92
67 Cannabinol
93
67.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
93
67.2 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
93
67.3 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
93
68 Cannabivarin
68.1 References
94
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
94
68.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
94
68.3 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
94
69 Caryophyllene
95
69.1 Natural sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
95
69.2 Compendial status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
95
69.3 Notes and references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
95
70 CB-13
98
70.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
98
70.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
98
71 CBS-0550
99
71.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
99
71.2 References
99
72 CP 47,497
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
100
72.1 Homologue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

72.2 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
72.2.1 Germany . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
72.2.2 France . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
72.2.3 Latvia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
72.2.4 Lithuania . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
72.2.5 Sweden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
72.2.6 Romania . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
72.2.7 United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
CONTENTS
ix
72.3 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

72.4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
73 CP 55,244
102
73.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

73.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
74 CP 55,940
103
74.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

74.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
75 Dexanabinol
104
75.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

76 Dimethylheptylpyran
105
76.1 Eects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

76.2 Investigation as non-lethal incapacitating agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
76.3 Isomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
76.4 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
77 Docosatetraenoylethanolamide
107
77.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

78 Drinabant
108
78.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108

78.2 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
79 EAM-2201
109
79.1 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

79.2 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
79.3 Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
79.4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
80 Endocannabinoid reuptake inhibitor
110
80.1 Etymology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110

80.2 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
80.3 Use in medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
80.4 Examples of eCBRIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
80.5 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
80.6 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
81 Endocannabinoid system
112
81.1 Basic overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112

81.1.1 Expression of receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
81.1.2 Endocannabinoid synthesis, release, and degradation . . . . . . . . . . . . . . . . . . . . . 112
CONTENTS
81.1.3 Binding and intracellular eects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
81.1.4 Binding and neuronal excitability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
81.2 Functions of the endocannabinoid system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
81.2.1 Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
81.2.2 Appetite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
81.2.3 Energy balance & metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
81.2.4 Stress response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
81.2.5 Immune function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
81.2.6 Female reproduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
81.2.7 Autonomic nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
81.2.8 Analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
81.2.9 Thermoregulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
81.2.10 Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
81.3 Experimental use of CB1 -/- phenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
81.4 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
81.5 Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
81.6 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
82 Endocannabinoid transporters
82.1 References
83 GW-405,833
120
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
121
83.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

84 GW-842,166X
84.1 References
85 Hemopressin
122
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
123
85.1 Role in diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

85.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
85.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
86 HU-210
124
86.1 Recreational use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

86.2 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
86.2.1 United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
86.2.2 New Zealand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
86.3 Other HU Cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
86.4 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
86.5 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
86.6 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
87 HU-243
126
87.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
CONTENTS
87.2 References
xi
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
88 HU-308
127
88.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

88.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
89 HU-331
128
89.1 Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

89.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
89.3 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
90 11-Hydroxy-THC
90.1 References
130
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
91 9-nor-9-Hydroxyhexahydrocannabinol
131
91.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

91.2 References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
92 Ibipinabant
132
92.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132

92.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
93 IDFP
133
93.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

93.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
94 2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4-nonylphenyl)cyclohex-1-ene
134
94.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134

95 JTE 7-31
135
95.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

95.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
96 JTE-907
136
96.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

96.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
97 JWH-015
137
97.1 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

97.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
98 JWH-051
138
98.1 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138

99 JWH-057
139
99.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
xii
CONTENTS
99.2 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
100JWH-120
140
100.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140

100.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
101JWH-122
141
101.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

101.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
102JWH-133
142
102.1Legal Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

102.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
102.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

103JWH-148
143
103.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143

103.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
104JWH-149
144
104.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144

104.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
105JWH-161
145
105.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
106JWH-176
146
106.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146

106.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
107JWH-359
147
107.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
108JZL184
148
108.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148

108.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
109JZL195
149
109.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149

109.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
110KM-233
150
110.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

110.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
111L-759,633
151
CONTENTS
xiii
111.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

111.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
112L-759,656
152
112.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

112.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
113LASSBio-881
153
113.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
114LBP-1 (drug)
154
114.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

114.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
115Leelamine
155
115.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

115.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
116Levonantradol
156
116.1Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
116.2Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
116.3Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
116.4Side eects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
116.5See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
116.6Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
116.7References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
117List of AM cannabinoids
158
117.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

117.2Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
117.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
118List of JWH cannabinoids
161
118.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

118.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
119LY-2183240
164
119.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

119.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
120LY-320,135
165
120.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
121MAM-2201
166
121.1Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
xiv
CONTENTS
121.1.1 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
121.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
122MDA-19
167
122.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

122.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
123Menabitan
168
123.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168

123.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
124Methanandamide
169
124.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
125MK-9470
170
125.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
126N-(S)-Fenchyl-1-(2-morpholinoethyl)7-methoxyindole-3-carboxamide
171
126.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

126.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
126.3Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
127Nabazenil
127.1References
128Nabilone
173
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
174
128.1Medical uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

128.2Adverse eects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
128.3See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
128.4References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
129Nabitan
129.1References
130Nabiximols
176
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
177
130.1Availability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
130.2Eectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
130.3Side eects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
130.4Controversy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
130.5See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
130.6References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
130.7External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
131Naboctate
131.1References
180
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
CONTENTS
xv
132NESS-0327
181
132.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

132.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
133NESS-040C5
182
133.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182

133.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
134NMP-7
183
134.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
135Nonabine
135.1References
184
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
13611-nor-9-Carboxy-THC
136.1References
137O-1057
185
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
187
137.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187

137.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
138O-1125
188
138.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
139O-1238
189
139.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
140O-1269
190
140.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
141O-1602
191
141.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

141.2References
142O-1812
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
192
142.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

142.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
143O-1871
193
143.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

143.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
144O-1918
194
144.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

144.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
xvi
CONTENTS
145O-2050
195
145.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

145.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
146O-2113
196
146.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

146.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
147O-2372
197
147.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197

147.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
148O-2545
198
148.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198

148.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
149O-2694
199
149.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

149.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
150O-774
200
150.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

150.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
151O-806
201
151.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
152O-823
202
152.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
153Org 27569
153.1References
154Org 28312
203
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
204
154.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

154.2References
155Org 28611
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
205
155.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

155.2References
156Otenabant
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
206
156.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206

156.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
157Parahexyl
207
CONTENTS
xvii
157.1Isomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
157.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
157.3References
158UR-144
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
208
158.1Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
158.2History of use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
158.3Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
158.4See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
158.5References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
158.6Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
159Perrottetinene
159.1References
160PF-03550096
210
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
211
160.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211

160.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
161PF-514273
212
161.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
162PipISB
213
162.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
163Pirnabine
163.1References
164PSB-SB-1202
214
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
215
164.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215

164.2References
165PSB-SB-487
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
216
165.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216

165.2References
166QUCHIC
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
217
166.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

166.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
167QUPIC
218
167.1Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
167.2Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
167.3See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
167.4References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
xviii
CONTENTS
168Rimonabant
219
168.1History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
168.2Uses/potential uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
168.2.1 Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
168.2.2 Smoking cessation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
168.2.3 Addiction behaviors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
168.2.4 Short-term memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
168.2.5 Blockage of cannabis eects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
168.3Other eects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
168.4Negative side eects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
168.5Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
168.6Brand names . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
168.7References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
169Rosonabant
222
169.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

169.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
170S-444,823
223
170.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223

170.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
171SDB-001
224
171.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

171.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
172SDB-006
225
172.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

172.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
173SER-601
226
173.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

173.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
174Serinolamide A
227
174.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

174.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
175SR-144,528
228
175.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228

175.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
176Stearoylethanolamide
229
176.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
CONTENTS
xix
177STS-135 (drug)
230
177.1Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
177.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
177.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
178Surinabant
231
178.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

178.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
179Taranabant
232
179.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

179.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
180Tedalinab
233
180.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233

180.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
181Tetrad test
234
181.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
182Tetrahydrocannabinol
182.1Eects
235
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
182.1.1 Appetite and taste
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
182.2Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
182.2.1 Discovery and structure identication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
182.2.2 Isomerism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
182.3Medical uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
182.3.1 Multiple sclerosis symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
182.3.2 Neurodegenerative disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
182.3.3 Other neurological disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
182.3.4 Other studies in humans
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
182.4Adverse eects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237

182.4.1 Acute toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
182.4.2 Cognitive eects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
182.4.3 Impact on psychosis
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
182.4.4 Other potential long-term eects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238

182.4.5 Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
182.5Mechanism of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
182.6Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
182.7Chemical synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
182.8Marinol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
182.8.1 Comparisons with medical marijuana
. . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
xx
CONTENTS
182.9Regulatory history
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
182.10See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241

182.11References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
182.12Further reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244

182.13External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
183Tetrahydrocannabinol-C4
246
183.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246

183.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
184Tetrahydrocannabinolic acid
247
184.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247

184.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
185Tetrahydrocannabivarin
249
185.1Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
185.2Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
185.3See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
185.4References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
185.5External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249

186THC-O-acetate
250
186.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
187THC-O-phosphate
187.1References
188Tinabinol
251
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
252
188.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252

188.2References
189URB602
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
253
189.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
190URB754
254
190.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
191VCHSR
255
191.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
192VDM-11
256
192.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256

192.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
193WIN 54,461
257
193.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
CONTENTS
193.2References
xxi
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
194WIN 55,212-2
258
194.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258

194.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
194.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259

195WIN 56,098
260
195.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260

195.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
196XLR-11 (drug)
261
196.1Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
196.2Recreational use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
196.3Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
196.4See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
196.5References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
197AM251
263
197.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263

197.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
198Aminoalkylindole
264
198.1Legality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
198.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
198.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
199Cannabipiperidiethanone
265
199.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265

199.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
200JWH-193
266
200.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266

200.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
201JWH-198
267
201.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267

201.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
202JWH-200
268
202.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268

202.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
203Pravadoline
269
203.1Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
xxii
CONTENTS
203.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269

203.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
204RCS-4
270
204.1Legality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
204.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
204.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
205Anandamide
271
205.1History
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
205.2Physiological functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271

205.3Synthesis and degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
205.4Medical benets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
205.5See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
205.6References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
205.7External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273

206N-Arachidonoyl dopamine
274
206.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274

206.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
206.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274

2072-Arachidonoylglycerol
275
207.1Occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
207.2Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
207.3Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
207.4Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
207.5See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
207.6References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
207.6.1 Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
207.6.2 General references . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
2082-Arachidonyl glyceryl ether
277
208.1Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
208.2Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
208.3Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
208.4See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
208.5References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
208.6External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278

209Oleamide
279
209.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279

209.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
CONTENTS
xxiii
210RVD-Hp
280
210.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280
211Virodhamine
281
211.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281

211.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
212HU-320
282
212.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282

212.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
213HU-336
283
213.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283

213.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
214HU-345
284
214.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284

214.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284
215Raphael Mechoulam
285
215.1Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
215.2Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
215.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
215.4Podcasts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
216John W. Human
286
216.1Law enforcement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286

216.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
216.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
217JWH-007
287
217.1Law . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
217.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
217.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
218Naphthoylindole
218.1History
288
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
218.2Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
218.3Usage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
218.4Detection in biological uids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
218.5Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
218.6Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
218.7See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
xxiv
CONTENTS
218.8References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
218.9External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291

219JWH-019
292
219.1Legal Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292

219.1.1 Poland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
219.1.2 Sweden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
219.1.3 UK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
219.1.4 USA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
219.2See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
219.3References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
220JWH-030
293
220.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293

220.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
221JWH-047
294
221.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294

221.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
222JWH-048
295
222.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295

222.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
223JWH-073
296
223.1Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
223.2Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
223.3Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
223.3.1 United States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
223.3.2 Australia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
223.3.3 New Zealand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
223.4See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
223.5References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
224JWH-081
298
224.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298

224.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
225JWH-098
299
225.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299

225.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
226JWH-116
300
226.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300
CONTENTS
xxv
226.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300
227JWH-147
301
227.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301

227.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
228JWH-164
302
228.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
229Phenylacetylindole
303
229.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
230JWH-175
304
230.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304

230.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
231JWH-184
305
231.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305

231.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
232JWH-185
306
232.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306

232.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
233JWH-196
307
233.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

233.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
234JWH-203
308
234.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308

234.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308
235JWH-210
309
235.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309

235.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
236JWH-249
310
236.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310

236.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310
237JWH-250
311
237.1History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
237.2References
238JWH-251
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
312
238.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
xxvi
CONTENTS
239JWH-302
313
239.1References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
240JWH-307
314
240.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314

240.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314
241JWH-398
315
241.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315

241.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
242JWH-424
316
242.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316

242.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
243Naphthoylindole
243.1History
317
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
243.2Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
243.3Usage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
243.4Detection in biological uids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
243.5Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
243.6Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
243.7See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
243.8References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
243.9External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320

244Phenylacetylindole
321
244.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
245RCS-8
322
245.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322

245.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
246Intravenous Marijuana Syndrome
323
246.1References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
247Mellow Yellow coeeshop
324
247.1Citations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
247.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
247.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324

248The Night Train Seizure
325
248.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325

248.2References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
CONTENTS
249PSN-375,963
xxvii
326
249.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326

249.2References
250PSN-632,408
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
327
250.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327

250.2References
251Soma Seeds
251.1References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
328
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
251.2External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328

252TM-38837
329
252.1See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329

252.2References
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
252.3External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329

252.4Text and image sources, contributors, and licenses . . . . . . . . . . . . . . . . . . . . . . . . . . 330
252.4.1 Text . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
252.4.2 Images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
252.4.3 Content license . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
Chapter 1
Cannabinoid
Cannabinoids are a class of diverse chemical compounds that act on cannabinoid receptors on cells that
repress neurotransmitter release in the brain. These
receptor proteins include the endocannabinoids (produced naturally in the body by humans and animals),[1]
the phytocannabinoids (found in cannabis and some
other plants), and synthetic cannabinoids (manufactured chemically). The most notable cannabinoid is
the phytocannabinoid 9 -tetrahydrocannabinol (THC),
the primary psychoactive compound of cannabis.[2][3]
Cannabidiol (CBD) is another major constituent of the
plant, representing up to 40% in extracts of the plant
resin.[4] There are at least 85 dierent cannabinoids isolated from cannabis, exhibiting varied eects.[5]
including the hippocampus.[1] They are also found in the

cerebellum and in both male and female reproductive systems. CB1 receptors are absent in the medulla oblongata,
the part of the brain stem responsible for respiratory and
cardiovascular functions. Thus, there is not the risk of
respiratory or cardiovascular failure that can be produced
by some drugs. CB1 receptors appear to be responsible
for the euphoric and anticonvulsive eects of cannabis.
Synthetic cannabinoids encompass a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids
(cannabimimetics) including the aminoalkylindoles, 1,5diarylpyrazoles, quinolines, and arylsulfonamides, as well
as eicosanoids related to the endocannabinoids.[2]
CB2 receptors are predominantly found in the immune

system, or immune-derived cells[8] with the greatest density in the spleen. While found only in the peripheral
nervous system, a report does indicate that CB2 is expressed by a subpopulation of microglia in the human
cerebellum.[9] CB2 receptors appear to be responsible for
the anti-inammatory and possibly other therapeutic effects of cannabis.[8]
1.1.2 Cannabinoid receptor type 2

Main article: Cannabinoid receptor type 2
1.1 Cannabinoid receptors

1.2 Phytocannabinoids
Before the 1980s, it was often speculated that cannabinoids produced their physiological and behavioral eects
via nonspecic interaction with cell membranes, instead
of interacting with specic membrane-bound receptors.
The discovery of the rst cannabinoid receptors in the
1980s helped to resolve this debate. These receptors are
common in animals, and have been found in mammals,
birds, sh, and reptiles. At present, there are two known
types of cannabinoid receptors, termed CB1 and CB2 ,[1]
with mounting evidence of more.[6] The human brain has
more cannabinoid receptors than any other G proteincoupled receptor (GPCR) type.[7]
1.1.1
1.2.1 Cannabis-derived cannabinoids

The classical cannabinoids are concentrated in a viscous resin produced in structures known as glandular
trichomes. At least 85 dierent cannabinoids have been
isolated from the Cannabis plant[5] To the right, the main
classes of cannabinoids from Cannabis are shown. The
best studied cannabinoids include tetrahydrocannabinol
(THC), cannabidiol (CBD) and cannabinol (CBN).
Types
Cannabinoid receptor type 1
All classes derive from cannabigerol-type compounds and

dier mainly in the way this precursor is cyclized.[10] The
classical cannabinoids are derived from their respective
CB1 receptors are found primarily in the brain, more 2-carboxylic acids (2-COOH) by decarboxylation (catspecically in the basal ganglia and in the limbic system, alyzed by heat, light, or alkaline conditions).[11]
Main article: Cannabinoid receptor type 1
CHAPTER 1. CANNABINOID
Tetrahydrocannabinol
Main
article:
Tetrahydrocannabinol (THC) is the primary psychoactive component of the Cannabis plant.

Delta9tetrahydrocannabinol (9 -THC, THC) and delta8tetrahydrocannabinol (8 -THC), mimic the action of
anandamide, a neurotransmitter produced naturally in the
body. These two THCs produce the eects associated
with cannabis by binding to the CB1 cannabinoid receptors in the brain. THC appears to ease moderate pain
(analgesic) and to be neuroprotective, while also oering
the potential to reduce neuroinammation and to stimulate neurogenesis.[12] THC has approximately equal anity for the CB1 and CB2 receptors.[13]
The bracts surrounding a cluster of Cannabis sativa owers are
coated with cannabinoid-laden trichomes
Cannabidiol
Main article: Cannabidiol
Cannabidiol (CBD) is not psychoactive, and was thought

not to aect the psychoactivity of THC.[14] However,
recent evidence shows that smokers of cannabis with
a higher CBD/THC ratio were less likely to experience schizophrenia-like symptoms.[15] This is supported
by psychological tests, in which participants experience
less intense psychotic-like eects when intravenous THC
was co-administered with CBD (as measured with a
PANSS test).[16] Cannabidiol has little anity for CB1
and CB2 receptors but acts as an indirect antagonist of
cannabinoid agonists.[17] Recently it was found to be
an antagonist at the putative new cannabinoid receptor, GPR55, a GPCR expressed in the caudate nucleus
and putamen.[18] Cannabidiol has also been shown to act
as a 5-HTA receptor agonist,[19] an action that is involved in its antidepressant,[20][21] anxiolytic,[21][22] and
neuroprotective[23][24] eects.
Cannabis indica plant
CBG (Cannabigerol)
CBC (Cannabichromene)
CBL (Cannabicyclol)
CBV (Cannabivarin)
THCV (Tetrahydrocannabivarin)
CBDV (Cannabidivarin)
CBCV (Cannabichromevarin)
CBGV (Cannabigerovarin)
CBGM (Cannabigerol Monomethyl Ether)
It appears to relieve convulsion, inammation, anxiety,

and nausea.[17] CBD has a greater anity for the CB2
receptor than for the CB1 receptor.[17]
CBD shares a precursor with THC and is the main
cannabinoid in low-THC Cannabis strains. CBD apparently plays a role in preventing the short-term memory
loss associated with THC in mammals.
Some research suggests that the antipsychotic eects of
cannabidiol potentially represent a novel mechanism in
the treatment of schizophrenia.[25]
Researchers at California Pacic Medical Center discovered CBDs ability to turn o the activity of ID1, the
gene responsible for metastasis in breast and other types
of cancers, including the particularly aggressive triple
negative breast cancer.[26][27][28] The researchers hope to
start human trials soon.[29]
Cannabinol
Main article: Cannabinol
1.2. PHYTOCANNABINOIDS
Cannabinol (CBN) is the primary product of THC degradation, and there is usually little of it in a fresh plant. CBN
content increases as THC degrades in storage, and with
exposure to light and air. It is only mildly psychoactive.
Its anity to the CB2 receptor is higher than for the CB1
receptor.[30]
Cannabigerol
Main article: Cannabigerol
There is potential for confusion because there are different numbering systems used to describe the position
of this double bond. Under the dibenzopyran numbering system widely used today, the major form of THC
is called 9 -THC, while the minor form is called 8 THC. Under the alternate terpene numbering system,
these same compounds are called 1 -THC and 6 -THC,
respectively.
Length
Most classical cannabinoids are 21-carbon
compounds. However, some do not follow this rule, primarily because of variation in the length of the side-chain
attached to the aromatic ring. In THC, CBD, and CBN,
this side-chain is a pentyl (5-carbon) chain. In the most
common homologue, the pentyl chain is replaced with a
propyl (3-carbon) chain. Cannabinoids with the propyl
side-chain are named using the sux varin, and are desarticle:
ignated, for example, THCV, CBDV, or CBNV.
Cannabigerol (CBG) is non-psychotomimetic but still affects the overall eects of Cannabis. It acts as an 2 adrenergic receptor agonist, 5-HTA receptor antagonist,
and CB1 receptor antagonist.[31] It also binds to the CB2
receptor.[31]
Tetrahydrocannabivarin
Main
Tetrahydrocannabivarin (THCV) is prevalent in cer- 1.2.2 Cannabinoids from other plants

tain central Asian and southern African strains of
Cannabis.[32][33] It is an antagonist of THC at CB1 recep- Phytocannabinoids are known to occur in several plant
species besides cannabis. These include Echinacea
tors and attenuates the psychoactive eects of THC.[34]
purpurea, Echinacea angustifolia, Echinacea pallida,
Acmella oleracea, Helichrysum umbraculigerum, and
Cannabidivarin Main article: Cannabidivarin
Radula marginata.[36] The best-known cannabinoids that
are not derived from Cannabis are the lipophilic alka[36]
At
Although cannabidivarin (CBDV) is usually a minor mides (alkylamides) from Echinacea species.
least
25
dierent
alkylamides
(dodeca-2E,4E,8Z,10E/Zconstituent of the cannabinoid prole, enhanced levels
of CBDV have been reported in feral cannabis plants tetraenoic-acid-isobutylamides) have been identied, and
them have shown anities to the CB2 from the northwest Himalayas, and in hashish from some of[37][38]
receptor.
In Echinacea species, cannabinoids are
[33][35]
Nepal.
found throughout the plant structure, but are most concentrated in the roots and owers.[39][40] Yangonin found
in the Kava plant is a ligand on the CB1 receptor.[41]
Cannabichromene Main article: Cannabichromene
Tea (Camellia sinensis) catechins have an anity for
human cannabinoid receptors.[42] A widespread dietary
Cannabichromene (CBC) is non-psychoactive and does
cannabinoid, beta-caryophyllene, a component from the
not aect the psychoactivity of THC.[14] More comessential oil of cannabis and other medicinal plants, has
mon in tropical cannabis varieties. Eects include antialso been identied as a selective agonist of peripheral
inammatory and analgesic.
CB2 -receptors, in vivo.[43]
Biosynthesis Cannabinoid production starts when an
enzyme causes geranyl pyrophosphate and olivetolic acid
to combine and form CBGA. Next, CBGA is independently converted to either CBG, THCA, CBDA or CBCA
by four separate synthase, FAD-dependent dehydrogenase enzymes. There is no evidence for enzymatic conversion of CBDA or CBD to THCA or THC. For the
propyl homologues (THCVA, CBDVA and CBCVA),
there is a similar pathway that is based on CBGVA from
divarinolic acid instead of olivetolic acid.
Most of the phytocannabinoids are nearly insoluble in water but are soluble in lipids, alcohols, and other non-polar
organic solvents.
1.2.3 Cannabis plant prole
Cannabis plants can exhibit wide variation in the quantity

and type of cannabinoids they produce. The mixture of
cannabinoids produced by a plant is known as the plants
cannabinoid prole. Selective breeding has been used to
control the genetics of plants and modify the cannabinoid
prole. For example, strains that are used as ber (comDouble bond position In addition, each of the commonly called hemp) are bred such that they are low in psypounds above may be in dierent forms depending on the choactive chemicals like THC. Strains used in medicine
position of the double bond in the alicyclic carbon ring. are often bred for high CBD content, and strains used for
recreational purposes are usually bred for high THC con- 1.2.6 Natural occurrence
tent or for a specic chemical balance.
Quantitative analysis of a plants cannabinoid prole is of- Main article: Medical_cannabis Dierence between
ten determined by gas chromatography (GC), or more re- C. indica and C. sativa
liably by gas chromatography combined with mass spectrometry (GC/MS). Liquid chromatography (LC) techniques are also possible, and, unlike GC methods, can
dierentiate between the acid and neutral forms of the
cannabinoids. There have been systematic attempts to
monitor the cannabinoid prole of cannabis over time,
but their accuracy is impeded by the illegal status of the
plant in many countries.
Cannabis indica may have a CBD:THC ratio 45 times

that of Cannabis sativa.
1.2.7 History
Cannabinoids were rst discovered in the 1940s, when
CBD and CBN were identied. The structure of THC
was rst determined in 1964.
Due to molecular similarity and ease of synthetic conversion, CBD was originally believed to be a natural pre1.2.4 Pharmacology
cursor to THC. However, it is now known that CBD and
THC are produced independently in the cannabis plant
Cannabinoids can be administered by smoking, vaporizfrom the precursor CBG.
ing, oral ingestion, transdermal patch, intravenous injection, sublingual absorption, or rectal suppository. Once in
the body, most cannabinoids are metabolized in the liver,
especially by cytochrome P450 mixed-function oxidases, 1.3 Endocannabinoids
mainly CYP 2C9. Thus supplementing with CYP 2C9
inhibitors leads to extended intoxication.
For more details on the roles and regulation of the endoSome is also stored in fat in addition to being metabo- cannabinoids, see Endocannabinoid system.
lized in the liver. 9 -THC is metabolized to 11-hydroxy- Endocannabinoids are substances produced from within
9 -THC, which is then metabolized to 9-carboxy-THC.
Some cannabis metabolites can be detected in the body
several weeks after administration. These metabolites
are the chemicals recognized by common antibody-based
drug tests"; in the case of THC or others, these loads
do not represent intoxication (compare to ethanol breath
tests that measure instantaneous blood alcohol levels), but
an integration of past consumption over an approximately
month-long window. This is because they are fat-soluble,
lipophilic molecules that accumulate in fatty tissues.[44]
1.2.5
Separation
Cannabinoids can be separated from the plant by

extraction with organic solvents. Hydrocarbons and
alcohols are often used as solvents. However, these solvents are ammable and many are toxic. Butane may be
used, which evaporates extremely quickly. Supercritical
solvent extraction with carbon dioxide is an alternative
technique. Although this process requires high pressures
(73 atmospheres or more), there is minimal risk of re
or toxicity, solvent removal is simple and ecient, and
extract quality can be well controlled. Once extracted,
cannabinoid blends can be separated into individual components using wiped lm vacuum distillation or other
distillation techniques. However, to produce high-purity
cannabinoids, chemical synthesis or semisynthesis is generally required.
Anandamide, an endogenous ligand of CB1 and CB2
the body that activate cannabinoid receptors. After the

discovery of the rst cannabinoid receptor in 1988, scientists began searching for an endogenous ligand for the
receptor.
1.3.1 Types of endocannabinoid ligands

Arachidonoylethanolamine (Anandamide or AEA)
Main article: Arachidonoylethanolamine
In 1992, in Raphael Mechoulam's lab, the rst such compound was identied as arachidonoyl ethanolamine and
named anandamide, a name derived from the Sanskrit
1.3. ENDOCANNABINOIDS
word for bliss and -amide. Anandamide is derived from
arachidonic acid. It has a pharmacology similar to THC,
although its chemical structure is dierent. Anandamide
binds to the central (CB1 ) and, to a lesser extent, peripheral (CB2 ) cannabinoid receptors, where it acts as a
partial agonist. Anandamide is about as potent as THC
at the CB1 receptor.[45] Anandamide is found in nearly
all tissues in a wide range of animals.[46] Anandamide
has also been found in plants, including small amounts
in chocolate.[47]
Two
analogs
of
anandamide,
7,10,13,16docosatetraenoylethanolamide
and
homo-linolenoylethanolamine, have similar pharmacology.
All of these are members of a family of signalling
lipids called N-acylethanolamines, which also includes
the noncannabimimetic palmitoylethanolamide and
oleoylethanolamide, which possess anti-inammatory
and orexigenic eects, respectively.
Many Nacylethanolamines have also been identied in plant
seeds[48] and in molluscs.[49]
2-Arachidonoylglycerol (2-AG)
5
N-Arachidonoyl dopamine (NADA)
Main article: N-Arachidonoyl dopamine
Discovered in 2000, NADA preferentially binds to the
CB1 receptor.[54] Like anandamide, NADA is also an
agonist for the vanilloid receptor subtype 1 (TRPV1), a
member of the vanilloid receptor family.[55][56]
Virodhamine (OAE)
Main article: Virodhamine
A fth endocannabinoid, virodhamine, or Oarachidonoyl-ethanolamine (OAE), was discovered
in June 2002. Although it is a full agonist at CB2 and
a partial agonist at CB1 , it behaves as a CB1 antagonist in vivo. In rats, virodhamine was found to be
present at comparable or slightly lower concentrations
than anandamide in the brain, but 2- to 9-fold higher
concentrations peripherally.[57]
Main article: 2-Arachidonoylglycerol

Another endocannabinoid, 2-arachidonoylglycerol, binds
to both the CB1 and CB2 receptors with similar anity, acting as a full agonist at both.[45] 2-AG is present
at signicantly higher concentrations in the brain than
anandamide,[50] and there is some controversy over
whether 2-AG rather than anandamide is chiey responsible for endocannabinoid signalling in vivo.[1] In particular, one in vitro study suggests that 2-AG is capable of
stimulating higher G-protein activation than anandamide,
although the physiological implications of this nding are
not yet known.[51]
2-Arachidonyl glyceryl ether (noladin ether)

Main article: 2-Arachidonyl glyceryl ether
Lysophosphatidylinositol (LPI)
Recent evidence has highlighted lysophosphatidylinositol
as the endogenous ligand to novel endocannabinoid receptor GPR55, making it a strong contender as the sixth
endocannabinoid.[58]
1.3.2 Function
Endocannabinoids serve as intercellular 'lipid messengers', signaling molecules that are released from one
cell and activating the cannabinoid receptors present on
other nearby cells. Although in this intercellular signaling role they are similar to the well-known monoamine
neurotransmitters, such as acetylcholine and dopamine,
endocannabinoids dier in numerous ways from them.
For instance, they are used in retrograde signaling between neurons. Furthermore, endocannabinoids are
lipophilic molecules that are not very soluble in water.
They are not stored in vesicles, and exist as integral constituents of the membrane bilayers that make up cells.
They are believed to be synthesized 'on-demand' rather
than made and stored for later use. The mechanisms
and enzymes underlying the biosynthesis of endocannabinoids remain elusive and continue to be an area of active
research.
In 2001, a third, ether-type endocannabinoid, 2arachidonyl glyceryl ether (noladin ether), was isolated
from porcine brain.[52] Prior to this discovery, it had been
synthesized as a stable analog of 2-AG; indeed, some controversy remains over its classication as an endocannabinoid, as another group failed to detect the substance at
any appreciable amount in the brains of several dierent mammalian species.[53] It binds to the CB1 cannabinoid receptor (K = 21.2 nmol/L) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds primarily to the CB1 receptor, and The endocannabinoid 2-AG has been found in bovine and
human maternal milk.[59]
only weakly to the CB2 receptor.[45]
6
Retrograde signal
Dronabinol (Marinol), is 9 -tetrahydrocannabinol
(THC), used as an appetite stimulant, anti-emetic,
and analgesic
Conventional neurotransmitters are released from a

presynaptic cell and activate appropriate receptors on
Nabilone (Cesamet, Canemes), a synthetic cannabia postsynaptic cell, where presynaptic and postsynaptic
noid and an analog of Marinol. It is Schedule II undesignate the sending and receiving sides of a synapse,
like Marinol, which is Schedule III
respectively. Endocannabinoids, on the other hand, are
described as retrograde transmitters because they most
Sativex, a cannabinoid extract oral spray containing
commonly travel backward against the usual synaptic
THC, CBD, and other cannabinoids used for neutransmitter ow. They are, in eect, released from the
ropathic pain and spasticity in 22 countries includpostsynaptic cell and act on the presynaptic cell, where
ing England, Canada and Spain. Sativex develops
the target receptors are densely concentrated on axonal
whole-plant cannabinoid medicines
terminals in the zones from which conventional neurotransmitters are released. Activation of cannabinoid re Rimonabant (SR141716), a selective cannabinoid
ceptors temporarily reduces the amount of conventional
(CB1 ) receptor inverse agonist once used as an antineurotransmitter released. This endocannabinoid mediobesity
drug under the proprietary name Acomplia.
ated system permits the postsynaptic cell to control its
It
was
also
used for smoking cessation
own incoming synaptic trac. The ultimate eect on
the endocannabinoid-releasing cell depends on the nature of the conventional transmitter being controlled. For Other notable synthetic cannabinoids include:
instance, when the release of the inhibitory transmitter
GABA is reduced, the net eect is an increase in the ex JWH-018, a potent synthetic cannabinoid agonist
citability of the endocannabinoid-releasing cell. On the
discovered by Dr. John W. Human at Clemson
converse, when release of the excitatory neurotransmitUniversity. It is being increasingly sold in legal
ter glutamate is reduced, the net eect is a decrease in
smoke blends collectively known as spice. Several
the excitability of the endocannabinoid-releasing cell.
countries and states have moved to ban it legally.
Range
Endocannabinoids are hydrophobic molecules. They cannot travel unaided for long distances in the aqueous
medium surrounding the cells from which they are released, and therefore act locally on nearby target cells.
Hence, although emanating diusely from their source
cells, they have much more restricted spheres of inuence
than do hormones, which can aect cells throughout the
body.
1.4 Synthetic cannabinoids

Historically, laboratory synthesis of cannabinoids were
often based on the structure of herbal cannabinoids, and
a large number of analogs have been produced and tested,
especially in a group led by Roger Adams as early as 1941
and later in a group led by Raphael Mechoulam. Newer
compounds are no longer related to natural cannabinoids
or are based on the structure of the endogenous cannabinoids.
Synthetic cannabinoids are particularly useful in experiments to determine the relationship between the structure and activity of cannabinoid compounds, by making systematic, incremental modications of cannabinoid
molecules.
JWH-073
CP-55940, produced in 1974, this synthetic
cannabinoid receptor agonist is many times more
potent than THC.
Dimethylheptylpyran
HU-210, about 100 times as potent as THC[60]
HU-331 a potential anti-cancer drug derived from
cannabidiol that specically inhibits topoisomerase
II.
SR144528, a CB2 receptor antagonist
WIN 55,212-2, a potent cannabinoid receptor
agonist
JWH-133, a potent selective CB2 receptor agonist
Levonantradol (Nantrodolum), an anti-emetic and
analgesic but not currently in use in medicine
AM-2201, a potent cannabinoid receptor agonist
1.5 Table of natural cannabinoids
Medications containing natural or synthetic cannabinoids From es:Cannabinoide#Tabla de cannabinoides naturales.

or cannabinoid analogs:
1.7. REFERENCES
1.6 See also

Cannabinoid receptor antagonist
Cancer and nausea
1.7 References
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[29] Marijuana Compound Fights Cancer; Human Trials
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Mary E.; Beletskaya, Irina; Razdan, Raj K. (2000).
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Pertwee, RG (2010). Evidence that the plant cannabinoid cannabigerol is a highly potent 2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. British Journal of Pharmacology 159 (1): 12941.
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[38] Raduner, S; Majewska, A; Chen, J; Xie, X; Hamon, J;
Faller, B; Altmann, K; Gertsch, J (2006). Alkylamides
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AND
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IMMUNOMODULATORY EFFECTS (PDF). J. Biol. Chem. 281 (20):
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[39] Perry, Nigel; Van Klink, John; Burgess, Elaine; Parmenter, Graeme (2007). Alkamide Levels inEchinacea
purpurea: A Rapid Analytical Method Revealing Dierences among Roots, Rhizomes, Stems, Leaves and Flowers. Planta Medica 63 (1): 5862. doi:10.1055/s-2006957605. PMID 17252329.
[40] He, X; Lin, L; Bernart, MW; Lian, L (1998). Analysis
of alkamides in roots and achenes of Echinacea purpurea
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[41] Ligresti, A.; Villano, R.; Allar, M.; Ujvry, I. N.; Di
Marzo, V. (2012). Kavalactones and the endocannabinoid system: The plant-derived yangonin is a novel CB1
1.8. FURTHER READING
receptor ligand. Pharmacological Research 66 (2): 163

169. doi:10.1016/j.phrs.2012.04.003. PMID 22525682.
[42] Korte, G.; Dreiseitel, A.; Schreier, P.; Oehme, A.;
Locher, S.; Geiger, S.; Heilmann, J.; Sand, P.G.
(2010). Tea catechins anity for human cannabinoid receptors.
Phytomedicine 17 (1): 1922.
doi:10.1016/j.phymed.2009.10.001. PMID 19897346.
[43] Gertsch, J; Leonti, M; Raduner, S; Racz, I; Chen, J;
Xie, X; Altmann, K; Karsak, M; Zimmer, A (2008).
Beta-caryophyllene is a dietary cannabinoid. PNAS 105
(26): 90999104. doi:10.1073/pnas.0803601105. PMC
2449371. PMID 18574142.
[44] Ashton CH (February 2001). Pharmacology and eects
of cannabis: a brief review. Br J Psychiatry 178 (2):
101106. doi:10.1192/bjp.178.2.101. PMID 11157422.
Because they are extremely lipid soluble, cannabinoids
accumulate in fatty tissues, reaching peak concentrations
in 4-5 days. They are then slowly released back into other
body compartments, including the brain. They are then
slowly released back into other body compartments, including the brain. Because of the sequestration in fat, the
tissue elimination half-life of THC is about 7 days, and
complete elimination of a single dose may take up to 30
days.
[52] Hanu, Lumr; Abu-La, Saleh; Fride, Ester; Breuer,

Aviva; Vogel, Zvi; Shalev, Deborah E.; Kustanovich,
Irina; Mechoulam, Raphael (2001). 2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1
receptor. Proceedings of the National Academy of Sciences 98 (7): 36625. doi:10.1073/pnas.061029898.
PMC 31108. PMID 11259648.
[53] Oka, Saori; Tsuchie, Akiko; Tokumura, Akira; Muramatsu, Mayumi; Suhara, Yoshitomo; Takayama, Hiroaki; Waku, Keizo; Sugiura, Takayuki (2003). Etherlinked analogue of 2-arachidonoylglycerol (noladin ether)
was not detected in the brains of various mammalian
species. Journal of Neurochemistry 85 (6): 1374
81. doi:10.1046/j.1471-4159.2003.01804.x. PMID
12787057.
[54] Bisogno, Tiziana; Melck, Dominique; Bobrov, Mikhail
Yu.; Gretskaya, Natalia M.; Bezuglov, Vladimir V.;
De Petrocellis, Luciano; Di Marzo, Vincenzo (2000).
N-acyl-dopamines: Novel synthetic CB1 cannabinoidreceptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo.
Biochemical Journal 351 (3): 81724. doi:10.1042/02646021:3510817. PMC 1221424. PMID 11042139.
[45] Grotenhermen, Franjo (2005). Cannabinoids. Current

Drug Target -CNS & Neurological Disorders 4 (5): 507.
doi:10.2174/156800705774322111.
[55] Bisogno, T; Ligresti, A; Dimarzo, V (2005). The endocannabinoid signalling system: Biochemical aspects.
38. doi:10.1016/j.pbb.2005.01.027. PMID 15935454.
[46] Martin, B.R.; Mechoulam, R.; Razdan, R.K. (1999).

Discovery and characterization of endogenous cannabinoids. Life Sciences 65 (67): 573. doi:10.1016/S00243205(99)00281-7.
[56] Ralevic, Vera (2003). Cannabinoid modulation of

peripheral autonomic and sensory neurotransmission.
European Journal of Pharmacology 472 (12): 121.
doi:10.1016/S0014-2999(03)01813-2. PMID 12860468.
[47] Di Tomaso, Emmanuelle; Beltramo, Massimiliano; Piomelli, Daniele (1996). Brain cannabinoids in chocolate. Nature 382 (6593): 6778. doi:10.1038/382677a0.
PMID 8751435.
[57] Porter, A. C.; Sauer, JM; Knierman, MD; Becker, GW;

Berna, MJ; Bao, J; Nomikos, GG; Carter, P; Bymaster,
FP; Leese, AB; Felder, CC (2002). Characterization
of a Novel Endocannabinoid, Virodhamine, with Antagonist Activity at the CB1 Receptor. Journal of Pharmacology and Experimental Therapeutics 301 (3): 10204.
doi:10.1124/jpet.301.3.1020. PMID 12023533.
[48] Chapman, K. D.; Venables, B; Markovic, R; Blair Jr, RW;

Bettinger, C (1999). N-Acylethanolamines in Seeds.
Quantication of Molecular Species and Their Degradation upon Imbibition. Plant Physiology 120 (4): 1157
64. doi:10.1104/pp.120.4.1157. PMC 59349. PMID
10444099.
[49] Sepe, Nunzio; De Petrocellis, Luciano; Montanaro,
Francesca; Cimino, Guido; Di Marzo, Vincenzo (1998).
Bioactive long chain N-acylethanolamines in ve species
of edible bivalve molluscs. Biochimica et Biophysica Acta
(BBA) Lipids and Lipid Metabolism 1389 (2): 10111.
doi:10.1016/S0005-2760(97)00132-X. PMID 9461251.
[50] Piomelli, Daniele; Schweitzer, Nephi; Piomelli, Paul
(1997). A second endogenous cannabinoid that modulates long-term potentiation. Nature 388 (6644): 7738.
doi:10.1038/42015. PMID 9285589.
[51] Savinainen, Juha R; Jrvinen, Tomi; Laine, Krista; Laitinen, Jarmo T (2001). Despite substantial degradation, 2arachidonoylglycerol is a potent full ecacy agonist mediating CB1receptor-dependent G-protein activation in rat
cerebellar membranes. British Journal of Pharmacology 134 (3): 66472. doi:10.1038/sj.bjp.0704297. PMC
1572991. PMID 11588122.
[58] Pieiro, Roberto; Falasca, Marco (2012). Lysophosphatidylinositol signalling: New wine from an old bottle. Biochimica et Biophysica Acta (BBA) Molecular and Cell Biology of Lipids 1821 (4): 694705.
doi:10.1016/j.bbalip.2012.01.009. PMID 22285325.
[59] Fride, E; Bregman, T; Kirkham, TC (2005). Endocannabinoids and food intake: Newborn suckling and appetite regulation in adulthood. Experimental biology and
medicine 230 (4): 22534. PMID 15792943.
[60] More medicinal uses for marijuana. Marijuana.org.
October 18, 2005. Archived from the original on 200512-21. Retrieved 2014-01-15.
1.8 Further reading

De Meijer, EP; Bagatta, M; Carboni, A; Crucitti, P;
Moliterni, VM; Ranalli, P et al. (2003). The inheritance of chemical phenotype in Cannabis sativa L.
10
Genetics 163 (1): 33546. PMC 1462421. PMID
12586720.
Devane, W.; Hanus, L; Breuer, A; Pertwee, R.;

Stevenson, L.; Grin, G et al. (1992). Isolation
and structure of a brain constituent that binds to the
cannabinoid receptor. Science 258 (5090): 1946
9. doi:10.1126/science.1470919. PMID 1470919.
Elsohly, Mahmoud A.; Slade, Desmond (2005).
Chemical constituents of marijuana: The complex mixture of natural cannabinoids. Life Sciences
78 (5): 53948. doi:10.1016/j.lfs.2005.09.011.
PMID 16199061.
Racz, I.; Nadal, X.; Alferink, J.; Baos, J. E.;

Rehnelt, J.; Martn, M. et al. (2008). Crucial Role
of CB2 Cannabinoid Receptor in the Regulation
of Central Immune Responses during Neuropathic
Pain. Journal of Neuroscience 28 (46): 1212535.
doi:10.1523/JNEUROSCI.3400-08.2008.
PMC
3844839. PMID 19005077.
Turner, C. E.; Mole, M. L.; Hanus, L.; Elsohly, H.
N. (1981). Constituents of Cannabis sativa. XIX.
Isolation and Structure Elucidation of Cannabiglendol, A Novel Cannabinoid from an Indian Variant. Journal of Natural Products 44 (1): 2733.
doi:10.1021/np50013a005.
Hanus, Lumir; Gopher, Asher; Almog, Shlomo;

Mechoulam, Raphael (1993). Two new unsaturated fatty acid ethanolamides in brain 1.9
that bind to the cannabinoid receptor. Journal of Medicinal Chemistry 36 (20): 30324. 1.9.1
doi:10.1021/jm00072a026. PMID 8411021.
Hanus, L (1987). Biogenesis of cannabinoid substances in the plant. Acta Universitatis Palackianae
Olomucensis Facultatis Medicae 116: 4753. PMID
2962461.
Hanu, L.; Krej, Z. (1975). Isolation of two
new cannabinoid acids from Cannabis sativa L. of
Czechoslovak origin. Acta Univ. Olomuc., Fac.
Med 74: 161166.
Hanu, L.; Krej, Z.; Hruban, L. (1975). Isolation of cannabidiolic acid from Turkish variety of
cannabis cultivated for bre. Acta Univ. Olomuc.,
Fac. Med 74: 167172.
External links
Cannabinoid information
Bela Szabo: Pharmacology of Cannabinoid Receptors BIOTREND Reviews No. 02, February 2008
Marijuana and Medicine Assessing the Science
Base (Institute of Medicine) 1999 at National
Academies Press
House of Lords Report Cannabis (United Kingdom) 1998 at Parliament of the United Kingdom
Cannabis: A Health Perspective and Research
Agenda 1997 at World Health Organization
Chemical Ecology of Cannabis (J. Intl. Hemp Assn.
- 1994)
Kfalvi, Attila, ed. (2008). Cannabinoids and

the Brain. doi:10.1007/978-0-387-74349-3. ISBN
978-0-387-74348-6.
THC (tetrahydrocannabinol) accumulation in glands

of Cannabis (Cannabaceae)
Nicoll, Roger A.; Alger, Bradley E. (2004). The

Brains Own Marijuana. Scientic American 291
(6): 6875. doi:10.1038/scienticamerican120468. PMID 15597982.
Therapeutic Potential in Spotlight at Cannabinoid

Researchers Meeting at California Cannabis Research Medical Group
Non-psychotropic plant cannabinoids: new thera Mechoulam, Raphael; Ben-Shabat, Shimon; Hanus,
peutic opportunities from an ancient herb
Lumir; Ligumsky, Moshe; Kaminski, Norbert E.;
Schatz, Anthony R. et al. (1995). Identication of an endogenous 2-monoglyceride, present 1.9.2 Cannabinoid research organizations
in canine gut, that binds to cannabinoid recep International Cannabinoid Research Society
tors. Biochemical Pharmacology 50 (1): 83
90. doi:10.1016/0006-2952(95)00109-D. PMID
The Canadian Consortium for the Investigation of
7605349.
Cannabinoids
Racz, I.; Nadal, X.; Alferink, J.; Baos, J. E.;

Rehnelt, J.; Martn, M. et al. (2008). Interferonis a Critical Modulator of CB2 Cannabinoid
Receptor Signaling during Neuropathic Pain.
Journal of Neuroscience 28 (46): 1213645.
doi:10.1523/JNEUROSCI.3402-08.2008.
PMC
3844840. PMID 19005078.
Chapter 2
Entourage eect
Entourage eect is a phrase that was introduced in
cannabinoid science in 1998 by S. Ben-Shabat, with
Raphael Mechoulam, to represent a novel endogenous
cannabinoid molecular regulation route. Biological activity assayed together with inactive compounds. References whole plant and whole person caregiver synergy
treatments over isolated compound pharmacological
dosages.[1][2][3][4][5][6][7][8]
2.1 External links

Dr. Sanjay Gupta: Medical marijuana and 'the entourage eect'
2.2 References
[1] Lee, Martin A. (Sep 13, 2013). Smoke Signals: A Social
History of Marijuana-Medical, Recreational and Scientic.
Scribner. p. 465. ISBN 978-1439102619.
[2] Ben-Shabat, Shimon (July 17, 1998). An entourage
eect: inactive endogenous fatty acid glycerol esters
enhance 2-arachidonoyl-glycerol cannabinoid activity.
doi:10.1016/S0014-2999(98)00392-6.
[3] Andersson, Karl-Erik (Feb 4, 2011). Urinary Tract.
eBook: Springer Science & Business Media. p. 438.
[4] Newnes (March 5, 2010). Comprehensive Natural Products II: Chemistry and Biology:. eBook: Google. p. 220.
[5] Guy, Georey William (July 1, 2004). The Medicinal
Uses of Cannabis and Cannabinoids (1st ed.). Pharmaceutical Press. p. 114. ISBN 978-0853695172.
[6] Castle, David (May 27, 2004). Marijuana and Madness:
Psychiatry and Neurobiology. eBook: Google. p. 8.
[7] Russo, Ethan B (Aug 2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage eects. Br J Pharmacol 163 (7): 13441364.
doi:10.1111/j.1476-5381.2011.01238.x.
[8] Gardner, Fred (2011). Terpenoids, 'minor' cannabinoids contribute to 'entourage eect' of Cannabis-based
medicines. The Journal of Cannavis in Clinical Practice:
1.
11
Chapter 3
Synthetic cannabis
its metabolites in human urine. The synthetic cannabinoids contained in synthetic cannabis products have been
made illegal in many European countries. On November 24, 2010, the US Drug Enforcement Administration announced it would use emergency powers to ban
many synthetic cannabinoids within a month.[4] Prior to
the announcement, several US states had already made
them illegal under state law. In the US, as of March
1, 2011, ve cannabinoids, JWH-018, JWH-073, CP47,497, JWH-200, and cannabicyclohexanol have been
placed on Schedule I of the Controlled Substances Act
(and are therefore illegal to possess or use in the US); the
Drug Enforcement Administration claims that said action
is to avoid an imminent hazard to the public safety.[5][6]
In July 2012, the Synthetic Drug Abuse Prevention Act of
A bag of Spice brand herbal incense
2012 was signed into law. It banned synthetic compounds
commonly found in synthetic cannabis, placing them unCommercially known as Synthetic cannabis (synthetic
der Schedule I of the Controlled Substances Act.[7]
marijuana), or technically cannabinoid research
chemicals, is any designer drug that mimics the effects of cannabis.[1] There are several psychoactive articial cannabinoid families (eg AM-xxx, HU-xxx, JWHxxx, CP xx) that are used as designer drugs sprayed on
herbs and sold as natural highs under brand names like
K2[2] and Spice,[3] both of which are genericized trade- 3.1 Misnomer
marks used for any synthetic cannabis product. Synthetic
cannabis is often termed spice product.
There is controversy about calling Spice and K2 synthetic
When synthetic cannabis blends rst went on sale in the cannabis. Synthetic marijuana is a misnomer accordearly 2000s, it was thought that they achieved an eect ing to Lewis Nelson, MD, a medical toxicologist at the
through a mixture of natural herbs. Laboratory anal- NYU School of Medicine. Its really quite dierent,
ysis in 2008 showed that this is not the case, and that and the eects are much more unpredictable. Its danthey in fact contain synthetic cannabinoids that act on the gerous, and there is no quality control in what you are
body in a similar way to cannabinoids naturally found in getting.[8] Since the term synthetic does not apply to the
cannabis, such as THC. A large and complex variety of plant but rather to the chemical that the plant contains
synthetic cannabinoids, most often cannabicyclohexanol, (tetrahydrocannabinol), the term synthetic cannabinoid is
JWH-018, JWH-073, or HU-210, are used in an attempt more appropriate.[9] Research on the safety of synthetic
to avoid the laws that make cannabis illegal, making syn- cannabinoids is now becoming available. Initial studthetic cannabis a designer drug. It has been sold under ies are focused on the role of synthetic cannabinoids in
various brand names, online, in head shops, and at some psychosis. Synthetic cannabis may precipitate psychosis
gas stations.
and in some cases it may be prolonged. Some studies sugIt is often marketed as "herbal incense"; however, some gest that synthetic cannabinoid intoxication is associated
brands market their products as herbal smoking blends. with acute psychosis, worsening of previously stable psyIn either case, the products are usually smoked by users. chotic disorders, and it may trigger a chronic (long-term)
Although synthetic cannabis does not produce positive re- psychotic disorder among vulnerable individuals such as
sults in drug tests for cannabis, it is possible to detect those with a family history of mental illness.[10][11]
12
3.3. SAFETY
3.2 Ingredients
Synthetic cannabis is claimed by the manufacturers to
contain a mixture of traditionally used medicinal herbs,
each of which producing mild eects, with the overall blend resulting in the cannabis-like intoxication produced by the product. Herbs listed on the packaging of Spice include Canavalia maritima (Coastal Jackbean), Nymphaea caerulea (Blue Egyptian water lily),
Scutellaria nana (dwarf skullcap), Pedicularis densiora
(Indian warrior), Leonotis leonurus (lions tail), Zornia
latifolia (maconha brava), Nelumbo nucifera (lotus), and
Leonurus sibiricus (honeyweed). However, when the
product was analyzed by laboratories in Germany and
elsewhere, it was found that many of the characteristic ngerprint molecules expected to be present from
the claimed plant ingredients were not present. There
were also large amounts of synthetic tocopherol present.
This suggested that the actual ingredients might not be
the same as those listed on the packet, and a German
government risk assessment of the product conducted in
November 2008 concluded that it was unclear as to what
the actual plant ingredients were, where the synthetic
tocopherol had come from, and whether the subjective
cannabis-like eects were actually produced by any of
the claimed plant ingredients or instead caused by a synthetic cannabinoid drug.
3.2.1
Articial cannabinoids
In January 2009, researchers at the University of Freiburg

in Germany announced that an active substance in Spice
was an undisclosed analogue of the synthetic cannabinoid CP 47,497.[12] Later that month, CP 47,497 along
with its dimethylhexyl, dimethyloctyl and dimethylnonyl
homologues, were added to the German controlled drug
schedules.[13][14] In May the analogue of CP 47,497 was
named cannabicyclohexanol.[15]
In July 2010, it was announced that JWH-018 is one of
the active components in at least three versions of Spice,
which had been sold in a number of countries around the
world since 2002, often marketed as incense.[16][17][18][19]
Another potent synthetic cannabinoid, HU-210, has been
reported to have been found in Spice seized by U.S.
Customs and Border Protection.[20] An analysis of samples acquired four weeks after the German prohibition of
JWH-018 took place found that the compound had been
replaced with JWH-073.[21]
Dierent ratios of JWH-018 and CP 47,497 and their
analogues have been found in dierent brands of synthetic cannabis[22] and manufacturers constantly change
the composition of their products.[23] The amount of
JWH-018 in Spice has been found to vary from 0.2% to
3%.[24]
13
not produce classical cannabis intoxication eects. This
includes substituted cathinone derived stimulant drugs
such as 4-methylbuphedrone and 4-methyl-alpha-PPP,
and psychedelic tryptamine derivatives such as 4-HODET.[25][26] In 2013 a designer opioid drug AH-7921 was
detected in smoking blends in Japan, along with several
novel cannabinoids and a cathinone analogue.[27]
New Zealand
An analysis of 41 dierent synthetic cannabis blends
sold commercially in New Zealand, conducted by the
Institute of Environmental Science and Research and released in July 2011, found 11 dierent synthetic cannabinoid ingredients used: including JWH-018, JWH-073,
AM-694, AM-2201, RCS-4, RCS-4 butyl homologue,
JWH-210, JWH-081, JWH-250 (or possibly JWH-302,
isomer not determined), JWH-203, and JWH-122
with between one and ve dierent active ingredients,
though JWH-018 was present in 37 of the 41 blends
tested. In two brands the benzodiazepine anxiolytic
drug phenazepam was also found, which is classied as
a prescription medicine in New Zealand, and so these
brands were ordered to be removed from the market
by emergency recall.[28][29] Since this time, a further 15
cannabinoid compounds have been detected as ingredients of synthetic cannabis blends in New Zealand and
banned as temporary class drugs.[30] In 2013 another hypnotic medication, zaleplon was found to have been used
as an active ingredient in a blend that had been sold in
New Zealand during 2011-2012.[31]
3.3 Safety
No ocial studies have been conducted on the eects of
synthetic cannabinoids on humans (as is usually the case
with known toxic and/or illegal compounds).[36] However, reports describing eects seen in patients seeking
medical care after taking synthetic cannabinoids have
been published. Compared to cannabis and its active
cannabinoid THC, the adverse eects are often much
more severe and can include hypertension, tachycardia,
myocardial infarction,[37] agitation, vomiting, hallucinations, psychoses, seizures, convulsions[38] and panic
attacks.[39][40][41][42][43] Among individuals who need
emergency treatment after using synthetic cannabis, the
most common symptoms are accelerated heartbeat, high
blood pressure, nausea, blurred vision, hallucination and
agitation.[44] Other symptoms included epileptic seizures,
acute psychosis, and heart attacks.[44]
At least one death has been linked to overdose of synthetic cannabinoids[45] and in Colorado three deaths in
September 2013 have been investigated for being linked
to synthetic cannabinoids.[46] In December 2012, after
two weeks of daily synthetic cannabis use, a 17-year old
Other non-cannabinoid ingredients have also been found girl suered multiple strokes and subsequent brain damin synthetic cannabis blends around the world, but they do age, leaving her blind and paralyzed.[47]
14
CHAPTER 3. SYNTHETIC CANNABIS
These more severe adverse eects in contrast to use of 3.5 Legal status
marijuana are believed to stem from the fact that many
of the synthetic cannabinoids are full agonists to the
3.5.1 Europe
cannabinoid receptors, CB1R and CB2R, compared to
THC which is only a partial agonist and thus not able
Austria The Austrian Ministry of Health announced on
to saturate and activate all of the receptor population no
December 18, 2008 that Spice would be controlled
[48]
matter of dose and resulting concentration. It has also
under Paragraph 78 of their drug law on the grounds
been seen that phase 1 metabolism of JWH-018 results
that it contains an active substance that aects the
in at least nine monohydroxylated metabolites and with
functions of the body, and the legality of JWH-018
at least three of the metabolites shown to have full agois under review.[55][56][57]
nistic eect on CB1R which compared to metabolism of
THC only results in one psychoactive monohydroxylated Germany JWH-018, CP 47,497 and the C6, C8 and C9
metabolite. This may further explain the increased toxihomologues of CP 47,497 are illegal in Germany
city of synthetic cannabinoids compared to THC.[45]
since January 22, 2009.[14][58]
Professor John W. Human, who rst synthesised many
of the cannabinoids used in synthetic cannabis, is quoted Finland Spice blends are classied as a medicine in Finland, and, therefore, it is illegal to order them withas saying, People who use it are idiots.[36] You don't
out a prescription. In practice, it is not possible to
know what its going to do to you.[49] A user who conget a prescription.
sumed 3 g of Spice Gold every day for several months
showed withdrawal symptoms, similar to those associated with withdrawing from the use of narcotics. Doc- France JWH-018, CP 47,497 (and its homologues) and
HU-210 were all made illegal in France on February
tors treating the user also noted that his use of the
[50]
24, 2009.[59]
product showed signs associated with addiction.
One
case has been reported wherein a user, who had previwith a variety
ously suered from cannabis-induced recurrent psychotic Ireland From June 2010, JWH-018, along
[60]
of
other
designer
drugs,
is
illegal.
episodes, suered reactivation of his symptoms after
using Spice. Psychiatrists treating him have suggested
Latvia JWH-018, JWH-073, CP 47,497 (and its homothat the lack of an antipsychotic chemical, similar to
logues) and HU-210 are all banned in Latvia as well
cannabidiol found in natural cannabis, may make synas leonotis leonurus.[61]
thetic cannabis more likely to induce psychosis than natural cannabis.[51]
Poland JWH-018 and many of the herbs mentioned on
the ingredient lists of Spice and similar preparaStudies are currently available which suggest an assotions were made illegal in May 2009. The bill was
ciation between synthetic cannabinoids and psychosis.
passed by Polish Sejm,[62][63] Polish Senat[64] and
Physicians should be aware that the use of synthetic
was signed by the President.[65]
cannabinoids can be associated with psychosis and investigate possible use of synthetic cannabinoids in patients with inexplicable psychotic symptoms. In contrast Romania Spice was made illegal in Romania on February 15, 2010.[66]
to most other recreational drugs, the dramatic psychotic
state induced by use of synthetic cannabinoids has been
reported in multiple cases to persist for several weeks, Russia On April 9, 2009, the Chief Medical Ocer of
the Russian Federation issued a resolution on reand in one case for seven months, after complete cessa[52]
inforcing control over the sales of smoking blends.
tion of drug use. Individuals with risk factors for psyThese blends, marketed under the trade names AMchotic disorders should be counseled against using syn[53]
HI-CO, Dream, Spice (Gold, Diamond), Zoom, Exthetic cannabinoids.
ses, Yucatn Fire and others, have been declared
to contain Salvia divinorum, Hawaiian Wood Rose,
and Blue Lotus, and are prohibited to be sold. These
substances have been found to have psychotropic,
3.4 Drug testing
narcotic eects, contain poisonous components and
represent potential threat for humans. The resoluSpice does not cause a positive drug test for cannabis
tion does not mention JWH-018 or other synthetic
or other illegal drugs using GC-MS-screening with
cannabinoids.[67] On January 14, 2010, the Russian
library search, multi-target screening by LC-MS/MS,
government issued a statement including 23 synor immunological screening procedures.[22][50] A study
thetic cannabinoids found in smoking blends Hawaihas been conducted into the detection of metabolites of
ian Rose and Blue Lotus on the list of prohibited
JWH-018 in urine; the metabolites are mainly conjugates
narcotic and psychotropic substances. Thus, all of
with glucuronic acid and can be reliably detected by GC
these plants and compounds are now illegal in the
MS/MS and LCMS/MS.[54]
Russian Federation.[68]
3.5. LEGAL STATUS

Slovakia Spice is legal in Slovakia. The National AntiDrug Unit is considering adding it to the list of controlled substances.[69] The latest anti-drug law version (468/2009) valid since January 2010 still does
not mention active compounds of Spice.[70]
15
passed on September 18, 2013 that bans entire families of synthetic drugs instead of only banning existing compounds that have been identied.[82][83] The
introduction of this law makes NSW the rst state
in Australia to completely ban substances with psychoactive properties.[83]
Sweden CP 47,497-C6, CP 47,497-C7, CP 47,497-C8,

CP 47,497-C9, JWH-018, JWH-073 and HU-210
it is claswere all made illegal in Sweden on September 15, New Zealand Spice is illegal in New Zealand,
[84]
sied
as
a
Class
C
controlled
drug.
The
New
2009. The bill was accepted on July 30, 2009 and
Zealand
Parliament
passed
a
law
in
July
2013
ban[71]
was put in eect on September 15, 2009.
ning the sale of legal highs in dairies and supermarkets, but allowing some low risk drugs to continue
Switzerland Spice has been banned in Switzerland.[72]
to be sold through speciality licensed shops.[85] SynTurkey Spice a.k.a Bonzai added to the list of drugs
thetic cannabinoids, as well as all other 'legal highs
and psychotropic substances in 07.01.2011 by the
were outlawed at midnight on 7 May 2014, after a
law which numbered as 2011/1310 B.K.K. (Februlaw was passed a week prior by the New Zealand
ary 13, 2011 and the Ocial Gazette No. 27845)
government.[86]
[73]
United Kingdom Spice was legal in the United King3.5.5 North America
dom until December 2009, when it was classied as
[74]
a Class B drug.
Canada
3.5.2
South America
Chile The Chilean Ministry of Health on April 24,

2009 declared the sale of synthetic cannabis to be
illegal.[75]
Spice and specic forms of JWHxxx are not specically

prohibited in Canada, but synthetic cannabis is listed as a
schedule II drug.[87][88] Health Canada is debating on the
subject.[89][90]
United States
3.5.3
Asia
See also: JWH-018 United States

South Korea South Korea ocially added JWH-018,
CP 47,497 and HU-210 to the controlled substance The case of David Mitchell Rozga, an American teenager
list on July 1, 2009, eectively making these chem- from Indianola, Iowa, United States, brought internaicals illegal.[76]
tional attention to K2. Rozga shot himself in the head
Japan Japan has banned JWH-018, CP 47, 497, and ho- with a family owned hunting rie in an apparent suicide
in June 6, 2010. After news of Rozgas death, it was remologues, and HU-210 since October 2009
ported by friends that they had smoked K2 with Rozga
United Arab Emirates The United Arab Emirates had approximately one hour before his death. The nature of
stated that Spice was an illegal substance and posses- his death and reports from numerous family members,
sion or intent to sell would be a jailable oense.[77] had led investigators to believe that it was likely Rozga
was under the inuence of a mind-altering substance, at
the time of his death. The death of Rozga has been used
3.5.4 Australasia
as a face of political lobbying against the continuation of
K2, and other legal synthetic drugs, such as bath salts.[91]
Australia On June 17, 2011, the Western Australian
government banned all of the synthetic cannabi- Following the incident, an act to ban the use and distribunoids found in already existing products, including tion of the drug was proposed by the US Senator Chuck
brands such as Kronic, Kalma, Voodoo, Kaos, and Grassley of Iowa as the David Mitchell Rozga Act. It was
legislation by the United States Congress
Mango Kush. Western Australia was the rst state approved into [92]
in
June
2011.
On July 10, 2012, President Barack
in Australia to prohibit the sale of certain synthetic
signed
the
Synthetic Drug Abuse Prevention Act
Obama
[78][79]
On June 18, 2013, an interim
cannabinoids.
of
2012
into
law.
It banned synthetic compounds comban made a large list of product brands and synthetic
monly
found
in
synthetic
marijuana, placing them under
[80]
substances illegal to sell anywhere in Australia.
Schedule
I
of
the
Controlled
Substances Act.[7]
This ban lapsed on October 13, 2013, and a permanent ban has not been imposed.[81] Synthetic Prior to that, some compounds within synthetic cannabis
cannabis remains illegal in NSW, where a bill was (HU-210) were scheduled in the USA under federal law,
16
while others (JWH-073) have been temporarily scheduled until nal determination of their status can be
made.[93][94][95][96] The Drug Enforcement Administration (DEA) considers it to be a drug of concern,[97]
citing "...a surge in emergency-room visits and calls to
poison-control centers. Adverse health eects associated
with its use include seizures, hallucinations, paranoid behavior, agitation, anxiety, nausea, vomiting, racing heartbeat, and elevated blood pressure.[98][99]
Several states independently passed acts making it illegal under state law, including Kansas in March 2010,[100]
Georgia and Alabama in May 2010,[101][102] Tennessee
and Missouri in July 2010,[103][104] Louisiana in August
2010, Mississippi in September 2010, and Iowa.[105] An
emergency order was passed in Arkansas in July 2010
banning the sale of synthetic cannabis.[106] In October
2010, the Oregon Board of Pharmacy listed synthetic
cannabinoid chemicals on its Schedule 1 of controlled
substance, which means that the sale and possession of
these substances is illegal under the Oregon Uniform
Controlled Substances Act.[107] According to the National
Conference of State Legislatures, several other states are
also considering legislation, including New Jersey, New
York, Florida, and Ohio.[104] Illinois passed a law on July
27, 2010 banning all synthetic cannabinoids that goes
into eect January 1, 2011.[108] Michigan banned synthetic cannabinoids in October 2010,[109] and the South
Dakota Legislature passed a ban on these products which
was signed into law by Gov. Dennis Daugaard on February 23, 2012 (and which took immediate eect under an
emergency clause of the state constitution).[110] Indiana
banned synthetic cannabinoids in a law which became effective in March 2012.[111] North Carolina banned synthetic cannabis by a unanimous vote of the state senate,
due to concerns that its contents and eects are reasonably similar to natural cannabis, and may cause equal effects in terms of psychological dependency.[112][113]
Following cases in Japan involving the use of synthetic
cannabis by Navy, Army and Marine Corps personnel
resulted in the ocial banning of it,[114] a punitive general order issued on January 4, 2010 by the Commander
Marine Corps Forces, Pacic prohibits the actual or attempted possession, use, sale, distribution or manufacture of synthetic cannabis as well as any derivative, analogue or variant of it.[115] On June 8, 2010, the U.S.
Air Force issued a memorandum that banned the possession and use of Spice, or any other mood-altering
substance except alcohol or tobacco, among its service
members.[116]
On November 24, 2010, the DEA announced that
it would make JWH-018, JWH-073, JWH-200, CP47,497, and cannabicyclohexanol, which are often
found in synthetic cannabis, illegal using emergency
powers.[117] They will be placed in Schedule I of the Controlled Substances Act, within a month of the announcement, and the ban will last for at least a year.[118][119] The
temporary ban, for at least a year, came into eect on

March 1, 2011.[120]
On October 20, 2011, the Louisiana State University
football program announced that it had suspended three
players, including star cornerback Tyrann Mathieu, who
tested positive for synthetic cannabis.[121]
3.6 History
According to the Psychonaut Web Mapping Research
Project, synthetic cannabis products, sold under the brand
name Spice, rst appeared in Europe in 2004.[122] The
brand Spice was released in 2004 by the now-dormant
company The Psyche Deli in London, UK. In 2006 the
brand gained popularity. According to the Financial
Times, the assets of The Psyche Deli rose from 65,000 in
2006 to 899,000 in 2007.[123] The EMCDDA reported
in 2009 that 'Spice' products were identied in 21 of the
30 participating countries. Because 'Spice' was the dominant brand until 2009, the competing brands that started
to appear from 2008 on were also dubbed 'Spice'. Spice
can, therefore, refer to both the brand 'Spice', as to all
herbal blends with synthetic cannabinoids added.
A survey of readers of Mixmag in the UK in 2009 found
that one in eight respondents had used synthetic cannabis,
compared to 85% who had used cannabis.[124]
3.6.1 Slang terms

In addition to K2 and Spice, other street names include
Black Mamba (Turnera diusa), Bombay Blue, Genie,
and Zohai.[7] According to Partnership at Drugfree.org,
other names also include Bliss, Blaze, JWH 018, 073,
250, Yucatan Fire, Skunk, Moon Rocks[125] and Bonzai
(esp. in Turkey)[73]
3.7 References
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Retrieved March 1, 2011.
[99] Ben Paynter: The Big Business of Synthetic Highs,
Bloomerg Businessweek June, 2011
[80] Bradbury, David (June 18, 2013). Competition and Consumer Act 2010 - Consumer Protection Notice No. 3 of [100] The Associated Press. How major issues fared in Kansas
Legislature. CNBC. May 23, 2010. Accessed: May 23,
2013 - Imposition of Interim Ban on Certain Consumer
2010
Goods Containing Synthetic Drug Substances. Retrieved
October 28, 2013.
[101] Simmons, Andria (May 24, 2010). Governor signs bill
[81] Synthetic drug substances - national interim ban.
to outlaw synthetic marijuana. ajc.com. Retrieved June
ACCC. Retrieved October 28, 2013.
19, 2010.
20
[102] May 20, 2010 (May 20, 2010). Alabama Coalition Gets [120] Meserve, Jeanne (February 28, 2011). DEA imposes
Salvia and K2 Banned in Their State. CADCA. Reemergency ban to control synthetic marijuana. CNN.
trieved August 24, 2010.
Retrieved March 1, 2011.
[103] Haas, Brian. 'K2', 'K3' synthetic drugs are illegal in TN [121] Schlabach, Mark (October 20, 2011). Sources: LSU
starting July 1. The Tennessean. May 30, 2010. Acplayers had positive tests. ESPN.com. Retrieved Novemcessed: June 17, 2010
ber 4, 2011.
[104] Gay, Malcolm. (2010-07-10) Synthetic Marijuana Spurs [122] Spice Report Psychonaut Web Mapping Research Project
State Bans. New York Times. Retrieved on August 7,
[123] The story of Spice. Financial Times. February 13,
2011.
2009. Retrieved September 19, 2010.
[105] Iowa Code 124.204(4)(u) (dening a Schedule I controlled substance to include synthetic equivalents of the [124] Winstock, A.; Mitcheson, L.; Deluca, P.; Davey, Z.;
Corazza, O.; Schifano, F. (2010). Mephedrone, new
substances contained in the Cannabis plant, or in the
kid for the chop?". Addiction (Abingdon, England) 106
resinous extractives of such plant, and synthetic sub(1): 154161. doi:10.1111/j.1360-0443.2010.03130.x.
stances, derivatives, and their isomers with similar chemPMID 20735367.
ical structure and pharmacological activity to those substances contained in the plant....)
[125] K2 Spice via Partnership at Drugfree.org
[106] Gavin Lesnick (July 2, 2010). Beebe signs emergency ban on K2. Arkansas Online (Arkansas Democrat
Gazette). Retrieved July 26, 2010.
3.8 External links
[107] Synthetic Cannabis Controlled Substance Information. Retrieved October 16, 2010.
Erowid
[108] Daniel Martynowicz. Illinois Bans Synthetic Cannabinoids. Retrieved September 14, 2010.
Synthetic cannabinoid prole European Monitoring

Centre for Drugs and Drug Addiction
[109] http://www.michigan.gov/lara/0,4601,7-154-10573_
11472-280858--,00.html
[110] Argus Leader, "New law bans synthetic drugs, by John
Hult (February 23rd 2012 - retrieved on May 14th, 2012).
[111] http://www.in.gov/attorneygeneral/2974.htm
[112] NC Senate OKs synthetic pot ban. WRAL-TV. 10
February 2011. Retrieved 27 September 2012.
[113] Make Synthetic Cannabinoids Illegal. General Assembly of North Carolina. 31 January 2011. Retrieved 27
September 2012.
[114] Allan, David; Fisher, Cindy. Ruling Claries 'Legal' Drug
Policy. Stars and Stripes via Military.com. May 23, 2010.
Accessed: May 23, 2010
[115] Marines Ban Spice Drug. Military.com. May 23, 2010.
Accessed: May 23, 2010
[116] Air Force ocials ban use and possession of spice,
mood-altering substances. Air Force News. June 17,
2010. Accessed: June 18, 2010. Af.mil. Retrieved June
19, 2010.
[117] DEA Moves to Emergency Control Synthetic Marijuana. DEA Public Aairs. U.S. Drug Enforcement Administration. November 24, 2010. Retrieved February
19, 2011.
[118] Grim, Ryan (November 24, 2010). K2 Crackdown:
DEA Using Emergency Powers To Ban Fake Pot. Huington Post. Retrieved November 24, 2010.
[119] By the CNN Wire Sta (November 24, 2010). Feds
move to ban 'fake pot'". CNN. Retrieved November 24,
2010.
Chapter 4
4-HTMPIPO
4-HTMPIPO is a synthetic cannabinoid drug rst identied in smoking products purchased from online vendors
in 2012.[1] 4-HTMPIPO is the product resulting from
the electrophilic addition of water to the cyclopropane
moiety of synthetic cannabinoid UR-144.[1] Nothing is
known about the in vitro or in vivo pharmacology of 4HTMPIPO.
4.1 See also

AB-001
JWH-018
UR-144
XLR-11
4.2 References
[1] Kavanagh, P.; Grigoryev, A.; Savchuk, S.; Mikhura, I.;
Formanovsky, A. (2013). UR-144 in products soldviathe
Internet: Identication of related compounds and characterization of pyrolysis products. Drug Testing and Analysis: n/a. doi:10.1002/dta.1456.
21
Chapter 5
5F-PB-22
5F-PB-22 or Quinolin-8-yl 1-(5-uoropentyl)1Hindole-3-8-carboxylate is a designer drug and a possible cannabinoid agonist. The structure of 5F-PB-22 appears to have been designed with an understanding of
structure-activity relationships within the indole class of
cannabinoids on the Forendex website of potential drugs
of abuse.[1]
In January 2014, 5F-PB-22 was designated as a Schedule
I controlled substance in the United States.[2]
5.1 See also

AM-2201
JWH-018
QUCHIC
QUPIC
SDB-001
5.2 References
[1] 5F-PB-22 page on Forendex
[2] Behonick, G; Shanks, K. G.; Firchau, D. J.; Mathur, G;
Lynch, C. F.; Nashelsky, M; Jaskierny, D. J.; Meroueh, C
(2014). Four Postmortem Case Reports with Quantitative Detection of the Synthetic Cannabinoid, 5F-PB-22.
Journal of analytical toxicology. doi:10.1093/jat/bku048.
PMID 24876364.
22
Chapter 6
A-40174
A-40174 (SP-1) is an analgesic drug which acts as a potent cannabinoid receptor agonist, and was developed by
Abbott Laboratories in the 1970s.[1]
6.1 See also

A-41988
Menabitan
6.2 References
[1] Reggio, Patricia H., ed. (2009). The Cannabinoid Receptors. doi:10.1007/978-1-59745-503-9. ISBN 978-158829-712-9.
23
Chapter 7
A-41988
A-41988 (BW29Y) is an analgesic drug which acts as a
cannabinoid agonist. It was developed by Abbott Laboratories in the 1970s,[1][2] and researched for potential
use in the treatment of glaucoma,[3] but never commercialised.
7.1 See also

A-40174
Menabitan
7.2 References
[1] Winn, M.; Arendsen, D.; Dodge, P.; Dren, A.; Dunnigan, D.; Hallas, R.; Hwang, K.; Kyncl, J.; Lee,
Y. H.; Plotniko, N.; Young, P.; Zaugg, H. (1976).
Drugs derived from cannabinoids. 5. Delta6a,10aTetrahydrocannabinol and heterocyclic analogs containing
aromatic side chains. Journal of Medicinal Chemistry
19 (4): 461471. doi:10.1021/jm00226a003. PMID
817021.
[2] Guterman A, Somani P, Bachand RT. Clinical Pharmacology and Therapeutics 1979; 25:227.
[3] Tiedeman, J. S.; Shields, M. B.; Weber, P. A.; Crow,
J. W.; Cocchetto, D. M.; Harris, W. A.; Howes, J. F.
(1981). Eect of synthetic cannabinoids on elevated
intraocular pressure. Ophthalmology 88 (3): 270277.
doi:10.1016/s0161-6420(81)35052-0. PMID 7015221.
24
Chapter 8
A-796,260
A-796,260 is a drug developed by Abbott Laboratories
that acts as a potent and selective cannabinoid CB2
receptor agonist. Replacing the aromatic 3-benzoyl or
3-naphthoyl group found in most indole derived cannabinoids with the 3-tetramethylcyclopropylmethanone
group, imparts signicant selectivity for CB2 , and
A-796,260 was found to be a highly selective CB2
agonist with little anity for CB1 , having a CB2 K of
4.6 nM vs 945 nM at CB1 .[1] It has potent analgesic
and anti-inammatory actions in animal models, being
especially eective in models of neuropathic pain, but
without producing cannabis-like behavioral eects.[2]
8.1 See also

A-834,735
A-836,339
JWH-200
UR-144
XLR-11
8.2 References
[1] Frost, J. M., et al. (2010). Indol-3-ylcycloalkyl Ketones:
Eects of N1 Substituted Indole Side Chain Variations on
CB2 Cannabinoid Receptor Activity. Journal of Medicinal Chemistry 53 (1): 295. doi:10.1021/jm901214q.
PMID 19921781.
[2] Yao BB, et al. (January 2008). In vitro and in vivo characterization of A-796260: a selective cannabinoid CB2
receptor agonist exhibiting analgesic activity in rodent
pain models. British Journal of Pharmacology 153 (2):
390401. doi:10.1038/sj.bjp.0707568. PMC 2219533.
PMID 17994110.
25
Chapter 9
A-834,735
A-834,735 is a drug developed by Abbott Laboratories that acts as a potent cannabinoid receptor full
agonist at both the CB1 and CB2 receptors, with
a K of 12nM at CB1 and 0.21nM at CB2 . Replacing the aromatic 3-benzoyl or 3-naphthoyl group
found in most indole derived cannabinoids, with the 3tetramethylcyclopropylmethanone group of A-834,735
and related compounds, imparts signicant selectivity for
CB2 , with most compounds from this group found to be
highly selective CB2 agonists with little anity for CB1 .
However low nanomolar CB1 binding anity is retained
with certain heterocyclic 1-position substituents such as
(N-methylpiperidin-2-yl)methyl (cf. AM-1220, AM1248), or the (tetrahydropyran-4-yl)methyl substituent of
A-834,735, resulting in compounds that still show significant anity and ecacy at both receptors despite being
CB2 selective overall.[1][2][3][4][5]
9.1 See also

A-796,260
AB-001
JTE 7-31
UR-144
XLR-11
9.2 References
[1] Dart M, et al. (2006). 1-Alkyl-3-keto-indoles: identication and in vitro characterization of a series of potent cannabinoid ligands. In 2006 Symposium on the
Cannabinoids. International Cannabinoid Research Society: Burlington, VT.
[2] Poso, A.; Human, J. W. (2008). Targeting the cannabinoid CB2 receptor: modelling and structural determinants
of CB2 selective ligands. British Journal of Pharmacology 153 (2): 335. doi:10.1038/sj.bjp.0707567. PMC
2219524. PMID 17982473.
26
[3] Chin CL, et al. (January 2008). Dierential eects of

cannabinoid receptor agonists on regional brain activity
using pharmacological MRI. British Journal of Pharmacology 153 (2): 36779. doi:10.1038/sj.bjp.0707506.
PMC 2219521. PMID 17965748.
[4] Frost, J. M., et al.
(2008).
Indol-3-yltetramethylcyclopropyl Ketones: Eects of Indole
Ring Substitution on CB2 Cannabinoid Receptor Activity. Journal of Medicinal Chemistry 51 (6): 1904.
doi:10.1021/jm7011613. PMID 18311894.
PMID 19921781.
Chapter 10
A-836,339
A-836,339 is a drug developed by Abbott Laboratories
that acts as a potent cannabinoid receptor full agonist. It
is selective for CB2 , with K values of 0.64nM at CB2
vs 270nM at the psychoactive CB1 receptor, but while it
exhibits selective analgesic, anti-inammatory and antihyperalgesic eects at low doses,[1] its high ecacy at
both targets results in typical cannabis-like eects appearing at higher doses, despite its low binding anity
for CB1 .[2]
10.1 References
[1] McGaraughty, S., et al. (2009). A CB(2) receptor agonist, A-836339, modulates wide dynamic range neuronal
activity in neuropathic rats: contributions of spinal and peripheral CB(2) receptors. Neuroscience 158 (4): 1652
1661. doi:10.1016/j.neuroscience.2008.11.015. PMID
19063946.
[2] Yao, B., et al. (2009). Characterization of a cannabinoid CB2 receptor-selective agonist, A-836339 2,2,3,3tetramethyl-cyclopropanecarboxylic acid 3-(2-methoxyethyl)4,5-dimethyl-3H-thiazol-(2Z)-ylidene-amide, using in vitro pharmacological assays, in vivo pain models,
and pharmacological magnetic resonance imaging. The
Journal of Pharmacology and Experimental Therapeutics
328 (1): 141151. doi:10.1124/jpet.108.145011. PMID
18931146.
27
Chapter 11
AB-001
AB-001 or 1-pentyl-3-(1-adamantoyl)indole is a
designer drug that was found as an ingredient in synthetic
cannabis smoking blends in Ireland in 2010 and Hungary
and Germany in 2011.[1][2][3] It is unclear who AB-001
was originally developed by, but it is structurally related
to compounds such as AM-1248 and its corresponding
1-(tetrahydropyran-4-ylmethyl) analogue, which are
known to be potent cannabinoid agonists with moderate
to high selectivity for CB2 over CB1 .[4][5] The rst
published synthesis and pharmacological evaluation of
AB-001 revealed that it acts as a full agonist at CB1
(EC50 = 35 nM) and CB2 receptors (EC50 = 48 nM).[6]
However, AB-001 was found to possess only weak
cannabimimetic eects in rats at doses up to 30 mg/kg,
making it less potent than carboxamide analogue SDB001, which possesses potent cannabimimetic activity at
doses of 3 mg/kg.[6]
11.1 See also

A-834,735
and identication of the new potential synthetic cannabinoids 1-pentyl-3-(2-iodobenzoyl)indole and 1-pentyl-3(1-adamantoyl)indole in seized bulk powders in Hungary. Forensic Science International 214 (13): 2732.
[2] Research on Head Shop drugs in Dublin: Part 2
[3] Grigoryev, A.; Kavanagh, P.; Melnik, A. (2012). The
detection of the urinary metabolites of 3-\(adamantan1-yl)carbonyl]1-pentylindole (AB-001), a novel
cannabimimetic, by gas chromatography-mass spectrometry. Drug Testing and Analysis 4 (6): 519524.
doi:10.1002/dta.350. PMID 22102533.
[4] US patent 7820144, Makriyannis A, Deng H, Receptor selective cannabimimetic aminoalkylindoles, granted
2010-10-26
PMID 19921781.
[6] Banister, S. D.; Wilkinson, S. M.; Longworth, M.;
Stuart, J.; Apetz, N.; English, K.; Brooker, L.;
Goebel, C.; Hibbs, D. E.; Glass, M.; Connor, M.;
McGregor, I. S.; Kassiou, M. (2013). The synthesis and pharmacological evaluation of adamantanederived indoles: Novel cannabimimetic drugs of abuse.
ACS Chemical Neuroscience 4 (7): 130403084729007.
doi:10.1021/cn400035r.
AB-005
AM-1248
JWH-018
JWH-250
RCS-4
RCS-8
SDB-001
N-(S)-Fenchyl-1-(2-morpholinoethyl)7methoxyindole-3-carboxamide
(1-Pentylindol-3-yl)-(2,2,3,3tetramethylcyclopropyl)methanone
11.2 References
[1] Jankovics, P. T.; Vradi, A. S.; Tlgyesi, L. S.; Lohner,
S.; Nmeth-Palots, J. L.; Balla, J. Z. (2012). Detection
28
Chapter 12
AB-005
AB-005 or [1-[(1-methyl-2-piperidinyl)methyl]1Hindol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone is a designer drug oered by online
vendors as a cannabimimetic agent. The structure and
pharmacological activity of AB-005 was published in
2010, prior to its commercial availability in 2012, where
it was reported to have high anity for both CB1 (K =
5.5 nM) and CB2 receptors (K = 0.48 nM).[1] AB-005
features groups found in other previously reported
synthetic cannabinoids: the tetramethylcyclopropane
group of UR-144 and XLR-11 as well as the (1-methyl2-piperidinyl)methyl substituent of AM-1248 and
AM-1220. No information regarding the in vivo activity
of AB-005 has been published, and only anecdotal
reports are known of its psychoactivity in humans.
12.1 Legal status

Psychoactive products in New Zealand containing this
drug have been given interim approval under recent psychoactive substances legislation.[2]
12.2 See also

AB-001
AM-1248
AM-1220
JWH-018
UR-144
XLR-11
12.3 References
PMID 19921781.
29
[2] Ministry of Health Manat Hauora Interim Product

Approvals, Ministry of Health NZ, New Zealand, 2 January 2013. Retrieved on 2 January 2013.
Chapter 13
AB-CHMINACA
AB-CHMINACA is an indazole-based synthetic
cannabinoid. It is a potent agonist of the CB1 receptor.[1]
13.1 References
[1] AB-CHMINACA, Cayman Chemicals
30
Chapter 14
AB-FUBINACA
AB-FUBINACA is a drug that acts as a potent agonist
for the cannabinoid receptors, with K values of 0.9nM
at CB1 and 23.2nM at CB2 . It was originally developed
by Pzer in 2009 as an analgesic medication,[1] but was
never pursued for human use. Subsequently in 2012, this
compound was discovered as an ingredient in synthetic
cannabis blends in Japan,[2] along with a related compound AB-PINACA which had not previously been reported.
In January 2014, AB-FUBINACA was designated as a
Schedule I controlled substance in the United States.[3]
14.1 See also

AB-PINACA
ADB-FUBINACA
ADBICA
APICA
APINACA
Benzydamine
NESS-040C5
PF-03550096
14.2 References
[1] Buchler IP et al, INDAZOLE DERIVATIVES. WO
2009/106982
[2] Uchiyama, N.; Matsuda, S.; Wakana, D.; KikuraHanajiri, R.; Goda, Y. (2012). New cannabimimetic
indazole derivatives, N-(1-amino-3-methyl-1-oxobutan2-yl)1-pentyl-1H-indazole-3-carboxamide
(ABPINACA) and N-(1-amino-3-methyl-1-oxobutan-2yl)1-(4-uorobenzyl)1H-indazole-3-carboxamide
(AB-FUBINACA) identied as designer drugs in
illegal products.
Forensic Toxicology 31:
93.
doi:10.1007/s11419-012-0171-4.
31

PMID 24876364.
Chapter 15
AB-PINACA
AB-PINACA is a compound that was rst identied
as a component of synthetic cannabis products in Japan
in 2012.[1] The pharmacological properties of this compound have not been formally studied or reported in the
scientic literature, but it is presumably a cannabinoid
agonist as it was found alongside a structurally related
compound AB-FUBINACA which had previously been
reported as a cannabinoid agonist in a 2009 Pzer
patent.[2][3]
15.1 See also

AB-FUBINACA
ADB-PINACA
APINACA
PF-03550096
15.2 References
[1] Uchiyama, N.; Matsuda, S.; Wakana, D.; KikuraHanajiri, R.; Goda, Y. (2012). New cannabimimetic
indazole derivatives, N-(1-amino-3-methyl-1-oxobutan2-yl)1-pentyl-1H-indazole-3-carboxamide
(ABPINACA) and N-(1-amino-3-methyl-1-oxobutan-2yl)1-(4-uorobenzyl)1H-indazole-3-carboxamide
(AB-FUBINACA) identied as designer drugs in
illegal products.
Forensic Toxicology 31:
93.
doi:10.1007/s11419-012-0171-4.
2009/106980
2009/106982
32
Chapter 16
Abnormal cannabidiol
Abnormal cannabidiol (abn-cbd) is a synthetic
regioisomer of cannabidiol, which unlike most other
cannabinoids produces vasodilator eects, lowers blood
pressure, and induces cell migration, cell proliferation
and mitogen-activated protein kinase activation in
microglia, but without producing any psychoactive
eects.[1][2] It has been shown that the actions of abnormal cannabidiol are mediated through a site separate
from the CB1 and CB2 receptors,[2][3] which responds
to abnormal cannabidiol, O-1602, and the endogenous
ligands: anandamide (AEA), N-arachidonoyl glycine
(NAGly) and N-arachidonoyl L-serine.[2][4][5][6] Multiple
lines of evidence support the proposed identication
of this novel target in microglia as the previously
orphan receptor GPR18.[2] Another possible target of abnormal cannabidiol is GPR55, which has
also received much attention as a putative cannabinoid
receptor,[7][8] although a growing body of evidence points
to lysophosphatidylinositol (LPI) as the endogenous ligand for GPR55.[9][10] Further research suggests there are
yet more additional cannabinoid receptors.[11][12][13][14]
the putative abnormal cannabidiol receptor. BMC Neuroscience 11: 44. doi:10.1186/1471-2202-11-44. PMC
2865488. PMID 20346144.
[3] Jarai, Z. (1999). Cannabinoid-induced mesenteric
vasodilation through an endothelial site distinct from
Proceedings of the NaCB1 or CB2 receptors.
tional Academy of Sciences 96 (24): 1413614141.
doi:10.1073/pnas.96.24.14136. PMC 24203. PMID
10570211.
[4] Walter, L; Franklin, A; Witting, A; Wade, C; Xie, Y;
Kunos, G; MacKie, K; Stella, N (2003). Nonpsychotropic cannabinoid receptors regulate microglial cell
migration. Journal of Neuroscience 23 (4): 13981405.
PMID 12598628.
[5] Oertler, L; Mo, FM; Btkai, S; Liu, J; Begg, M; Razdan,
RK; Martin, BR; Bukoski, RD; Kunos, G (2003). Selective ligands and cellular eectors of a G protein-coupled
endothelial cannabinoid receptor. Molecular Pharmacology 63 (3): 699705. doi:10.1124/mol.63.3.699. PMID
12606780.
[6] Milman, G; Maor, Y; Abu-La, S; Horowitz, M; Gallily,
R; Batkai, S; Mo, FM; Oertaler, L; Pacher, P; Kunos,
G; Mechoulam, R (2006). N-arachidonoyl l-serine, an
endocannabinoid-like brain constituent with vasodilatory
properties. Proceedings of the National Academy of Sciences of the United States of America 103 (7): 24282433.
doi:10.1073/pnas.0510676103. PMC 1413724. PMID
16467152.
16.1 See also

Cannabinoids
Cannabinoid receptors
Cannabidiol
[7] McCollum, L; Howlett, AC; Mukhopadhyay, S

(2007). Anandamide-mediated CB1/CB2 cannabinoid
receptorindependent nitric oxide production in rabbit
aortic endothelial cells. The Journal of Pharmacology
and Experimental Therapeutics 321 (3): 930937.
doi:10.1124/jpet.106.117549. PMID 17379772.
O-1918
16.2 References
[1] Adams, MD; Earnhardt, JT; Martin, BR; Harris, LS;
Dewey, WL; Razdan, RK (1977).
A cannabinoid with cardiovascular activity but no overt behavioral eects.
Experientia 33 (9): 12041205.
doi:10.1007/BF01922330. PMID 891878.
[8] Ryberg, E; Larsson, N; Sjgren, S; Hjorth, S; Hermansson, NO; Leonova, J; Elebring, T; Nilsson, K; Drmota, T;
Greasley, PJ (2007). The orphan receptor GPR55 is a
novel cannabinoid receptor. British Journal of Pharmacology 152 (7): 10921101. doi:10.1038/sj.bjp.0707460.
PMC 2095107. PMID 17876302.
[2] McHugh D, Hu SS, Rimmerman N, Juknat A, Vogil

Z, Walker JM, Bradshaw HB (March 2010). Narachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18,
[9] Kapur, A; Zhao, P; Sharir, H; Bai, Y; Caron, MG; Barak,

LS; Abood, ME (2009). Atypical Responsiveness of the
Orphan Receptor GPR55 to Cannabinoid Ligands. The
Journal of Biological Chemistry 284 (43): 2981729827.
33
34
CHAPTER 16. ABNORMAL CANNABIDIOL
doi:10.1074/jbc.M109.050187. PMC 2785612. PMID

19723626.
[10] Henstridge, CM; Balenga, NA; Ford, LA; Ross, RA;
Waldhoer, M; Irving, AJ (2009). The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoAdependent Ca2+ signaling and NFAT activation. The
FASEB journal : ocial publication of the Federation of
American Societies for Experimental Biology 23 (1): 183
193. doi:10.1096/fj.08-108670. PMID 18757503.
[11] Brown AJ (November 2007). Novel cannabinoid receptors. British Journal of Pharmacology 152 (5): 567
575. doi:10.1038/sj.bjp.0707481. PMC 2190013. PMID
17906678.
[12] Johns, D. G.; Behm, D. J.; Walker, D. J.; Ao, Z.; Shapland, E. M.; Daniels, D. A.; Riddick, M.; Dowell, S.;
Staton, P. C.; Green, P.; Shabon, U.; Bao, W.; Aiyar, N.;
Yue, T. -L.; Brown, A. J.; Morrison, A. D.; Douglas, S.
A. (2009). The novel endocannabinoid receptor GPR55
is activated by atypical cannabinoids but does not mediate their vasodilator eects. British Journal of Pharmacology 152 (5): 825831. doi:10.1038/sj.bjp.0707419.
PMC 2190033. PMID 17704827.
[13] McHugh, D; Tanner, C; Mechoulam, R; Pertwee, RG;
Ross, RA (2008). Inhibition of human neutrophil
chemotaxis by endogenous cannabinoids and phytocannabinoids: evidence for a site distinct from CB1
and CB2. Molecular Pharmacology 73 (2): 441450.
doi:10.1124/mol.107.041863. PMID 17965195.
[14] Kreutz, S; Koch, M; Bttger, C; Ghadban, C; Korf,
HW; Dehghani, F (2009). 2-Arachidonoylglycerol elicits neuroprotective eects on excitotoxically lesioned dentate gyrus granule cells via abnormal-cannabidiol-sensitive
receptors on microglial cells. Glia 57 (3): 286294.
doi:10.1002/glia.20756. PMID 18837048.
Chapter 17
ADB-FUBINACA
ADB-FUBINACA is a designer drug identied in
synthetic cannabis blends in Japan in 2013.[1] The (S)
enantiomer of ADB-FUBINACA is claimed in Pzer
patent WO 2009/106982, with a K value of 0.36nM at
CB1 .[2] ADB-FUBINACA features a carboxamide group
at the 3-indazole position, like SDB-001 and STS-135.
ADB-FUBINACA appears to be the product of rational
drug design, since it diers from AB-FUBINACA only
by the replacement of the isopropyl group with a tertbutyl group. The stereochemistry of the tert-butyl sidechain in the illicitly sold product is unresolved. Nothing is known of the pharmacological activity of ADBFUBINACA in humans or other animals.
17.1 See also

AB-FUBINACA
ADB-PINACA
ADBICA
APINACA
PF-03550096
SDB-001
STS-135
17.2 References
Two new-type
2009/106982
35
Chapter 18
ADB-PINACA
ADB-PINACA is a cannabinoid designer drug that is an
ingredient in some synthetic cannabis products.[1][2] It has
been linked to multiple hospitalizations due to its use.[3]
In the United States, it is a Schedule I controlled substance.[4]
18.1 See also

AB-PINACA
APINACA
ADB-FUBINACA
18.2 References
[1] ADB-PINACA. Forendex.
[2] ADB-PINACA. Forensic Drug Review.
[3] CDC: 221 sickened by synthetic pot in Colorado. USA
Today. December 12, 2013.
[4] Schedules of controlled substances: temporary placement of four synthetic cannabinoids into Schedule I. Final
order. Fed Regist. 79 (27): 75777582. Feb 10, 2014.
PMID 24605391.
36
Chapter 19
ADBICA
ADBICA is a designer drug identied in synthetic
cannabis blends in Japan in 2013.[1] ADBICA had not
previously been reported in the scientic literature prior
to its sale as a component of synthetic cannabis blends.
ADBICA features a carboxamide group at the 3-indole
position, like SDB-001 and STS-135. The stereochemistry of the tert-butyl side-chain in the illicitly sold product is unresolved, though in a large series of indazole
derivatives structurally similar to ADBICA that are disclosed in Pzer patent WO 2009/106980, activity resides
exclusively in the (S) enantiomers.[2] Nothing is known
of the pharmacological activity of ADBICA in humans
or other animals.
19.1 See also

AB-FUBINACA
ADB-FUBINACA
APINACA
PF-03550096
SDB-001
STS-135
19.2 References
Two new-type
2009/106980
37
Chapter 20
Ajulemic acid
Ajulemic acid (AB-III-56, HU-239, IP-751, CPL 7075,
CT-3, Resunab) is a synthetic cannabinoid derivative of
the non-psychoactive THC metabolite 11-nor-9-carboxyTHC that shows useful analgesic and anti-inammatory
eects without causing a subjective high.[1] It is being developed for the treatment of neuropathic pain and
inammatory conditions such as arthritis.[2] It does not
however share the anti-emetic eects of other cannabinoids but may be useful for treating pain and chronic
inammatory conditions where nausea is not present.[3]
Side eects include dry mouth, tiredness and dizziness.
The mechanism of action has not yet been fully established, but ajulemic acid may activate the CB2 receptor in the periphery leading to production of resolving
eicosanoids. Studies in animals at doses up to 40 mg/kg
show minimal psychoactivity of ajulemic acid, comparable to that produced by tetrahydrocannabinol,.[4] Likewise, there was no dierence between ajulemic acid and
placebo on the cannabimimetic assay when used in humans at therapeutic doses.[5][6] A new highly puried
composition of ajulemic acid named Resunab is being developed by Corbus Pharmaceuticals (formerly JB Therapeutics)for the treatment of orphan life-threatening inammatory diseases.
20.1 References
[1] Burstein, S.; Karst, M.; Schneider, U.; Zurier, R. (2004).
Ajulemic acid: A novel cannabinoid produces analgesia without a high"". Life Sciences 75 (12): 15131522.
doi:10.1016/j.lfs.2004.04.010. PMID 15240185.
[2] Mitchell, V.; Aslan, S.; Safaei, R.; Vaughan, C. (2005).
Eect of the cannabinoid ajulemic acid on rat models of
neuropathic and inammatory pain. Neuroscience letters
382 (3): 231235. doi:10.1016/j.neulet.2005.03.019.
PMID 15925096.
[3] Burstein, S. (2005). Ajulemic acid (IP-751): synthesis, proof of principle, toxicity studies, and clinical trials. The AAPS journal 7 (1): E143E148.
doi:10.1208/aapsj070115.
PMC 2751505.
PMID
16146336.
[4] Vann, R.; Cook, C.; Martin, B.; Wiley, J. (2007).
Cannabimimetic properties of ajulemic acid. The Jour-
38
nal of Pharmacology and Experimental Therapeutics 320

(2): 678686. doi:10.1124/jpet.106.111625. PMC
2633725. PMID 17105826.
[5] Sumariwalla, P.; Gallily, R.; Tchilibon, S.; Fride, E.;
Mechoulam, R.; Feldmann, M. (2004). A novel synthetic, nonpsychoactive cannabinoid acid (HU-320) with
antiinammatory properties in murine collagen-induced
arthritis. Arthritis and rheumatism 50 (3): 985998.
doi:10.1002/art.20050. PMID 15022343.
[6] Sumariwalla, P.F., et al. (2004). Reply. Arthritis &
Rheumatism 50 (12): 4079. doi:10.1002/art.20806.
Chapter 21
AM-087
AM-087 is an analgesic drug that is a cannabinoid
agonist. It is a derivative of 8THC substituted on the
3-position side chain. AM-087 is a potent CB1 agonist
with a Ki of 0.43nM, making it around 100x more potent than THC itself. This is most likely due to the bulky
bromine substituent on the side chain.[1][2][3]
21.1 See also

AM-411
21.2 References
[1] Charalambous A, et al. Pharmacological evaluation
of halogenated delta 8-THC analogs. Pharmacology,
Biochemistry and Behaviour. 1991 Nov;40(3):509-12.
PMID 1666915
[2] Nikas SP, et al. The role of halogen substitution in classical cannabinoids: a CB1 pharmacophore model. AAPS
Journal. 2004 Oct 19;6(4):e30. PMID 15760095
[3] Roger Pertwee. Cannabinoids. Handbook of Experimental Pharmacology Volume 168, p 269. Springer. ISBN
3-540-22565-X
39
Chapter 22
AM-1220
AM-1220 is a drug that acts as a potent and moderately selective agonist for the cannabinoid receptor CB1 ,
with around 19x selectivity for CB1 over the related
CB2 receptor.[1] It was originally invented in the early
1990s by a team led by Thomas D'Ambra at Sterling
Winthrop,[2] but has subsequently been researched by
many others, most notably the team led by Alexandros
Makriyannis at the University of Connecticut. The
(piperidin-2-yl)methyl side chain of AM-1220 contains
a stereocenter, so there are two enantiomers with quite
dierent potency, the (R) enantiomer having a K of
0.27nM at CB1 while the (S) enantiomer has a much
weaker K of 217nM.[3] A number of related compounds
are known with similar potent cannabinoid activity, with
modications such as substitution of the indole ring at
the 2- or 6- positions, the naphthoyl ring substituted at
the 4- position or replaced by substituted benzoyl rings
or other groups, or the 1-(N-methylpiperidin-2-ylmethyl)
group replaced by similar heterocyclic groups such as
N-methylpyrrolidin-2-ylmethyl or N-methylmorpholin3-ylmethyl.[4][5][6] AM-1220 was rst detected as an ingredient of synthetic cannabis smoking blends in 2010.[7]
AM-2201
AM-2233
Cannabipiperidiethanone
22.2 References
Cannabimimetic indole derivatives, granted 2001-0607
[2] US patent 5068234, Thomas E. D'Ambra et al., 3arylcarbonyl-1-(C-attached-N-heteryl)1H-indoles,
granted 1991-11-26
[3] D'ambra, T. (1996). C-Attached aminoalkylindoles:
potent cannabinoid mimetics. Bioorganic & Medicinal Chemistry Letters 6: 1714. doi:10.1016/0960894X(95)00560-G.
[4] Hongfeng Deng (2000). Design and synthesis of selective
cannabinoid receptor ligands: Aminoalkylindole and other
heterocyclic analogs (PhD. Dissertation). University of
Connecticut.
[5] Willis, P. G.; Pavlova, O. A.; Chefer, S. I.; Vaupel, D.
B.; Mukhin, A. G.; Horti, A. G. (2005). Synthesis
and StructureActivity Relationship of a Novel Series of
Aminoalkylindoles with Potential for Imaging the Neuronal Cannabinoid Receptor by Positron Emission Tomography. Journal of Medicinal Chemistry 48 (18):
5813. doi:10.1021/jm0502743. PMID 16134948.
[6] US patent 7820144, Alexandros Makriyannis, et al.,
Receptor selective cannabimimetic aminoalkylindoles,
granted 2010-10-26
Related
1-(N-methylpyrrolidin-2-ylmethyl)
methylmorpholin-3-ylmethyl) derivatives
and
[7] Head Shop Legal Highs Active Constituents Identication Chart (July - August 2010)
1-(N-
22.1 See also

A-834,735
AM-1221
AM-1248
40
Chapter 23
AM-1221
AM-1221 is a drug that acts as a potent and selective
agonist for the cannabinoid receptor CB2 , with a K of
0.28nM at CB2 and 52.3nM at the CB1 receptor, giving
it around 180x selectivity for CB2 .[1] The 2-methyl and
6-nitro groups on the indole ring both tend to increase
CB2 anity while generally reducing anity at CB1 , explaining the high CB2 selectivity of AM-1221. However
despite this relatively high selectivity for CB2 , its CB1
anity is still too strong to make it useful as a truly selective CB2 agonist, so the related compound AM-1241
is generally preferred for research purposes.[2][3]
23.1 See also

AM-630
AM-1220
AM-1235
AM-2233
UR-144
23.2 References
Connecticut.
[3] Manera, C; Tuccinardi, T; Martinelli, A (2008). Indoles and related compounds as cannabinoid ligands.
Mini reviews in medicinal chemistry 8 (4): 37087.
doi:10.2174/138955708783955935. PMID 18473928.
41
Chapter 24
AM-1235
AM-1235
(1-(5-uoropentyl)3-(naphthalen-1oyl)6-nitroindole) is a drug that acts as a potent and
reasonably selective agonist for the cannabinoid receptor
CB1 .
24.3 References
[2] Deng, Hongfeng (2000). Design and synthesis of selective cannabinoid receptor ligands: Aminoalkylindole and
other heterocyclic analogs (PhD. Dissertation). University
of Connecticut.
24.1 Pharmacology
24.1.1
Pharmacodynamics
AM-1235 is a cannabinoid receptor agonist with K of

1.5nM at CB1 compared to 20.4nM at CB2 .[1] While
the 6-nitro substitution on the indole ring reduces anity
for both CB1 and CB2 relative to the unsubstituted parent compound AM-2201, CB2 anity is reduced much
more, resulting in a CB1 selectivity of around 13x.[2] This
is in contrast to other related compounds such as AM1221 where a 6-nitro substitution instead confers signicant selectivity for CB2 .[3]
24.1.2
[1] US patent 7241799, Makriyannis A, Deng H,

Pharmacokinetics
Main article: Pharmacokinetic data of JWH-018 are

generally applicable to AM-1235.
AM-1235 metabolism diers only slightly from that
of JWH-018. AM-1235 N-dealkylation produces uoropentane instead of pentane (or plain alkanes in general). It has been speculated that the uoropentane might
function as an alkylating agent or is further metabolized into toxic uoroacetic acid. This is not true since
uoroalkanes do not act as alkylating agents under normal conditions and uneven uoroalkane chains metabolize into substantially less toxic uoropropanoic acid.[4][5]
24.2 See also

AM-906
AM-2389
O-1812
42

[4] Millington JE, Pattison FLM. TOXIC FLUORINE COMPOUNDS: XII. ESTERS OF FLUOROALCOHOLS. Canadian Journal of Chemistry.
1956 Nov;34(11):1532-1541.
[5] Pattison FLM, Howell WC, Woolford RG. TOXIC
FLUORINE COMPOUNDS: XIII. -FLUOROALKYL
ETHERS. Canadian Journal of Chemistry.
1957
Feb;35(2):141-148.
Chapter 25
AM-1241
AM-1241
(1-(methylpiperidin-2-ylmethyl)3-(2iodo-5-nitrobenzoyl)indole) is a chemical from the
aminoalkylindole family that acts as a potent and selective agonist for the cannabinoid receptor CB2 ,[1][2]
with a K of 3.4nM at CB2 and 80x selectivity over the
related CB1 receptor.[3][4] It has analgesic eects in
animal studies, particularly against atypical pain such
as hyperalgesia and allodynia.[5] This is thought to be
mediated through CB2 -mediated peripheral release of
endogeous opioid peptides,[6] as well as direct activation
of the TRPA1 channel.[7] It has also shown ecacy in
the treatment of amyotrophic lateral sclerosis in animal
models.[8][9]
25.1 Eects in bone cancer model

The antihyperalgesic eects of AM-1241 were investigated in a murine bone cancer model. Sarcoma cells were
injected into the femur of a mouse, and then mice were
injected twice daily with AM-1241. Treatment with AM1241 reduced both spontaneous and evoked pain, as well
as reducing the bone loss and subsequent fractures due
to the tumor. Pretreatment with the CB2 antagonist SR144,528 reversed the acute eects of AM-1241 on both
spontaneous and evoked pain, while having no eect on
its own.[10]
25.2 See also
[2] Bingham B, et al. (August 2007). Species-specic in

vitro pharmacological eects of the cannabinoid receptor
2 (CB2) selective ligand AM1241 and its resolved enantiomers. British Journal of Pharmacology 151 (7): 1061
17549048.
[3] Ibrahim MM, et al. (September 2003). Activation of
CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors
not present in the CNS. Proceedings of the National
Academy of Sciences of the United States of America 100
(18): 1052933. doi:10.1073/pnas.1834309100. PMC
193595. PMID 12917492.
[4] Marriott KS, Human JW (2008). Recent advances in
the development of selective ligands for the cannabinoid
CB(2) receptor. Current Topics in Medicinal Chemistry
8 (3): 187204. doi:10.2174/156802608783498014.
PMID 18289088.
[5] Beltramo M, et al. (March 2006). CB2 receptormediated antihyperalgesia: possible direct involvement
of neural mechanisms. The European Journal of
Neuroscience 23 (6): 15308. doi:10.1111/j.14609568.2006.04684.x. PMID 16553616.
[6] Ibrahim MM, et al.
(February 2005).
CB2
cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proceedings of the National Academy of Sciences of the United States of America 102 (8): 3093
8. doi:10.1073/pnas.0409888102. PMC 549497. PMID
15705714.
[7] Akopian AN, Ruparel NB, Patwardhan A, Hargreaves
KM (January 2008). Cannabinoids desensitize capsaicin
and mustard oil responses in sensory neurons via TRPA1
activation. Journal of Neuroscience 28 (5): 1064
75. doi:10.1523/JNEUROSCI.1565-06.2008. PMID
18234885.
AM-1220
AM-1248
AM-2233
25.3 References
[1] Yao BB, et al. (September 2006). In vitro pharmacological characterization of AM1241: a protean agonist at
the cannabinoid CB2 receptor?". British Journal of Pharmacology 149 (2): 14554. doi:10.1038/sj.bjp.0706838.
PMC 2013801. PMID 16894349.
43
[8] Kim K, Moore DH, Makriyannis A, Abood ME (August 2006). AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in
a mouse model of amyotrophic lateral sclerosis. European Journal of Pharmacology 542 (1-3): 1005.
doi:10.1016/j.ejphar.2006.05.025. PMID 16781706.
[9] Shoemaker JL, et al (April 2007). The CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic
44
CHAPTER 25. AM-1241
mouse model of amyotrophic lateral sclerosis when initiated at symptom onset. Journal of Neurochemistry
101 (1): 8798. doi:10.1111/j.1471-4159.2006.04346.x.
PMC 2819701. PMID 17241118.
[10] Lozano, Alysia (April 2010).
A cannabinoid 2
receptor agonist attenuates bone cancer-induced pain
and bone loss. Life Sciences 86 (17-18): 64653.
doi:10.1016/j.lfs.2010.02.014. PMC 2871326. PMID
20176037. Retrieved 18 December 2011.
Chapter 26
AM-1248
AM-1248 is a drug that acts as a moderately potent
agonist for both the cannabinoid receptors CB1 and CB2 ,
but with some dispute between sources over its exact
potency and selectivity. Replacing the 3-(1-naphthoyl)
group found in many indole derived cannabinoid ligands,
with an adamantoyl group, generally confers signicant
CB2 selectivity,[1] but reasonable CB1 anity and selectivity is retained when an N-methylpiperidin-2-ylmethyl
substitution is used at the indole 1-position.[2][3] The
related compound 1-pentyl-3-(1-adamantoyl)indole was
identied as having been sold as a cannabinoid designer
drug in Hungary in 2011, along with another synthetic
cannabinoid AM-679.[4]
26.1 See also

A-834,735
AB-001
AM-411
AM-1220
AM-2233
26.2 References
PMID 19921781.
[2] US patent 7820144, Makriyannis A, Deng H, Receptor selective cannabimimetic aminoalkylindoles, granted
2010-10-26
45
[4] Jankovics P, et al. (August 2011). Detection and

identication of the new potential synthetic cannabinoids 1-pentyl-3-(2-iodobenzoyl)indole and 1-pentyl-3(1-adamantoyl)indole in seized bulk powders in Hungary. Forensic Science International 214 (1-3): 2732.
Chapter 27
AM-1714
AM-1714 is a drug that acts as a reasonably selective
agonist of the peripheral cannabinoid receptor CB2 , with
sub-nanomolar anity and 490x selectivity over the related CB1 receptor. In animal studies it has both analgesic
and anti-allodynia eects. The 9-methoxy derivative
AM-1710 has similar CB2 anity but only 54x selectivity over CB1 .[1][2]
27.1 See also

Cannabinol
Canbisol
27.2 References
[1] Khanolkar AD, Lu D, Ibrahim M, Duclos RI Jr, Thakur
GA, Malan TP Jr, Porreca F, Veerappan V, Tian X,
George C, Parrish DA, Papahatjis DP, Makriyannis A.
Cannabilactones: a novel class of CB2 selective agonists
with peripheral analgesic activity. Journal of Medicinal Chemistry. 2007 Dec 27;50(26):6493-500. PMID
18038967
[2] Rahn EJ, Zvonok AM, Thakur GA, Khanolkar AD,
Makriyannis A, Hohmann AG. Selective activation of
cannabinoid CB2 receptors suppresses neuropathic nociception induced by treatment with the chemotherapeutic
agent paclitaxel in rats. Journal of Pharmacology and Experimental Therapeutics. 2008 Nov;327(2):584-91. doi:
10.1124/jpet.108.141994. PMID 18664590
46
Chapter 28
AM-2201
AM-2201
(1-(5-uoropentyl)3-(1- AM-2201 metabolism diers only slightly from that
naphthoyl)indole) is a research chemical that acts as a of JWH-018. AM-2201 N-dealkylation produces uopotent but nonselective full agonist for the cannabinoid ropentane instead of pentane (or plain alkanes in general).
receptor. It is part of the AM series of cannabinoids
discovered by Alexandros Makriyannis at Northeastern
University.
28.3 Detection
A forensic standard of AM-2201 is available, and the
compound has been posted on the Forendex website of
potential drugs of abuse.[5]
28.1 Hazards
AM-2201 is widely regarded by recreational users of synthetic cannabinoids as one of the most potent and possibly the most potent substance available in this class of
drugs. As the dosage is much smaller than other synthetic
cannabinoids, accidental overdose becomes more likely.
There have been anecdotal reports of individuals experiencing panic attacks and vomiting at doses as small as 2
mg. Convulsions have been reported[1] including at doses
as low as 10 mg.[2] Caution should be taken if using this
substance as it is active at doses as small as 500 g, has
a very steep dose-response curve, and tolerance builds up
very quickly to the eects.
Recreational use of AM-2201 in the United States has led
to it being specically listed in a proposed 2011 amendment to the Controlled Substances Act, aiming to add
a number of synthetic drugs into Schedule I.[3] As of
November 2011, there have been no reports of death associated with the drug. The acute toxicity and long term
side eects associated with the use of AM-2201 are unknown.
28.4 See also

AM-2233
AM-694
AM-1235
AM-2232
JWH-018
28.5 References
[1] David McQuade, Simon Hudson, Paul I. Dargan, David
M. Wood (March 2013). First European case of convulsions related to analytically conrmed use of the synthetic
cannabinoid receptor agonist AM-2201. European Journal of Clinical Pharmacology 69 (3): 373376.
[2] ekaJ (20 February 2011). The Night I Killed My
Friends. Erowid.org. Retrieved 11 June 2012.
28.2 Pharmacology
AM-2201 is a full agonist for cannabinoid receptors.
Anities are: with a K of 1.0nM at CB1 and 2.6nM
at CB2 .[4] The 4-methyl functional analog MAM-2201
probably has similar anities.
[3] Synthetic Drug Control Act of 2011. H.R. 1254, 112th

Congress, 1st Session (2011).
[5] Southern Association of Forensic Scientists
28.2.1
Pharmacokinetics
See also: JWH-018 Pharmacokinetics
47
Chapter 29
AM-2232
AM-2232
(1-(4-cyanobutyl)3-(naphthalen-1oyl)indole) is a drug that acts as a potent but unselective
agonist for the cannabinoid receptors, with a K of
0.28nM at CB1 and 1.48nM at CB2 .[1]
29.1 See also

AM-2201
O-1057
O-1812
29.2 References
48
Chapter 30
AM-2233
AM-2233 is a drug that acts as a highly potent full agonist for the cannabinoid receptors, with a K of 1.8nM at
CB1 and 2.2nM at CB2 as the active (R) enantiomer.[1] It
was developed as a selective radioligand for the cannabinoid receptors and has been used as its 131 I derivative
for mapping the distribution of the CB1 receptor in the
brain.[2][3][4][5][6][7] AM-2233 was found to fully substitute for THC in rats, with a potency lower than that of
JWH-018 but higher than WIN 55,212-2.[8]
30.1 See also
[5] Dhawan, J.; Deng, H.; Gatley, S. J.; Makriyannis, A.;

Akinfeleye, T.; Bruneus, M.; Dimaio, A. A.; Gifford, A. N. (2006). Evaluation of the in vivo receptor occupancy for the behavioral eects of cannabinoids using a radiolabeled cannabinoid receptor agonist, R-[125/131I]AM2233. Synapse 60 (2): 93101.
doi:10.1002/syn.20277. PMID 16715483.
[6] Leung K (Dec 12, 2006). R-2-[131I]Iodophenyl(1-(1-methylpiperidin-2-ylmethyl)1H-indol-3yl)methanone.
Molecular Imaging and Contrast
Agent Database (MICAD) [Internet]. PMID 20641836.
[7] Pei, Y., et al. (2008). Ligand-Binding Architecture
of Human CB2 Cannabinoid Receptor: Evidence for
Receptor Subtype-Specic Binding Motif and Modeling GPCR Activation. Chemistry & Biology 15: 1207.
doi:10.1016/j.chembiol.2008.10.011.
AM-679
AM-694
AM-1220
[8] Jrbe TU, Deng H, Vadivel SK, Makriyannis A (September 2011). Cannabinergic aminoalkylindoles, including AM678=JWH018 found in 'Spice', examined using drug (9-tetrahydrocannabinol) discrimination for
rats. Behavioural Pharmacology 22 (5-6): 498507.
doi:10.1097/FBP.0b013e328349fbd5. PMC 3212432.
PMID 21836461.
AM-1221
AM-1241
30.2 References
[1] Hongfeng Deng (2000). Design and synthesis of selective cannabinoid receptor ligands: Aminoalkylindole and
other heterocyclic analogs (PhD Dissertation). University
of Connecticut.
[2] Deng H, et al. (October 2005). Potent cannabinergic indole analogues as radioiodinatable brain imaging agents
for the CB1 cannabinoid receptor. Journal of Medicinal
Chemistry 48 (20): 638692. doi:10.1021/jm050135l.
PMID 16190764.
[3] Hanu, L. R. O.; Mechoulam, R. (2005). Cannabinoid chemistry: an overview. Cannabinoids as Therapeutics. Milestones in Drug Therapy MDT. p. 23.
doi:10.1007/3-7643-7358-X_2. ISBN 3-7643-7055-6.
[4] Shen CP, et al. (February 2006). F200A substitution
in the third transmembrane helix of human cannabinoid
CB1 receptor converts AM2233 from receptor agonist to
inverse agonist. European Journal of Pharmacology 531
(13): 416. doi:10.1016/j.ejphar.2005.12.026. PMID
16438957.
49
Chapter 31
AM-2389
AM-2389 is a classical cannabinoid derivative which acts
as a potent and reasonably selective agonist for the CB1
receptor, with a K of 0.16 nM, and 26x selectivity over
the related CB2 receptor. It has high potency in animal
tests of cannabinoid activity, and a medium duration of
action.[1][2] Replacing the 1',1'-dimethyl substitution of
the dimethylheptyl side chain of classical cannabinoids
with cyclopropyl or cyclopentyl results in higher potency
than cyclobutyl, but only the cyclobutyl derivatives show
selectivity for CB1 over CB2 .[3] High selectivity for CB1
over CB2 is dicult to achieve (cf. AM-906, AM-1235),
as almost all commonly used CB1 agonists have similar or greater anity for CB2 than CB1 , and the only
truly highly selective CB1 agonists known as of 2012 are
eicosanoid derivatives such as O-1812.
31.1 See also

HHC
AMG-36
AMG-41
31.2 References
[1] Nikas SP, et al. Novel 1',1'-chain substituted hexahydrocannabinols: 9-hydroxy-3-(1-hexyl-cyclobut-1-yl)hexahydrocannabinol (AM2389) a highly potent cannabinoid receptor 1 (CB1) agonist. Journal of Medicinal
Chemistry. 2010 Oct 14;53(19):6996-7010. PMID
20925434
[2] Jrbe TU, et al. AM2389, a high-anity, in vivo potent CB(1)-receptor-selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia
testing in mice. Psychopharmacology (Berlin). 2011 Oct
12. PMID 21989802
[3] Papahatjis DP, et al. C1'-cycloalkyl side chain pharmacophore in tetrahydrocannabinols. Journal of Medicinal Chemistry. 2007 Aug 23;50(17):4048-60. PMID
17672444
50
Chapter 32
AM-4030
AM-4030 is an analgesic drug which is a cannabinoid receptor agonist. It is a derivative of HU-210 which has
been substituted with a 6-((E)3-hydroxyprop-1-enyl)
group. This adds a southern aliphatic hydroxyl group
to the molecule as seen in the CP-series of nonclassical
cannabinoid drugs, and so AM-4030 represents a hybrid
structure between the classical and nonclassical cannabinoid families,[1] with the 6-hydroxyalkyl chain rigidied
with a double bond with dened stereochemistry. This
gives AM-4030 a greater degree of selectivity, so while
it is still a potent agonist at both CB1 and CB2 , it is reasonably selective for CB1 , with a K of 0.7nM at CB1 and
8.6nM at CB2 , a selectivity of around 12x.[2][3] Resolution of the enantiomers of AM-4030 yields an even more
potent compound, although with less selectivity, with the
(-) enantiomer AM-4030a having a K of 0.6nM at CB1
and 1.1nM at CB2 .[4]
32.1 See also

AM-919
AM-938
32.2 References
3-540-22565-X
[2] Tius MA, Hill WA, Zou XL, Busch-Petersen J,
Kawakami JK, Fernandez-Garcia MC, Drake DJ, Abadji
V, Makriyannis A. Classical/non-classical cannabinoid
hybrids; stereochemical requirements for the southern
hydroxyalkyl chain. Life Sciences. 1995;56(23-24):200712. PMID 7776825
[3] Drake DJ, Jensen RS, Busch-Petersen J, Kawakami JK,
Concepcion Fernandez-Garcia M, Fan P, Makriyannis
A, Tius MA. Classical/nonclassical hybrid cannabinoids:
southern aliphatic chain-functionalized C-6beta methyl,
ethyl, and propyl analogues. Journal of Medicinal Chemistry. 1998 Sep 10;41(19):3596-608. PMID 9733485
[4] Thakur GA, Palmer SL, Harrington PE, Stergiades IA,
Tius MA, Makriyannis A. Enantiomeric resolution of a
51
novel chiral cannabinoid receptor ligand. Journal of Biochemical and Biophysical Methods. 2002 Dec 31;54(13):415-22. PMID 12543516
Chapter 33
AM-411
AM-411 is an analgesic drug that is a cannabinoid
agonist. It is a derivative of 8THC substituted with an
adamantyl group at the 3-position, demonstrating that the
binding pocket for the alkyl chain at this position can accommodate signicant bulk.
AM-411 is a potent and fairly selective CB1 full agonist
with a K of 6.80nM, but is still also a moderately potent
CB2 agonist with a K of 52.0nM.[1] It produces similar
eects to other cannabinoid agonists such as analgesia,
sedation, and anxiolysis.[2][3]
33.1 See also

AM-087
AM-1248
KM-233
33.2 References
[1] Lu D, et al. Adamantyl cannabinoids: a novel class of
cannabinergic ligands. Journal of Medicinal Chemistry.
2005 Jul 14;48(14):4576-85. PMID 15999995
[2] Jrbe TU, DiPatrizio NV, Lu D, Makriyannis A. (-)Adamantyl-delta8-tetrahydrocannabinol (AM-411), a selective cannabinoid CB1 receptor agonist: eects on
open-eld behaviors and antagonism by SR-141716 in
rats. Behavioural Pharmacology. 2004 Nov;15(7):51721. PMID 15472574
[3] McLaughlin PJ, et al. Behavioral eects of the novel
cannabinoid full agonist AM 411. Pharmacology, Biochemistry and Behaviour. 2005 May;81(1):78-88. PMID
15894067
52
Chapter 34
AM-630
AM-630 (6-Iodopravadoline) is a drug that acts as a potent and selective inverse agonist for the cannabinoid receptor CB2 , with a K of 32.1nM at CB2 and 165x selectivity over CB1 , at which it acted as a weak partial agonist.[1][2] It is used in the study of CB2 mediated responses
and has been used to investigate the possible role of CB2
receptors in the brain.[3][4] AM-630 is signicant as one
of the rst indole derived cannabinoid ligands substituted
on the 6-position of the indole ring, a position that has
subsequently been found to be important in determining
anity and ecacy at both the CB1 and CB2 receptors,
and has led to the development of a large number of related derivatives.[5][6][7][8][9]
34.1 See also
97482. doi:10.1016/j.biopsych.2009.09.024.
19931854.
PMID
[5] Eissenstat, M. A.. et al. (1995). Aminoalkylindoles:

Structure-Activity Relationships of Novel Cannabinoid
Mimetics. Journal of Medicinal Chemistry 38 (16):
3094. doi:10.1021/jm00016a013. PMID 7636873.
[6] Hongfeng Deng. Design and synthesis of selective
cannabinoid receptor ligands: Aminoalkylindole and
other heterocyclic analogs. PhD Dissertation, University
of Connecticut, 2000.
[7] Hynes J, et al. (September 2002). C-3 Amidoindole cannabinoid receptor modulators. Bioorganic
& Medicinal Chemistry Letters 12 (17):
2399
402. doi:10.1016/S0960-894X(02)00466-3. PMID
12161142.
[8] Frost, J. M., et al.
(2008).
Indol-3-yltetramethylcyclopropyl Ketones: Eects of Indole
Ring Substitution on CB2 Cannabinoid Receptor Activity. Journal of Medicinal Chemistry 51 (6): 1904.
doi:10.1021/jm7011613. PMID 18311894.
WIN 48,098 (Pravadoline)

WIN 54,461 (6-Bromopravadoline)
AM-1221
[9] Adam, J. M., et al. (2010). Design, synthesis, and

structureactivity relationships of indole-3-carboxamides
as novel water soluble cannabinoid CB1 receptor agonists. MedChemComm 1: 54. doi:10.1039/c0md00022a.
34.2 References
[1] Ross RA, et al. (February 1999). Agonist-inverse
agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656, and AM630.
10188977.
[2] Murataeva, N.; MacKie, K.; Straiker, A. (2012). The
CB2-preferring agonist JWH015 also potently and efcaciously activates CB1 in autaptic hippocampal neurons. Pharmacological Research 66 (5): 43742.
doi:10.1016/j.phrs.2012.08.002. PMC 3601544. PMID
22921769.
[3] Morgan NH, Stanford IM, Woodhall GL (September
2009). Functional CB2 type cannabinoid receptors
at CNS synapses. Neuropharmacology 57 (4): 356
19616018.
[4] Ishiguro H, et al. (May 2010). Brain cannabinoid CB2
receptor in schizophrenia. Biological Psychiatry 67 (10):
53
Chapter 35
AM-6545
AM-6545 is a drug which acts as a peripherally selective silent antagonist for the CB1 receptor, and was developed for the treatment of obesity. Other cannabinoid
antagonists such as rimonabant have been marketed for
this application, but have subsequently been withdrawn
from sale because of centrally mediated side eects such
as depression and nausea. Because AM-6545 does not
cross the bloodbrain barrier to any signicant extent, it
does not produce these kinds of side eects, but has still
been shown to eectively reduce appetite and food consumption in animal studies.[1][2][3][4]
35.1 See also

CB-13 a peripherally selective cannabinoid agonist
O-2050 a centrally active CB1 silent antagonist
Methylnaltrexone a peripherally selective mu opioid receptor antagonist
TM-38837 - another peripherally selective cannabinoid antagonist
35.2 References
[1] Tam, J.; Vemuri, V. K.; Liu, J.; Btkai, S. N.; Mukhopadhyay, B.; Godlewski, G.; Osei-Hyiaman, D.; Ohnuma, S.;
Ambudkar, S. V.; Pickel, J.; Makriyannis, A.; Kunos, G.
(2010). Peripheral CB1 cannabinoid receptor blockade
improves cardiometabolic risk in mouse models of obesity. Journal of Clinical Investigation 120 (8): 2953
2966. doi:10.1172/JCI42551. PMC 2912197. PMID
20664173. PMID 20664173
[2] Randall PA, Vemuri VK, Segovia KN, Torres EF,
Hosmer S, Nunes EJ, Santerre JL, Makriyannis A,
Salamone JD. The novel cannabinoid CB1 antagonist
AM6545 suppresses food intake and food-reinforced behavior. Pharmacology, Biochemistry and Behavior. 2010
Nov;97(1):179-84. PMID 20713079
[3] Cluny NL, Vemuri VK, Chambers AP, Limebeer CL,
Bedard H, Wood JT, Lutz B, Zimmer A, Parker LA,
54
Makriyannis A, Sharkey KA. A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause
malaise, in rodents. British Journal of Pharmacology.
2010 Oct;161(3):629-42. PMID 20880401
[4] Jrbe TU, LeMay BJ, Vemuri VK, Vadivel SK, Zvonok
A, Makriyannis A. Central mediation and dierential
blockade by cannabinergics of the discriminative stimulus eects of the cannabinoid CB1 receptor antagonist
rimonabant in rats. Psychopharmacology (Berlin). 2011
Aug;216(3):355-65. PMID 21369753
Chapter 36
AM-679 (cannabinoid)
This article is about the cannabinoid agonist. For the
FLAP inhibitor, see AM-679 (FLAP inhibitor).
AM-679 is a drug that acts as a moderately potent agonist
for the cannabinoid receptors, with a K of 13.5nM at
CB1 and 49.5nM at CB2 .[1] AM-679 was one of the
rst 3-(2-iodobenzoyl)indole derivatives that was found to
have signicant cannabinoid receptor anity, and while
AM-679 itself has only modest anity for these receptors, it was subsequently used as a base to develop several more specialised cannabinoid ligands that are now
widely used in research, including the potent CB1 agonists AM-694 and AM-2233, and the selective CB2 agonist AM-1241.[2] AM-679 was rst identied as having
been sold as a cannabinoid designer drug in Hungary in
2011, along with another novel compound 1-pentyl-3-(1adamantoyl)indole.[3]
36.1 See also

RCS-4
AM-694
AM-2233
36.2 References
Connecticut.
[3] Jankovics P, et al. (August 2011). Detection and
identication of the new potential synthetic cannabinoids 1-pentyl-3-(2-iodobenzoyl)indole and 1-pentyl-3(1-adamantoyl)indole in seized bulk powders in Hungary. Forensic Science International 214 (1-3): 2732.
55
Chapter 37
AM-694
AM-694 (1-(5-uoropentyl)3-(2-iodobenzoyl)indole)
is a drug that acts as a potent and selective agonist for the
cannabinoid receptor CB1 . It is used in scientic research
for mapping the distribution of CB1 receptors. No public
data about AM-694 metabolism is known. AM-694 has
already emerged as a designer drug.
37.3 References
37.1 Pharmacology
AM-694 is an agonist for cannabinoid receptors. Anities are: with a K of 0.08nM at CB1 and 18x selectivity over CB2 with a K 1.44nM.[1] It is unclear what is
responsible for this unusually high CB1 binding anity,
but it makes the 18 F radiolabelled derivative of AM-694
useful for mapping the distribution of CB1 receptors in
the body.[2]
37.1.1
Pharmacokinetics
Main article: Pharmacokinetic data of JWH-018 are

generally applicable to AM-694.
AM-694 metabolism diers only slightly from that of
JWH-018. AM-694 N-dealkylation produces uoropentane instead of pentane (or plain alkanes in general). It
has been speculated that the uoropentane might function
as an alkylating agent or is further metabolized into toxic
uoroacetic acid. This is not true since uoroalkanes do
not act as alkylating agents under normal conditions and
uneven uoroalkane chains metabolize into substantially
less toxic uoropropanoic acid.[3][4]
37.2 See also

AM-679
AM-2201
AM-2233
56

[2] Willis PG, Katoch-Rouse R, Horti AG. Regioselective F18 radiolabeling of AM694, a CB1 cannabinoid receptor
ligand. Journal of Labelled Compounds and Radiopharmaceuticals 2003;46(9):799-804. doi:10.1002/jlcr.720
[3] Millington JE, Pattison FLM. TOXIC FLUORINE COMPOUNDS: XII. ESTERS OF FLUOROALCOHOLS. Canadian Journal of Chemistry.
1956 Nov;34(11):1532-1541.
[4] Pattison FLM, Howell WC, Woolford RG. TOXIC
FLUORINE COMPOUNDS: XIII. -FLUOROALKYL
ETHERS. Canadian Journal of Chemistry.
1957
Feb;35(2):141-148.
Chapter 38
AM-855
AM-855 is an analgesic drug which is a cannabinoid
agonist. It is a derivative of 8 Tetrahydrocannabinol with
a conformationally restricted side chain which has been
bound into a fourth ring fused to the aromatic A-ring of
the cannabinoid skeleton. AM-855 is an agonist at both
CB1 and CB2 with moderate selectivity for CB1 , with a
K of 22.3nM at CB1 and 58.6nM at CB2 .[1]
38.1 References
[1] Khanolkara, Atmaram D.; Dai Lua, Pusheng Fana, Xiaoyu Tiana and Alexandros Makriyannis (August 1999).
Novel conformationally restricted tetracyclic analogs
of 8 -tetrahydrocannabinol. Bioorganic & Medicinal
Chemistry Letters 9 (15): 211924. doi:10.1016/S0960894X(99)00355-8. PMID 10465529.
57
Chapter 39
AM-905
agonist with a conformationally restricted side chain. It
is a potent and reasonably selective agonist for the CB1
cannabinoid receptor, with a K of 1.2nM at CB1 and
5.3nM at CB2 .[1]
39.1 References
[1] Papahatjis DP, Kourouli T, Abadji V, Goutopoulos
A, Makriyannis A. Pharmacophoric requirements for
cannabinoid side chains: multiple bond and C1'substituted delta 8-tetrahydrocannabinols. Journal of
Medicinal Chemistry. 1998 Mar 26;41(7):1195-200.
PMID 9544219
58
Chapter 40
AM-906
agonist with a conformationally restricted side chain. It
is a potent and selective agonist for the CB1 cannabinoid
receptor, with a K of 0.8nM at CB1 and 9.5nM at CB2 ,
a selectivity of almost 12x.[1]
40.1 See also

AM-1235
AM-2389
40.2 References
[1] Papahatjis DP, et al. Pharmacophoric requirements
for cannabinoid side chains: multiple bond and C1'substituted delta 8-tetrahydrocannabinols. Journal of
PMID 9544219
59
Chapter 41
AM-919
receptor agonist. It is a derivative of HU-210 which
has been substituted with a 6-(3-hydroxypropyl) group.
This adds a southern aliphatic hydroxyl group to the
molecule as seen in the CP-series of nonclassical cannabinoid drugs, and so AM-919 represents a hybrid structure between the classical and nonclassical cannabinoid
families.[1]
AM-919 is somewhat less potent than HU-210 itself, but
is still a potent agonist at both CB1 and CB2 with moderate selectivity for CB1 , with a K of 2.2nM at CB1 and
3.4nM at CB2 .[2][3]
41.1 See also

AM-4030
41.2 References
3-540-22565-X
60
Chapter 42
AM-938
receptor agonist. It is a derivative of HU-210 which
has been substituted with a 6-(3-hydroxyprop-1-ynyl)
group. This adds a southern aliphatic hydroxyl group
to the molecule as seen in the CP-series of nonclassical cannabinoid drugs, and so AM-938 represents a
hybrid structure between the classical and nonclassical
cannabinoid families,[1] with the 6-hydroxyalkyl chain
rigidied with a triple bond. This gives AM-938 a greater
degree of selectivity, so while it is still a potent agonist at
both CB1 and CB2 , it is reasonably selective for CB2 ,
with a K of 0.3nM at CB2 and 1.2nM at CB1 , a selectivity of around 4x.[2][3]
42.1 See also

AM-4030
42.2 References
3-540-22565-X
61
Chapter 43
AM404
AM404,
also
known
as
Narachidonoylaminophenol,[1] is an active metabolite
of paracetamol (acetaminophen), responsible for all or
part of its analgesic action.[2] Chemically, it is the amide
formed from 4-aminophenol and arachidonic acid.
43.1 Pharmacology
AM404 was originally reported to be an endogenous
cannabinoid reuptake inhibitor, preventing the transport
of anandamide and other related compounds back from
the synaptic cleft, much in the same way that common selective serotonin reuptake inhibitor (SSRI) antidepressants prevent the reuptake of serotonin. Earlier work on the mechanism of AM404 suggested that
the inhibition of fatty acid amide hydrolase (FAAH) by
AM404 was responsible for all of its attributed reuptake properties, since intracellular FAAH hydrolysis of
anandamide changes the intra/extracellular anandamide
equilibrium.[3] However, this is not the case, as newer
research on FAAH knockout mice has found that brain
cells internalize anandamide through a selective transport
mechanism which is independent of FAAH activity.[4]
This mechanism is inhibited by AM404.
AM404 is also a TRPV1 agonist and inhibitor of
cyclooxygenase COX-1 and COX-2, thus attenuating
prostaglandin synthesis. AM404 is thought to induce its analgesic action through its activity on the
endocannabinoid, COX, and TRPV systems, all of which
are present in pain and thermoregulatory pathways.[5]
43.2 See also

VDM-11
43.3 References
[1] Rogosch T, Sinning C, Podlewski A, Watzer B, Schlosburg J, Lichtman AH, Cascio MG, Bisogno T, Di Marzo
V, Nsing R, Imming P (January 2012). Novel bioactive metabolites of dipyrone (metamizol)". Bioorg. Med.
62
Chem. 20 (1): 1017. doi:10.1016/j.bmc.2011.11.028.

PMC 3248997. PMID 22172309.
[2] Ottani A, Leone S, Sandrini M, Ferrari A, Bertolini A
(February 2006). The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1
receptors. Eur. J. Pharmacol. 531 (13): 2801.
doi:10.1016/j.ejphar.2005.12.015. PMID 16438952.
[3] Glaser ST, Abumrad NA, Fatade F, Kaczocha M,
Studholme KM, Deutsch DG (April 2003). Evidence
against the presence of an anandamide transporter.
Proc. Natl. Acad. Sci. U.S.A. 100 (7): 426974.
doi:10.1073/pnas.0730816100. PMC 153082. PMID
12655057.
[4] Fegley, D.; Kathuria, S.; Mercier, R.; Li, C.; Goutopoulos, A.; Makriyannis, A.; Piomelli, D. (11 May 2004).
Anandamide transport is independent of fatty-acid amide
hydrolase activity and is blocked by the hydrolysisresistant inhibitor AM1172. Proceedings of the National Academy of Sciences 101 (23): 87568761.
doi:10.1073/pnas.0400997101.
[5] Hgesttt ED, Jnsson BA, Ermund A, Andersson DA,
Bjrk H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM (September 2005).
Conversion of acetaminophen to the bioactive N-acylphenolamine AM404
via fatty acid amide hydrolase-dependent arachidonic acid
conjugation in the nervous system (pdf). J. Biol. Chem.
280 (36): 3140512. doi:10.1074/jbc.M501489200.
PMID 15987694.
Chapter 44
AMG-1
AMG-1 is an analgesic drug which is a cannabinoid
agonist. It is a derivative of 8THC with a rigidied and
extended 3-position side chain. AMG-1 is a potent agonist at both CB1 and CB2 with moderate selectivity for
CB1 , with a K of 0.6nM at CB1 vs 3.1nM at CB2 .[1]
44.1 References
[1] Papahatjis DP, Nikas SP, Kourouli T, Chari R, Xu
W, Pertwee RG, Makriyannis A. Pharmacophoric requirements for the cannabinoid side chain. Probing the
cannabinoid receptor subsite at C1'. Journal of Medicinal
Chemistry. 2003 Jul 17;46(15):3221-9. PMID 12852753
63
Chapter 45
AMG-3
agonist. It is a derivative of 8THC substituted with a
dithiolane group on the 3-position side chain.[1] AMG-3
is a potent agonist at both CB1 and CB2 receptors with
a K of 0.32nM at CB1 and 0.52nM at CB2 ,[2][3] and
its particularly high binding anity has led to it being
used as a template for further structural development of
novel cannabinoid drugs.[4] It has sedative and analgesic
eects, with analgesia lasting for up to 36 hours after
administration.[5]
45.1 References
[1] Mavromoustakos T, Theodoropoulou E, Zervou M,
Kourouli T, Papahatjis D. Structure elucidation and
conformational properties of synthetic cannabinoids ()2-(6a,7,10,10a-tetrahydro-6,6,9-trimethyl-1-hydroxy6H-dibenzo[b,d]pyranyl)2-hexyl-1,3-dithiolane
and
its methylated analog. Journal of Pharmaceutical and
Biomedical Analysis. 1999 Jan;18(6):947-56. PMID
9925329
[2] Papahatjis DP, Kourouli T, Abadji V, Goutopoulos
A, Makriyannis A. Pharmacophoric requirements for
cannabinoid side chains: multiple bond and C1'substituted delta 8-tetrahydrocannabinols. Journal of
PMID 9544219
[3] Papahatjis DP, Nikas SP, Kourouli T, Chari R, Xu
W, Pertwee RG, Makriyannis A. Pharmacophoric requirements for the cannabinoid side chain. Probing the
cannabinoid receptor subsite at C1'. Journal of Medicinal
Chemistry. 2003 Jul 17;46(15):3221-9. PMID 12852753
[4] Durdagi S, Papadopoulos MG, Papahatjis DP, Mavromoustakos T. Combined 3D QSAR and molecular docking studies to reveal novel cannabinoid ligands with optimum binding activity. Bioorganic and Medicinal Chemistry Letters. 2007 Dec 15;17(24):6754-63. PMID
17980589
[5] Antoniou K, Galanopoulos A, Vlachou S, Kourouli T,
Nahmias V, Thermos K, Panagis G, Daifoti Z, Marselos
M, Papahatjis D, Spyraki C. Behavioral pharmacological
properties of a novel cannabinoid 1',1'-dithiolane delta8THC analog, AMG-3. Behavioural Pharmacology. 2005
Sep;16(5-6):499-510. PMID 16148456
64
Chapter 46
AMG-36
agonist. It is a derivative of 8THC substituted with a
cyclopentane group on the 3-position side chain. AMG36 is a potent agonist at both CB1 and CB2 with moderate
selectivity for CB1 , with a K of 0.4nM at CB1 vs 1.9nM
at CB2 .[1][2]
46.1 References
[1] Papahatjis DP, et al. Pharmacophoric requirements for
the cannabinoid side chain. Probing the cannabinoid receptor subsite at C1'. Journal of Medicinal Chemistry.
2003 Jul 17;46(15):3221-9. PMID 12852753
17672444
65
Chapter 47
AMG-41
agonist. It is a derivative of 8-THC substituted with a
cyclopropyl group on the C1'-position of the C3-alkyl side
chain. AMG-41 is a potent agonist at both CB1 and CB2 ,
with a K of 0.4nM at CB1 vs 0.9nM at CB2 .[1][2][3]
47.1 References
[1] Papahatjis DP, Nikas SP, Andreou T, Makriyannis A. Novel 1',1'-chain substituted Delta(8)tetrahydrocannabinols.
Bioorganic and Medicinal
Chemistry Letters. 2002 Dec 16;12(24):3583-6. PMID
12443781
[2] Papahatjis DP, et al. Pharmacophoric requirements for
the cannabinoid side chain. Probing the cannabinoid receptor subsite at C1'. Journal of Medicinal Chemistry.
2003 Jul 17;46(15):3221-9. PMID 12852753
17672444
66
Chapter 48
APINACA
This article is about the synthetic cannabinoid drug. For
the Japanese girl group, see AKB48.
48.3 References
AKB48 (APINACA, N-(1-adamantyl)1-pentyl-1Hindazole-3-carboxamide) is a drug that acts as a reasonably potent agonist for the cannabinoid receptors,[1]
with a K of 304.5nM and a EC50 of 585nM at CB1 .
It had never previously been reported in the scientic
or patent literature, and was rst identied by laboratories in Japan in March 2012 as an ingredient in
synthetic cannabis smoking blends, along with a related
compound APICA.[2] Structurally it closely resembles
cannabinoid compounds from patent WO 2003/035005
but with a simple pentyl chain on the indazole 1-position,
and AKB48 falls within the claims of this patent despite
not being disclosed as an example. AKB48 was made illegal in Japan in 2012,[3] and was banned as a temporary
class drug in New Zealand from 13 July 2012.[4] It has
been banned in Latvia since 14 November 2013. The
DEA announced its intent to schedule 16 May 2013. [5]

23063179.
[2] Uchiyama, N.; Kawamura, M.; Kikura-Hanajiri,
R.; Goda, Y. (2012). Identication of two newtype synthetic cannabinoids, N-(1-adamantyl)1pentyl-1H-indole-3-carboxamide (APICA) and N-(1adamantyl)1-pentyl-1H-indazole-3-carboxamide (APINACA), and detection of ve synthetic cannabinoids,
AM-1220, AM-2233, AM-1241, CB-13 (CRA-13), and
AM-1248, as designer drugs in illegal products. Forensic
Toxicology 30 (2): 114. doi:10.1007/s11419-012-01367.
[3] Designation of Shitei Yakubutsu (designated substances) based on the provision of the Pharmaceutical Affairs Law (1960, Law No.145)" (PDF).
[4] Temporary Class Drug Notice. Department of Internal
Aairs. New Zealand. 5 July 2012.
48.1 Detection
A forensic standard of AKB48 is available, and the compound has been posted on the Forendex website of potential drugs of abuse.[6]
[5] url=http://www.justice.gov/dea/divisions/hq/2013/
hq051613.shtml
[6] http://forendex.southernforensic.org/index.php/detail/
index/1221
http://www.gpo.gov/fdsys/pkg/FR-2013-04-12/
html/2013-08671.htm
48.2 See also

AB-001
AB-FUBINACA
AB-PINACA
ADB-FUBINACA
ADB-PINACA
RCS-4
RCS-8
SDB-001
STS-135
67
Chapter 49
AR-231,453
AR-231,453 is an agonist for the suggested novel
cannabinoid receptor GPR119.[1]
49.1 See also

PSN-375,963
PSN-632,408
49.2 References
[1] Semple G, Fioravanti B, Pereira G, Calderon I, Uy J, Choi
K, Xiong Y, Ren A, Morgan M, Dave V, Thomsen W, Unett DJ, Xing C, Bossie S, Carroll C, Chu ZL, Grottick AJ,
Hauser EK, Leonard J, Jones RM. (2008). Discovery of
the rst potent and orally ecacious agonist of the orphan
G-protein coupled receptor 119.. J Med Chem. 51 (17):
51725175. doi:10.1021/jm8006867. PMID 18698756.
68
Chapter 50
Arachidonyl-2'-chloroethylamide
Arachidonyl-2'-chloroethylamide (ACEA) is a synthetic agonist of the cannabinoid receptor 1 (CB1R).
ACEA is considered to be a selective cannabinoid agonist as it binds primarily to the CB1R and has low anity
to the cannabinoid receptor 2 (CB2R) (K = 1.4 nM for
CB1R; K = 3100 nM for CB2R). [1]
50.1 References
[1] Hillard, CJ; Manna, S; Greenberg, MJ; Dicamelli, R;
Ross, RA; Stevenson, LA; Murphy, V; Pertwee, RG;
Campbell, WB (1999). Synthesis and characterization
of potent and selective agonists of the neuronal cannabinoid receptor (CB1)". The Journal of Pharmacology and
Experimental Therapeutics 289 (3): 142733. PMID
10336536.
69
Chapter 51
Arachidonylcyclopropylamide
Arachidonylcyclopropylamide (ACPA) is a synthetic
agonist of the cannabinoid receptor 1 (CB1R). ACPA
is considered to be a selective cannabinoid agonist as it
binds primarily to the CB1R and has low anity to the
cannabinoid receptor 2 (CB2R) (K = 2.2 nM for CB1R;
K = 700 nM for CB2R).[1]
51.1 References
[1] Hillard, CJ, et al. (1999). Synthesis and characterization of potent and selective agonists of the neuronal
cannabinoid receptor (CB1)". The Journal of Pharmacology and Experimental Therapeutics 289 (3): 142733.
PMID 10336536.
70
Chapter 52
N-Arachidonylglycine
N-Arachidonylglycine (NAGly) is a carboxylic analog
of the endocannabinoid anandamide.[1] Since it was rst
synthesized in 1996,[2] NAGly has been a primary focus of the relatively contemporary eld of lipidomics
due to its wide range of signaling targets in the brain,
the immune system and throughout various other bodily systems. In combination with 2arachidonoyl glycerol (2AG), NAGly has enabled the identication of a
family of lipids often referred to as endocannabinoids.[3]
Recently, NAGly has been found to bind to G-protein
coupled receptor 18 (GPR18), the putative abnormal
cannabidiol receptor.[4][5] NaGly is found throughout the
body and research on its explicit functions is on going.
52.1 Synthesis
The exact biosynthesis of NaGly is not completely understood, but there are two proposed pathways found
in vitro for its biosynthesis: 1) enzymatically regulated
conjugation of arachidonic acid and glycine and 2) the
oxidative metabolism of the endogenous cannabinoid
anandamide.[6][7] In the rst pathway, Cytochrome c catalyzes the in vitro synthesis of NaGly from arachidonoyl
coenzyme A and glycine in the presence of hydrogen
peroxide.[8] In the second pathway, alcohol dehydrogenase catalyzes the oxidation of anandamide into Narachidonoyl glycine.[9]
52.2 Research
52.2.1
Eects on the nervous system
NAGly has been hypothesized to have a neurophysiological function of pain suppression, supported by evidence that it suppresses formalin-induced pain behavior in rats.[10] In particular, peripherally administered
NAGly inhibited phase 2 pain behavior, suggesting either a direct suppresion of nociceptive aerents on the
nerve or an indirect modulation of the aerents interstitial environment.[10] In either case, these ndings hold
promise for NAGly as a means of mitigating postoperative or chronic pain. NAGly is also eective in acute pain
models, reducing mechanical allodynia and thermal hyperalgesia induced by intraplantar injection of Fruends
complete adjuvant.[11] Similar mechanical allydonia induced by partial ligation of the sciatic nerve was also reduced by NaGly.[12] Other arachidonic acid-amino acid
conjugates did not have the same eects and the actions
of NaGly were not aected by cannabinoid receptor agonists in either study, suggesting a novel non-cannabinoid
receptor mediated approach to alleviate inammatory
pain.[11][12]
NaGly was shown to be endogenous ligand for the Gprotein couple receptor GPR92 along with farnesyl pyrophosphate.[13] In the dorsal root ganglia (DRG), where
GPR92 was found to be localized NaGly increased intracellular calcium levels in DRG neurons, indicating a role
of NaGly in the sensory nervous system through the activation of GPR92.[13]
52.2.2 Eects on the immune system

NAGly has been the focus of research on the immune system because of its antinociceptive eects and inhibitory
action on components of the immune system. Specifically, it signicantly inhibited TNF and IFN production, and it shows potential as a therapeutic treatment for chronic inammation.[14] Moreover, NAGly has
been shown to act as a substrate for cyclooxygenase-2
(COX-2), the enzyme primarily known for producing
prostaglandins associated with increases in inammation
and hyperalgesia. In many mammalian tissues that express COX-2, signicant levels of NAGly are naturally
present, and in these tissues COX-2 selectively metabolizes NAGly prostaglandin (PG) H2 glycine and HETEGly.[15]
52.2.3 Cell migration

NAGly has been hypothesized to induce cell migration in BV-2 microglia cells.[4] The same research
suggests that this migration occurs through GPR18.
This was veried using GPR18 transfected HEK-293
cells. The same migration wasn't witnessed using nontransfected and GPR55 transfected HEK-293.[4] Addi-
71
72
CHAPTER 52. N-ARACHIDONYLGLYCINE
tionally, tetrahydrocannabinol and NaGly are full agonists

at the GPR18 receptors and induce migration in human
endometrial HEC-1B cells.[16] Understanding functions
of NaGly in such structures provides a promising future
in helping treat diseases such as endometriosis.
52.2.4
Other targets
Insulin secretion
ligand for orphan G-protein-coupled receptor GPR18..

Biochemical and biophysical research communications 347
(3): 82732. PMID 16844083.
[6] Bradshaw, Heather B; Rimmerman, Neta; Hu, Sherry;
Benton, Valery M; Stuart, Jordyn M; Masuda, Kim; Cravatt, Benjamin F; O'Dell, David K; Walker, J Michael (1
January 2009). The endocannabinoid anandamide is a
precursor for the signaling lipid N-arachidonoyl glycine
by two distinct pathways. BMC Biochemistry 10 (1): 14.
doi:10.1186/1471-2091-10-14.
NaGly was identied as a novel insulin secretagogue and

was shown to increase intracellular calcium concentration through stimulation of voltage dependent calcium
channels.[17] Additionally, this action was dependent on
extracellular glucose level.[17]
[7] Aneetha, Halikhedkar; ODell, David K.; Tan, Bo;

Walker, J. Michael; Hurley, Thomas D. (1 January
2009). Alcohol dehydrogenase-catalyzed in vitro oxidation of anandamide to N-arachidonoyl glycine, a
lipid mediator: Synthesis of N-acyl glycinals. Bioorganic & Medicinal Chemistry Letters 19 (1): 237241.
doi:10.1016/j.bmcl.2008.10.087.
Additional biochemical interactions
[8] McCue, JM; Driscoll, WJ; Mueller, GP (Jan 11, 2008).

Cytochrome c catalyzes the in vitro synthesis of arachidonoyl glycine.. Biochemical and biophysical research
communications 365 (2): 3227. PMID 17986381.
NaGly has been shown to inhibit the glycine transporter

GLYT2a in a non-competitive fashion with arachidonic
acids and secondary messenger systems of GLYT2a, suggesting a novel recognition site for the N-arachodnoyl
amino acids, especially because other conjugated amino
acids had similar eects.[18]
52.3 References
[1] Burstein, Sumner; Huang, S.M.; Petros, T.J.; Rossetti, R.G.; Walker, J.M.; Zurier, R.B. (30 April
2002). Regulation of anandamide tissue levels by
N-arachidonylglycine. Biochemical Pharmacology 64
(7): 11471150. doi:10.1016/S0006-2952(02)01301-1.
PMID 12234618.
[2] Sheskin, Tzviel; Hanus, L.; Slager, J.; Vogel, Z.;
Mechoulam, R. (1997). Structural Requirements for
Binding of Anandamide-Type Compounds to the Brain
Cannabinoid Receptor. Journal of Medicinal Chemistry 40 (5): 659667. doi:10.1021/jm960752x. PMID
9057852.
[3] Bradshaw, Heather; Rimmerman, N.; Hu, S.J.; Burstein,
S.; Walker, J.M. (2009). Novel Endogenous N-Acyl
Glycines: Identication and Characterization. Vitamins and Hormones. Vitamins & Hormones 81:
191205. doi:10.1016/S0083-6729(09)81008-X. ISBN
9780123747822. PMID 19647113.
[4] McHugh, Douglas; Hu, Sherry SJ; Rimmerman, Neta;
Juknat, Ana; Vogel, Zvi; Walker, J Michael; Bradshaw,
Heather B (1 January 2010). N-arachidonoyl glycine,
an abundant endogenous lipid, potently drives directed
cellular migration through GPR18, the putative abnormal cannabidiol receptor. BMC Neuroscience 11 (1): 44.
doi:10.1186/1471-2202-11-44.
[5] Kohno, M; Hasegawa, H; Inoue, A; Muraoka, M;
Miyazaki, T; Oka, K; Yasukawa, M (Sep 1, 2006).
Identication of N-arachidonylglycine as the endogenous
[9] Aneetha, H; O'Dell, DK; Tan, B; Walker, JM; Hurley,

TD (Jan 1, 2009). Alcohol dehydrogenase-catalyzed in
vitro oxidation of anandamide to N-arachidonoyl glycine,
a lipid mediator: synthesis of N-acyl glycinals.. Bioorganic & medicinal chemistry letters 19 (1): 23741. PMID
19013794.
[10] Huang, Susan M.; Bisogno, T., Petros, T.J., Chang, S.Y.,
Zavitsanos, P.A., Zipkin, R.E., Sivakumar, R., Coop, A.,
Maeda, D.Y., De Petrocellis, L., Burstein, S., Di Marzo,
V., Walker, J.M. (November 16, 2001). Identication
of a New Class of Molecules, the Arachidonyl Amino
Acids, and Characterization of One Member That Inhibits
Pain. The Journal of Biological Chemistry 276 (46):
4263942644. doi:10.1074/jbc.M107351200. PMID
11518719.
[11] Succar, Rebecca; Mitchell, Vanessa A; Vaughan, Christopher W (August 2007). Actions of N-arachidonylglycine in a rat inammatory pain model. Molecular Pain
3 (1): 24. doi:10.1186/1744-8069-3-24.
[12] Vuong, Leeza A.Q.; Mitchell, Vanessa A.; Vaughan,
Christopher W. (1 January 2008).
Actions of
N-arachidonyl-glycine in a rat neuropathic pain
model.
Neuropharmacology 54 (1): 189193.
doi:10.1016/j.neuropharm.2007.05.004.
[13] Oh, D. Y.; Yoon, J. M.; Moon, M. J.; Hwang, J.I.; Choe, H.; Lee, J. Y.; Kim, J. I.; Kim, S.; Rhim,
H.; O'Dell, D. K.; Walker, J. M.; Na, H. S.; Lee,
M. G.; Kwon, H. B.; Kim, K.; Seong, J. Y. (22 May
2008). Identication of Farnesyl Pyrophosphate and NArachidonylglycine as Endogenous Ligands for GPR92.
doi:10.1074/jbc.M708908200.
[14] Ferrante, A; Poulos A; Pitt M; Easton C; Sleigh M; Rathjen D; Widmer F. Methods of Treating Immunopathologies Using Polyunsaturated Fatty Acids. United States
patent publication WO 97/38688.
52.3. REFERENCES
[15] Prusakiewicz, J; Kingsley P; Kozak K; Marnett L

(2002). Selective oxygenation of N-arachidonylglycine
by cyclooxygenase-2. Biochemical and Biophysical Research Communications (296): 612617.
[16] McHugh, Douglas; Page, Jeremy; Dunn, Emily;
Bradshaw, Heather B (1 April 2012).
"9Tetrahydrocannabinol and N-arachidonyl glycine
are full agonists at GPR18 receptors and induce
migration in human endometrial HEC-1B cells.
doi:10.1111/j.1476-5381.2011.01497.x.
[17] Ikeda, Yukio; Iguchi, Haruhisa; Nakata, Masanori; Ioka,
Ryoichi X.; Tanaka, Toshiya; Iwasaki, Satoshi; Magoori,
Kenta; Takayasu, Shinobu; Yamamoto, Tokuo T.; Kodama, Tatsuhiko; Yada, Toshihiko; Sakurai, Takeshi;
Yanagisawa, Masashi; Sakai, Juro (1 August 2005).
Identication of N-arachidonylglycine, U18666A, and
4-androstene-3,17-dione as novel insulin Secretagogues.
Biochemical and Biophysical Research Communications
333 (3): 778786. doi:10.1016/j.bbrc.2005.06.005.
[18] Wiles, Amy L.; Pearlman, Rhonda-Jo; Rosvall, Mari;
Aubrey, Karin R.; Vandenberg, Robert J. (1 November
2006). N-Arachidonyl-glycine inhibits the glycine transporter, GLYT2a. Journal of Neurochemistry 99 (3):
781786. doi:10.1111/j.1471-4159.2006.04107.x.
73
Chapter 53
AZ-11713908
AZ-11713908 is a drug developed by AstraZeneca which
is a peripherally selective cannabinoid agonist, acting as
a potent agonist at the CB1 receptor and a partial agonist at CB2 . It has poor bloodbrain barrier penetration, and so while it is an eective analgesic in animal
tests, it produces only peripheral eects at low doses,
with much weaker symptoms of central eects compared
to other cannabinoid drugs such as WIN 55,212-2.[1] A
large number of related benzimidazole derived cannabinoid ligands are known.[2][3][4][5]
53.1 See also

AM-6545
CB-13
53.2 References
[1] Yu XH, Cao CQ, Martino G, Puma C, Morinville A, StOnge S, Lessard E, Perkins MN, Laird JM (November
2010). A peripherally restricted cannabinoid receptor
agonist produces robust anti-nociceptive eects in rodent
models of inammatory and neuropathic pain. Pain 151
(2): 33744. doi:10.1016/j.pain.2010.07.019. PMID
20696525.
[2] Verbist BM, De Cleyn MA, Surkyn M, Fraiponts
E, Aerssens J, Nijsen MJ, Gijsen HJ (April 2008).
5-Sulfonyl-benzimidazoles as selective CB2 agonists.
Bioorganic & Medicinal Chemistry Letters 18 (8): 25749.
doi:10.1016/j.bmcl.2008.03.048. PMID 18394887.
[3] Pag D, Balaux E, Boisvert L, Liu Z, Milburn C, Tremblay
M, Wei Z, Woo S, Luo X, Cheng YX, Yang H, Srivastava
S, Zhou F, Brown W, Tomaszewski M, Walpole C, Hodzic
L, St-Onge S, Godbout C, Salois D, Payza K, Payza K
(July 2008). Novel benzimidazole derivatives as selective
CB2 agonists. Bioorganic & Medicinal Chemistry Letters
18 (13): 3695700. doi:10.1016/j.bmcl.2008.05.073.
PMID 18522867.
[4] WO patent 2004/108688, LIU Z, PAG D, WALPOLE
C, YANG H, BENZIMIDAZOLE DERIVATIVES,
COMPOSITIONS CONTAINING THEM, PREPARATION THEREOF AND USES THEREOF, granted
16.12.2004
74
[5] WO patent 2004/108712, LIU Z, PAG D, WALPOLE

C, YANG H, BENZIMIDAZOLE DERIVATIVES,
COMPOSITIONS CONTAINING THEM, PREPARATION THEREOF AND USES THEREOF, granted
16.12.2004
Chapter 54
BAY 38-7271
Originally synthesized by chemist Wayne E. Kenney,
BAY 38-7271 (KN 38-7271) is a drug which is a
cannabinoid receptor agonist developed by Bayer AG. It
has analgesic and neuroprotective eects and is used in
scientic research, with proposed uses in the treatment of
traumatic brain injury.[1][2] It is a full agonist with around
the same potency as CP 55,940 in animal studies, and has
fairly high anity for both CB1 and CB2 receptors, with
K values of 2.91nM at CB1 and 4.24nM at CB2 .[3][4] It
has now been licensed to KeyNeurotek Pharmaceuticals
for clinical development,[5] and is currently in Phase II
trials.[6] But its development appears stopped.
54.1 References
[1] Mauler F, Horvth E, De Vry J, Jger R, Schwarz T, Sandmann S, Weinz C, Heinig R, Bttcher M. BAY 38-7271:
a novel highly selective and highly potent cannabinoid receptor agonist for the treatment of traumatic brain injury.
CNS Drug Reviews. 2003 Winter;9(4):343-58. PMID
14647528
[2] Mauler F, Hinz V, Augstein KH, Fassbender M, Horvth
E. Neuroprotective and brain edema-reducing ecacy of
the novel cannabinoid receptor agonist BAY 38-7271.
Brain Research. 2003 Oct 31;989(1):99-111. PMID
14519516
[3] Mauler F, Mittendorf J, Horvth E, De Vry J. Characterization of the diarylether sulfonylester (-)-(R)3(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-triuoro1-sulfonate (BAY 38-7271) as a potent cannabinoid
receptor agonist with neuroprotective properties. Journal
of Pharmacology and Experimental Therapeutics. 2002
Jul;302(1):359-68. PMID 12065738
[4] De Vry J, Rdiger Jentzsch K. Discriminative stimulus
eects of BAY 38-7271, a novel cannabinoid receptor
agonist. European Journal of Pharmacology. 2002 Dec
20;457(2-3):147-52. PMID 12464360
[5] Pipeline
[6] KeyNeurotek Pharmaceuticals AG Reports Positive
Phase I Data of Its Cannabinoid Receptor-Agonist
75
Chapter 55
BAY 59-3074
BAY 59-3074 is a drug which is a cannabinoid receptor
partial agonist developed by Bayer AG. It has analgesic
eects and is used in scientic research. It is orally active
in animals, and has modest anity for both CB1 and CB2
receptors, with K values of 48.3nM at CB1 and 45.5nM
at CB2 .[1][2]
55.1 References
[1] De Vry J, Denzer D, Reissmueller E, Eijckenboom
M, Heil M, Meier H, Mauler F. 3-[2-cyano-3(triuoromethyl)phenoxy]phenyl-4,4,4-triuoro-1butanesulfonate (BAY 59-3074): a novel cannabinoid
Cb1/Cb2 receptor partial agonist with antihyperalgesic
and antiallodynic eects. Journal of Pharmacology and
Experimental Therapeutics. 2004 Aug;310(2):620-32.
PMID 15140913
[2] De Vry J, Jentzsch KR. Discriminative stimulus eects
of the structurally novel cannabinoid CB1/CB2 receptor
partial agonist BAY 59-3074 in the rat. European Journal
of Pharmacology. 2004 Nov 28;505(1-3):127-33. PMID
15556145
76
Chapter 56
BML-190
BML-190 (Indomethacin morpholinylamide) is a drug
used in scientic research that acts as a selective CB2
inverse agonist.[1] BML-190 is structurally derived from
the NSAID indomethacin but has a quite dierent biological activity.[2] The activity produced by this compound
is disputed, with some sources referring to it as a CB2
agonist rather than an inverse agonist;[3][4] this may reect an error in classication, or alternatively it may produce dierent eects in dierent tissues, more research
is required to resolve this dispute.
56.1 References
[1] New, DC; Wong, YH (2003). BML-190 and AM251
act as inverse agonists at the human cannabinoid CB2
receptor: signalling via cAMP and inositol phosphates.
FEBS Letters 536 (13): 15760. doi:10.1016/S00145793(03)00048-6. PMID 12586356.
[2] Klegeris, A; Bissonnette, CJ; McGeer, PL (2003).
Reduction of human monocytic cell neurotoxicity and
cytokine secretion by ligands of the cannabinoid-type CB2
receptor. British Journal of Pharmacology 139 (4): 775
12813001.
[3] Melck, D; De Petrocellis, L; Orlando, P; Bisogno, T;
Laezza, C; Bifulco, M; Di Marzo, V (2000). Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human
breast and prostate cancer cell proliferation. Endocrinology 141 (1): 11826. doi:10.1210/en.141.1.118. PMID
10614630.
[4] Scutt, A; Williamson, EM (2007). Cannabinoids stimulate broblastic colony formation by bone marrow cells indirectly via CB2 receptors. Calcied tissue international
80 (1): 509. doi:10.1007/s00223-006-0171-7. PMID
17205329.
77
Chapter 57
(C6)-CP 47,497
(C6)-CP 47,497 (CP 47,497 dimethylhexyl homologue)
is a synthetic cannabinoid, a CP 47,497 homologue.
Its
systematic
name
is
2-[(1R,3S)3hydroxycyclohexyl]5-(1,1-dimethylhexyl)phenol.
57.1 See also

Synthetic cannabis
(C7)-CP 47,497 (CP 47,497 itself)
(C8)-CP 47,497
(C9)-CP 47,497
78
Chapter 58
(C9)-CP 47,497
(C9)-CP 47,497 (CP 47,497 dimethylnonyl homologue)
is a synthetic cannabinoid, a CP 47,497 homologue.
Its
systematic
name
is
2-[(1R,3S)3hydroxycyclohexyl]5-(1,1-dimethylnonyl)phenol.
58.1 See also

Synthetic cannabis
(C6)-CP 47,497
(C7)-CP 47,497 (CP 47,497 itself)
(C8)-CP 47,497
79
Chapter 59
Canbisol
Canbisol (Nabidrox), is a synthetic cannabinoid derivative that is the dimethylheptyl homologue of 9-nor9hydroxyhexahydrocannabinol (HHC). It is a potent
agonist at both the CB1 and CB2 receptors, with a binding
anity of 0.1nM at CB1 and 0.2nM at CB2 .[1] It is
mainly used in scientic research, in receptor binding
studies to determine the structure and function of the
cannabinoid receptors,[2][3][4] but has been made illegal
in some countries due to its possible abuse potential as a
cannabinomimetic drug.[5]
59.1 See also

HU-210
HU-243
Nabilone
59.2 References
[1] Rhee MH, et al. (September 1997). Cannabinol derivatives: binding to cannabinoid receptors and inhibition of
adenylylcyclase. Journal of Medicinal Chemistry 40 (20):
322833. doi:10.1021/jm970126f. PMID 9379442.
[2] Rhee MH, et al. (December 2000). Functional role of
tryptophan residues in the fourth transmembrane domain
of the CB(2) cannabinoid receptor. Journal of Neurochemistry 75 (6): 248591. PMID 11080201.
[3] Rhee MH (September 2002). Functional role of serine
residues of transmembrane dopamin VII in signal transduction of CB2 cannabinoid receptor. Journal of Veterinary Science 3 (3): 18591. PMID 12514330.
[4] Zhang R, et al. (July 2005). Cysteine 2.59(89) in
the second transmembrane domain of human CB2 receptor is accessible within the ligand binding crevice:
evidence for possible CB2 deviation from a rhodopsin
template. Molecular Pharmacology 68 (1): 6983.
doi:10.1124/mol.104.007823. PMID 15840841.
[5] The Misuse of Drugs Act 1971 (Amendment) Order 2009
80
Chapter 60
Cannabichromene
Cannabichromene (abbreviated as CBC) is a cannabinoid found in the cannabis plant. It bears structural similarity to the other natural cannabinoids, including tetrahydrocannabinol, tetrahydrocannabivarin,
cannabidiol, and cannabinol, among others. Evidence has
suggested that it may play a role in the anti-inammatory
and anti-viral eects of cannabis, and may contribute to
the overall analgesic eects of medical cannabis. However, more research into the compound may be needed
before any denite medical eects can be veried.[1]
CBC has two stereoisomers. It is not scheduled by the
Convention on Psychotropic Substances. CBC is nonpsychotropic.[2]
60.1 Medical uses

A 2011 study in the British Journal of Pharmacology
found that CBD and CBC stimulated descending pathways of antinociception and caused analgesia by interacting with several target proteins involved in nociceptive
control.[2] A study in Neurochemistry International suggested that cannabichromene might stimulate the growth
of brain cells by stimulating adult neural stem progenitor cells (NSPCs). The study said our results suggest
that CBC raises the viability of NSPCs while inhibiting
their dierentiation into astroglia, possibly through upregulation of ATP and adenosine signalling.[3]
60.2 References
[1] Gaoni, Y.; Mechoulam, R. (1966). Cannabichromene, a
new active principle in hashish. Chemical Communications 1: 201. doi:10.1039/C19660000020.
[2] Maione, Sabatino; Piscitelli, Fabiana; Gatta, Luisa; Vita,
Daniela; De Petrocellis, Luciano; Palazzo, Enza; De
Novellis, Vito; Di Marzo, Vincenzo (2011). Nonpsychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through
several mechanisms of action.
British Journal of
Pharmacology 162 (3): 58496. doi:10.1111/j.14765381.2010.01063.x. PMID 20942863.
81
[3] Shinjyo, Noriko; Di Marzo, Vincenzo (2013). The effect of cannabichromene on adult neural stem/progenitor
cells. Neurochemistry International 63 (5): 4327.
doi:10.1016/j.neuint.2013.08.002. PMID 23941747.
Chapter 61
Cannabicyclohexanol
Cannabicyclohexanol (CCH, CP 47,497 dimethyloctyl homologue, (C8)-CP 47,497) is a cannabinoid receptor agonist drug, developed by Pzer in 1979. On 19
January 2009, the University of Freiburg in Germany announced that an analog of CP 47,497 was the main active ingredient in the herbal incense product Spice, specifically the 1,1-dimethyloctyl homologue of CP 47,497,
which is now known as cannabicyclohexanol.[2][3][4][5]
The 1,1-dimethyloctyl homologue of CP 47,497 is in fact
several times more potent than the parent compound,[6]
which is somewhat unexpected as the 1,1-dimethylheptyl
is the most potent substituent in classical cannabinoid
compounds such as HU-210.[7]
61.1 See also

Synthetic cannabis
(C6)-CP 47,497
(C7)-CP 47,497 (CP 47,497 itself)
(C9)-CP 47,497
O-1871
61.2 References
[1] Cook, Morgan (2011-02-28). Synthetic marijuana illegal as of Tuesday. North County Times (San Diego). Retrieved 2011-02-28.
[2] Hauptwirksto von Spice identiziert, University
of Freiburg http://www.pr.uni-freiburg.de/pm/2009/pm.
2009-01-19.19/
[3] Spice - weitere Analyseresultate http://www.
basg.at/servlet/sls/Tornado/web/ages/content/
4E5A4B86295BF5C0C125753E006A5E3C
[4] Auwrter V, et al. 'Spice' and other herbal blends: harmless incense or cannabinoid designer drugs? Journal of
Mass Spectrometry. 2 February 2009. PMID 19189348
82

Y (May 2010).
Forensic Science International 198 (1-3):
318.
[6] Compton DR, Johnson MR, Melvin LS, Martin BR. Pharmacological prole of a series of bicyclic cannabinoid
analogs: classication as cannabimimetic agents. Journal
Jan;260(1):201-9. PMID 1309872
[7] Martin BR, et al. Behavioral, biochemical, and molecular
modeling evaluations of cannabinoid analogs. Pharmacology, Biochemistry and Behavior. 1991 Nov;40(3):471-8.
PMID 1666911
Chapter 62
Cannabicyclol
Cannabicyclol (CBL) is a non-psychotomimetic
cannabinoid found in the Cannabis species. CBL is
a degradative product like cannabinol. Light converts
cannabichromene to CBL.
It has 16 stereoisomers. It is not scheduled by Convention
on Psychotropic Substances.
62.1 See also

Cannabinoids
Cannabis
Medical marijuana
62.2 External links

CTDs Cannabicyclol page from the Comparative
Toxicogenomics Database
Erowid Compounds found in Cannabis sativa
http://www.wiley-vch.de/stmdata/pdf/
CompoundList.pdf
http://www.a1b2c3.com/drugs/mj028.htm
83
Chapter 63
Cannabidiol
Not to be confused with Cannabinol.
63.1.2 Neurological eects
Cannabidiol (CBD) is one of at least 85 active

cannabinoids identied in cannabis.[4] It is a major
phytocannabinoid, accounting for up to 40% of the
plants extract.[5] CBD is considered to have a wider
scope of medical applications than tetrahydrocannabinol
(THC).[5] An orally-administered liquid containing CBD
has received orphan drug status in the US, for use as a
treatment for dravet syndrome, under the brand name
Epidiolex.[6]
A 2010 study found that strains of cannabis containing higher concentrations of cannabidiol did not produce
short-term memory impairment vs. strains with similar concentrations of THC, but lower concentrations of
CBD. The researchers attributed this attenuation of memory eects to CBDs role as a CB1 antagonist. Transdermal CBD is neuroprotective in animals.[8]
63.1 Clinical applications
63.1.3 Psychotropic eect
The bud of a Cannabis sativa ower coated with trichomes
63.1.1
Antimicrobial actions
Cannabidiols strong antioxidant properties have been

shown to play a role in the compounds neuroprotective
and anti-ischemic eects.[9]
CBD has anti-psychotic eects and may counteract the

potential psychotomimetic eects of THC on individuals with latent schizophrenia;[5] some reports show it to
be an alternative treatment for schizophrenia that is safe
and well-tolerated.[10] Studies have shown CBD may reduce schizophrenic symptoms due to its apparent ability
to stabilize disrupted or disabled NMDA receptor pathways in the brain, which are shared and sometimes contested by norepinephrine and GABA.[10][11] Leweke et al.
performed a double blind, 4 week, explorative controlled
clinical trial to compare the eects of puried cannabidiol and the atypical antipsychotic amisulpride on improving the symptoms of schizophrenia in 42 patients with
acute paranoid schizophrenia. Both treatments were associated with a signicant decrease of psychotic symptoms after 2 and 4 weeks as assessed by Brief Psychiatric
Rating Scale and Positive and Negative Syndrome Scale.
While there was no statistical dierence between the
two treatment groups, cannabidiol induced signicantly
fewer side eects (extrapyramidal symptoms, increase in
prolactin, weight gain) when compared to amisulpride.[12]
Studies have shown cannabidiol decreases activity of the
limbic system[13] and decreases social isolation induced
by THC.[14] Cannabidiol has also been shown to reduce
anxiety in social anxiety disorder.[15][16]
CBD absorbed transcutaneously may attenuate the in- Chronic cannabidiol administration in rats was found
creased sebum production at the root of acne, according to produce anxiogenic-like eects, indicating that
to an untested hypothesis.[7]
prolonged treatment with cannabidiol might incite
84
63.4. PHARMACOLOGY
85
anxiogenic eects.[17] Those results have been contested cannabionoid prole consistently around 1% cannabidiol
by,[18] and contradict [19] whose experimentation cover (CBD) with THC less than 0.1%.[32]
the same duration.
Extraction can be done with olive oil, ethanol, or CO2,
Cannabidiol has demonstrated antidepressant-like eects and other nonpolar to semipolar solvents.
in animal models of depression.[20][21][22]
Hemp world production is around 30000 tonnes per year.
63.1.4
Dravet syndrome
See also: Charlottes Web (cannabis)

Dravet syndrome is a rare form of epilepsy that is dicult to treat. Dravet syndrome, also known as Severe Myoclonic Epilepsy of Infancy (SMEI), is a rare and catastrophic form of intractable epilepsy that begins in infancy.
Initial seizures are most often prolonged events and in the
second year of life other seizure types begin to emerge.[23]
While high prole and anecdotal reports of results from
high-CBD/low-THC preparations have sparked interest
in treatment with cannabinoids,[24] there is insucient
medical evidence to draw conclusions about their safety
or ecacy.[24][25]
63.4 Pharmacology
63.4.1 Pharmacodynamics
Cannabidiol has a very low anity for CB1 and CB2

receptors but acts as an indirect antagonist of their
agonists.[9] While one would assume that this would cause
cannabidiol to reduce the eects of THC, it may potentiate THCs eects by increasing CB1 receptor density or
through another CB1 -related mechanism.[33] It is also an
inverse agonist of CB2 receptors.[9][34] Recently, it was
found to be an antagonist at the putative new cannabinoid
receptor, GPR55, a GPCR expressed in the caudate nucleus and putamen.[35] Cannabidiol has also been shown
to act as a 5-HTA receptor agonist,[36] an action which
is involved in its antidepressant,[20][37] anxiolytic,[37][38]
and neuroprotective[39][40] eects. Cannabidiol is an
63.2 CBD-enhanced cannabis
allosteric modulator of and -opioid receptors.[41]
Decades ago, selective breeding by growers in US dra- Cannabidiols pharmacological eects have also been atreceptor agonism and intracellular
matically lowered the CBD content of cannabis; their cus- tributed to PPAR-
[5]
calcium
release.
tomers preferred varietals that were more mind-altering
due to a higher THC, lower CBD content.[26] To meet the
demands of medical cannabis patients, growers are cur63.4.2 Pharmacokinetic interactions
rently developing more CBD-rich strains.[27]
In November 2012, Tikun Olam, an Israeli medical
cannabis facility announced a new strain of the plant
which has only cannabidiol as an active ingredient, and
virtually no THC, providing some of the medicinal benets of cannabis without the euphoria.[28][29] The researchers said the cannabis plant, enriched with CBD,
can be used for treating diseases like rheumatoid arthritis, colitis, liver inammation, heart disease and diabetes. Research on CBD enhanced cannabis began in
2009, resulting in Avidekel, a cannabis strain that contains 15.8% CBD and less than 1% THC. Raphael Mechoulam, a cannabinoid researcher, said "...Avidekel is
thought to be the rst CBD-enriched cannabis plant with
no THC to have been developed in Israel.[30] In February
2014, a patent application was led for a cannabis plant
named 'avidekel'.[31]
63.3 Industrial hemp
There is some preclinical evidence to suggest that

cannabidiol may reduce THC clearance, modestly increasing THCs plasma concentrations resulting in a
greater amount of THC available to receptors, increasing the eect of THC in a dose-dependent manner.[42][43]
Despite this the available evidence in humans suggests no
signicant eect of CBD on THC plasma levels.[44]
63.4.3 Pharmaceutical preparations

Nabiximols (USAN, trade name Sativex) is an
aerosolized mist for oral administration containing
a near 1:1 ratio of CBD and THC. The drug was
approved by Canadian authorities in 2005 to alleviate
pain associated with multiple sclerosis.[45][46][47]
63.5 Isomerism
Several industrial hemp varieties can be legally cultivated in western Europe. They might seem to contain Based on: Nagaraja, Kodihalli Nanjappa, Synthesis of
very small portion of cannabinoid, which is true in one delta-3-cannabidiol and the derived rigid analogs, Arisense. Nevertheless a variety such as Fedora 17 has a zona University 1987.
86
CHAPTER 63. CANNABIDIOL

hemp oil high in cannabidiol, are legal in the United States
for this reason.
Some cannabidiol oil is derived from marijuana and is
therefore high in THC.[61] This type of cannabidiol oil
would be considered a Schedule I as a result. However,
cannabidiol derived from industrial hemp is legal and unscheduled itself.[61] In other words, cannabidiols legal
status depends on where it is derived from, as cannabidiol
itself is not scheduled.[57]
Cannabidiol numbering
63.8 US patent
See also: Tetrahydrocannabinol#Isomerism, Abnormal
In October 2003, U.S. patent #6630507 entitled
cannabidiol.
Cannabinoids as antioxidants and neuroprotectants was
assigned to The United States Of America As Represented By The Department Of Health And Human Ser63.6 Chemistry
vices. The patent was led in April 1999 and listed as the
inventors: Aidan J. Hampson, Julius Axelrod, and MaurCannabidiol is insoluble in water but soluble in organic izio Grimaldi, who all held positions at the National Instisolvents, such as pentane. At room temperature it is a tute of Mental Health (NIMH) in Bethesda, MD, which is
colorless crystalline solid.[48] In strongly basic medium part of the National Institutes of Health (NIH), an agency
and the presence of air it is oxidized to a quinone.[49] Un- of the United States Department of Health and Human
der acidic conditions it cyclizes to THC.[50] The synthesis Services (HHS). The patent mentions cannabidiols abilof cannabidiol has been accomplished by several research ity as an antiepileptic, to lower intraocular pressure in the
groups.[51][52][53]
treatment of glaucoma, lack of toxicity or serious side effects in large acute doses, its neuroprotectant properties,
its ability to prevent neurotoxicity mediated by NMDA,
AMPA, or kainate receptors; its ability to attenuate glu63.6.1 Biosynthesis
tamate toxicity, its ability to protect against cellular damCannabis produces CBD-carboxylic acid through the age, its ability to protect brains from ischemic damage,
same metabolic pathway as THC, until the last step, its anxiolytic eect, and its superior antioxidant activity
where CBDA synthase performs catalysis instead of which can be used in the prophylaxis and treatment of
oxidation associated diseases.[62]
THCA synthase.[54]
On November 17, 2011, the Federal Register published
that the National Institutes of Health of the United States
Department of Health and Human Services was contem63.7 Legal status
plating the grant of an exclusive patent license to practice
the invention embodied in U.S. Patent 6,630,507 to the
Cannabidiol is not scheduled by the Convention on Psy- company KannaLife based in New York, for the develchotropic Substances.
opment and sale of cannabinoid and cannabidiol based
Cannabidiol is a Schedule II drug in Canada.[55]
therapeutics for the treatment of hepatic encephalopathy
in humans.[63][64][65]
Cannabidiols legal status in the United States:
On July 9, 2012 KannaLife Sciences, Inc. (KannaLife) Signed an Exclusive License Agreement With
National Institutes of Health Oce of Technology
Transfer (NIH-OTT) aka the United States Federal
Government for the Commercialization of U.S. Patent
6,630,507, Cannabinoids as Antioxidants and NeuroMarijuana is dened by 21 U.S.C. 802(16), which is part protectants (the 507 Patent).
of the Controlled Substances Act. The mature stalks and
seeds of the Cannabis sativa L. plant, as well as prod- http://www.kannalife.com/
ucts derived from the mature stalks and seeds are ex- kannalife-sciences-inc-signs-exclusive-license-agreement-with-national-in
plicitly exempt from classication as marijuana.[57][58][59] On March 31, 2014 KannaLife Sciences, Inc.
Under this exception, what are known as industrial hemp- (KannaLife) and Kannaway LLC (Kannaway, a
nished products are legally imported into the United multi-level marketing program similar to Amway),
States each year.[60] Hemp nished products, including have entered into a ve year sales, marketing
While the DEA Drug Schedule classies THC (Tetrahydrocannabinols) and marijuana as Schedule I, cannabidiol
is not found on the list.[56] Other synthetic cannabinoids
such as JWH-019,073,081,122,200,203,250,398 are also
listed in Schedule I, but cannabidiol is absent.[56]
63.9. REFERENCES
87
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HM; Fries, GR; Aguiar, BW; Kapczinski, F; Hallak, JE;
Zuardi, AW; Crippa JA; Quevedo, J (October 2011).
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antidepressant-like eects in the forced swimming test
and increases brain-derived neurotrophic factor levels in
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[23] http://www.dravetfoundation.org/dravet-syndrome/
what-is-dravet-syndrome#sthash.jAC0bZ89.dpuf What
is Dravet Syndrome?
[24] Melville, Nancy A. (14 Aug 2013), Seizure Disorders Enter Medical Marijuana Debate, Medscape Medical News.,
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[25] Gloss D, Vickrey B (13 June 2012). Cannabinoids
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[26] Romney, Lee (13 September 2012). On the frontier of
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[27] Good, Alastair (26 October 2010). Growing marijuana
that won't get you high. The Daily Telegraph (London).
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without the high (video). CNN. An Israeli company has
cultivated a new type of medical marijuana.
[29] Solon, Olivia (5 July 2012). Medical Marijuana Without
the High. Wired.com
[30] Lubell, Maayan (3 July 2012). What a drag, Israeli rm
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63.10. EXTERNAL LINKS
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[57] Denition of marijuana under the Controlled Substances
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[59] Hemp Industries Assn., v. Drug Enforcement Admin., 9th

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[60] Hemp, Many denitions of common terms associated with
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[62] US patent 6630507, Hampson, Aidan J.; Axelrod, Julius;

Grimaldi, Maurizio, Cannabinoids as antioxidants and
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63.10 External links

Project CBD Non-prot educational service dedicated to promoting and publicizing research into the
medical utility of cannabidiol.
Chapter 64
Cannabidivarin
Cannabidivarin (CBDV) is a non-psychoactive
cannabinoid found in Cannabis. It is a homolog of
cannabidiol (CBD), with the side-chain shortened by
two methylene bridges (CH2 units). Plants with relatively high levels of CBDV have been reported in feral
populations of C. indica ( = C. sativa ssp. indica var.
karistanica) from northwest India, and in hashish from
Nepal.[1][2]
Similarly to CBD, it has 7 double bond isomers and
30 stereoisomers (see: Cannabidiol#Double bond isomers and their stereoisomers). It is not scheduled by
Convention on Psychotropic Substances.
64.1 See also

Cannabinoids
Cannabis
Medical marijuana
64.2 References
[1] Turner, C.E., P. C. Cheng, G.S. Lewis, M.H.Russell and
G.K. Sharma. 1979. Constituents of Cannabis sativa XV:
Botanical and chemical prole of Indian variants. Planta
medica 37(3): 217-225.
[2] Hillig, Karl W. and Paul G. Mahlberg. 2004. A chemotaxonomic analysis of cannabinoid variation in Cannabis
(Cannabaceae). American Journal of Botany 91(6): 966975.
64.3 External links

90
Chapter 65
Cannabigerol
Cannabigerol (CBG) is a non-psychoactive cannabinoid
found in the Cannabis genus of plants. Cannabigerol is
found in higher concentrations in hemp rather than in varieties of Cannabis cultivated for high THC content and
their corresponding psychoactive properties.
Cannabigerol has been found to act as a high anity
2 -adrenergic receptor agonist, moderate anity 5HTA receptor antagonist, and low anity CB1 receptor antagonist.[1] It also binds to the CB2 receptor, but
whether it acts as an agonist or antagonist at this site is
unknown.[1]
Cannabigerol has been shown to relieve interocular pressure, which may be of benet in the treatment of
glaucoma.[2][3] It can also be used to treat inammatory
bowel disease. [4]
It has two E/Z isomers. It is not scheduled by Convention
on Psychotropic Substances.
65.1 See also

Cannabinoid
Medical cannabis
65.2 References
[1] Cascio MG, Gauson LA, Stevenson LA, Ross RA, Pertwee R (December 2009). Evidence that the plant
cannabinoid cannabigerol is a highly potent alpha(2)adrenoceptor agonist and moderately potent 5HT receptor antagonist. British Journal of Pharmacology 159
(1): 129141. doi:10.1111/j.1476-5381.2009.00515.x.
PMC 2823359. PMID 20002104.
[2] Colasanti, B. (1990). A comparison of the ocular
and central eects of delta 9-tetrahydrocannabinol and
cannabigerol. Journal of ocular pharmacology 6 (4):
259269. doi:10.1089/jop.1990.6.259. PMID 1965836.
[3] Colasanti, B.; Craig, C.; Allara, R. (1984). Intraocular pressure, ocular toxicity and neurotoxicity after administration of cannabinol or cannabigerol. Experimental eye research 39 (3): 251259. doi:10.1016/00144835(84)90013-7. PMID 6499952.
91
[4] http://www.ncbi.nlm.nih.gov/pubmed/23415610
Chapter 66
Cannabinoidergic
Cannabinoidergic, or cannabinergic, means related to
the endocannabinoid neurotransmitters. As with terms
such as dopaminergic and serotonergic, related proteins
and cellular components involved endocannabinoid signaling, such as the cannabinoid (CB1 ) receptor, as well
as exogenous compounds, such as phytocannabinoids
or other cannabinoids which modulate the activity of
endocannabinoid system, can be described as cannabinoidergic.[1]
66.1 See also

Adenosinergic
Cholinergic
GABAergic
Glutamatergic
Glycinergic
Histaminergic
Monoaminergic
Opioidergic
66.2 References
[1] Palmer, SL; Thakur GA; Makriyannis A (December
31, 2002). Cannabinergic ligands. Chemistry and
physics of lipids 121 (1-2): 319. doi:10.1016/s00093084(02)00143-3. PMID 12505686.
92
Chapter 67
Cannabinol
Not to be confused with Cannabidiol.
Cannabinol (CBN) is a weak psychoactive cannabinoid
found only in trace amounts in Cannabis sativa
and Cannabis indica.[5] It is mostly a metabolite of
tetrahydrocannabinol (THC).[6] CBN acts as a weak
agonist of CB1 receptors but has a higher anity to
CB2 receptors, with lower anities in comparison to
THC.[7][8] Because of its somewhat selective CB2 agonism, it is used experimentally as an immunosuppressant.
[8] Petitet F, Jeantaud B, Reibaud M, Imperato A, Dubroeucq

MC (1998). Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of delta9tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors. Life Sciences
63 (1): PL16. doi:10.1016/S0024-3205(98)00238-0.
PMID 9667767.
67.3 External links
In contrast to tetrahydrocannabinol, it has no double

bond isomers nor stereoisomers. It is not scheduled by
Convention on Psychotropic Substances.
67.1 See also

Cannabinoids
67.2 References
[1] Cannabinol in the ChemIDplus database.
[2] David R. Lide (2012). CRC Handbook of Chemistry and
Physics. CRC Press. pp. 390. ISBN 1-43988049-2.
[3] Sigma-Aldrich Co., Cannabinol solution, 1.0 mg/mL in
methanol, analytical standard, for drug analysis.
[4] Biotrend: Cannabinol (PDF: 21 kB)
[5] Karniol IG, Shirakawa I, Takahashi RN, Knobel E, Musty
RE (1975). Eects of delta9-tetrahydrocannabinol and
cannabinol in man. Pharmacology 13 (6): 50212.
doi:10.1159/000136944. PMID 1221432.
[6] McCallum ND, Yagen B, Levy S, Mechoulam R (May
1975). Cannabinol: a rapidly formed metabolite of delta1- and delta-6-tetrahydrocannabinol. Experientia 31 (5):
5201. doi:10.1007/bf01932433. PMID 1140243.
[7] Mahadevan A, Siegel C, Martin BR, Abood ME, Beletskaya I, Razdan RK (October 2000). Novel cannabinol probes for CB1 and CB2 cannabinoid receptors.
doi:10.1021/jm0001572. PMID 11020293.
93
Chapter 68
Cannabivarin
Cannabivarin, also known as cannabivarol or CBV, is
a non-psychoactive cannabinoid found in minor amounts
in the hemp plant Cannabis sativa. It is an analog of
cannabinol (CBN) with the side chain shortened by two
methylene bridges (-CH2 -). CBV is an oxidation product
of tetrahydrocannabivarin (THCV, THV).[1]
It has no double bond isomers nor stereoisomers. It is not
scheduled by Convention on Psychotropic Substances.
68.1 References
[1] Keith Bailey, Denise Gagn (October 1975). Distinction
of synthetic cannabidiol, cannabichromene, and cannabivarin by GLC using on-column methylation. Journal of Pharmaceutical Sciences 64 (10): 17191720.
doi:10.1002/jps.2600641033.
68.2 See also

Cannabinoids
Cannabis
Medical marijuana
68.3 External links

94
Chapter 69
Caryophyllene
Black Caraway (Carum nigrum) [7.8%][13]
Caryophyllene /kri.flin/, or ()--caryophyllene, is

a natural bicyclic sesquiterpene that is a constituent of
many essential oils, especially clove oil, the oil from the
stems and owers of Syzygium aromaticum (cloves),[1]
the essential oil of hemp Cannabis sativa,[2] rosemary
Rosmarinus ocinalis,[3] and hops.[4] It is usually found as
a mixture with isocaryophyllene (the cis double bond isomer) and -humulene (obsolete name: -caryophyllene),
a ring-opened isomer. Caryophyllene is notable for having a cyclobutane ring, a rarity in nature.
Cloves (Syzygium aromaticum)[1] [1.7%19,5% of

clove bud essential oil][14][15]
Hops (Humulus lupulus)[16] [5.114.5%][17]
Basil (Ocimum spp.)[18] [5.310.5% O. gratissimum;
4.019.8% O. micranthum][19]
Oregano
(Origanum
[4.9%15.7][21][22]
Caryophyllene is one of the chemical compounds that

contributes to the spiciness of black pepper. In a
study conducted by Jrg Gertsch et al. from the Swiss
Federal Institute of Technology (ETH Zurich), betacaryophyllene was shown to be selective agonist of
cannabinoid receptor type-2 (CB2 ) and to exert signicant cannabimimetic antiinammatory eects in mice.[2]
Antinociceptive,[5] neuroprotective,[6] anxiolytic and antidepressant [7] and anti-alcoholism [8] activity have been
uncovered. Because the widespread plant natural product
beta-caryophyllene is an FDA approved food additive and
ingested daily with food it is the rst dietary cannabinoid.
Whether this compound is able to modulate inammatory
processes in humans via the endocannabinoid system is
yet unknown. Beta-caryophyllene does not bind to the
centrally expressed cannabinoid receptor type-1 (CB1 )
and therefore does not exert psychomimetic eects.
Black pepper (Piper nigrum) [7.29%][23]

West African Pepper (Piper guineense) [57.59%
(black); 51.75% (white)][23]
Lavender (Lavandula angustifolia) [4.62% of
lavender oil][24]
Rosemary (Rosmarinus ocinalis)[3] [0.18.3%][25]
True cinnamon (Cinnamomum zeylanicum) [6.9
11.1%][26]
Malabathrum (Cinnamomum tamala) [25.3%][27]
The rst total synthesis of caryophyllene in 1964 by E.J.

Corey was considered one of the classic demonstrations
of the possibilities of synthetic organic chemistry at the
time.[9]
Caryophyllene oxide is the component responsible for
cannabis identication by drug-sning dogs[10][11]
vulgare)[20]
Cananga odorata [3.1%10.7%][28]

Copaiba oil (Copaifera spp.)
[29][30][31][32]
69.2 Compendial status

Food Chemical Codex [33], [34]
69.1 Natural sources

The approximate quantity of caryophyllene in the
essential oil of each source is given in square brackets
([ ]):
69.3 Notes and references
Cannabis, hemp, marijuana (Cannabis sativa)[2]

[3.837.5% of cannabis ower essential oil][12]
95
[1] Ghelardini C, Galeotti N, Di Cesare Mannelli L, Mazzanti G, Bartolini A (2001). Local anaesthetic activity of beta-caryophyllene.
Farmaco 56 (57):
3879. doi:10.1016/S0014-827X(01)01092-8. PMID
11482764.
96
[2] Gertsch J, Leonti M, Raduner S, et al. (July 2008).

Beta-caryophyllene is a dietary cannabinoid. Proceedings of the National Academy of Sciences of
the United States of America 105 (26): 9099104.
doi:10.1073/pnas.0803601105. PMC 2449371. PMID
18574142.
[3] Ormeo E, Baldy V, Ballini C, Fernandez C (September 2008). Production and diversity of volatile terpenes from plants on calcareous and siliceous soils: effect of soil nutrients. J. Chem. Ecol. 34 (9): 121929.
doi:10.1007/s10886-008-9515-2. PMID 18670820.
[4] Glenn Tinseth, Hop Aroma and Flavor, January/February
1993,
Brewing
Techniques.
<http://realbeer.com/hops/aroma.html>
Accessed
July 21, 2010.
CHAPTER 69. CARYOPHYLLENE
[13] Singh G, Marimuthu P, de Heluani CS, Catalan CA (January 2006). Antioxidant and biocidal activities of Carum
nigrum (seed) essential oil, oleoresin, and their selected
components. J. Agric. Food Chem. 54 (1): 17481.
doi:10.1021/jf0518610. PMID 16390196.
[14] Alma, M. Hakk; Erta, Murat; Nitz, Siegfrie; Kollmannsberger, Hubert (May 2007). Lucia, Lucian A.;
Hubbe, Martin A., eds. Chemical composition and content of essential oil from the bud of cultivated Turkish clove (PDF). BioResources (Raleigh, North Carolina,
USA: North Carolina State University) 2 (2): 265269.
ISSN 1930-2126. Retrieved September 6, 2010. The results showed that the essential oils mainly contained about
[...] 3.56% -Caryophyllene
[15] Clove Essential Oil
[5] Katsuyama S., Mizoguchi H., Kuwahata H., et al.

(2013). Involvement of peripheral cannabinoid and
opioid receptors in -caryophyllene-induced antinociception. European journal of pain 17 (5): 664675.
doi:10.1002/j.1532-2149.2012.00242.x.
[16] Wang G, Tian L, Aziz N, et al.

(November
2008).
Terpene Biosynthesis in Glandular Trichomes of Hop. Plant Physiol. 148 (3): 125466.
doi:10.1104/pp.108.125187. PMC 2577278. PMID
18775972.
[6] Guimares-Santos, Adriano (2012).

Copaiba OilResin Treatment Is Neuroprotective and Reduces Neutrophil Recruitment and Microglia Activation after
Motor Cortex Excitotoxic Injury.
Evidence-Based
Complementary and Alternative Medicine 2012: 19.
doi:10.1155/2012/918174. PMC 3291111.
[17] Bernotien, Genovait; Nivinskien, Ona; Butkien, Rita;

Mockut, Danut (2004). Chemical composition of essential oils of hops (Humulus lupulus L.) growing wild in
Auk taitija. Chemija. 2 (Vilnius, Lithuania: Lithuanian
Academy of Sciences) 4: 3136. ISSN 0235-7216. Retrieved September 6, 2010.
[7] Bahi Amine, Al Mansouri Shamma, Al Memari Elyazia,

Al Ameri Mouza, Nurulain Syed M., Ojha Shreesh.
(2014). "-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and
depression in mice.. Physiology & behavior 135: 119
124. doi:10.1016/j.physbeh.2014.06.003.
[18] Zheljazkov VD, Cantrell CL, Tekwani B, Khan SI (January 2008). Content, composition, and bioactivity of
the essential oils of three basil genotypes as a function
of harvesting. J. Agric. Food Chem. 56 (2): 3805.
doi:10.1021/jf0725629. PMID 18095647.
[8] Al Mansouri Shamma, Ojha Shreesh, Al Maamari

Elyazia, Al Ameri Mouza, Nurulain Syed M., Bahi
Amine. (2014). The cannabinoid receptor 2 agonist, -caryophyllene, reduced voluntary alcohol intake and attenuated ethanol-induced place preference
and sensitivity in mice.. Pharmacology, biochemistry, and behavior. 2014;124C:260-268 124: 260268.
doi:10.1016/j.pbb.2014.06.025.
[9] Corey EJ, Mitra RB, Uda H (1964). Total Synthesis of d,l-Caryophyllene and d,l-Isocaryophyllene. Journal of the American Chemical Society 86 (3): 485492.
doi:10.1021/ja01057a040.
[10] Taming THC: potential cannabis synergy and
phytocannabinoid-terpenoid entourage eects Ethan
B Russo. Br J Pharmacol. 2011 August; 163(7):
13441364.
[19] Silva, Maria Goretti de Vasconcelos; Matos, Francisco

Jos de Abreu; Lopes, Paulo Roberto Oliveira; Silva,
Fbio Oliveira; Holanda, Mrcio Tavares (August 2,
2004). Cragg, Gordon M.; Bolzani, Vanderlan S.; Rao,
G. S. R. Subba, eds. Composition of essential oils
from three Ocimum species obtained by steam and microwave distillation and supercritical CO2 extraction
(PDF). Arkivoc (ARKAT USA, Inc.) 2004 (vi): 6671.
doi:10.3998/ark.5550190.0005.609. ISSN 1424-6376.
Retrieved September 6, 2010.
[20] Harvala C, Menounos P, Argyriadou N (February 1987).
Essential Oil from Origanum dictamnus. Planta Med.
53 (1): 1079. doi:10.1055/s-2006-962640. PMID
17268981.
[11] Stahl E, Kunde R. Die Leitsubstanzen der HaschischSuchhunde. Kriminalistik: Z Gesamte Kriminal Wiss
Prax. 1973;27:385389.
[21] Calvo-Irabien, L. M.; Yam-Puc, J. A.; Dzib, G.;

Escalante-Erosa, F.; Pea-Rodriguez, L. M. (July
2009). Eect of Postharvest Drying on the Composition of Mexican Oregano (Lippia graveolens) Essential Oil. Journal of Herbs, Spices & Medicinal Plants
(London, UK: Taylor & Francis) 15 (3): 281287.
doi:10.1080/10496470903379001. ISSN 1540-3580.
[12] Mediavilla, Vito; Simon Steinemann. Essential oil of

Cannabis sativa L. strains. International Hemp Association. Retrieved 11 July 2008.
[22] The essential oil of Origanum vulgare L. ssp. vulgare

growing wild in vilnius district (Lithuania) Phytochemistry. 2001 May;57(1):65-9.
69.3. NOTES AND REFERENCES
97
[23] Jirovetz L, Buchbauer G, Ngassoum MB, Geissler M

(November 2002). Aroma compound analysis of Piper
nigrum and Piper guineense essential oils from Cameroon
using solid-phase microextraction-gas chromatography,
solid-phase microextraction-gas chromatography-mass
spectrometry and olfactometry. J Chromatogr A 976
(12): 26575. doi:10.1016/S0021-9673(02)00376-X.
PMID 12462618.
[24] A. Prashar, I. C. Locke, C. S. Evans (2004). Cytotoxicity
of lavender oil and its major components to human skin
cells. Cell Proliferation 37 (3), 221229.
[25] Jamshidi, R.; Afzali, Z.; Afzali, D. (February 2009).
Chemical Composition of Hydrodistillation Essential Oil
of Rosemary in Dierent Origins in Iran and Comparison
with Other Countries (PDF). American-Eurasian Journal of Agricultural & Environmental Sciences (Pakistan:
IDOSI Publications) 5 (1): 7881. ISSN 1990-4053. Retrieved September 6, 2010.
[26] Kaul PN, Bhattacharya AK, Rao BRR, et al. (2003).
Volatile constituents of essential oils isolated from
dierent parts of cinnamon (Cinnamomum zeylanicum
Blume)". Journal of the Science of Food and Agriculture
83 (1): 5355. doi:10.1002/jsfa.1277.
[27] Ahmed A, Choudhary MI, Farooq A, et al. (2000).
Essential oil constituents of the spice Cinnamomum
tamala (Ham.) Nees & Eberm.. Flavour and Fragrance Journal 15 (6): 388390. doi:10.1002/10991026(200011/12)15:6<388::AID-FFJ928>3.0.CO;2-F.
[28] Ylang Ylang Essential Oil
[29] . PMID 22466849. Missing or empty |title= (help)
[30] . PMID 21095089. Missing or empty |title= (help)
[31] http://staff.najah.edu/sites/default/files/Within_plant_
distribution_and_emission_of_sesquiterpenes_from_
Copaifera_officinalis.pdf
[32] http://www.rain-tree.com/copaiba.htm
[33] The United States Pharmacopeial Convention. Revisions
to FCC, First Supplement. Retrieved 29 June 2009.
[34] Therapeutic Goods Administration.
stances. Retrieved 29 June 2009.
Chemical sub-
Chapter 70
CB-13
CB-13 (SAB-378)[1] is a cannabinoid drug, which acts
as a potent agonist at both the CB1 and CB2 receptors,
but has poor bloodbrain barrier penetration, and so produces only peripheral eects at low doses, with symptoms of central eects such as catalepsy only appearing
at much higher dose ranges. It has antihyperalgesic properties in animal studies,[2] and has progressed to preliminary human trials.[3]
70.1 See also

AM-6545
AZ-11713908
70.2 References
[1] Cluny, N. L.; Keenan, C. M.; Duncan, M.; Fox, A.;
Lutz, B.; Sharkey, K. A. (2010). Naphthalen-1-yl(4-pentyloxynaphthalen-1-yl)methanone (SAB378), a Peripherally Restricted Cannabinoid CB1/CB2 Receptor
Agonist, Inhibits Gastrointestinal Motility but Has No Effect on Experimental Colitis in Mice. Journal of Pharmacology and Experimental Therapeutics 334 (3): 973.
doi:10.1124/jpet.110.169946. PMID 20571060.
[2] Dziadulewicz, E. K.; Bevan, S. J.; Brain, C. T.; Coote,
P. R.; Culshaw, A. J.; Davis, A. J.; Edwards, L. J.;
Fisher, A. J.; Fox, A. J.; Gentry, C.; Groarke, A.;
Hart, T. W.; Huber, W.; James, I. F.; Kesingland, A.;
La Vecchia, L.; Loong, Y.; Lyothier, I.; McNair, K.;
O'Farrell, C.; Peacock, M.; Portmann, R.; Schopfer, U.;
Yaqoob, M.; Zadrobilek, J. (2007). Naphthalen-1-yl-(4pentyloxynaphthalen-1-yl)methanone: A Potent, Orally
Bioavailable Human CB1/CB2Dual Agonist with Antihyperalgesic Properties and Restricted Central Nervous System Penetration. Journal of Medicinal Chemistry 50 (16):
38513856. doi:10.1021/jm070317a. PMID 17630726.
[3] Gardin A, Kucher K, Kiese B, Appel-Dingemanse S
(April 2009). Cannabinoid receptor agonist 13, a
novel cannabinoid agonist: rst in human pharmacokinetics and safety. Drug Metabolism and Disposition: the Biological Fate of Chemicals 37 (4): 82733.
doi:10.1124/dmd.108.024000. PMID 19144772.
98
Chapter 71
CBS-0550
CBS-0550 is a drug developed by Taisho Pharmaceutical, which acts as a potent and selective cannabinoid
CB2 receptor agonist, with 1400x selectivity for CB2 over
the related CB1 receptor. Unlike most cannabinoid agonists, CBS-0550 has good solubility in water, and in animal studies it was found to produce analgesic and antihyperalgesic eects.[1]
71.1 See also

A-836,339
SER-601
71.2 References
[1] Ohta H, et al. Imine derivatives as new potent and selective CB2 cannabinoid receptor agonists with an analgesic
action. Bioorganic and Medicinal Chemistry. 2008 Feb
1;16(3):1111-24. PMID 18006322
99
Chapter 72
CP 47,497
CP 47,497 or (C7)-CP 47,497 is a cannabinoid receptor 72.2
agonist drug, developed by Pzer in the 1980s.[1] It has
analgesic eects and is used in scientic research. It is a
72.2.1
potent CB1 agonist with a K of 2.1nM.[2][3][4]
Legal status
Germany
On 22 January 2009, CP 47,497 was added

to the German controlled drug schedules
(Betubungsmittelgesetz),[12] along with its dimethylhexyl, dimethyloctyl and dimethylnonyl homologues.[13]
72.1 Homologue
On the 19th of January 2009, the University of Freiburg
in Germany announced that an analog of CP 47,497 is
the main active ingredient in the herbal incense product Spice, specically the 1,1-dimethyloctyl homologue
of CP 47,497. Both the dimethylheptyl and dimethyloctyl homologues were detected in dierent batches,
with considerable variation in the concentration present
in dierent samples that were analysed. The weaker
dimethylhexyl and dimethylnonyl homologues were not
found in any batches of smoking blends tested, but
have been legally scheduled alongside the others in
some jurisdictions, to forestall any potential use for this
purpose.[5][6][7] The 1,1-dimethyloctyl homologue of CP
47,497 is in fact several times more potent than the parent compound,[8] which is somewhat unexpected as the
1,1-dimethylheptyl is the most potent substituent in classical cannabinoid compounds such as HU-210.[9] The
unapproved use of these compounds in herbal smoking
blends has led to a resurgence in legitimate scientic research into their use,[10] and consequently the C8 homologue of CP 47,497 has been assigned a proper name,
cannabicyclohexanol.[11]
72.2.2 France
CP 47,497 and its C6, C8, and C9 homologues were
made illegal in France on 24 February 2009.[14]
72.2.3 Latvia
made illegal in Latvia on 28 November 2009.[15]
72.2.4 Lithuania
made illegal in Lithuania on 5 June 2009.[16]
72.2.5 Sweden
CP 47,497 and its C6, C7, C8, and C9 homologues were
made illegal in Sweden on 15 September 2009.
72.2.6 Romania
CP 47,497 and its C6, C7, C8, and C9 homologues were
made illegal in Romania on 15 February 2010.(Illegal
Substances in Romania after 15.02.2010
72.2.7 United States

Cannabicyclohexanol
As of March 1, 2011, it is a schedule 1 drug.[17][18]

100
72.4. REFERENCES
72.3 See also

(C6)-CP 47,497
(C8)-CP 47,497
(C9)-CP 47,497
CP 50,556-1
CP 55,244
CP 55,940
CP-945,598
HHC
O-1871
72.4 References
[1] Weissman A, Milne GM, Melvin LS Jr. Cannabimimetic
activity from CP-47,497, a derivative of 3phenylcyclohexanol.
Journal of Pharmacology and
Experimental Therapeutics. 1982 Nov;223(2):516-23.
PMID 6290642
[2] Shim JY, Welsh WJ, Howlett AC. Homology model of
the CB1 cannabinoid receptor: sites critical for nonclassical cannabinoid agonist interaction. Biopolymers.
2003;71(2):169-89. PMID 12767117
[3] Roger Pertwee. Cannabinoids. Handbook of Experimental Pharmacology Volume 168. Springer. ISBN 3-54022565-X
[4] Little PJ, et al. Pharmacology and stereoselectivity
of structurally novel cannabinoids in mice. Journal
of Pharmacology and Experimental Therapeutics 1988;
247:10461051.
[5] Hauptwirksto von Spice identiziert, University
of Freiburg http://www.pr.uni-freiburg.de/pm/2009/pm.
2009-01-19.19/
[6] Spice - weitere Analyseresultate http://www.
basg.at/servlet/sls/Tornado/web/ages/content/
4E5A4B86295BF5C0C125753E006A5E3C
[7] Auwrter V, et al. 'Spice' and other herbal blends: harmless incense or cannabinoid designer drugs? Journal of
Mass Spectrometry. 2009 Feb 2. PMID 19189348
[8] Compton DR, Johnson MR, Melvin LS, Martin BR. Pharmacological prole of a series of bicyclic cannabinoid
analogs: classication as cannabimimetic agents. Journal
Jan;260(1):201-9. PMID 1309872
[9] Martin BR, et al. Behavioral, biochemical, and molecular
modeling evaluations of cannabinoid analogs. Pharmacology, Biochemistry and Behavior. 1991 Nov;40(3):471-8.
PMID 1666911
101
[10] Uchiyama N, et al. Eects of synthetic cannabinoids on

electroencephalogram power spectra in rats. Forensic Science International. 2011 Jun 1. PMID 21640532
Y (May 2010).
Forensic Science International 198 (1-3):
318.
[12] Modedroge Spice ist verboten!
[13] BGBl I Nr. 3 vom 21.01.2009, 22. BtMndV vom 19.
Januar 2009, S. 4950.
[14] Dcrets, arrts, circulaires: Arrt du 24 fvrier 2009
modiant larrt du 22 fvrier 1990 xant la liste des substances classes comme stupants
[15] Grozjumi Ministru kabineta 2005.gada 8.novembra
noteikumos Nr.847 Noteikumi par Latvij kontroljamajm narkotiskajm vielm, psihotropajm vielm un
prekursoriem
[16] http://www3.lrs.lt/pls/inter3/dokpaieska.showdoc_l?p_
id=345197
[17] Cook, Morgan (2011-02-28). Synthetic marijuana illegal as of Tuesday. North County Times (San Diego). Retrieved 2011-02-28.
[18] https://federalregister.gov/a/2011-4428
Chapter 73
CP 55,244
CP 55,244 is a compound which is a cannabinoid receptor agonist. It has analgesic eects and is used in scientic
research. It is an extremely potent CB1 full agonist with a
K of 0.21nM, making it more potent than the commonly
used full agonist HU-210.[1]
73.1 See also

CP 47,497
73.2 References
[1] Grin G, Wray EJ, Martin BR, Abood ME. Cannabinoid
agonists and antagonists discriminated by receptor binding in rat cerebellum. British Journal of Pharmacology.
1999 Oct;128(3):684-8.
doi:10.1038/sj.bjp.0702806
PMID 10516649
102
Chapter 74
CP 55,940
CP 55,940 is a cannabinoid which mimics the eects of
naturally occurring THC (one of the psychoactive compounds found in cannabis). CP 55,940 was created by
Pzer in 1974 but was never marketed. It is currently
used to study the endocannabinoid system. Some eects
that have been noted are a greatly decreased rates of lever
pressing in exposed mice, and a greater reaction to opiates in exposed mice.
A study found that CP 55,940 can upregulate 5-HT2A
receptors in mice.[1]
CP 55,940 is 45 times more potent than 9 -THC, and
fully antagonized by rimonabant (SR141716A).[2]
CP 55,940 is considered a full agonist at both CB1 and
CB2 receptors and has K values of 0.58nM and 0.68nM
respectively, but is an antagonist at GPR55, the putative
CB3 " receptor.[3]
CP 55,940 showed protective eects on rat brain mitochondria upon paraquat exposure.[4]
It also showed neuroprotective eects by reducing intracellular calcium release and reducing hippocampal cell
death in cultured neurons subjected to high levels of
NMDA.[5]
of binding sites for [3 H]-SR 141716A, a selective brain

(CB1) cannabinoid receptor antagonist, in rodent brain.
Life Sciences 58 (15): 12391247. doi:10.1016/00243205(96)00085-9. PMID 8614277.
[3] Kapur, A.; Zhao, P.; Sharir, H.; Bai, Y.; Caron, M. G.;
Barak, L. S.; Abood, M. E. (2009). Atypical responsiveness of the orphan receptor GPR55 to cannabinoid
ligands. The Journal of Biological Chemistry 284 (43):
2981729827. doi:10.1074/jbc.M109.050187. PMC
2785612. PMID 19723626.
[4] Velez-Pardo, C.; Jimenez-Del-Rio, M.; Lores-Arnaiz, S.;
Bustamante, J. (2010). Protective eects of the synthetic cannabinoids CP55,940 and JWH-015 on rat brain
mitochondria upon paraquat exposure. Neurochemical
Research 35 (9): 13231332. doi:10.1007/s11064-0100188-1. PMID 20514518.
[5] Zhuang, S. Y.; Bridges, D.; Grigorenko, E.; McCloud, S.; Boon, A.; Hampson, R. E.; Deadwyler, S.
A. (2005). Cannabinoids produce neuroprotection by
reducing intracellular calcium release from ryanodinesensitive stores. Neuropharmacology 48 (8): 1086
15910885.
CP 55,940 induced cell death in NG 108-15 Mouse neuroblastoma x Rat glioma hybrid brain cancer (genetically
engineered mouse x rat brain cancer) cells.[6][7]
[6] Tomiyama, K.; Funada, M. (2011). Cytotoxicity of synthetic cannabinoids found in 'Spice' products: The role
of cannabinoid receptors and the caspase cascade in the
NG 108-15 cell line. Toxicology Letters 207 (1): 1217.
doi:10.1016/j.toxlet.2011.08.021. PMID 21907772.
74.1 See also
[7] General Cell Collection: NG108-15. Public Health

England Culture Collections.
CP 47,497
74.2 References
[1] Franklin, J. M.; Carrasco, G. A. (2013). Cannabinoid receptor agonists upregulate and enhance serotonin
2A (5-HTA) receptor activity via ERK1/2 signaling.
Synapse 67 (3): 145159. doi:10.1002/syn.21626. PMID
23151877.
[2] Rinaldi-Carmona, M.; Pialot, F.; Congy, C.; Redon,
E.; Barth, F.; Bachy, A.; Brelire, J. C.; Soubri, P.;
le Fur, G. (1996). Characterization and distribution
103
Chapter 75
Dexanabinol
Dexanabinol (HU-211 or ETS2101[1] ) is a synthetic
cannabinoid derivative that is the unnatural enantiomer
of the potent cannabinoid agonist HU-210.[2] Unlike
other cannabinoid derivatives, HU-211 does not act as a
cannabinoid receptor agonist, but instead has NMDA antagonist eects.[3] It therefore does not produce cannabislike eects, but is anticonvulsant and neuroprotective,
and is widely used in scientic research as well as currently being studied for practical applications such as
treatment of head injury or stroke or cancer.[4][5][6] It was
shown to be safe in clinical trials[7] and is currently undergoing Phase I trials for the treatment of brain cancer.[8]
75.1 References
[1] e-therapeutics Clinical Development Pipeline
[2] Pop E (September 2000). Nonpsychotropic synthetic
cannabinoids. Current Pharmaceutical Design 6 (13):
134760. doi:10.2174/1381612003399446. PMID
10903397.
[3] Feigenbaum JJ, et al.
(December 1989).
Nonpsychotropic cannabinoid acts as a functional
N-methyl-D-aspartate receptor blocker. Proceedings of
the National Academy of Sciences of the United States of
America 86 (23): 95847. doi:10.1073/pnas.86.23.9584.
PMC 298542. PMID 2556719.
[4] Biegon A; Joseph AB (August 1995). Development of
HU-211 as a neuroprotectant for ischemic brain damage.
Neurological Research 17 (4): 27580. PMID 7477742.
[5] Darlington CL (October 2003). Dexanabinol: a novel
cannabinoid with neuroprotective properties. IDrugs :
the Investigational Drugs Journal 6 (10): 9769. PMID
14534855.
[6] Vink R; Nimmo AJ (January 2009). Multifunctional
drugs for head injury. Neurotherapeutics : the Journal
of the American Society for Experimental NeuroTherapeutics 6 (1): 2842. doi:10.1016/j.nurt.2008.10.036. PMID
19110197.
[7] Maas AI, et al. (January 2006). Ecacy and safety
of dexanabinol in severe traumatic brain injury: results
of a phase III randomised, placebo-controlled, clinical
trial. Lancet Neurol 5 (1): 3845. doi:10.1016/S14744422(05)70253-2. PMID 16361021.
104
[8] University of California, San Diego "Synthetic Cannabinoid May Be Used as Brain Cancer Treatment". (28
September 2012) Laboratory Equipment. Retrieved 28
September 2012.
Chapter 76
Dimethylheptylpyran
Dimethylheptylpyran
(DMHP,
3-(1,2dimethylheptyl)-6a,10a -THC, 1,2-dimethylheptyl3 THC, A-40824, EA-1476) is a synthetic analogue of
THC, which was invented in 1949 during attempts to
elucidate the structure of 9 -THC, the active component
of cannabis.[1] DMHP is a pale yellow, viscous oil which
is insoluble in water, but dissolves in alcohol or non-polar
solvents.
76.1 Eects
DMHP is similar in structure to THC, diering only in
the position of one double bond, and the replacement of
the 3-pentyl chain with a 3-(1,2-dimethylheptyl) chain.[2]
It produces similar activity to THC, such as sedative effects, but is considerably more potent,[3] especially having
much stronger analgesic and anticonvulsant eects than
THC, although comparatively weaker psychological effects. It is thought to act as a CB1 agonist, in a similar
manner to other cannabinoid derivatives.[4]
76.2 Investigation as non-lethal incapacitating agent

DMHP and its O-acetate ester were extensively investigated by the US military chemical weapons program
in the Edgewood Arsenal experiments, as possible nonlethal incapacitating agents.[5]
DMHP has three stereocenters and consequently has
eight possible stereoisomers, which dier considerably
in potency. The racemic mix of all eight isomers of
the O-acetyl ester was given the code number EA-2233,
with the eight individual isomers numbered EA-2233-1
through EA-2233-8. The most potent isomer was EA2233-2, with an active dose range in humans of 0.52.8
g/kg (i.e. ~35200 g for a 70 kg adult). Active doses
varied markedly between individuals, but when the dose
of EA-2233 was taken up to 12 mg, all volunteers were
considered to be incapable of performing military duties,
with the eects lasting as long as 23 days.
ducing the active metabolite 11-hydroxy-DMHP, but the

lipophilicity of DMHP is even higher than that of THC
itself, giving it a long duration of action and an extended half-life in the body of between 2039 hours, with
the half-life of the 11-hydroxy-DMHP metabolite being
longer than 48 hours.
Cannabinoids as a class are generally safe compounds
with a large safety margin, making potent cannabinoid drugs ideal as potential non-lethal incapacitating
agents. DMHP and its esters produce sedation and
mild hallucinogenic eects similar to large doses of
THC, but in addition to this they also cause pronounced
hypotension (low blood pressure) which occurs at doses
well below the hallucinogenic dose, and can lead to severe
dizziness, fainting, ataxia and muscle weakness, sucient
to make it dicult to stand upright or carry out any kind
of vigorous physical activity (an eect known colloquially as couch lock). The acute toxicity of DMHP was
found to be low in both human and animal studies, with
the ratio of ED50 to LD50 (Therapeutic Index) in animals
being around 2000x, with death ultimately resulting from
a combination of hypotension and hypothermia and preventable with supportive treatment.
The combination of strong incapacitating eects and a
favourable safety margin led the Edgewood Arsenal team
to conclude that DMHP and its derivatives, especially
the O-acetyl ester of the most active isomer, EA-2233-2,
were among the more promising non-lethal incapacitating
agents to come out of their research program. However
they were disadvantaged by producing severe hypotension at incapacitating doses, and were not as eective as
the more widely publicised anticholinergic agents such
as 3-Quinuclidinyl benzilate which had also already been
weaponised.[6] Funding for continued development was
ultimately not approved, and the cannabinoid research
program was indenitely suspended along with the rest
of the Edgewood Arsenal experiments in the late 1970s,
in accordance with the US commitment to cease research
into chemical weapons under disarmament treaties.
DMHP is metabolised in a similar manner to THC, pro105
106
Dibenzopyran and monoterpenoid numbering of tetrahydrocannabinol derivatives
76.3 Isomerism
Note that 6H-dibenzo[b,d]pyran-1-ol is the same as 6Hbenzo[c]chromen-1-ol.
See also: Tetrahydrocannabinol Isomerism
76.4 References
[1] Adams R, Harfenist M, Loewe S (1949).
Journal of the American Chemical Society 71 (5): 1624.
doi:10.1021/ja01173a023.
[2] Razdan RK (1980). The Total Synthesis of Cannabinoids. Total Synthesis of Natural Products, Volume 4.
Wiley-Interscience. doi:10.1002/9780470129678.ch2.
ISBN 9780471054603.
[3] Wilkison, DM; Pontzer, N; Hosko, MJ (1982). Slowing of cortical somatosensory evoked activity by delta 9tetrahydrocannabinol and dimethylheptylpyran in alphachloralose-anesthetized cats. Neuropharmacology 21
(7): 7059. doi:10.1016/0028-3908(82)90014-4. PMID
6289158.
[4] Parker, LA; Mechoulam, R (2003). Cannabinoid agonists and antagonists modulate lithium-induced conditioned gaping in rats. Integrative physiological and behavioral science : the ocial journal of the Pavlovian Society 38 (2): 13345. doi:10.1007/BF02688831. PMID
14527182.
[5] Possible Long-Term Health Eects of Short-Term Exposure To Chemical Agents. Vol. 2: Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants.
Commission on Life Sciences. The National Academies
Press. 1984. pp. 7999.
[6] Ketchum, James S. (2006) Chemical Warfare Secrets Almost Forgotten. ChemBooks Inc. ISBN 978-1-42430080-8
CHAPTER 76. DIMETHYLHEPTYLPYRAN
Chapter 77
Docosatetraenoylethanolamide
Docosatetraenoylethanolamide (DEA) is an endogenous ethanolamide that has been shown to act on the
cannabinoid (CB1 ) receptor.[1] DEA is similar in structure to anandamide (AEA, a recognized endogenous ligand for the CB1 receptor), containing docosatetraenoic
acid in place of arachidonic acid. While DEA has been
shown to bind to the CB1 receptor with similar potency
and ecacy as AEA, its role as a cannabinergic neurotransmitter is not well understood.
77.1 References
[1] Hanus, L., Gopher, A., Almog, S., et al. (1993). Two
new unsaturated fatty acid ethanolamides in brain that
bind to the cannabinoid receptor. J Med Chem 36
(20): 30323034. doi:10.1021/jm00072a026. PMID
8411021.
107
Chapter 78
Drinabant
Drinabant (INN; AVE-1625) is a drug that acts as a
selective CB1 receptor antagonist, which was under investigation varyingly by Sano-Aventis as a treatment for
obesity, schizophrenia, Alzheimers disease, Parkinsons
disease, and nicotine dependence.[1][2][3] Though initially
studied as a potential treatment for a variety of dierent medical conditions, Sano-Aventis eventually narrowed down the therapeutic indications of the compound
to just appetite suppression. Drinabant reached phase IIb
clinical trials for this purpose in the treatment of obesity but was shortly thereafter discontinued,[4] likely due
to the observation of severe psychiatric side eects including anxiety, depression, and thoughts of suicide in
patients treated with the now-withdrawn rimonabant, another CB1 antagonist that was also under development by
Sano-Aventis.[5]
78.1 See also

78.2 References
[1] Lange JH, Kruse CG (2008). Cannabinoid CB1 receptor antagonists in therapeutic and structural perspectives. Chemical Record (New York, N.Y.) 8 (3): 15668.
doi:10.1002/tcr.20147. PMID 18563799.
[2] Kwon MO, Herrling P (2005). List of drugs in development for neurodegenerative diseases. Update September 2005. Neuro-degenerative Diseases 2 (2): 61108.
doi:10.1159/000089285. PMID 16909049.
[3] Gerald Litwack (14 August 2009). Anandamide. Academic Press. p. 172. ISBN 978-0-12-374782-2. Retrieved 13 May 2012.
[4] Reggio, Patricia H. (2009). Toward the design of
cannabinoid CB1 receptor inverse agonists and neutral antagonists. Drug Development Research 70 (8).
doi:10.1002/ddr.20337. ISSN 0272-4391.
[5] Lee HK, Choi EB, Pak CS (2009). The current status and future perspectives of studies of cannabinoid
108
receptor 1 antagonists as anti-obesity agents. Current Topics in Medicinal Chemistry 9 (6): 482503.
doi:10.2174/156802609788897844. PMID 19689362.
Chapter 79
EAM-2201
EAM-2201 (4'-ethyl-AM-2201, 5"-uoro-JWH-210)
is a drug that presumably acts as a potent agonist for the
cannabinoid receptors. It had never previously been reported in the scientic or patent literature, and was rst
identied by laboratories in Japan in July 2012 as an ingredient in synthetic cannabis smoking blends.[1] Like the
closely related MAM-2201 which had been rst reported
around a year earlier, EAM-2201 thus appears to be another novel compound invented by designer drug suppliers specically for recreational use. Structurally, EAM2201 is a hybrid of two known cannabinoid compounds
JWH-210 and AM-2201, both of which had previously
been used as active ingredients in synthetic cannabis
blends before being banned in many countries.
79.4 References
79.1 Pharmacology
Nothing has been published on the pharmacology of
EAM-2201, though it presumably has similar properties
to the closely related AM-2201 and JWH-210, which are
both full agonists and unselectively bind to CB1 and CB2
cannabinoid receptors with low nanomolar anity.
79.2 Legal status

EAM-2201 was banned in New Zealand as a temporary
class drug from 6 December 2012, after reports of addiction and psychosis associated with use of products
containing EAM-2201 as an active ingredient, however
this has been protested by some users who claim to have
found medical benets in the treatment of conditions such
as phantom limb pain, since medicinal marijuana is not
available in New Zealand and synthetic cannabis products
are used as a legal alternative.[2][3]
79.3 Detection
A forensic standard of EAM-2201 is available and commonly used in mass spectrometry, and the compound has
been cited on the Forendex website of potential drugs of
abuse.[4][5]
109

23063179.
[2] I was possessed by a demon, says ex-legal high user. New
Zealand Herald, Monday 1 Oct 2012
[3] Amputee: K2 'takes away my pain'. New Zealand Herald,
Wednesday 28 Nov 2012
[4] https://www.caymanchem.com/app/template/Product.
vm/catalog/ISO00127
[5] Peter Rsner, G. Fritschi, Southern Association of
Forensic Scientists, http://forendex.southernforensic.
org/uploads/references/Molecular_Index_Of_
_Cannabimimetics_(2).pdf
Chapter 80
Endocannabinoid reuptake inhibitor

Endocannabinoid reuptake inhibitors (eCBRIs), also
called cannabinoid reuptake inhibitors (CBRIs), are
drugs which limit or completely stop the reabsorption
of endocannabinoid neurotransmitters into their corresponding pre-synaptic neurons.
80.1 Etymology
There are several parts to the phrase endocannabinoid
reuptake inhibitor. First, a reuptake inhibitor is a substance that prevents its respective neurotransmitters from
being reabsorbed into the pre-sypnatic neurones, which
makes them continually recycle themselves, thus creating
a large increase in neurotransmission. Next, a cannabinoid is simply a class of closely related substances such as
Tetrahydrocannabinol and Cannabidiol. 'Endo' is a prex used to describe a cannabinoid that is naturally found
within an animal. In retrospect, an endocannabinoid reuptake inhibitor is a substance that when ingested by an
animal prevents reuptake of its endogenous cannabinoids.
Endocannabinoid uptake inhibitors that bind to fatty acid
binding protons (FABPs) have been described.
docannabinoid system using VDM-11 and AA-5-HT reduced the ultimate size of the tumors in the treated rats.
These ndings suggest that the use of cannabinoids and/or
eCBR inhibitors could be used to eectively treat tumors
and/or cancer, which only adds to the controversy around
cannabinoids and the cannabis plant as medicine.
As one might expect, combining a cannabinoid receptor
antagonist with an eCBRI reverses the eects of the reuptake inhibitor, and therefore could hinder treatment.
Cannabinoid receptor antagonists aren't something common, so normally this isn't something to worry about. But
if smoked cannabis or cannabis extract is to be used as
a treatment, it would be necessary to cultivate varieties
with little to no amounts of these compounds, as they are
found in low concentrations in most varieties. One example of these antagonist compounds which is found in the
cannabis plant is THCV (tetrahydrocannabivarin).
80.4 Examples of eCBRIs

AM404
O-2093
80.2 Pharmacology
OMDM-2
The inhibition of endocannabinoid reuptake raises the

amount of those neurotransmitters available in the
synaptic cleft and therefore increases neurotransmission.
Following the increase of neurotransmission in the endocannabinoid system is the stimulation of its functions
which, in humans, include: suppression of pain perception (analgesia), increased appetite, mood elevation and
inhibition of short-term memory.
UCM-707
VDM-11
URB597
80.5 See also

Endocannabinoid system
80.3 Use in medicine

Other than toxicity research and recreational use, eCBRIs
could have some potential in ghting tumors and possibly cancer. A study done in 2004 on rats with thyroid tumors showed that reuptake inhibition of the en110
Reuptake inhibitor
Endocannabinoid transporters
80.6. REFERENCES
80.6 References
1. http://www.fasebj.org/cgi/content/full/18/13/1606
2. http://www.ncbi.nlm.nih.gov/pubmed/16770320
3. PLOS ONE
111
Chapter 81
Endocannabinoid system
The endocannabinoid system is a group of neuromodulatory lipids and their receptors in the brain that are involved in a variety of physiological processes including
appetite, pain-sensation, mood, and memory; it mediates
the psychoactive eects of cannabis and, broadly speaking, includes:
that cannabinoids will have in modulating specic aspects

of behavior related to the site of expression. For example,
in rodents, the highest concentration of cannabinoid binding sites are in the basal ganglia and cerebellum, regions
of the brain involved in the initiation and coordination of
movement.[10] In humans, cannabinoid receptors exist in
much lower concentration in these regions, which helps
The endogenous arachidonate-based lipids, explain why cannabinoids possess a greater ecacy in alanandamide (N-arachidonoylethanolamide, AEA) tering rodent motor movements than they do in humans.
and 2-arachidonoylglycerol (2-AG); these are A recent analysis of cannabinoid binding in CB1 and
known as "endocannabinoids" and are physio- CB2 receptor knockout-mice found cannabinoid responlogical ligands for the cannabinoid receptors. siveness even when these receptors were not being exEndocannabinoids are all eicosanoids.[1]
pressed, indicating that an additional binding receptor
may be present in the brain.[10] Binding has been demon The enzymes that synthesize and degrade the endo- strated by 2-arachidonoylglycerol (2-AG) on the TRPV1
cannabinoids, such as fatty acid amide hydrolase or receptor suggesting that this receptor may be a candidate
monoacylglycerol lipase.
for the established response.[11]
The cannabinoid receptors CB1 and CB2 , two G
protein-coupled receptors that are located in the
81.1.2
central and peripheral nervous systems.
The endocannabinoid system has been studied using genetic and pharmacological methods. These studies have
revealed that cannabinoids act as neuromodulators[2][3][4]
for a variety of physiological processes, including motor
learning,[5] synaptic plasticity,[6] appetite,[7] and pain
sensation.[8]
81.1 Basic overview

81.1.1
Expression of receptors
For a more thorough description on receptor localization,

see Cannabinoid receptor type 1 (CB1 ) and Cannabinoid
receptor type 2 (CB2 ).
Endocannabinoid synthesis,
lease, and degradation
re-
During neurotransmission, the pre-synaptic neuron releases neurotransmitters into the synaptic cleft which bind
to cognate receptors expressed on the post-synaptic neuron. Based upon the interaction between the transmitter
and receptor, neurotransmitters may trigger a variety of
eects in the post-synaptic cell, such as excitation, inhibition, or the initiation of second messenger cascades.
Based on the cell, these eects may result in the onsite synthesis of endogenous cannabinoids anandamide
or 2-AG by a process that is not entirely clear, but results from an elevation in intracellular calcium.[9] Expression appears to be exclusive, so that both types of endocannabinoids are not co-synthesized. This exclusion is
based on synthesis-specic channel activation: a recent
study found that in the bed nucleus of the stria terminalis,
calcium entry through voltage-sensitive calcium channels
produced an L-type current resulting in 2-AG production, while activation of mGluR1/5 receptors triggered
the synthesis of anandamide.[11]
Cannabinoid binding sites exist throughout the central

and peripheral nervous systems. The two most relevant receptors for cannabinoids are the CB1 and CB2 receptors, which are expressed predominantly in the brain Evidence suggests that the depolarization-induced inux
and immune system respectively.[9] Density of expression of calcium into the post-synaptic neuron causes the acvaries based on species and correlates with the ecacy tivation of an enzyme called transacylase. This enzyme
112
81.1. BASIC OVERVIEW

is suggested to catalyze the rst step of endocannabinoid
biosynthesis by converting phosphatidylethanolamine,
a membrane-resident phospholipid, into N-acylphosphatidylethanolamine
(NAPE).
Experiments
have shown that phospholipase D cleaves NAPE to
yield anandamide.[12][13] In NAPE-phospholipase D
(NAPEPLD)-knockout mice, cleavage of NAPE is reduced in low calcium concentrations, but not abolished,
suggesting multiple, distinct pathways are involved in
anandamide synthesis.[14] The synthesis of 2-AG is less
established and warrants further research.
113
but also the PI3/PKB and MEK/ERK pathway (GalveRoperh et al., 2002; Davis et al., 2005; Jones et al.,
2005; Graham et al., 2006). Results from rat hippocampal gene chip data after acute administration of
tetrahydrocannabinol (THC) showed an increase in the
expression of transcripts encoding myelin basic protein,
endoplasmic proteins, cytochrome oxidase, and two cell
adhesion molecules: NCAM, and SC1; decreases in expression were seen in both calmodulin and ribosomal
RNAs (Kittler et al., 2000). In addition, CB1 activation
has been demonstrated to increase the activity of tranOnce released into the extracellular space by a puta- scription factors like c-Fos and Krox-24 (Graham et al.,
2006).
tive endocannabinoid transporter, messengers are vulnerable to glial cell inactivation. Endocannabinoids are
taken up by a transporter on the glial cell and degraded
by fatty acid amide hydrolase (FAAH), which cleaves 81.1.4 Binding and neuronal excitability
anandamide into arachidonic acid and ethanolamine or
monoacylglycerol lipase (MAGL), and 2-AG into arachi- The molecular mechanisms of CB1 -mediated changes
donic acid and glycerol.[15] While arachidonic acid is a to the membrane voltage have also been studied in desubstrate for leukotriene and prostaglandin synthesis, it tail. CB1 agonists reduce calcium inux by blocking
N-, P/Q- and L-type
is unclear whether this degradative byproduct has novel the activity of voltage-dependent
[19][20]
[16][17]
calcium
channels.
In
addition
to acting on calfunctions in the central nervous system.
Emerging
cium
channels,
activation
of
Gi/o
and
Gs, the two most
data in the eld also points to FAAH being expressed
commonly
coupled
G-proteins
to
cannabinoid
receptors,
in postsynaptic neurons complementary to presynaptic
has
been
shown
to
modulate
potassium
channel
activity.
neurons expressing cannabinoid receptors, supporting the
Recent
studies
have
found
that
CB
activation
specif1
conclusion that it is major contributor to the clearance
ically
facilitates
GIRK,
a
potassium
channel
belonging
and inactivation of anandamide and 2-AG after endo[20]
Both Guo & Ikeda and Binzen et
cannabinoid reuptake.[10] A neuropharmacological study to the Kir3 family.
al.
performed
a
series
of immunohistochemistry experdemonstrated that an inhibitor of FAAH (URB597) seiments
that
demonstrated
CB1 co-localized with GIRK
lectively increases anandamide levels in the brain of roand
Kv1.4
potassium
channels,
suggesting that these two
dents and primates. Such approaches could lead to the
[21]
may
interact
in
physiological
contexts.
development of new drugs with analgesic, anxiolytic-like
and antidepressant-like eects, which are not accompa- In the central nervous system, CB1 receptors inuence
nied by overt signs of abuse liability.[18]
neuronal excitability, reducing the incoming synaptic
[22]
This mechanism, known as presynaptic inhiNotably, a series of recent studies have found that the input.
bition,
occurs
when a postsynaptic neuron releases enexpression of endocannabinoids does not correlate with
docannabinoids
in retrograde transmission, which then
the distribution of cannabinoid receptors in the brain,
bind
to
cannabinoid
receptors on the presynaptic termisuggesting that these molecules may also be interactnal.
CB
receptors
then
reduce the amount of neurotrans1
ing with other receptors or be involved with other cell
[10]
mitter
released,
so
that
subsequent
excitation in the presyprocesses.
naptic neuron results in diminished eects on the postsynaptic neuron. It is likely that presynaptic inhibition uses
many of the same ion channel mechanisms listed above,
81.1.3 Binding and intracellular eects
although recent evidence has shown that CB1 receptors
Cannabinoid receptors are G-protein coupled receptors can also regulate neurotransmitter release by a non-ion
located on the pre-synaptic membrane. While there have channel mechanism, i.e. through Gi/o-mediated inhibibeen some papers that have linked concurrent stimulation of adenylyl cyclase and Protein Kinase A.[23] Still,
tion of dopamine and CB1 receptors to an acute rise in direct eects of CB1 receptors on membrane excitabilcyclic adenosine monophosphate (cAMP) production, it ity have been reported, and strongly impact the ring of
is generally accepted that CB1 activation via cannabi- cortical neurons[24] In a series of behavioral experiments,
noids causes a decrease in cAMP concentration by inhi- Palazzo et al. demonstrated that NMDA, an ionotropic
bition of adenylyl cyclase and a rise in the concentration glutamate receptor, and the metabotropic glutamate reof mitogen-activated protein kinase (MAP kinase).[1][10] ceptors (mGluRs) work in concert with CB1 to induce
The relative potency of dierent cannabinoids in inhi- analgesia in mice, although the mechanism underlying
bition of adenylyl cyclase correlates with their varying this eect is unclear. Together, these ndings suggest that
ecacy in behavioral assays. This inhibition of cAMP CB1 inuences neuronal excitability by a variety of mechis followed by phosphorylation and subsequent activa- anisms, and these eects are relevant to perception and
tion of not only a suite of MAP kinases (p38/p42/p44), behavior.
114
CHAPTER 81. ENDOCANNABINOID SYSTEM
81.2 Functions of the endocannabinoid system
ilar post-synaptic receptor dependencies were found in

the striatum, but here both eects relied on presynaptic
CB1 receptors.[11] These ndings provide the brain a direct mechanism to selectively inhibit neuronal excitabil81.2.1 Memory
ity over variable time scales. By selectively internalizing
dierent receptors, the brain may limit the production of
Mice treated with tetrahydrocannabinol (THC) show sup- specic endocannabinoids to favor a time scale in accorpression of long-term potentiation in the hippocampus, a dance with its needs.
process that is essential for the formation and storage of
long-term memory.[25] These results concur with anecdotal evidence suggesting that smoking Cannabis impairs
short-term memory.[26] Consistent with this nding, mice
without the CB1 receptor show enhanced memory and 81.2.2 Appetite
long-term potentiation indicating that the endocannabinoid system may play a pivotal role in the extinction of old Evidence for the role of the endocannabinoid system in
memories. In contrast, a recent study found that the high- food-seeking behavior comes from a variety of cannabidose treatment of rats with the synthetic cannabinoid HU- noid studies. Emerging data suggests that THC acts via
210 over several weeks resulted in stimulation of neural CB1 receptors in the hypothalamic nuclei to directly ingrowth in the rats hippocampus region, a part of the lim- crease appetite.[30] It is thought that hypothalamic neubic system playing a part in the formation of declarative rons tonically produce endocannabinoids that work to
and spatial memories.[27] Taken together, these ndings tightly regulate hunger. The amount of endocannabisuggest that the eects of endocannabinoids on memory noids produced is inversely correlated with the amount of
are dependent on what type of neurons are being targeted leptin in the blood.[31] For example, mice without leptin
(excitatory vs. inhibitory) and the location of these net- not only become massively obese but express abnormally
works in the brain.
high levels of hypothalamic endocannabinoids as a comRole in hippocampal neurogenesis
In the adult brain, the endocannabinoid system facilitates
the neurogenesis of hippocampal granule cells.[27][28] In
the subgranular zone of the dentate gyrus, multipotent
neural progenitors (NP) give rise to daughter cells that,
over the course of several weeks, mature into granule
cells whose axons project to and synapse onto dendrites
on the CA3 region.[29] NPs in the hippocampus have been
shown to possess fatty acid amide hydrolase (FAAH) and
express CB1 and utilize 2-AG.[28] Intriguingly, CB1 activation by endogenous or exogenous cannabinoids promote NP proliferation and dierentiation; this activation
is absent in CB1 knockouts and abolished in the presence
of antagonist.[27][28]
pensatory mechanism.[7] Similarly, when these mice were

treated with an endocannabinoid inverse agonists, such as
rimonabant, food intake was reduced.[7] When the CB1
receptor is knocked-out in mice, these animals tend to
be leaner and less hungry than wild-type mice. A related
study examined the eect of THC on the hedonic (pleasure) value of food and found enhanced dopamine release
in the nucleus accumbens and increased pleasure-related
behavior after administration of a sucrose solution.[32]
A related study found that endocannabinoids aect taste
perception in taste cells[33] In taste cells, endocannabinoids were shown to selectively enhance the strength of
neural signaling for sweet tastes, whereas leptin decreased
the strength of this same response. While there is need
for more research, these results suggest that cannabinoid
activity in the hypothalamus and nucleus accumbens is
related to appetitive, food-seeking behavior.[30]
Induction of synaptic depression

The inhibitory eects of cannabinoid receptor stimulation on neurotransmitter release have caused this system
to be connected to various forms of depressant plasticity. A recent study conducted with the bed nucleus of
the stria terminalis found that the endurance of the depressant eects was mediated by two dierent signaling
pathways based on the type of receptor activated. 2AG was found to act on presynaptic CB1 receptors to
mediate retrograde short-term depression (STD) following activation of L-type calcium currents, while anandamide was synthesized after mGluR5 activation and
triggered autocrine signalling onto postsynapic TRPV1
receptors that induced long-term depression (LTD). Sim-
81.2.3 Energy balance & metabolism

The endocannabinoid system has been shown to have a
homeostatic role by controlling several metabolic functions, such as energy storage and nutrient transport. It
acts on peripheral tissues such as adipocytes, hepatocytes,
the gastrointestinal tract, the skeletal muscles and the endocrine pancreas. It has also been implied in modulating
insulin sensitivity. Through all of this, the endocannabinoid system may play a role in clinical conditions, such
as obesity, diabetes, and atherosclerosis, which may also
give it a cardiovascular role.[34]
81.2. FUNCTIONS OF THE ENDOCANNABINOID SYSTEM
81.2.4
Stress response
While the secretion of glucocorticoids in response to

stressful stimuli is an adaptive response necessary for
an organism to respond appropriately to a stressor, persistent secretion may be harmful. The endocannabinoid system has been implicated in the habituation of
the hypothalamic-pituitary-adrenal axis (HPA axis) to repeated exposure to restraint stress. Studies have demonstrated dierential synthesis of anandamide and 2-AG
during tonic stress. A decrease of anandamide was found
along the axis that contributed to basal hypersecretion
of corticosterone; in contrast, an increase of 2-AG was
found in the amygdala after repeated stress, which was
negatively correlated to magnitude of the corticosterone
response. All eects were abolished by the CB1 antagonist AM251, supporting the conclusion that these eects
were cannabinoid-receptor dependent.[35] These ndings
show that anandamide and 2-AG divergently regulate the
HPA axis response to stress: while habituation of the
stress-induced HPA axis via 2-AG prevents excessive secretion of glucocorticoids to non-threatening stimuli, the
increase of basal corticosterone secretion resulting from
decreased anandamide allows for a facilitated response of
the HPA axis to novel stimuli.
Exploration, social behavior, and anxiety

Prolonged, systemic exposure to cannabinoids has often been associated with anti-social eects. To investigate this theory, a cannabinoid receptor-knockout mouse
study examined the eect that these receptors play on
exploratory behavior. Researchers selectively targeted
glutamatergic and GABAergic cortical interneurons and
studied results in open eld, novel object, and sociability tests. Eliminating glutamaterigic cannabinoid receptors led to decreased object exploration, social interactions, and increased aggressive behavior. In contrast, GABAergic cannabinoid receptor-knockout mice
showed increased exploration of objects, socialization,
and open eld movement.[36] These contrasting eects
reveal the importance of the endocannabinoid system
in regulating anxiety-dependent behavior. Results suggest that glutamatergic cannabinoid receptors are not only
responsible for mediating aggression, but produce an
anxiolytic-like function by inhibiting excessive arousal:
excessive excitation produces anxiety that limited the
mice from exploring both animate and inanimate objects. In contrast, GABAergic neurons appear to control
an anxiogenic-like function by limiting inhibitory transmitter release. Taken together, these two sets of neurons
appear to help regulate the organisms overall sense of
arousal during novel situations.
115
81.2.5 Immune function

Evidence suggests that endocannabinoids may function as
both neuromodulators and immunomodulators in the immune system. Here, they seem to serve an autoprotective role to ameliorate muscle spasms, inammation, and
other symptoms of multiple sclerosis and skeletal muscle spasms.[1] Functionally, the activation of cannabinoid
receptors has been demonstrated to play a role in the
activation of GTPases in macrophages, neutrophils, and
BM cells. These receptors have also been implicated in
the proper migration of B cells into the marginal zone
(MZ) and the regulation of healthy IgM levels.[37] Interestingly, some disorders seem to trigger an upregulation
of cannabinoid receptors selectively in cells or tissues related to symptom relief and inhibition of disease progression, such as in that rodent neuropathic pain model, where
receptors are increased in the spinal cord microglia, dorsal root ganglion, and thalmic neurons.[9]
Multiple sclerosis
Historical records from ancient China and Greece suggest that preparations of Cannabis Indica were commonly
prescribed to ameliorate multiple sclerosis-like symptoms such as tremors and muscle pain. Modern research
has conrmed these eects in a study on diseased mice,
wherein both endogenous and exogenous agonists showed
ameliorating eects on tremor and spasticity. It remains
to be seen whether pharmaceutical preparations such as
dronabinol have the same eects in humans.[38][39] Due to
increasing use of medical Cannabis and rising incidence
of multiple sclerosis patients who self-medicate with the
drug, there has been much interest in exploiting the endocannabinoid system in the cerebellum to provide a legal and eective relief.[26] In mouse models of multiple
sclerosis, there is a profound reduction and reorganization
of CB1 receptors in the cerebellum.[40] Serial sections of
cerebellar tissue subjected to immunohistochemistry revealed that this aberrant expression occurred during the
relapse phase but returned to normal during the remitting
phase of the disease.[40] Other studies suggest that CB1
agonists promote the survival of oligodendrocytes in vitro
in the absence of growth and trophic factors; in addition,
these agonist have been shown to promote mRNA expression of myelin lipid protein. (Kittler et al., 2000; MollnaHolgado et al., 2002). Taken together, these studies point
to the exciting possibility that cannabinoid treatment may
not only be able to attenuate the symptoms of multiple
sclerosis but also improve oligodendrocyte function (reviewed in Pertwee, 2001; Mollna-Holgado et al., 2002).
2-AG stimulates proliferation of a microglial cell line by
a CB2 receptor dependent mechanism, and the number
of microglial cells is increased in multiple sclerosis.[41]
116
81.2.6
Female reproduction
See also: Cannabis in pregnancy

The developing embryo expresses cannabinoid receptors
early in development that are responsive to anandamide
secreted in the uterus. This signaling is important in regulating the timing of embryonic implantation and uterine receptivity. In mice, it has been shown that anandamide modulates the probability of implantation to the
uterine wall. For example, in humans, the likelihood of
miscarriage increases if uterine anandamide levels are too
high or low.[42] These results suggest that intake of exogenous cannabinoids (e.g. marijuana) can decrease the likelihood for pregnancy for women with high anandamide
levels, and alternatively, it can increase the likelihood for
pregnancy in women whose anandamide levels were too
low.[43][44]
81.2.7
Autonomic nervous system
Peripheral expression of cannabinoid receptors led researchers to investigate the role of cannabinoids in the
autonomic nervous system. Research found that the CB1
receptor is expressed presynaptically by motor neurons
that innervate visceral organs. Cannabinoid-mediated inhibition of electric potentials results in a reduction in
noradrenaline release from sympathetic nervous system
nerves. Other studies have found similar eects in endocannabinoid regulation of intestinal motility, including
the innervation of smooth muscles associated with the digestive, urinary, and reproductive systems.[10]
names Normast and PeaPure as nutraceuticals.

Endocannabinoids are involved in placebo induced analgesia responses.[46]
81.2.9 Thermoregulation
Anandamide and N-arachidonoyl dopamine (NADA)
have been shown to act on temperature-sensing TRPV1
channels, which are involved in thermoregulation.[47]
TRPV1 is activated by the exogenous ligand capsaicin,
the active component of chili peppers, which is structurally similar to endocannabinoids. NADA activates
the TRPV1 channel with an EC50 of approximately of
50 nM. The high potency makes it the putative endogenous TRPV1 agonist.[48] Anandamide has also been
found to activate TRPV1 on sensory neuron terminals,
and subsequently cause vasodilation.[10] TRPV1 may also
be activated by methanandamide and arachidonyl-2'chloroethylamide (ACEA).[1]
81.2.10 Sleep
Increased endocannabinoid signaling within the central

nervous system promotes sleep-inducing eects.
Intercerebroventricular administration of anandamide in
rats has been shown to decrease wakefulness and increase
slow-wave sleep and REM sleep.[49] Administration of
anandamide into the basal forebrain of rats has also
been shown to increase levels of adenosine, which plays
a role in promoting sleep and suppressing arousal.[50]
REM sleep deprivation in rats has been demonstrated to
increase CB1 receptor expression in the central nervous
system.[51] Furthermore, anandamide levels possess a
81.2.8 Analgesia
circadian rhythm in the rat, with levels being higher in
At the spinal cord, cannabinoids suppress noxious- the light phase of the day, which is when rats are usually
stimulus-evoked responses of neurons in the dorsal horn, asleep or less active, since they are nocturnal.[52]
possibly by modulating descending noradrenaline input
from the brainstem.[10] As many of these bers are primarily GABAergic, cannabinoid stimulation in the spinal
81.3 Experimental use of CB1 -/column results in disinhibition that should increase noradrenaline release and attenuation of noxious-stimuliphenotype
processing in the periphery and dorsal root ganglion.
The endocannabinoid most researched in pain is
palmitoylethanolamide. Palmitoylethanolamide is a fatty
amine related to anandamide, but saturated and although
initially it was thought that palmitoylethanolamide would
bind to the CB1 and the CB2 receptor, later it was found
that the most important receptors are the PPAR-alpha
receptor, the TRPV receptor and the GRP55 receptor.
Palmitoylethanolamide has been evaluated for its analgesic actions in a great variety of pain indications[45]
and found to be safe and eective. Basically these data
are proof of concept for endocannabinoids and related
fatty amines to be therapeutically useful analgesics;
palmitoylethanolamide is available under the brand
Neuroscientists often utilize transgenic CB1 knock-out

mice to discern novel roles for the endocannabinoid
system. While CB1 knock-out mice are healthy and
live into adulthood, there are signicant dierences between CB1 knock-out and wild-type mice. When subjected to a high-fat diet, CB1 knockout mice tend to
be about sixty percent leaner and slightly less hungry
than wildtype.[53] Compared to wildtype, CB1 knockout mice exhibit severe decits in motor learning, memory retrieval, and increased diculty in completing the
Morris water maze.[5][54][55] There is also evidence indicating that these knockout animals have an increased incidence and severity of stroke and seizure.[56][57]
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[48] Huang SM, Bisogno T, Trevisani M, et al. (June

2002). An endogenous capsaicin-like substance with
high potency at recombinant and native vanilloid VR1
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Neumeister A, Normandin MD, Pietrzak RH, et

al. (2013). Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder:
A positron emission tomography study. Molecular Psychiatry. doi:10.1038/mp.2013.61. Lay summary ScienceDaily (May 14, 2013).
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Martnez-Gonzlez D, Drucker-Coln R, Prospro-Garca
O (November 1998). Anandamide modulates sleep
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doi:10.1016/S0006-8993(98)00969-X. PMID 9813364.
Fldy C, Malenka RC, Sdhof TC (May

2013).
Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling.
Neuron 78 (3): 498509.
doi:10.1016/j.neuron.2013.02.036.
PMC
3663050. PMID 23583622. Lay summary
ScienceDaily (April 11, 2013).
[50] Santucci V, Storme JJ, Soubri P, Le Fur G (1996).

Arousal-enhancing properties of the CB1 cannabinoid
receptor antagonist SR 141716A in rats as assessed by
electroencephalographic spectral and sleep-waking cycle
analysis. Life Sci. 58 (6): PL10310. doi:10.1016/00243205(95)02319-4. PMID 8569415.
[51] Wang L, Yang T, Qian W, Hou X (January 2011). The
role of endocannabinoids in visceral hyposensitivity induced by rapid eye movement sleep deprivation in rats:
regional dierences. Int. J. Mol. Med. 27 (1): 11926.
doi:10.3892/ijmm.2010.547. PMID 21057766.
[52] Murillo-Rodriguez E, Dsarnaud F, Prospro-Garca
O (May 2006).
Diurnal variation of arachidonoylethanolamine,
palmitoylethanolamide
and
oleoylethanolamide in the brain of the rat. Life Sci.
79 (1): 307. doi:10.1016/j.lfs.2005.12.028. PMID
16434061.
[53] Ravinet Trillou C, Delgorge C, Menet C, Arnone M,
Soubri P (2004). CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced
obesity and enhanced leptin sensitivity.
Int.
J.
Obes. Relat. Metab. Disord. 28 (4): 6408.
doi:10.1038/sj.ijo.0802583. PMID 14770190.
[54] Varvel SA, Lichtman AH (2002). Evaluation of CB1
receptor knockout mice in the Morris water maze.
J. Pharmacol.
Exp.
Ther.
301 (3): 91524.
doi:10.1124/jpet.301.3.915. PMID 12023519.
Puighermanal E, Marsicano G, Busquets-Garcia

A, Lutz B, Maldonado R, Ozaita A (September
2009). Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling. Nat. Neurosci. 12 (9): 11528.
doi:10.1038/nn.2369. PMID 19648913. Lay summary ScienceDaily (August 4, 2009).
Niehaus JL, Liu Y, Wallis KT, et al. (December
2007). CB1 cannabinoid receptor activity is modulated by the cannabinoid receptor interacting protein CRIP 1a. Mol. Pharmacol. 72 (6): 1557
66. doi:10.1124/mol.107.039263. PMC 2644445.
PMID 17895407. Lay summary ScienceDaily
(November 30, 2007).
81.6 External links

Homepage of the ICRS - The International Cannabinoid Research Society
Homepage of the ECSN - The Endocannabinoid
System Network
Chapter 82
Most neurotransmitters are water-soluble and require
transmembrane proteins to transport them across the
cell membrane. The endocannabinoids (anandamide,
AEA, and 2-arachidonoylglycerol, 2-AG) on the other
hand, are non-charged lipids that readily cross lipid
membranes.[1][2][3][4][5] However, since the endocannabinoids are water immiscible, protein transporters have
been described that act as carriers to solubilize and
transport the endocannabinoids through the aqueous
cytoplasm. These include the heat shock proteins
(Hsp70s) and fatty acid binding proteins for anandamide
(FABPs).[6][7] FABP inhibitors attenuate the breakdown
of anandamide by the enzyme fatty acid amide hydrolase (FAAH) in cell culture.[6] One of these inhibitors
(SB-FI-26), isolated from a virtual library of a million
compounds, belongs to a class of compounds (named
the truxilloids) that act as a anti-nociceptive agent
with mild anti-inammatory activity in mice.[8] These
truxillic acids and their derivatives have been known to
have anti-inammatory and anti-nociceptive eects in
mice[9] and are active components of a Chinese herbal
medicine ((-)-Incarvillateine Incarvillea sinensis) used to
treat rheumatism and pain in human. The blockade of
anandamide transport may, at least in part, be the mechanism through which these compounds exert their antinociceptive eects.
82.1 References
[1] Kaczocha, Martin; Lin, Qingqing; Nelson, Lindsay D.;
McKinney, Michelle K.; Cravatt, Benjamin F.; London,
Erwin; Deutsch, Deutsch (2012). Anandamide Externally Added to Lipid Vesicles Containing-Trapped Fatty
Acid Amide Hydrolase (FAAH) Is Readily Hydrolyzed
in a Sterol-Modulated Fashion. ACS Chemical Neuroscience 3 (5): 364368. doi:10.1021/cn300001w. PMID
22860204.
[2] Bojesen, Inge N.; Hansen, Harald S. (2005). Membrane
transport of anandamide through resealed human red
blood cell membranes. The Journal of Lipid Research.
46 no. (8): 16521659. doi:10.1194/jlr.M400498JLR200.
[3] Kaczocha, Martin; Hermann, Anita; Glaser, Sherrye T.;
Bojesen, Inge N.; Deutsch, Dale G. (2006). Anandamide
120
Uptake Is Consistent with Rate-limited Diusion and Is

Regulated by the Degree of Its Hydrolysis by Fatty Acid
Amide Hydrolase. The Journal of Biological Chemistry
281 (14): 90669075. doi:10.1074/jbc.M509721200.
PMID 16461355.
[4] Sandberg, A.; Fowler, C.J. (2005). Measurement
of saturable and non-saturable components of anandamide uptake into P19 embryonic carcinoma cells
in the presence of fatty acid-free bovine serum albumin.. Chemistry and Physics of Lipids 134 (2): 131
139. doi:10.1016/j.chemphyslip.2004.12.010. PMID
15784231.
[5] Di Pasquale, E.; Chahinian, H.; Sanchez, P.; Fantini, J.
(2009). The Insertion and Transport of Anandamide
in Synthetic Lipid Membranes Are Both CholesterolDependent [Translated title]. PLoS ONE 4 (3): e4989.
doi:10.1371/journal.pone.0004989. PMID 19330032.
[6] Kaczocha, M.; Glaser, S.T.; Deutsch, D.G. (2009).
Identication of intracellular carriers for the endocannabinoid anandamide. Proceedings of the National
(15): 63756380. doi:10.1073/pnas.0901515106. PMC
2669397. PMID 19307565.
[7] Oddi, S.; Fezza, F.; Pasquariello, N.; D'Agostino, A.;
Catanzaro, G.; De Simone, C.; Rapino, C.; FinazziAgro, A.; Maccarrone, M. (2009). Molecular identication of albumin and Hsp70 as cytosolic anandamidebinding proteins. Chemistry & Biology 16 (6): 624632.
doi:10.1016/j.chembiol.2009.05.004. PMID 19481477.
[8] Berger, W.T.; Ralph, B.P.; Kaczocha, M.; Sun, J.; Balius, T.E.; Rizzo, R.C.; Haj-Dahmane, S.; Ojima, I.;
Deutsch, D.G. (2012). Targeting Fatty Acid Binding
Protein (FABP) Anandamide Transporters A Novel
Strategy for Development of Anti-Inammatory and
Anti-Nociceptive Drugs. PLoS ONE 12 (7): e50968.
[9] Nakamura, M.; Chi, Y.M.; Yan, W.M.; Nakasugi, Y.;
Yoshizawa, T.; Irino, N.; Hashimoto, F.; Kinjo, J.; Nahara, T.; Sakurada, S. (1999). Strong antinociceptive effect of incarvillateine, a novel monoterpene alkaloid from
Incarvillea sinensis. Journal of Natural Products 62 (9):
12931294. doi:10.1021/np990041c. PMID 10514316.
Chapter 83
GW-405,833
GW-405,833 (L-768,242) is a drug that acts as a potent
and selective partial agonist for the cannabinoid receptor subtype CB2 , with an EC50 of 0.65nM and selectivity
of around 1200x for CB2 over CB1 receptors.[1][2] Animal studies have shown it to possess antiinammatory and
anti-hyperalgesic eects at low doses, followed by ataxia
and analgesic eects when the dose is increased.[3][4] Selective CB2 agonist drugs such as GW-405,833 are hoped
to be particularly useful in the treatment of allodynia and
neuropathic pain for which current treatment options are
often inadequate.[5][6]
83.1 References
[1] Human JW. The search for selective ligands for the
CB2 receptor. Current Pharmaceutical Design. 2000
Sep;6(13):1323-37.
doi:10.2174/1381612003399347
PMID 10903395
[2] Marriott KS, Human JW. Recent advances in the
development of selective ligands for the cannabinoid
CB(2) receptor. Current Topics in Medicinal Chemistry.
2008;8(3):187-204. doi:10.2174/156802608783498014
PMID 18289088
[3] Clayton N, Marshall FH, Bountra C, O'Shaughnessy CT.
CB1 and CB2 cannabinoid receptors are implicated in inammatory pain. Pain. 2002 Apr;96(3):253-60. PMID
11972997
[4] Valenzano KJ, Tafesse L, Lee G, Harrison JE, Boulet JM,
Gottshall SL, Mark L, Pearson MS, Miller W, Shan S,
Rabadi L, Rotshteyn Y, Chaer SM, Turchin PI, Elsemore DA, Toth M, Koetzner L, Whiteside GT. Pharmacological and pharmacokinetic characterization of the
cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and
catalepsy. Neuropharmacology. 2005 Apr;48(5):658-72.
PMID 15814101
[5] Beltramo M, Bernardini N, Bertorelli R, Campanella M,
Nicolussi E, Fredduzzi S, Reggiani A. CB2 receptormediated antihyperalgesia: possible direct involvement
of neural mechanisms. European Journal of Neuroscience. 2006 Mar;23(6):1530-8. doi:10.1111/j.14609568.2006.04684.x PMID 16553616
121
[6] Leichsenring A, Andriske M, Bcker I, Stichel CC,

Lbbert H. Analgesic and antiinammatory eects of
cannabinoid receptor agonists in a rat model of neuropathic pain. Naunyn Schmiedebergs Archives of Pharmacology. 2009 Jan 18. PMID 19152053
Chapter 84
GW-842,166X
GW-842,166X is a drug which acts as a potent and selective cannabinoid CB2 receptor agonist, with a novel
chemical structure based on a pyrimidine core. It has
potent analgesic, anti-inammatory and anti-hyperalgesic
actions in animal models, but without cannabis-like behavioural eects due to its extremely low anity for the
CB1 receptor.[1][2][3]
84.1 References
[1] Giblin GM, O'Shaughnessy CT, Naylor A, Mitchell WL,
Eatherton AJ, Slingsby BP, Rawlings DA, Goldsmith P,
Brown AJ, Haslam CP, Clayton NM, Wilson AW, Chessell IP, Wittington AR, Green R (May 2007). Discovery
of
2-[(2,4-dichlorophenyl)amino]-N-[(tetrahydro2H-pyran-4-yl)methyl]4-(triuoromethyl)5pyrimidinecarboxamide, a selective CB2 receptor
agonist for the treatment of inammatory pain.
doi:10.1021/jm061195+. PMID 17477516.
[2] Giblin GM, Billinton A, Briggs M, Brown AJ, Chessell IP, Clayton NM, Eatherton AJ, Goldsmith P,
Haslam C, Johnson MR, Mitchell WL, Naylor
A, Perboni A, Slingsby BP, Wilson AW (October
2009). Discovery of 1-[4-(3-chlorophenylamino)1methyl-1H-pyrrolo[3,2-c]pyridin-7-yl]1-morpholin4-ylmethanone (GSK554418A), a brain penetrant
5-azaindole CB2 agonist for the treatment of chronic
pain. Journal of Medicinal Chemistry 52 (19): 57858.
doi:10.1021/jm9009857. PMID 19743867.
[3] Han, S.; Thatte, J.; Jones, R. M. (2009). Chapter 11:
Recent Advances in the Discovery of CB2 Selective Agonists. Annual Reports in Medicinal Chemistry 44: 227.
doi:10.1016/S0065-7743(09)04411-X.
122
Chapter 85
Hemopressin
Hemopressin (Hp) is an alpha hemoglobin fragment with
the sequence PVNFKFLSH, originally identied in extracts of rat brain using an enzyme capture technique.[1]
It binds cannabinoid receptors, acting as an inverse agonist at CB1 receptors.[2] Longer forms of hemopressin
containing 2-3 additional amino acids on the N-terminus
have been identied in extracts of mouse brain. These
longer hemopressin peptides, named RVD-Hp and VDHp, bind to CB1 receptors and are agonists.[3] In addition to the Hp peptides from alpha hemoglobin, a related
peptide from beta hemoglobin has been found in mouse
brain extracts; this peptide, named VD-Hp, is also an
agonist at CB1 cannabinoid receptors.[3]
85.3 References
The original Hp peptide reduces sensitivity to painful

stimuli in an experimental model of hyperalgesia.[4] Hp
also reduces food intake in mice.[5] However, it remains
to be shown if Hp is an endogenous brain peptide. The
original purication used boiling acid to extract the peptide from rat brain, and hot acid can specically cleave
D-P bonds. The N-terminally-extended forms RVDHp and VD-Hp may represent the true endogenous
forms.[6]
[1] Rioli V, Gozzo FC, Heimann AS, et al. (March

2003). Novel natural peptide substrates for endopeptidase 24.15, neurolysin, and angiotensin-converting enzyme.
J. Biol.
Chem.
278 (10): 854755.
doi:10.1074/jbc.M212030200. PMID 12500972.
[2] Heimann AS, Gomes I, Dale CS, et al. (December 2007).
Hemopressin is an inverse agonist of CB1 cannabinoid receptors. Proc. Natl. Acad. Sci. U.S.A.
104 (51): 2058893. Bibcode:2007PNAS..10420588H.
doi:10.1073/pnas.0706980105. PMC 2154475. PMID
18077343.
[3] Gomes I, Grushko JS, Golebiewska U, et al. (September 2009). Novel endogenous peptide agonists of
cannabinoid receptors. FASEB J. 23 (9): 3020
9. doi:10.1096/fj.09-132142. PMC 2735371. PMID
19380512.
[4] Dale CS, Pagano Rde L, Rioli V, et al. (March
2005). Antinociceptive action of hemopressin in experimental hyperalgesia. Peptides 26 (3): 4316.
doi:10.1016/j.peptides.2004.10.026. PMID 15652650.
[5] Dodd GT, Mancini G, Lutz B, et al. (May 2010). The
peptide hemopressin acts through CB1 cannabinoid receptors to reduce food intake in rats and mice. J Neurosci.
30 (21): 736976. doi:10.1523/JNEUROSCI.545509.2010. PMID 20505104.
85.1 Role in diet

Scientists at the University of Manchester have discovered that hemopressin could be used as an appetite suppressant without having the side eects of many other
drugs that are used for this purpose. In laboratory tests
hemopressin was administrated to mice and rats, which
signicantly reduced food intake. Hemopressin works by
aecting the reward centres of the brain which make us
feel happy when we eat too much. A further research
should be carried out in order to conrm these eects
and the safety on people.[7]
85.2 See also

RVD-Hp
123
[6] Gelman JS, Sironi J, Castro LM, et al. (May 2010).

Hemopressins and other hemoglobin-derived peptides
in mouse brain: comparison between brain, blood, and
heart peptidome and regulation in Cpefat/fat mice. J
Neurochem. 113 (4): 87180. doi:10.1111/j.14714159.2010.06653.x. PMC 2867603. PMID 20202081.
[7] http://uk.health.lifestyle.yahoo.net/
hemopressin-naturally-supresses-appetite.htm
Chapter 86
HU-210
HU-210 is a synthetic cannabinoid that was rst
synthesized in 1988 from (1R,5S)-myrtenol[3] by a group
led by Professor Raphael Mechoulam at the Hebrew University.[4][5][6] HU-210 is 100 to 800 times more potent
than natural THC from cannabis and has an extended duration of action.[7] HU-210 is the ()1,1-dimethylheptyl
analog of 11-hydroxy- 8 - tetrahydrocannabinol; in
some references it is called 1,1-dimethylheptyl- 11hydroxytetrahydrocannabinol. The abbreviation HU
stands for Hebrew University.
86.2 Legal status

HU-210 is a schedule I controlled substance under the
Controlled Substances Act. [14]
To view national schedule, see: List of Schedule I drugs
(US),
The (+) enantiomer of HU-210 has almost all of the

cannabinoid activity, with the () enantiomer HU-211 86.2.2 New Zealand
being inactive as a cannabinoid but instead acting as an
Banned in New Zealand as of 8 May 2014.
NMDA antagonist having neuroprotective eects.[8][9]
HU-210 promotes proliferation, but not dierentiation,
of cultured embryonic hippocampal neural stem and
progenitor cells likely via a sequential activation of CB1
receptors, G/ proteins, and ERK signaling. It was
also indicated by this increased neural growth to entail
antianxiety and antidepressant eects.[10]
86.3 Other HU Cannabinoids

HU-211
HU-210, alongside other synthetic cannabinoids like

WIN 55,212-2 and JWH-133, is implicated in preventing the inammation caused by amyloid beta proteins
involved in Alzheimers disease, in addition to preventing cognitive impairment and loss of neuronal markers. This anti-inammatory action is induced through
the activation of cannabinoid receptors, which prevents
microglial activation that elicits the inammation. In addition, cannabinoids completely abolish neurotoxicity related to microglia activation in rat models.[11]
HU-239
HU-210 is a potent analgesic with many of the same effects as natural THC.
HU-336
HU-243
HU-308
HU-320
HU-331
HU-345
86.1 Recreational use
[15]
86.4 See also
According to the U.S. Customs and Border Protection,

HU-210 was discovered in Spice Gold incense products seized at the US border in January 2009. Over
100 pounds of Spice products were seized based on
this nding.[12] HU-210 was also detected in three Spice
products in the UK, as reported in June 2009.[13]
124
Spice (drug)
CP 47,497
JWH-018
86.5 References
[1] http://www.deadiversion.usdoj.gov/drugs_concern/
spice/spice_hu210.htm
[2] http://www.deadiversion.usdoj.gov/schedules/
orangebook/c_cs_alpha.pdf
[3] Mechoulam, R., Lander, N., Breuer, A., Zahalka,
J. Synthesis of the Individual, Pharmacologically Distinct, Enantiomers of a Tetrahydrocannabinol Derivative.
Tetrahedron: Asymmetry. 1990. Vol 1, No 5. pp 315318.
[4] Mechoulam, R., et al. (1988). Enantiomeric cannabinoids: stereospecicity of psychotropic activity. Experientia 44 (9): 762764. doi:10.1007/BF01959156. PMID
3416993.
[5] Little PJ, Compton DR, Mechoulam R, Martin BR. Stereochemical eects of 11-OH-8-THC-dimethylheptyl in
mice and dogs. Pharmacology, Biochemistry, and Behavior. 1989 Mar;32(3):661-666.
[6] Jrbe, T.; Hiltunen, A.; Mechoulam, R. (1989). Stereospecicity of the discriminative stimulus functions of
the dimethylheptyl homologs of 11-hydroxy-delta 8tetrahydrocannabinol in rats and pigeons. The Journal
of Pharmacology and Experimental Therapeutics 250 (3):
10001005. PMID 2550611.
[7] Devane, W. A., et al. (1992). A novel probe for the
cannabinoid receptor. Journal of Medical Chemistry 35
(11): 20652069. doi:10.1021/jm00089a018. PMID
1317925.
[8] Howlett, A.; Champion, T.; Wilken, G.; Mechoulam,
R. (1990).
Stereochemical eects of 11-OH-8tetrahydrocannabinol-dimethylheptyl to inhibit adenylate cyclase and bind to the cannabinoid receptor.
Neuropharmacology 29 (2): 161. doi:10.1016/00283908(90)90056-W. PMID 2158635.
[9] Darlington CL (October 2003). Dexanabinol: a novel
cannabinoid with neuroprotective properties. IDrugs :
the Investigational Drugs Journal 6 (10): 9769. PMID
14534855.
[10] Jiang, W., et al. (2005). Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like eects. The
Journal of Clinical Investigation 115 (11): 3104
3116. doi:10.1172/JCI25509. PMC 1253627. PMID
16224541.
[11] Ramrez Bg, E. A. ; Blzquez, C.; Gmez Del Pulgar,
T.; Guzmn, M.; De Ceballos, M. L. (2005). Prevention of Alzheimers disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. Journal of Neuroscience 25 (8):
19041913. doi:10.1523/JNEUROSCI.4540-04.2005.
PMID 15728830.
[12] Lab Results Conrm CBP in Ohio Discover Synthetic
Narcotics in Incense Packets - CBP.gov.
125
[13] EMCDDA Action on new drugs brieng paper: Understanding the Spice phenomenon.
[14] Spice Cannabinoid - HU-210.
[15] https://www.drugfoundation.org.nz/
synthetic-cannabinoids/what-they-are
86.6 External links

Comment in Nature on the article about neurogenesis.
Chapter 87
HU-243
HU-243 (AM-4056) is a synthetic cannabinoid drug that
is a single enantiomer of the hydrogenated derivative of
the commonly used reference agonist HU-210. It is a potent agonist at both the CB1 and CB2 receptors, with a
binding anity of 0.041nM at the CB1 receptor, making it marginally more potent than HU-210, which had
an anity of 0.061nM in the same assay.[1]
87.1 See also

AM-2389
Nabidrox
Nabilone
87.2 References
[1] Stern, E.; Lambert, D. M. (2007).
Medicinal
Chemistry Endeavors around the Phytocannabinoids. Chemistry & Biodiversity 4 (8): 17071728.
doi:10.1002/cbdv.200790149. PMID 17712816.
126
Chapter 88
HU-308
HU-308 is a drug that acts as a cannabinoid agonist. It
is highly selective for the CB2 receptor subtype, with
a selectivity of over 5000x for CB2 vs CB1 .[1] The
synthesis and characterization took place in the laboratory of Prof. Mechoulam at the Hebrew University of
Jerusalem in the late 1990s. It has analgesic eects,[2]
promotes proliferation of neural stem cells,[3] and protects both liver and blood vessel tissues against oxidative
stress via inhibition of TNF-.[4][5]
88.1 See also

HU-210
HU-320
88.2 References
[1] Hanus, L., et al. (1999). HU-308: a specic
agonist for CB(2), a peripheral cannabinoid receptor.
Proceedings of the National Academy of
Sciences of the United States of America 96 (25):
1422814233.
Bibcode:1999PNAS...9614228H.
doi:10.1073/pnas.96.25.14228. PMC 24419. PMID
10588688.
[2] Labuda, C.; Koblish, M.; Little, P. (2005). Cannabinoid CB2 receptor agonist activity in the hindpaw
incision model of postoperative pain.
European
Journal of Pharmacology 527 (13):
172174.
doi:10.1016/j.ejphar.2005.10.020. PMID 16316653.
[3] Palazuelos, J., et al. (2006). Non-psychoactive CB2
cannabinoid agonists stimulate neural progenitor proliferation. The FASEB journal : ocial publication of the
Federation of American Societies for Experimental Biology
20 (13): 24052407. doi:10.1096/fj.06-6164fje. PMID
17015409.
[4] Rajesh, M.; Pan, H.; Mukhopadhyay, P.; Batkai, S.; OseiHyiaman, D.; Hasko, G.; Liaudet, L.; Gao, B.; Pacher, P.
(2007). Pivotal Advance: Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion
injury by attenuating oxidative stress, inammatory response, and apoptosis. Journal of leukocyte biology
82 (6): 13821389. doi:10.1189/jlb.0307180. PMC
2225476. PMID 17652447.
127
[5] Rajesh, M., et al. (2007). CB2-receptor stimulation attenuates TNF--induced human endothelial cell
activation, transendothelial migration of monocytes, and
monocyte-endothelial adhesion. American journal of
physiology. Heart and circulatory physiology 293 (4):
H2210H2218. doi:10.1152/ajpheart.00688.2007. PMC
2229632. PMID 17660390.
Chapter 89
HU-331
HU-331 is a quinone anticarcinogenic drug synthesized
from cannabidiol, a cannabinoid in the Cannabis sativa
plant. It showed a great ecacy against oncogenic human cells. HU-331 does not cause arrest in cell cycle, cell apoptosis or caspase activation. HU-331 inhibits DNA topoisomerase II even at nanomolar concentrations, but has shown a negligible eect on the action
of DNA topoisomerase I. The cannabinoid quinone HU331 is a very specic inhibitor of topoisomerase II, compared with most known anticancer quinones.[1] One of
the main objectives of these studies is the development
of a new quinone derived compound that produces antineoplastic activity while maintaining low toxicity at therapeutic doses.
89.1 Mechanism of action

Inhibitors of topoisomerases can act at two dierent levels. First inhibiting topoisomerase, which stabilize the
topoisomerase-DNA complex and thus introduce DNA
breaks in the wires that lead to apoptosis, then inhibiting the catalytic activity of topoisomerase, which hinders
the activity of these enzymes without introducing breaks
into the DNA chains. HU-331 seems to be a catalytic
inhibitor of topoisomerase II, probably by enzymatic ligation to the protein. This molecule does not cause damage
to DNA, but protects cells from damage, natural, or induced by other inhibitors of topoisomerase II that act as
inhibitors of topoisomerase. Even when 60% of the target cells are killed by treatment with HU-331, other cells
nucleic content remains unharmed, with less breakage of
DNA chains that control important cellular functions.[2]
Doxorubicin, like other anticancer quinones, was used for
chemotherapy in human cancers for many years. The
mechanism of action of these drugs has been the subject of considerable controversy since chemotherapeutic
drugs exert their cytotoxic eect on target cells by nonspecic mechanisms. The doxorubicin damages DNA by
intercalation, the generation of reactive oxygen species
and inhibition of DNA topoisomerase I and II. This
leads to breaking the chains of DNA single and double strands. The protein associated with these ruptures
are the topoisomerase II and DNA damage is catalyzed
by this enzyme.[2] Thus, while doxorubicin and other

anthraquinones act through many mechanisms such as
apoptosis, abrogation of the cell cycle cell, activation of
caspases, generation of ROS, inhibition of both topoisomerases, activation of intracellular secondary messengers, etc. Hu-331 is more active and less toxic, since it
generates reactive oxygen species in the heart and has a
specic activity that gives great potential to develop as a
new anticancer drug, according to Kogan et al.[2]
Cannabinoids can act as anticancer compounds killing
several oncogenic cells followed by direct interaction with
cannabinoid receptors. The growth of glioma is inhibited
by a selective activation of the CB2 cannabinoid receptor
and endogenous cannabinoids such as anandamide inhibit
the proliferation of cells involved in lung cancer. The
reason behind the antitumor eect of HU-331 appears
unknown as cannabinoid receptor antagonists do not inhibit HU-331, despite being mediated by a cannabinoid
receptor. The HU-331 exerts an antiangiogenic eect accompanied by apoptosis of endothelial cells. Although in
some studies. HU-331 has not caused the death of cells
by oncogenic apoptosis. The conclusion that would lead
cells to apoptosis based on treatment with the drug did not
increase the proportion of cells containing DNA Lues in
the sub-G1 phase and have not found the expression of
caspase-3 in cancer cells.[2]
89.2 See also

HU-210
HU-320
HU-336
89.3 References
128
[1] Kogan N.M. et al. (2007). HU-331, a novel cannabinoidbased anticancer topoisomerase II inhibitor. Mol. Cancer Ther. 6 (1): 173183. doi:10.1158/1535-7163.MCT06-0039. PMID 17237277.
[2] Kogan N.M. et al. (2007). A Cannabinoid Anticancer Quinone, HU-331, Is More Potent and Less Car-
89.3. REFERENCES
diotoxic Than Doxorubicin: A Comparative in Vivo

Study. J. Pharmacol. Exp. Ther. 322 (2): 646653.
doi:10.1124/jpet.107.120865. PMID 17478614.
129
Chapter 90
11-Hydroxy-THC
11-Hydroxy-9 -tetrahydrocannabinol, abbreviated
as 11-OH-THC, is the main active metabolite of
THC which is formed in the body after cannabis
consumption.[1] 11-Hydroxy-THC has been shown to
be active in its own right,[2] but the eects produced
are not necessarily identical to those of THC.[3] This
might partially explain the biphasic eects of cannabis,
whereby some eects such as increased appetite tend to
be delayed rather than occurring immediately when the
drug is consumed.[4]
11-Hydroxy-THC is subsequently metabolised further
to 11-nor-9-carboxy-THC, which is not psychoactive
but might still play a role in the analgesic and antiinammatory eects of cannabis.
90.1 References
[1] Johnson JR, Jennison TA, Peat MA, Foltz RL (1984).
Stability of delta 9-tetrahydrocannabinol (THC), 11hydroxy-THC, and 11-nor-9-carboxy-THC in blood and
plasma. Journal of analytical toxicology 8 (5): 2024.
doi:10.1093/jat/8.5.202. PMID 6094914.
[2] Turkanis SA, Karler R (1988). Changes in neurotransmitter release at a neuromuscular junction of the lobster caused by cannabinoids. Neuropharmacology 27 (7):
73742. doi:10.1016/0028-3908(88)90083-4. PMID
2901683.
[3] Hollister LE, Gillespie HK (1975). Action of delta-9tetrahydrocannabinol. An approach to the active metabolite hypothesis. Clin. Pharmacol. Ther. 18 (6): 7149.
PMID 1204277.
[4] Lemberger, L; Martz, R; Rodda, B; Forney, R;
Rowe, H (1973). Comparative Pharmacology of 9Tetrahydrocannabinol and its Metabolite, 11-OH-9Tetrahydrocannabinol. The Journal of Clinical Investigation 52 (10): 24117. doi:10.1172/JCI107431. PMC
302499. PMID 4729039.
130
Chapter 91
9-nor-9-Hydroxyhexahydrocannabinol
9-nor9-Hydroxyhexahydrocannabinol (HHC), is a
synthetic cannabinoid derivative which resulted from
early modications to the structure of THC, in a search
for the simplest compound that could still full the binding requirements to produce cannabis-like activity.[1][2]
HHC is active in its own right with similar potency to
THC, but further simplication and variation of this parent structure lead to more potent, yet structurally simpler derivatives such as CP 47,497 and CP 55,940,[3][4][5]
which after several steps of modication have become
quite structurally distinct from THC, while HHC on the
other hand is still substantially similar in structure to
THC.
The discovery of this simplied class of cannabinoid
derivatives was highly signicant in terms of the
widespread use of CP 55,940 for early scientic research
into the cannabinoid receptors,[6] as well as later work using more complex compounds such as CP 55,244 to map
the CB1 binding site in more detail, but aside from these
specic applications, these compounds attracted little attention and no compounds from this series were developed for medical use despite favourable safety proles in
animal studies. Unexpectedly, some 25 years later, these
compounds came back into prominence when an obscure
derivative (C8)-CP 47,497 was found to have been sold
as the active ingredient in the herbal cannabis substitute
product Spice,[7] which ironically has led to a resurgence
of interest into laboratory-conducted scientic research
of this family of drugs.
91.1 See also

AM-2389
HU-243
91.2 References
[1] Johnson MR, et al. Potent Analgetics Derived From 9Nor-9-Hydroxyhexahydrocannabinol. NIDA Research
Monograph 34; 1980. pp 68-74.
131
[2] Melvin LS, Johnson MR. Structure-Activity Relationships of Tricyclic and Nonclassical Bicyclic Cannabinoids. NIDA Research Monograph 79; 1987. pp 31-47.
[3] Weissman, A; Milne, GM; Melvin Jr, LS (1982).
Cannabimimetic activity from CP-47,497, a derivative
of 3-phenylcyclohexanol. The Journal of Pharmacology
and Experimental Therapeutics 223 (2): 51623. PMID
6290642.
[4] Melvin, LS, et al. (1984). A cannabinoid derived prototypical analgesic. Journal of Medical Chemistry 27 (1):
6771. doi:10.1021/jm00367a013. PMID 6690685.
[5] Compton, DR; Johnson, MR; Melvin, LS; Martin, BR
(1992). Pharmacological prole of a series of bicyclic
cannabinoid analogs: classication as cannabimimetic
agents. The Journal of Pharmacology and Experimental
Therapeutics 260 (1): 2019. PMID 1309872.
[6] Devane, WA, et al. (1988). Determination and characterization of a cannabinoid receptor in rat brain. Molecular Pharmacology 34 (5): 60513. PMID 2848184.
[7] Auwrter, V, et al. (2009). "'Spice' and other herbal
doi:10.1002/jms.1558. PMID 19189348.
Chapter 92
Ibipinabant
Ibipinabant (SLV319, BMS-646,256) is a drug used
in scientic research which acts as a potent and highly
selective CB1 antagonist.[1] It has potent anorectic effects in animals,[2] and was researched for the treatment
of obesity, although CB1 antagonists as a class have
now fallen out of favour as potential anorectics following the problems seen with rimonabant, and so ibipinabant is now only used for laboratory research, especially structure-activity relationship studies into novel
CB1 antagonists.[3][4][5]
92.1 See also

92.2 References
[1] Lange, JH; Coolen, HK; Van Stuivenberg, HH; Dijksman,
JA; Herremans, AH; Ronken, E; Keizer, HG; Tipker, K et
al. (2004). Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines
as potent and selective CB(1) cannabinoid receptor antagonists. Journal of Medical Chemistry 47 (3): 62743.
doi:10.1021/jm031019q. PMID 14736243.
[2] Need, AB; Davis, RJ; Alexander-Chacko, JT; Eastwood,
B; Chernet, E; Phebus, LA; Sindelar, DK; Nomikos, GG
(2006). The relationship of in vivo central CB1 receptor
occupancy to changes in cortical monoamine release and
feeding elicited by CB1 receptor antagonists in rats. Psychopharmacology 184 (1): 2635. doi:10.1007/s00213005-0234-x. PMID 16328376.
[3] Lange, JH; Van Stuivenberg, HH; Veerman, W; Wals,
HC; Stork, B; Coolen, HK; McCreary, AC; Adolfs, TJ;
Kruse, CG (2005). Novel 3,4-diarylpyrazolines as potent cannabinoid CB1 receptor antagonists with lower
lipophilicity. Bioorganic & Medicinal Chemistry Letters 15 (21): 47948. doi:10.1016/j.bmcl.2005.07.054.
PMID 16140010.
[4] Srivastava, BK; Joharapurkar, A; Raval, S; Patel, JZ; Soni,
R; Raval, P; Gite, A; Goswami, A et al. (2007). Diaryl dihydropyrazole-3-carboxamides with signicant in
vivo antiobesity activity related to CB1 receptor antagonism: synthesis, biological evaluation, and molecular
132
modeling in the homology model. Journal of Medical

Chemistry 50 (24): 595166. doi:10.1021/jm061490u.
PMID 17979261.
[5] Srivastava, BK; Soni, R; Joharapurkar, A; Sairam,
KV; Patel, JZ; Goswami, A; Shedage, SA; Kar, SS et
al. (2008). Bioisosteric replacement of dihydropyrazole of 4S-(-)3-(4-chlorophenyl)-N-methyl-N'(4-chlorophenyl)-sulfonyl-4-phenyl-4,5-dihydro-1Hpyrazole-1-caboxamidine (SLV-319) a potent CB1
receptor antagonist by imidazole and oxazole. Bioorganic & Medicinal Chemistry Letters 18 (3): 9638.
doi:10.1016/j.bmcl.2007.12.036. PMID 18207393.
Chapter 93
IDFP
IDFP is an organophosphorus compound related to the
nerve agent sarin. Like sarin, IDFP is an irreversible
inhibitor for a number of dierent enzymes that normally
serve to break down neurotransmitters, however the long
alkyl chain of IDFP makes it dramatically weaker as an
inhibitor of acetylcholinesterase (AChE), with an IC50
of only 6300nM, while it is a potent inhibitor of two
enzymes monoacylglycerol lipase (MAGL), the primary
enzyme responsible for degrading the endocannabinoid
2-arachidonoylglycerol (2-AG), and fatty acid amide hydrolase (FAAH), the primary enzyme that degrades the
other main endocannabinoid anandamide. The IC50 of
IDFP is 0.8nM at MAGL, and 3.0nM at FAAH. Inhibition of these two enzymes causes markedly increased levels of both anandamide and 2-AG in the brain, resulting
in increased cannabinoid signalling and typical cannabinoid behavioral eects in animal studies, while its lack of
potency at AChE means that no cholinergic symptoms are
produced.[1][2][3][4] Despite its similar chemical structure
to the banned nerve agents, the long alkyl chain of IDFP
causes it to fall outside the denition of toxic chemicals
under the Chemical Weapons Convention,[5] and since it
also does not exhibit the potent AChE inhibition of related organophosphorus compounds, IDFP is not subject
to the same stringent legal controls.
93.1 See also

Methoxy arachidonyl uorophosphonate
4-Nonylphenylboronic acid
93.2 References
[1] Nomura, D. K.; Blankman, J. L.; Simon, G. M.; Fujioka,
K.; Issa, R. S.; Ward, A. M.; Cravatt, B. F.; Casida, J.
E. (2008). Activation of the endocannabinoid system by
organophosphorus nerve agents. Nature Chemical Biology 4 (6): 373378. doi:10.1038/nchembio.86. PMC
2597283. PMID 18438404.
[2] Casida, J. E.; Nomura, D. K.; Vose, S. C.; Fujioka,
K. (2008). Organophosphate-sensitive lipases modulate
133
brain lysophospholipids, ether lipids and endocannabinoids. Chemico-Biological Interactions 175 (13): 355
364. doi:10.1016/j.cbi.2008.04.008. PMC 2582404.
PMID 18495101.
[3] Ruby, M. A.; Nomura, D. K.; Hudak, C. S. S.;
Mangravite, L. M.; Chiu, S.; Casida, J. E.; Krauss,
R. M. (2008). Overactive endocannabinoid signaling impairs apolipoprotein E-mediated clearance of
triglyceride-rich lipoproteins. Proceedings of the National Academy of Sciences 105 (38): 1456114566.
doi:10.1073/pnas.0807232105. PMC 2567196. PMID
18794527.
[4] Ruby, M. A.; Nomura, D. K.; Hudak, C. S. S.; Barber, A.; Casida, J. E.; Krauss, R. M. (2011). Bartolomucci, Alessandro, ed. Acute Overactive Endocannabinoid Signaling Induces Glucose Intolerance,
Hepatic Steatosis, and Novel Cannabinoid Receptor 1
Responsive Genes.
PLoS ONE 6 (11): e26415.
PMC 3208546.
PMID 22073164.
[5] CWC Schedule 1 Part A. Toxic Chemicals
Chapter 94
2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4nonylphenyl)cyclohex-1-ene
2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4nonylphenyl)cyclohex-1-ene is an analgesic compound
which is a cannabinoid agonist. It is a ring-opened
cannabinoid derivative, an analogue of cannabidiol.
However, unlike cannabidiol, this compound produces
potent cannabis-like eects in animals, suggesting it acts
as a CB1 agonist.[1]
It can be synthesized by Birch reduction from the nonylanalog of cannabidiol.[2]
94.1 References
[1] Razdan, K. (1981). The Total Synthesis of Cannabinoids. In John Apsimon. The Total Synthesis of Natural
Products. Wiley Interscience. p. 245. ISBN 978-0-47105460-3. OCLC 19487018.
[2] Razdan RK, Pars HG, Thompson WR, Granchelli FE
(1974). Lithium-ammonia reduction of tetrahydrocannabinols. Tetrahedron Letters 15 (4950): 4315.
doi:10.1016/S0040-4039(01)92152-5.
134
Chapter 95
JTE 7-31
JTE 7-31 is a selective cannabinoid receptor agonist invented by Japan Tobacco.[1][2] It is a reasonably highly
selective CB2 agonist, but still retains appreciable anity
at CB1 , with a K of 0.088nM at CB2 vs 11nM at CB1 .
95.1 See also

A-834,735
JTE-907
MDA-19
S-444,823
95.2 References
[1] WO patent 1997/029079, Inaba T, Kaya T, Iwamura
H, Novel compounds and pharmaceutical use thereof,
granted 1997-14-08
[2] US patent 6017919, Inaba T, Kaya T, Iwamura H, Compounds and pharmaceutical use thereof, granted 200001-25
135
Chapter 96
JTE-907
JTE-907 is a drug used in scientic research that
acts as a selective CB2 inverse agonist.[1][2] It has
antiinammatory eects in animal studies,[3] thought to
be mediated by an interaction between the CB2 receptor
and IgE.[4]
96.1 See also

JTE 7-31
96.2 References
[1] Iwamura, H, et al. (2001). In vitro and in vivo pharmacological characterization of JTE-907, a novel selective ligand for cannabinoid CB2 receptor. The Journal
of Pharmacology and Experimental Therapeutics 296 (2):
4205. PMID 11160626.
[2] Raitio, KH, et al. (2006). Synthesis and SAR studies
of 2-oxoquinoline derivatives as CB2 receptor inverse agonists. Journal of Medical Chemistry 49 (6): 20227.
doi:10.1021/jm050879z. PMID 16539390.
[3] Ueda, Y, et al. (2005). Involvement of cannabinoid CB(2) receptor-mediated response and ecacy
of cannabinoid CB(2) receptor inverse agonist, JTE907, in cutaneous inammation in mice.
doi:10.1016/j.ejphar.2005.08.013. PMID 16153638.
[4] Ueda, Y; Miyagawa, N; Wakitani, K (2007). Involvement of cannabinoid CB2 receptors in the IgE-mediated
triphasic cutaneous reaction in mice. Life Sciences 80 (5):
4149. doi:10.1016/j.lfs.2006.09.026. PMID 17055000.
136
Chapter 97
JWH-015
JWH-015 is a chemical from the naphthoylindole family that acts as a subtype-selective cannabinoid agonist.
Its anity for CB2 receptors is 13.8 nM, while its anity for CB1 is 383 nM, meaning that it binds almost 28x
more strongly to CB2 than CB1 [1] However it still displays some CB1 activity, and in some model systems
can be very potent and ecacious at activating CB1
receptors,[2] and therefore it is not as selective as newer
drugs such as JWH-133.[3] It has been shown to possess
immunomodulatory eects,[4][5] and CB2 agonists may
be useful in the treatment of pain and inammation.[6][7]
It was discovered and named after Dr. John W. Human.
[3] Marriott KS, Human JW (2008). Recent advances in

the development of selective ligands for the cannabinoid
CB(2) receptor. Curr Top Med Chem 8 (3): 187204.
doi:10.2174/156802608783498014. PMID 18289088.
[4] Ghosh S, Preet A, Groopman JE, Ganju RK (July
2006).
Cannabinoid receptor CB2 modulates the
CXCL12/CXCR4-mediated chemotaxis of T lymphocytes.
Mol.
Immunol.
43 (14): 216979.
doi:10.1016/j.molimm.2006.01.005. PMID 16503355.
[5] Montecucco F, Burger F, Mach F, Steens S (March
2008).
CB2 cannabinoid receptor agonist JWH015 modulates human monocyte migration through dened intracellular signaling pathways. Am. J. Physiol. Heart Circ. Physiol. 294 (3): H114555.
doi:10.1152/ajpheart.01328.2007. PMID 18178718.
97.1 Metabolism
[6] Balter MB, Uhlenhuth EH (1992). Prescribing and use

of benzodiazepines: an epidemiologic perspective. J
Psychoactive Drugs 24 (1): 634. doi:10.1186/17422094-2-29. PMID 1352348.
JWH-015 has been shown in vitro to be metabolised

primarily by hydroxylation and N-dealkylation, and also
by epoxidation of the naphthalene ring,[8] similar to
the metabolic pathways seen for other aminoalkylindole
cannabinoids such as WIN 55,212-2.[9] Epoxidation
of polycyclic aromatic hydrocarbons (see for example benzo(a)pyrene toxicity) can produce carcinogenic
metabolites, although there is no evidence to show that
JWH-015 or other aminoalkylindole cannabinoids are actually carcinogenic in vivo. A study published in the
British Journal of Cancer shows that JWH-015 may signal certain cancers to shrink through a process called
apoptosis.[10]
[7] Romero-Sandoval A, Eisenach JC (April 2007).

Spinal cannabinoid receptor type 2 activation reduces
hypersensitivity and spinal cord glial activation after paw incision. Anesthesiology 106 (4): 78794.
doi:10.1097/01.anes.0000264765.33673.6c.
PMID
17413917.
[8] Zhang Q, Ma P, Cole RB, Wang G. Identication of in
vitro metabolites of JWH-015, an aminoalkylindole agonist for the peripheral cannabinoid receptor (CB2) by
HPLC-MS/MS. Analytical and Bioanalytical Chemistry.
2006 Nov;386(5):1345-55. PMID 16955257
97.2 References
[1] Aung MM, Grin G, Human JW, Wu M, Keel C,
Yang B, Showalter VM, Abood ME, Martin BR (August 2000). Inuence of the N-1 alkyl chain length
of cannabimimetic indoles upon CB1 and CB2 )receptor
binding. Drug Alcohol Depend 60 (2): 13340.
doi:10.1016/S0376-8716(99)00152-0. PMID 10940540.
[2] Murataeva N, Mackie K, Straiker A (November 2012).
The CB2-preferring agonist JWH015 also potently
and ecaciously activates CB1 in autaptic hippocampal neurons. Pharmacol. Res. 66 (5): 43742.
doi:10.1016/j.phrs.2012.08.002. PMC 3601544. PMID
22921769.
[9] Zhang Q, Ma P, Iszard M, Cole RB, Wang W, Wang

G (October 2002). In vitro metabolism of R(+)[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo
[1,2,3-de]1,4-benzoxazinyl]-(1-naphthalenyl) methanone
mesylate, a cannabinoid receptor agonist. Drug Metab.
Dispos. 30 (10): 107786. doi:10.1124/dmd.30.10.1077.
PMID 12228183.
[10] N Olea-Herrero, D Vara, S Malagarie-Cazenave, DazInhibition of human
Laviada (18 August 2009).
tumour prostate PC-3 cell growth by cannabinoids
R(+)-Methanandamide and JWH-015: Involvement of
CB2. British Journal of Cancer: 101, 940950.
doi:10.1038/sj.bjc.6605248. Retrieved 10 July 2014.
137
Chapter 98
JWH-051
JWH-051 is an analgesic drug which is a cannabinoid
agonist. Its chemical structure is closely related to that
of the potent cannabinoid agonist HU-210, with the only
dierence being the removal of the hydroxyl group at position 1 of the aromatic ring. It was discovered and named
after Dr. John W. Human.
JWH-051 retains high anity for the CB1 receptor, but
is a much stronger agonist for CB2 , with a Ki value of
14nM at CB2 vs 19nM at CB1 .[1] It was one of the rst
CB2 -selective ligands developed, although its selectivity
for CB2 is modest compared to newer compounds such
as HU-308.
It has similar eects to other cannabinoid agonists such
as sedation and analgesia, but with a relatively strong
antiinammatory eect due to its strong activity at
CB2 .[2][3][4]
98.1 References
[1] Human, JW, Yu, S, Showalter, V, Abood, ME, Wiley,
JL, Compton, DR, Martin, BR, Bramblett, RD, Reggio,
PH (1996). Synthesis and pharmacology of a very potent
cannabinoid lacking a phenolic hydroxyl with high anity
for the CB2 receptor. Journal of Medical Chemistry 39
(20): 38757. doi:10.1021/jm960394y. PMID 8831752.
[2] Human, JW (2000). The search for selective ligands
for the CB2 receptor. Current pharmaceutical design 6
(13): 132337. doi:10.2174/1381612003399347. PMID
10903395.
[3] Klein, TW, Newton, C, Friedman, H (1998). Cannabinoid receptors and the cytokine network. Advances
in experimental medicine and biology. Advances in
Experimental Medicine and Biology 437: 21522.
doi:10.1007/978-1-4615-5347-2_24. ISBN 978-0-30645838-5. PMID 9666274.
[4] Grin, G, Fernando, SR, Ross, RA, McKay, NG, Ashford, ML, Shire, D, Human, JW, Yu, S et al. (1997).
Evidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals. European Journal
of Pharmacology 339 (1): 5361. doi:10.1016/S00142999(97)01336-8. PMID 9450616.
138
Chapter 99
JWH-057
JWH-057, also known as deoxy-8-THC-DMH, is a selective cannabinoid ligand, with a binding anity of K =
2.9 1.6 nM for the CB2 subtype, and K = 23 7 nM
for CB1 .[1]
99.1 See also

JWH-015
JWH-018
JWH-019
JWH-073
99.2 References
[1] Human JW, Yu S, Showalter V, Abood ME, Wiley JL,
Compton DR, Martin BR, Bramblett RD, Reggio PH
(1996). Synthesis and Pharmacology of a Very Potent Cannabinoid Lacking a Phenolic Hydroxyl with High
Anity for the CB2 Receptor. J. Med. Chem. 39 (20):
38753877. doi:10.1021/JM960394Y.
139
Chapter 100
JWH-120
JWH-120 is a synthetic cannabimimetic that was discovered by John W. Human. It is the N-propyl analog of
JWH-122. It is a potent and selective ligand for the CB2
receptor, with a binding anity of K = 6.1 0.7 nM
at this subtype, and 173 times selectivity over the CB1
subtype.[1]
100.1 See also

JWH-122
JWH-193
JWH-210
JWH-398
100.2 References
[1] Human, J., et al. (2005). Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic
eects of naphthoyl substituents. New highly selective
CB(2) receptor agonists.. Bioorganic & Medicinal Chemistry 13 (1): 89112. doi:10.1016/j.bmc.2004.09.050.
PMID 15582455.
140
Chapter 101
JWH-122
JWH-122 is a synthetic cannabimimetic that was discovered by John W. Human. It is a methylated analogue of
JWH-018. It has a K of 0.69 nM at CB1 and 1.2 nM at
CB2 .[1]
101.1 See also

JWH-193
JWH-210
JWH-398
101.2 References
PMID 15582455.
141
Chapter 102
JWH-133
JWH-133 is a potent selective CB2 receptor agonist, with
a Ki of 3.4nM and selectivity of around 200x for CB2
over CB1 receptors. It was discovered by, and named
after, John W. Human.
JWH-133, alongside WIN 55,212-2 and HU-210, is

implicated in preventing the inammation caused by
Amyloid beta proteins involved in Alzheimers Disease,
in addition to preventing cognitive impairment and loss of
neuronal markers. This antiinamatory action is induced
through agonist action at cannabinoid receptors, which
prevents microglial activation that elicits the inammation. Additionally, cannabinoids completely abolish neurotoxicity related to microglia activation in rat models.
JNeurosci.org Prevention of Alzheimers Disease

Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation Also
has been shown to block grown of tumors. More
clinical studies and trials are needed.
It may be linked with anti-cancer properties, according to

pre-trial data from a 2010 study in Madrid. [1]
102.1 Legal Status

The substance commonly referred to as JWH-133
is not a scheduled substance in the U.S., although its
young age prevents it from having received the level of
government attention as with the older, more widely used
and well known chemicals. Low abuse potential makes
it less likely for regulation a priori relative to its sister
drugs such as JWH-018, as JWH-133 (chemical name
(6aR,10aR)3-(1,1-Dimethylbutyl)6a,7,10,10atetrahydro 6,6,9-trimethyl-6H-dibenzo[b,d]pyran) is
selective for the non-psychoactive CB2 receptor and
hence devoid of any psychoactive side eects or abuse
potential.[2]
102.2 References
[1] http://www.enewspf.com/index.
php/latest-news/health-and-fitness/
18029-marijuana-compound-halts-breast-cancer-tumor-growth-
[2] http://www.usdoj.gov/dea/pubs/scheduling.html
142
Chapter 103
JWH-148
JWH-148 is a synthetic cannabimimetic that was discovered by John W. Human. It is the indole 2-methyl analog of JWH-120. It is a moderately selective ligand for
the CB2 receptor, with a binding anity of K = 14.0
1.0 nM at this subtype, and more than 8 times selectivity
over the CB1 subtype.[1]
103.1 See also

JWH-120
JWH-122
JWH-193
JWH-210
JWH-398
103.2 References
PMID 15582455.
143
Chapter 104
JWH-149
JWH-149 is a synthetic cannabimimetic that was discovered by John W. Human. It is the N-pentyl analog of
JWH-148. It is a potent but only moderately selective ligand for the CB2 receptor, with a binding anity of K =
0.73 0.03 nM at this subtype, and more than 6 times
selectivity over the CB1 subtype.[1]
104.1 See also

JWH-120
JWH-122
JWH-148
JWH-193
JWH-210
JWH-398
104.2 References
PMID 15582455.
144
Chapter 105
JWH-161
JWH-161 is a cannabinoid derivative that was designed
by Dr John W. Human's team as a hybrid between the
dibenzopyran classical cannabinoid drugs and the novel
indole derivatives, in an attempt to unravel the dierences
in their binding modes to the CB1 receptor. While retaining structural elements from both families, JWH-161 has
a CB1 K of 19.0nM, although it was found to be slightly
weaker than THC in animal tests.[1]
105.1 References
[1] Human JW, Padgett LW (2005). Recent developments in the medicinal chemistry of cannabimimetic indoles, pyrroles and indenes. Current Medicinal Chemistry
12 (12): 1395411. doi:10.2174/0929867054020864.
PMID 15974991.
145
Chapter 106
JWH-176
JWH-176 is an analgesic drug which acts as a
cannabinoid receptor agonist. Its binding anity at the
CB1 receptor is only 26.0nM, making it more potent than
THC itself,[1] however JWH-176 is particularly notable in
that it is a hydrocarbon containing no heteroatoms. This
demonstrates that reasonably high-anity cannabinoid
binding and agonist eects can be produced by compounds with no hydrogen bonding capacity at all, relying merely on Van der Waals interactions to bind to the
receptor.[2] It was discovered by, and named after, Dr.
John W. Human.
106.1 See also

JWH-175
106.2 References
[1] Human JW, Padgett LW. Recent Developments in
the Medicinal Chemistry of Cannabimimetic Indoles,
Pyrroles and Indenes. Current Medicinal Chemistry, 2005;
12: 1395-1411.
3-540-22565-X
146
Chapter 107
JWH-359
JWH-359 is a dibenzopyran classical cannabinoid
drug, which is a potent and selective CB2 receptor agonist, with a K of 13.0nM and selectivity of around 220x
for CB2 over CB1 receptors. It is related to other dibenzopyran CB2 agonists such as JWH-133 and L-759,656
but with a chiral side chain which has made it useful in
mapping the shape of the CB2 binding site.[1][2] It was
discovered by, and named after, Dr. John W. Human.
107.1 References
[1] Human, J.; Bushell, S.; Joshi, S.; Wiley, J.; Martin,
B. (2006). Enantioselective synthesis of 1-methoxyand
1-deoxy-2'-methyl-delta8-tetrahydrocannabinols:
new selective ligands for the CB2 receptor. Bioorganic & Medicinal Chemistry 14 (1): 247262.
doi:10.1016/j.bmc.2005.08.013. PMID 16165365.
[2] Recent advances in the development of selective ligands for the cannabinoid CB(2) receptor. Curr Top Med Chem 8 (3): 187204. 2008.
doi:10.2174/156802608783498014. PMID 18289088.
147
Chapter 108
JZL184
JZL184 is an irreversible inhibitor for monoacylglycerol
lipase (MAGL), the primary enzyme responsible for
degrading the endocannabinoid 2-arachidonoylglycerol
(2-AG).[1] It displays high selectivity for MAGL over
other brain serine hydrolases, including the anandamidedegrading enzyme fatty acid amide hydrolase (FAAH),
thereby making it a useful tool for studying the eects
of endogenous 2-AG signaling, in vivo. Administration
of JZL184 to mice was reported to cause dramatic elevation of brain 2-AG leading to several cannabinoid-related
behavioral eects.
108.1 See also

JZL195
108.2 References
[1] Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE, Pavn FJ, Serrano AM, Selley DE, Parsons LH,
Lichtman AH, Cravatt BF (November 2008). Selective
blockade of 2-arachidonoylglycerol hydrolysis produces
cannabinoid behavioral eects. Nat. Chem. Biol. 5
(1): 3744. doi:10.1038/nchembio.129. PMC 2605181.
PMID 19029917.
148
Chapter 109
JZL195
JZL195 is a potent inhibitor of both fatty acid
amide hydrolase (FAAH) and monoacylglycerol lipase
(MAGL), the primary enzymes responsible for degrading the endocannabinoids anandamide (AEA) and 2arachidonoylglycerol (2-AG), respectively.[1]
109.1 See also

JZL184
109.2 References
[1] Long, J. Z.; Nomura, D. K.; Vann, R. E.; Walentiny, D.
M.; Booker, L.; Jin, X.; Burston, J. J.; Sim-Selley, L.
J.; Lichtman, A. H.; Wiley, J. L.; Cravatt, B. F. (2009).
Dual blockade of FAAH and MAGL identies behavioral processes regulated by endocannabinoid crosstalk in
vivo. Proceedings of the National Academy of Sciences
106 (48): 20270. doi:10.1073/pnas.0909411106.
149
Chapter 110
KM-233
KM-233 is a drug which is an analogue of 8tetrahydrocannabinol (THC), the less active but more stable isomer of the active component of Cannabis. km-233
diers from 8-THC by the pentyl side chain being replaced by a 1,1-dimethylbenzyl group. It has high binding anity in vitro for both the CB1 and CB2 receptors,
with a CB2 anity of 0.91nM and 13x selectivity over
the CB1 receptor.[1] In animal studies it has been found
to be eective for the treatment of glioma, a form of
brain tumor.[2] A large number of related analogues are
known where the 1,1-dimethylbenzyl group is substituted
or replaced by other groups, with a fairly well established
structure-activity relationship.[3][4][5][6][7]
110.1 See also

AM-411
AMG-36
110.2 References
[1] Krishnamurthy M, Ferreira AM, Moore BM 2nd. Synthesis and testing of novel phenyl substituted side-chain analogues of classical cannabinoids. Bioorganic and Medicinal Chemistry Letters. 2003 Oct 20;13(20):3487-90.
PMID 14505654
[2] Duntsch C, et al. Safety and ecacy of a novel cannabinoid chemotherapeutic, KM-233, for the treatment of
high-grade glioma. Journal of Neuro-oncology. 2006
Apr;77(2):143-52. PMID 16314952
[3] Nadipuram AK, et al. Synthesis and testing of novel classical cannabinoids: exploring the side chain ligand binding pocket of the CB1 and CB2 receptors. Bioorganic
and Medicinal Chemistry. 2003 Jul 17;11(14):3121-32.
PMID 12818675
[4] Durdagi S, et al. The application of 3D-QSAR studies
for novel cannabinoid ligands substituted at the C1' position of the alkyl side chain on the structural requirements
for binding to cannabinoid receptors CB1 and CB2. Journal of Medicinal Chemistry. 2007 Jun 14;50(12):2875-85.
PMID 17521177
150
[5] Krishnamurthy M, Gurley S, Moore BM 2nd. Exploring

the substituent eects on a novel series of C1'-dimethylaryl Delta8-tetrahydrocannabinol analogs. Bioorganic
and Medicinal Chemistry. 2008 Jul 1;16(13):6489-500.
PMID 18524604
[6] Ferreira AM, et al. Quantitative structure-activity relationship (QSAR) for a series of novel cannabinoid
derivatives using descriptors derived from semi-empirical
quantum-chemical calculations. Bioorganic and Medicinal Chemistry. 2009 Mar 15;17(6):2598-606. PMID
19250829
[7] Brogi S, et al. Three-dimensional quantitative structureselectivity relationships analysis guided rational design
of a highly selective ligand for the cannabinoid receptor 2. European Journal of Medicinal Chemistry. 2011
Feb;46(2):547-55. PMID 21183257
Chapter 111
L-759,633
L-759,633 is an analgesic drug that is a cannabinoid
agonist. It is a fairly selective agonist for the CB2
receptor, with selectivity of 163x for CB2 over CB1 .[1]
It produces some similar eects to other cannabinoid agonists such as analgesia, but with little or no sedative or
psychoactive eects due to its weak CB1 activity, and a
relatively strong antiinammatory eect due to its strong
activity at CB2 .[2][3]
111.1 See also

L-759,656
L-768,242
111.2 References
[1] Ross, RA, Brockie, HC, Stevenson, LA, Murphy, VL,
Templeton, F, Makriyannis, A, Pertwee, RG (1999).
Agonist-inverse agonist characterization at CB1 and
CB2 cannabinoid receptors of L759633, L759656 and
AM630. British Journal of Pharmacology 126 (3): 665
10188977.
[2] Human, JW (2000). The search for selective ligands
for the CB2 receptor. Current pharmaceutical design 6
(13): 132337. doi:10.2174/1381612003399347. PMID
10903395.
[3] Human, JW (2005).
CB2 receptor ligands.
doi:10.2174/1389557054368844. PMID 16026310.
151
Chapter 112
L-759,656
L-759,656 is an analgesic drug that is a cannabinoid
agonist. It is a highly selective agonist for the CB2
receptor, with selectivity of 414x for CB2 over CB1 ,[1]
although it is still not as selective as newer agents such as
HU-308.
It produces some similar eects to other cannabinoid agonists such as analgesia, but with little or no sedative or
psychoactive eects due to its weak CB1 activity, and a
relatively strong antiinammatory eect due to its strong
activity at CB2 .[2][3]
112.1 See also

L-759,633
L-768,242
112.2 References
[1] Ross, R.; Brockie, H.; Stevenson, L.; Murphy, V.;
Templeton, F.; Makriyannis, A.; Pertwee, R. (1999).
Agonist-inverse agonist characterization at CB1 and
CB2 cannabinoid receptors of L759633, L759656, and
AM630. British Journal of Pharmacology 126 (3): 665
10188977.
[2] Human, J. W. (2000). The search for selective ligands
for the CB2 receptor. Current pharmaceutical design
6 (13): 13231337. doi:10.2174/1381612003399347.
PMID 10903395.
[3] Human, J. W. (2005).
CB2 receptor ligands.
doi:10.2174/1389557054368844. PMID 16026310.
152
Chapter 113
LASSBio-881
LASSBio-881 is a drug which acts as both a non-selective
partial agonist of the CB1 and CB2 cannabinoid receptors, and also as an antagonist of the TRPV1 receptor, as well as having antioxidant eects. It has potent
anti-inammatory and anti-hyperalgesic eects in animal
studies.[1][2][3]
113.1 References
[1] Duarte CD, Tributino JL, Lacerda DI, Martins MV,
Alexandre-Moreira MS, Dutra F, Bechara EJ, De-Paula
FS, Goulart MO, Ferreira J, Calixto JB, Nunes MP,
Bertho AL, Miranda AL, Barreiro EJ, Fraga CA. Synthesis, pharmacological evaluation and electrochemical studies of novel 6-nitro-3,4-methylenedioxyphenylN-acylhydrazone derivatives: Discovery of LASSBio881, a new ligand of cannabinoid receptors. Bioorganic
and Medicinal Chemistry. 2007 Mar 15;15(6):2421-33.
PMID 17275312
[2] Tributino JL, Santos ML, Mesquita CM, Lima CK, Silva
LL, Maia RC, Duarte CD, Barreiro EJ, Fraga CA, Castro
NG, Miranda AL, Guimaraes MZ. LASSBio-881: an Nacylhydrazone transient receptor potential vanilloid subfamily type 1 antagonist orally eective against the hypernociception induced by capsaicin or partial sciatic ligation.
British Journal of Pharmacology. 2010 Apr;159(8):171623. PMID 20401963
[3] Santana P et al. NEUROACTIVE PROPERTIES OF
THE MULTIFUNCTIONAL PROTOTYPE LASSBio881: FOCUS ON THE CANNABINOID SYSTEM
153
Chapter 114
LBP-1 (drug)
LBP-1 is a drug originally developed by Organon
for the treatment of neuropathic pain,[1][2] and subsequently further developed by Merck after they acquired Organons patents following their merger with
Schering-Plough.[3][4][5] It acts as a potent and selective cannabinoid receptor agonist, with high potency at
both the CB1 and CB2 receptors, but low penetration
of the bloodbrain barrier. This makes LBP-1 peripherally selective, and while it was eective in animal models of neuropathic pain and allodynia, it did not produce
cannabinoid-appropriate responding suggestive of central
eects, at any dose tested.[6]
114.1 See also

Org 28312
Org 28611
114.2 References
[1] Julia Adam. Indole Derivatives. Patent WO 2008/101995
[2] Paul David Ratclie, Julia Adam-Worrall, Angus John
Morrison, Stuart John Francis, Takao Kiyoi. Indole
Derivatives. Patent US 7763732
[3] Morrison AJ, Adam JM, Baker JA, Campbell RA, Clark
JK, Cottney JE, Deehan M, Easson AM, Fields R, Francis S, Jeremiah F, Keddie N, Kiyoi T, McArthur DR,
Meyer K, Ratclie PD, Schulz J, Wishart G, Yoshiizumi
K. Design, synthesis, and structure-activity relationships
of indole-3-heterocycles as agonists of the CB1 receptor. Bioorganic and Medicinal Chemistry Letters. 2011
Jan 1;21(1):506-9. PMID 21075630
[4] Kiyoi T, Adam JM, Clark JK, Davies K, Easson AM,
Edwards D, Feilden H, Fields R, Francis S, Jeremiah
F, McArthur D, Morrison AJ, Prosser A, Ratclie PD,
Schulz J, Wishart G, Baker J, Campbell R, Cottney JE,
Deehan M, Epemolu O, Evans L. Discovery of potent and
orally bioavailable heterocycle-based cannabinoid CB1
receptor agonists. Bioorganic and Medicinal Chemistry
Letters. 2011 Mar 15;21(6):1748-53. PMID 21316962
154
[5] Ratclie P, Adam JM, Baker J, Bursi R, Campbell R,

Clark JK, Cottney JE, Deehan M, Easson AM, Ecker D,
Edwards D, Epemolu O, Evans L, Fields R, Francis S,
Harradine P, Jeremiah F, Kiyoi T, McArthur D, Morrison
A, Passier P, Pick J, Schnabel PG, Schulz J, Steinbrede H,
Walker G, Westwood P, Wishart G, de Haes JU. Design,
synthesis and structure-activity relationships of (indo-3yl) heterocyclic derivatives as agonists of the CB1 receptor. Discovery of a clinical candidate. Bioorganic and
Medicinal Chemistry Letters. 2011 Apr 15;21(8):2541-6.
PMID 21411321
[6] Adam JM, Clark JK, Davies K, Everett K, Fields R,
Francis S, Jeremiah F, Kiyoi T, Maidment M, Morrison
A, Ratclie P, Prosser A, Schulz J, Wishart G, Baker
J, Boyce S, Campbell R, Cottney JE, Deehan M, Martin I. Low brain penetrant CB1 receptor agonists for the
treatment of neuropathic pain. Bioorganic and Medicinal Chemistry Letters. 2012 Apr 15;22(8):2932-7. PMID
22421020
Chapter 115
Leelamine
Leelamine is a diterpene amine that has weak anity
for the cannabinoid receptors CB1 and CB2 , as well as
being an inhibitor of pyruvate dehydrogenase kinase.[1]
Optically active leelamine is also used as a chiral resolving agent for carboxylic acids.[2][3]
115.1 See also

THC
Resin acid
115.2 References
[1] Leelamine - Dehydroabietylamine - Cayman Chemical.
Retrieved May 20, 2013.
[2] US patent 3454626
[3] US patent 4559178
155
Chapter 116
Levonantradol
Levonantradol (CP 50,556-1) is a synthetic cannabinoid
analog of dronabinol (Marinol) developed by Pzer in the
1980s. It is around 30x more potent than THC, and exhibits antiemetic and analgesic eects via activation of
CB1 and CB2 cannabinoid receptors.[1] Levonantradol is
not currently used in medicine as dronabinol or nabilone
are felt to be more useful for most conditions, however it
is widely used in research into the potential therapeutic
applications of cannabinoids.[2][3][4]
drug must be dissolved in 5% ethanol, 5% emulphur,

and 90% sterile saline. Synthetic cannabinoids like Levonantradol readily cross the blood-brain barrier because
they are highly lipophilic and have low molecular weights.
Levonantradols bioavailability is variable due to the rst
pass metabolism.
116.1 Pharmacodynamics
Levonantradol has been clinically tested in cancer patients for its pain relief and antiemetic benets. Cancer patients that endure chemotherapy often develop intense nausea, and Levonantradol has been tested to reduce these emetic symptoms. It is often used instead
of THC because it has a higher ecacy. Levonantradol
also acts on pain pathways in the central nervous system, which enables the drug to alleviate pain. Studies
have shown an absence of emetic side eects within the
half-life of the Levonantradol administered. Other studies suggest that cannabinoid agonists can synergize opioid
anti-nociception. Cannabinoid receptors are located in
nociceptive pathways, and CBs can promote signal transduction in TRP channels. Although Levonantradol relieves nociceptive and postoperative pain, decreases nausea, and improves spasticity in addition to being more
eective than placebos, it has yet to be approved as legal medicine. Researchers have concluded that Levonantradol is no more eective than Codeine, which is why
they do not recommend expansion into clinical practice.
Levonantradol is a full CB1 receptor agonist. Cannabinoid receptors belong to the superfamily of G-protein
coupled receptors (GPCRs), and endogenous cannabinoids naturally activate GPCRs. GPCRs modulate
the inhibition of adenylyl cyclase and accumulation of
the second messenger, cyclic adenosine monophosphate
(cAMP). The CB1 receptor is the most common GPCR
in the central nervous system. The activation of CB1 Rs
decrease calcium conductance and increase potassium
conductance in the brain. CB signaling naturally modulates synaptic transmission and mediates psychoactivity, and synthetic cannabinoids mimic these same actions. Although the ecacy of Levonantradol is dependent on the level of GCPR activity, Full agonists like Levonantradol have the ability to activate GPCRs and convert
G into a high anity state for GTP or low anity state
for GDP. Previous studies suggest that Levonantradol has
a higher binding anity and ecacy than other similar
synthetic cannabinoids (e.g. 9 -THC).
116.3 Treatment
116.4 Side eects

116.2 Pharmacokinetics
Although Levonantradol has been extensively tested on
animals including cats, rodents, and non-human primates.
It has also been tested among cancer patient populations
in clinical trials. Levonantradol is most commonly administered intramuscularly (I.M.), however it can also be
administered orally. The dosage can range from 0.25 mg3.0 mg every 24 hours, and the half-life is 12 hours. In
order to administer Levonantradol intramuscularly, the
The side eects for Levonantradol include ptosis, sedation, and ataxia in non-human primates. In rodents, the
symptoms include dysphoria, memory impairment, motor incoordination, reduced concentration, and disorientation. Levonantradol also decreases startle response.
In humans, side eects include dry mouth, drowsiness,
dizziness, altered perception, mild sedation, and lack of
concentration. It can cause an increase in heart rate and
decrease in blood pressure. Euphoric symptoms rarely
occurred in subjects.
156
116.7. REFERENCES
116.5 See also

CP 47,497
116.6 Notes
[1] Little PJ, et al. Pharmacology and stereoselectivity
of structurally novel cannabinoids in mice. Journal
of Pharmacology and Experimental Therapeutics 1988;
247:10461051.
[2] Tramer MR, et al.
Cannabinoids for control of
chemotherapy induced nausea and vomiting: quantitative systematic review. British Medical Journal 2001 Jul
7;323(7303):16-21.
[3] Campbell FA, et al. Are cannabinoids an eective and
safe treatment option in the management of pain? A qualitative systematic review. British Medical Journal. 2001
Jul 7;323(7303):13-6.
[4] Ben Amar M. Cannabinoids in medicine: A review of
their therapeutic potential. Journal of Ethnopharmacology. 2006 Apr 21;105(1-2):1-25.
116.7 References
Childers, SR (Mar 10, 2006). Activation of Gproteins in brain by endogenous and exogenous
cannabinoids.. The AAPS journal 8 (1): E1127.
doi:10.1208/aapsj080113. PMC 2751429. PMID
16584117.
Hosking, R.D.; Zajicek, J.P. (2008). Therapeutic
potential of cannabis in pain medicine.
British Journal of Anaesthesia 101 (1): 5968.
doi:10.1093/bja/aen119.
McCarthy, LE; Borison, HL (AugSep 1981).
Antiemetic activity of N-methyllevonantradol and
nabilone in cisplatin-treated cats.. Journal of
clinical pharmacology 21 (89 Suppl): 30S37S.
doi:10.1002/j.1552-4604.1981.tb02570.x. PMID
6271834.
Milewich, L; Gant, NF; Schwarz, BE; Chen, GT;
MacDonald, PC (Mar 15, 1979). 5 alphaReductase activity in human placenta.. American
journal of obstetrics and gynecology 133 (6): 611
7. PMID 34324.
157
Chapter 117
List of AM cannabinoids
Alexandros Makriyannis is a professor in the Department of Medicinal Chemistry at Northeastern University,
where his research group has synthesized many new compounds with cannabinoid activity. Some of those are:
AM-087 an analgesic CB1 agonist derived from
8 THC substituted with a side chain on the 3position, it has a K of 0.43nM making it roughly
100x as potent as THC.
AM-251 an inverse agonist at the CB1
cannabinoid receptor that is structurally related to
SR141716A (rimonabant), but has a higher binding
anity with a K value of 7.5nM.[1]
AM-281
N-(morpholin-4-yl)1-(2,4dichlorophenyl)5-(4-iodophenyl)4-methyl1H-pyrazole-3-carboxamide[1]
AM-356 a synthetically created stable chiral analog of anandamide, it acts on the cannabinoid receptors with a K of 17.9nM at CB1 and 868nM at
CB2 .[2]
AM-374 palmitylsulfonyl uoride[3]
AM-381 stearylsulfonyl uoride
AM-404 an active metabolite of paracetamol
(acetaminophen) and a likely inhibitor of fatty acid
amide hydrolase (FAAH)
AM-411 an adamantyl-substituted derivative of
8 THC, it is a potent and fairly selective CB1 full
agonist with a K of 6.80nM. It is also a moderately
potent CB2 agonist with a K of 52.0nM.
AM-630 a potent and selective inverse agonist for
the cannabinoid receptor CB2 , with a K of 32.1nM
at CB2 and 165x selectivity over CB1 , at which it
acts as a weak partial agonist.
AM-661 1-(N-methyl-2-piperidine)methyl-2methyl-3-(2-iodo)benzoylindole[4]
AM-678 another name for JWH-018, it is a full
agonist at both cannabinoid receptors with some selectivity for CB2 .
158
AM-679 an iodobenzoylindole which acts as a

moderately potent agonist for the cannabinoid receptors, with a K of 13.5nM at CB1 and 49.5nM
at CB2 .
AM-694 an iodobenzoylindole which acts as a
potent and selective agonist for the CB1 cannabinoid
receptor, with a K of 0.08nM at CB1 and 18x selectivity over the related CB2 receptor (1.44nM).[5]
AM-735 3-bornyl-8-THC, a mixed CB1 / CB2
agonist with K of 8.9nM at CB1 and 7.4nM at
CB2 .[6]
AM-855 an analgesic derivative of
8 tetrahydrocannabinol, it is an agonist at both
CB1 and CB2 with moderate selectivity for CB1 ,
with a K of 22.3nM at CB1 and 58.6nM at CB2 .
AM-881 a chlorine-substituted stereoisomer of
anandamide whose K = 5.3nM at CB1 and 95nM at
CB2 .[2]
AM-883 an allyl-substituted stereoisomer of
anandamide whose K = 9.9nM at CB1 and 226nM
at CB2 .[2]
AM-905 a potent and reasonably selective agonist for the CB1 cannabinoid receptor, with a K of
1.2nM at CB1 and 5.3nM at CB2 .
AM-906 a potent and dodecally selective agonist for the CB1 cannabinoid receptor, with a K of
AM-919 a potent agonist at both CB1 and CB2
with moderate selectivity for CB1 , with a K of
2.2nM at CB1 and 3.4nM at CB2 . It is a derivative of
HU-210 and represents a hybrid structure between
the classical and nonclassical cannabinoid families.
with quadruple selectivity for CB2 , with a K of
117.1. SEE ALSO

AM-1116 a dimethylated stereoisomer of anandamide whose K = 7.4nM at CB1 .[2]
AM-1172 an endocannabinoid analog specically designed to be a potent and selective inhibitor
of AEA uptake that is resistant to FAAH hydrolysis.
AM-1220 a potent and selective analgesic CB1
agonist (as racemate) with a K of 3.88nM at CB1
and 73.4nM at CB2 , giving it 19x selectivity for
CB1 . (R) enantiomer has around 1000x higher anity for CB1 than (S) enantiomer.[7][8]
AM-1221 a potent and selective CB2 agonist with
a K of 0.28nM at CB2 and 52.3nM at CB1 , giving
it a selectivity of almost 187x.
AM-1235 a moderately CB1 selective agonist,
with a K of 1.5nM at CB1 and 20.4nM at CB2 , giving it a selectivity of around 13x.[9]
AM-1241 a potent and selective analgesic CB2
agonist with a K of 3.4nM at CB2 and 80x selectivity over CB1 .[10]
AM-1248 a moderately potent agonist with
some selectivity for CB1 , containing an unusual 3(adamant-1-oyl) substitution on the indole ring.
159
AM-3102 an analog of oleoylethanolamide, the
endogenous agonist for proliferator-activated receptor (PPAR). It also acts as a weak cannabinoid
agonist with K values of 33M at CB1 and 26M at
CB2 .
AM-4030 a potent agonist at both CB1 and CB2 ,
it is dodecally selective for CB1 , with a K of 0.7nM
at CB1 and 8.6nM at CB2 . It is a derivative of HU210 and represents a hybrid structure between the
classical and nonclassical cannabinoid families.
AM-4054 a potent but slow-onset agonist with
CB1 anity of 2.2nM and a 40x selectivity for CB1
over CB2 .[18][19]
AM-4113 a CB1 selective neutral antagonist.[20]
AM-6545 a peripherally selective silent antagonist of CB1 receptors.
117.1 See also

List of JWH cannabinoids
List of HU cannabinoids
List of CP cannabinoids
AM-1710 a CB2 selective cannabilactone with A more complete list can be found here
54x selectivity over CB1 .[11]
AM-1714 a CB2 selective cannabilactone with
490x selectivity over CB1 .[11]
with dodecal selectivity for CB1 , with a K of 1.4nM
at CB1 and 18.9nM at CB2 .[4]
with 10x selectivity for CB1 , with a K of 3.0M at
CB1 and 30nM at CB2 .[4]
AM-2232 a potent agonist at both CB1 and CB2 ,
with a K of 0.28nM at CB1 and 1.48nM at CB2 .[9]
117.3 References
[1] Lan, Ruoxi; Lu, Qian; Fan, Pusheng; Gatley, John;
Volkow, Nora D.; Fernando, Susanthi R.; Pertwee, Roger;
Makriyannis, Alexandros (1999). Design and synthesis
of the CB1 selective cannabinoid antagonist AM281: A
potential human SPECT ligand. AAPS PharmSci 1 (2):
3945. doi:10.1208/ps010204.
[2] Selwood, D. (2009). The Cannabinoid Receptors.
Edited by Patricia H. Reggio. ChemMedChem 4: 1949.
doi:10.1002/cmdc.200900286.
[3] Pacher, P.; Btkai, S; Kunos, G (2006). The Endocannabinoid System as an Emerging Target of Pharmacotherapy. Pharmacological Reviews 58 (3): 389
462. doi:10.1124/pr.58.3.2. PMC 2241751. PMID
16968947.
AM-2233 (R) enantiomer is potent and selective CB1 agonist used in 131 I radiolabelled
form to map distribution of CB1 receptors in
brain.[12][13][14][15][16][17]
[4] Hongfeng Deng. Design and synthesis of selective

cannabinoid receptor ligands: Aminoalkylindole and
other heterocyclic analogs. PhD Dissertation, University
of Connecticut, 2000.
AM-2389 classical cannabinoid derivative with

26x selectivity for CB1 .

160
[6] Lu D, Guo J, Duclos RI Jr, Bowman AL, Makriyannis

A. Bornyl- and isobornyl-Delta8-tetrahydrocannabinols: a
novel class of cannabinergic ligands. Journal of Medicinal Chemistry. 2008 Oct 23;51(20):6393-9. PMID
18826296
[7] D'ambra, T. (1996). C-Attached aminoalkylindoles:
potent cannabinoid mimetics. Bioorganic & Medicinal Chemistry Letters 6: 1714. doi:10.1016/0960894X(95)00560-G.
[8] Willis, P. G.; Pavlova, O. A.; Chefer, S. I.; Vaupel, D.
B.; Mukhin, A. G.; Horti, A. G. (2005). Synthesis
and StructureActivity Relationship of a Novel Series of
Aminoalkylindoles with Potential for Imaging the Neuronal Cannabinoid Receptor by Positron Emission Tomography. Journal of Medicinal Chemistry 48 (18):
5813. doi:10.1021/jm0502743. PMID 16134948.
2219524. PMID 17982473.
[11] Khanolkar AD, Lu D, Ibrahim M, Duclos RI Jr, Thakur
GA, Malan TP Jr, Porreca F, Veerappan V, Tian X,
George C, Parrish DA, Papahatjis DP, Makriyannis A.
Cannabilactones: a novel class of CB2 selective agonists
with peripheral analgesic activity. Journal of Medicinal Chemistry. 2007 Dec 27;50(26):6493-500. PMID
18038967
[12] Deng H, Giord AN, Zvonok AM, Cui G, Li X, Fan
P, Deschamps JR, Flippen-Anderson JL, Gatley SJ,
Makriyannis A (October 2005). Potent cannabinergic
indole analogues as radioiodinatable brain imaging agents
for the CB1 cannabinoid receptor. Journal of Medicinal
Chemistry 48 (20): 638692. doi:10.1021/jm050135l.
PMID 16190764.
[13] Hanu, L. R. O.; Mechoulam, R. (2005). Cannabinoid chemistry: an overview. Cannabinoids as Therapeutics. Milestones in Drug Therapy MDT. p. 23.
doi:10.1007/3-7643-7358-X_2. ISBN 3-7643-7055-6.
[14] Shen CP, Xiao JC, Armstrong H, Hagmann W, Fong
TM (February 2006). F200A substitution in the third
transmembrane helix of human cannabinoid CB1 receptor
converts AM2233 from receptor agonist to inverse agonist. European Journal of Pharmacology 531 (13): 41
6. doi:10.1016/j.ejphar.2005.12.026. PMID 16438957.
[15] Dhawan, J.; Deng, H.; Gatley, S. J.; Makriyannis, A.;
Akinfeleye, T.; Bruneus, M.; Dimaio, A. A.; Gifford, A. N. (2006). Evaluation of the in vivo receptor occupancy for the behavioral eects of cannabinoids using a radiolabeled cannabinoid receptor agonist, R-[125/131I]AM2233. Synapse 60 (2): 93101.
doi:10.1002/syn.20277. PMID 16715483.
CHAPTER 117. LIST OF AM CANNABINOIDS
[16] Leung K (Dec 12, 2006). R-2-[131I]Iodophenyl(1-(1-methylpiperidin-2-ylmethyl)1H-indol-3yl)methanone.

Molecular Imaging and Contrast
Agent Database (MICAD) [Internet]. PMID 20641836.
[17] Pei, Y., et al. (2008). Ligand-Binding Architecture
of Human CB2 Cannabinoid Receptor: Evidence for
Receptor Subtype-Specic Binding Motif and Modeling GPCR Activation. Chemistry & Biology 15: 1207.
doi:10.1016/j.chembiol.2008.10.011.
[18] [Paronis CA, Thakur GA, Vemuri K, Makriyannis A,
Bergman J. Eects of a Selective Cannabinoid Agonist and Antagonist on Body Temperature in Rats.
The FASEB Journal. April 2007 21 (Meeting Abstract
Supplement) A409. http://www.fasebj.org/cgi/content/
meeting_abstract/21/5/A409]
[19] Paronis, C. A.; Thakur, G. A.; Bajaj, S.; Nikas, S. P.;
Vemuri, V. K.; Makriyannis, A.; Bergman, J. (2012).
Diuretic eects of cannabinoids. Journal of Pharmacology and Experimental Therapeutics 344 (1): 814.
doi:10.1124/jpet.112.199331. PMID 23019138.
[20] Seely KA, Prather PL, James LP, Moran JH. Marijuanabased drugs: innovative therapeutics or designer drugs of
abuse? Molecular Interventions. 2011 Feb;11(1):36-51.
PMID 21441120
Chapter 118

The John W. Human research group at Clemson University synthesized over 450 cannabinoids. Some of those
are:
JWH-057 a 1-deoxy analog of 8-THC that has

very high anity for the CB2 receptor, but also has
high anity for the CB1 receptor.[2]
JWH-007 an analgesic chemical from the

naphthoylindole family, which acts as a cannabinoid
agonist at both the CB1 receptor and CB2 receptors,
with some selectivity for CB2 with a K of 2.9nM
2.6 and 9.5nM 4.5 at CB1 .[1]
JWH-073 an analgesic chemical from the naphthoylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It is
somewhat selective for the CB1 subtype with a K
of 8.9nM. It is found in some forms of synthetic
cannabis.
JWH-015 a chemical from the naphthoylindole

family, which acts as a subtype-selective cannabinoid agonist. Its anity for CB2 receptors is
13.8nM, while its anity for CB1 is 383nM, meaning that it binds almost 28x more strongly to CB2
than CB1 .[1]
JWH-018 an analgesic chemical from the naphthoylindole family, which acts as a full agonist at
both the CB1 and CB2 cannabinoid receptors, with
some selectivity for CB2 with a K of 2.9nM 2.6
and 9nM 5 at CB1 .[1] It is found in some forms of
synthetic cannabis.
JWH-019 an agonist at both CB1 and CB2 receptors, it has 1.77x selectivity for CB2 with a K of
5.55nM 2 and 9.8nM 2 at CB1 .
naphthoylpyrrole family, it is a partial agonist at CB1
receptors, with a K of 87nM, making it roughly half
the potency of THC.
JWH-047 a potent and selective agonist for the
CB2 receptor with a K of 0.9 nM, and a K of 59
3 nM at CB1 , it has a 65x selectivity for CB2 .[1]
JWH-048 a potent and selective agonist for the
CB2 receptor with a K of 0.49 nM 0.1, and a K
of 10.7 nM 1.0 at CB1 , it has a 22x selectivity for
CB2 .[1]
JWH-051 an analgesic, it has high anity for
the CB1 receptor, but is a much stronger agonist for
CB2 , with a K value of 0.03nM at CB2 vs 1.20nM
at CB1 . It was one of the rst CB2 -selective ligands
developed, although its selectivity for CB2 is modest
compared to newer compounds such as HU-308.
161
JWH-081 an analgesic chemical from the naphthoylindole family, which acts as an agonist at both
the cannabinoid receptors with a K of 1.2nM 0.03
at CB1 [3] and 12.4nM 2.2 at the CB2 receptors. It
is fairly selective for the CB1 subtype with approximately 10x the anity for CB2 . It is found in some
forms of synthetic cannabis.
JWH-098 a potent and fairly selective CB2 agonist with a K of 1.9nM 0.3 at CB2 and 4.5nM
0.1 at CB1 ,[3] giving it about 2.4x selectivity for
CB2 .
JWH-116 a CB1 ligand with a K of 52 5 nM[3]
JWH-120 a potent and 173-fold selective CB2
agonist with a K of 6.1nM 0.7, it is the N-propyl
homolog of JWH-122.[2]
1.2 at CB2 . It is found in some forms of synthetic
cannabis.
JWH-133 a potent and highly selective CB2 receptor agonist with a K of 3.4nM and selectivity of
around 200x for CB2 over CB1 receptors.[1]
JWH-139
3-(1,1-dimethylpropyl)6,6,9trimethyl-6a,7,10,10a-tetrahydro-6Hbenzo[c]chromene[4]
JWH-147 an analgesic drug from the naphthoylpyrrole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It is somewhat selective for the CB2 subtype, with a K of
11.0nM at CB1 vs 7.1nM at CB2 .
162
JWH-148 a moderately selective ligand for the
CB2 receptor, with a binding anity of K = 14.0
1.0 nM at this subtype, and more than 8 times selectivity over the CB1 subtype.[5]
JWH-149 a potent and fairly selective CB2 agonist with a K of 0.73nM 0.03 and 5.0nM 2.1 at
CB1 ,[3] giving it about 6.8x selectivity for CB2 .
JWH-161 a CB1 ligand with K of 19.0nM
JWH-164 a potent cannabinoid agonist with a K
of 6.6nM 0.7 at CB1 and 6.9nM 0.2 at CB2 .
JWH-166 a potent and highly selective CB2 agonist with a K of 1.9nM 0.08 at CB2 and 44nM
10 at CB1 giving it 23x selectivity for CB2 .[1]
JWH-167 a weak cannabinoid agonist from the
phenylacetylindole family with 1.77x selectivity for
CB1 with a K of 90nM 17 at CB1 and 159nM
14 at CB2 .[6]
JWH-171 an analgesic drug which acts as a
cannabinoid receptor agonist. Its binding anity at
the CB1 receptor is only 51nM, making it slightly
less potent than THC itself.
JWH-175 (1-pentylindol-3-yl)naphthalen-1ylmethane, 22nM at CB1 [3]
JWH-176
1-([(1E)3-pentylinden-1ylidine]methyl)naphthalene, 26nM at CB1 [3]

JWH-181 a potent cannabinoid agonist with 2.1x
selectivity for CB2 with a K of 0.62nM 0.04 and
1.3nM 0.1 at CB1 .
JWH-182 a potent cannabinoid agonist with
some selectivity for CB1 with a K of 0.65nM 0.03
and 1.1nM 0.1 at CB2 .
JWH-184 1-pentyl-1H-indol-3-yl-(4-methyl-1naphthyl)methane, 23nM at CB1 [3]
JWH-185 1-pentyl-1H-indol-3-yl-(4-methoxy1-naphthyl)methane, 17nM at CB1 [3]
JWH-192 (1-(2-morpholin-4-ylethyl)indol-3yl)4-methylnaphthalen-1-ylmethane, 41nM at
CB1 [3]
JWH-193 (1-(2-morpholin-4-ylethyl)indol-3yl)4-methylnaphthalen-1-ylmethanone, 6nM at
CB1 [3]
JWH-194 2-methyl-1-pentyl-1H-indol-3-yl-(4methyl-1-naphthyl)methane, 127nM at CB1 [3]
JWH-195 (1-(2-morpholin-4-ylethyl)indol-3yl)-naphthalen-1-ylmethane, 113nM at CB1 [3]
JWH-196
2-methyl-3-(1naphthalenylmethyl)1-pentyl-1H-Indole, 151nM
18 at CB1
CHAPTER 118. LIST OF JWH CANNABINOIDS

JWH-197 2-methyl-1-pentyl-1H-indol-3-yl-(4methoxy-1-naphthyl)methane, 323nM at CB1 [3]
JWH-198 (1-(2-morpholin-4-ylethyl)indol-3yl)4-methoxynaphthalen-1-ylmethanone, 10nM
at CB1 [3]
JWH-199 (1-(2-morpholin-4-ylethyl)indol-3yl)4-methoxynaphthalen-1-ylmethane, 20nM at
CB1 [3]
aminoalkylindole family, which acts as a cannabinoid receptor agonist. Its binding anity at the CB1
receptor is 42nM, around the same as that of THC,
but interestingly, its analgesic potency in vivo was
higher than that of other analogues with stronger
CB1 binding anity in vitro, around 3 times that of
THC but with less sedative eect, most likely reecting favorable pharmacokinetic characteristics.
It is found in some forms of synthetic cannabis.
phenylacetylindole family, which acts as a cannabinoid agonist with approximately equal anity at
both the CB1 and CB2 receptors, having a K of
8.0nM at CB1 and 7.0nM at CB2 . Similar to
the related 2'-methoxy compound JWH-250, JWH203 has a phenylacetyl group in place of the naphthoyl ring used in most aminoalkylindole cannabinoid compounds, and is the most potent compound
found in the phenylacetyl group.[6] It is found in
some forms of synthetic cannabis.
JWH-205 1-(2-methyl-1-pentylindol-3-yl)2phenylethanone, CB1 : 124nM 23 CB2 : 180nM
9 CB2 selectivity: 1.45x[6]
JWH-210 an analgesic chemical from the naphthoylindole family, which acts as a potent cannabinoid agonist at both the CB1 and CB2 receptors,
with K values of 0.46nM at CB1 and 0.69nM at
CB2 . It is one of the most potent 4-substituted naphthoyl derivatives in the naphthoylindole series, having a higher binding anity (i.e. lower K) at CB1
than both its 4-methyl and 4-n-propyl homologues
(JWH-122 and JWH-182 respectively), and than the
4-methoxy compound JWH-081.[1] It is found in
0.2 at CB1 giving it 3.6x selectivity over CB1 .[1]
JWH-220 19nM at CB1
JWH-229 1-methoxy-3-(1',1'-dimethylhexyl)8 -THC, a dibenzopyran classical cannabinoid
drug with a K of 4.6nM 2.0, it is a potent CB2
agonist.
118.1. SEE ALSO

JWH-234 a cannabinoid agonist that has 2.2x selectivity for CB2 with a K value of 8.4nM 1.8 at
CB2 and 3.8nM 0.6 at CB1 .
JWH-249 CB1 : 8.4nM 1.8 CB2 : 20nM 2
selectivity for CB1 : 2.38x[6]
JWH-250 an analgesic chemical from the phenylacetylindole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors, with a K
of 11nM at CB1 and 33nM at CB2 .[6] It is found in
JWH-251
(1-pentyl-3-(229nM 3
methylphenylacetyl)indole) CB1 :
CB2 : 146nM 36 selectivity for CB1 : 5x[6]
JWH-253
JWH-258 a potent and mildly selective CB1 agonist with a K of 4.6nM 0.6 and 10.5nM 1.3 at
CB2 .[1]
JWH-300 CB1 : 116nM CB2 : 5.3nM[2]
JWH-302
(1-pentyl-3-(3methoxyphenylacetyl)indole) CB1 : 17nM 2

CB2 : 89nM 15 selectivity for CB1 : 5.26x[6]
JWH-307 an analgesic drug from the naphthoylpyrrole family, which acts as a cannabinoid agonist at both the CB1 and CB2 receptors. It is somewhat selective for the CB2 subtype, with a K of
7.7nM at CB1 vs 3.3nM at CB2 .
JWH-336 CB1 : ~1.2nM CB2 : 36nM[2]
163
118.1 See also

List of AM cannabinoids
List of HU cannabinoids
List of CP cannabinoids
List of miscellaneous designer cannabinoids
118.2 References
[1] Human, JW, Zengin, G, Wu, MJ, Lu, J, Hynd, G,
Bushell, K, Tartal, C, Hurst, DP, Reggio, PH, Selley, DE,
Cassidy, MP, Wiley, JL, Martin, BR (2005). Structureactivity relationships for 1-alkyl-3-(1-naphthoyl)indoles
at the cannabinoid CB(1) and CB(2) receptors: steric
and electronic eects of naphthoyl substituents. New
highly selective CB(2) receptor agonists.
doi:10.1016/j.bmc.2004.09.050. PMID 15582455.
2219524. PMID 17982473.
[3] Human, JW, Mabon, R, Wu, MJ, Lu, J, Hart, R, Hurst,
DP, Reggio, PH, Wiley, JL, Martin, BR (2003). 3Indolyl-1-naphthylmethanes: New Cannabimimetic Indoles Provide Evidence for Aromatic Stacking Interactions with the CB1 Cannabinoid Receptor. Bioorganic & Medicinal Chemistry Letters 11 (4): 539549.
doi:10.1016/S0968-0896(02)00451-0. PMID 12538019.
JWH-350 a 11-nor-1-methoxy-3-(1',1'dimethylheptyl)9-hydroxyhexahydrocannabinol
with 33-fold selectivity for the CB2 receptor and
high CB2 receptor anity (K=12nM 1) has the
desirable combination of excellent CB2 anity
combined with little anity for the CB1 receptor.[2]
[4] Howlett, A. C.; Barth, F; Bonner, TI; Cabral, G; Casellas,

P; Devane, WA; Felder, CC; Herkenham, M; MacKie, K
(2002). International Union of Pharmacology. XXVII.
Classication of Cannabinoid Receptors. Pharmacological Reviews 54 (2): 161202. doi:10.1124/pr.54.2.161.
PMID 12037135.
JWH-359 a dibenzopyran classical cannabinoid drug with a K of 13.0nM and selectivity of

around 220x for CB2 , it is a potent and selective CB2
receptor agonist.
PMID 15582455.
JWH-387
1-pentyl-3-(4-bromo-1naphthoyl)indole, an analgesic chemical from

the naphthoylindole family, which acts as a potent
cannabinoid agonist at both receptors with a K of
JWH-398 an analgesic chemical from the naphthoylindole family, which acts as a potent cannabinoid agonist at both receptors with a K of 2.3nM at
CB1 and 2.8nM at CB2 .[7]
JWH-424 a potent and moderately selective CB2
agonist with a K of 5.44nM at CB2 and 20.9nM at
CB1 .
[6] Human, JW, Szklennik, PV, Almond, A, Bushell,

K, Selley, DE, He, H, Cassidy, MP, Wiley, JL,
Martin, BR (2005). 1-Pentyl-3-phenylacetylindoles,
a new class of cannabimimetic indoles.
doi:10.1016/j.bmcl.2005.06.008. PMID 16005223.
[7] The Cannabinoid Receptors.
doi:10.1007/978-159745-503-9. Retrieved 28 August 2013.
Chapter 119
LY-2183240
LY-2183240 is a drug which acts both as a potent inhibitor of the reuptake of the endocannabinoid
anandamide and as an inhibitor of fatty acid amide hydrolase (FAAH), the primary enzyme responsible for degrading anandamide. This leads to markedly elevated
anandamide levels in the brain, and LY-2183240 has
been shown to produce both analgesic and anxiolytic effects in animal models.[1][2][3][4]
Simmons RM, Li D, Iyengar S, Felder CC. Identication

of a high-anity binding site involved in the transport of
endocannabinoids. 2005 Dec; 102(49):17852-7. PMID
16314570
2.Jump up ^ Dickason-Chestereld AK, Kidd SR, Moore

SA, Schaus JM, Liu B, Nomikos GG, Felder CC. Pharmacological characterization of endocannabinoid transport and fatty acid amide hydrolase inhibitors. Cellular and Molecular Neurobiology. 2006 Jul-Aug;26(46):407-23. PMID 16736384 3.Jump up ^ Alexander
119.1 See also
JP, Cravatt BF. The putative endocannabinoid transport
blocker LY2183240 is a potent inhibitor of FAAH and
PF-04457845
several other brain serine hydrolases. Journal of the
American Chemical Society. 2006 Aug 2;128(30):9699 URB-597
704. PMID 16866524 4.Jump up ^ Maione S, Morera E, Marabese I, Ligresti A, Luongo L, Ortar G, Di
Marzo V. Antinociceptive eects of tetrazole inhibitors
119.2 References
of endocannabinoid inactivation: cannabinoid and noncannabinoid receptor-mediated mechanisms. British
[1] Dickason-Chestereld AK, Kidd SR, Moore SA, Schaus Journal of Pharmacology. 2008 Nov;155(5):775-82.
JM, Liu B, Nomikos GG, Felder CC. Pharmacological PMID 18660824 5.Jump up ^ Powers MS, Barrenha GD,
characterization of endocannabinoid transport and fatty Mlinac NS, Barker EL, Chester JA. Eects of the novel
acid amide hydrolase inhibitors. Cellular and Molecu- endocannabinoid uptake inhibitor, LY2183240, on fearlar Neurobiology. 2006 Jul-Aug;26(4-6):407-23. PMID
potentiated startle and alcohol-seeking behaviors in mice
16736384
selectively bred for high alcohol preference. Psychophar[2] Alexander JP, Cravatt BF. The putative endocannabi- macology (Berlin). 2010 Dec;212(4):571-83. PMID
noid transport blocker LY2183240 is a potent inhibitor 20838777
of FAAH and several other brain serine hydrolases.
Journal of the American Chemical Society. 2006 Aug
2;128(30):9699-704. PMID 16866524
[3] Maione S, Morera E, Marabese I, Ligresti A, Luongo L, Ortar G, Di Marzo V. Antinociceptive effects of tetrazole inhibitors of endocannabinoid inactivation: cannabinoid and non-cannabinoid receptormediated mechanisms. British Journal of Pharmacology.
2008 Nov;155(5):775-82. PMID 18660824
[4] Powers MS, Barrenha GD, Mlinac NS, Barker EL,
Chester JA. Eects of the novel endocannabinoid uptake inhibitor, LY2183240, on fear-potentiated startle and
alcohol-seeking behaviors in mice selectively bred for high
alcohol preference. Psychopharmacology (Berlin). 2010
Dec;212(4):571-83. PMID 20838777
1. Moore SA, Nomikos GG, Dickason-Chestereld AK,

Schober DA, Schaus JM, Ying BP, Xu YC, Phebus L,
164
Chapter 120
LY-320,135
LY-320,135 is a drug used in scientic research which
acts as a selective antagonist of the cannabinoid receptor
CB1 . It was developed by Eli Lilly and Company in the
1990s.
LY-320,135 displays fairly good selectivity, with a
binding anity for CB1 around 70x stronger than for
CB2 ,[1] but both its potency and selectivity are modest
compared to newer agents, and at higher doses it also
binds to a range of non-cannabinoid receptors. However
LY-320,135 is still fairly widely used in research, particularly for elucidating the mechanisms by which many CB1
antagonists act as inverse agonists at higher doses.[2]
120.1 References
[1] Felder CC, Joyce KE, Briley EM, Glass M, Mackie
KP, Fahey KJ, Cullinan GJ, Hunden DC, Johnson DW,
Chaney MO, Koppel GA, Brownstein M. LY320135, a
novel cannabinoid CB1 receptor antagonist, unmasks coupling of the CB1 receptor to stimulation of cAMP accumulation. Journal of Pharmacology and Experimental
Therapeutics. 1998 Jan;284(1):291-7. PMID 9435190
[2] Pertwee RG. Inverse agonism and neutral antagonism at
cannabinoid CB1 receptors. Life Sciences. 2005 Feb
4;76(12):1307-24. PMID 15670612
165
Chapter 121
MAM-2201
MAM-2201 (4'-methyl-AM-2201, 5"-uoro-JWH122) is a drug that presumably acts as a potent agonist
for the cannabinoid receptors. It had never previously
been reported in the scientic or patent literature, and
was rst identied by laboratories in the Netherlands
and Germany in June 2011 as an ingredient in synthetic
cannabis smoking blends.[1][2][3] Like RCS-4 and AB001, MAM-2201 thus appears to be a novel compound
invented by "research chemical" suppliers specically for
grey-market recreational use. Structurally, MAM-2201
is a hybrid of two known cannabinoid compounds JWH122 and AM-2201, both of which had previously been
used as active ingredients in synthetic cannabis blends before being banned in many countries. MAM-2201 has
been banned by being added to the temporary class drug
schedule in New Zealand, eective from 13 July 2012.[4]
121.2 References
[2] Moosmann, B., et al. (2012). Separation and structural characterization of the synthetic cannabinoids
JWH-412 and 1-(5-uoropentyl)1H-indol-3yl]-(4methylnaphthalen-1-yl)methanone
using
GCMS,
NMR analysis and a ash chromatography system.
Forensic Science International 220 (13): e17e22.
[3] Simolka, K., et al. (2012). Analysis of synthetic cannabinoids in spice-like herbal highs: Snapshot of the German market in summer 2011. Analytical and Bioanalytical Chemistry 404 (1): 157171. doi:10.1007/s00216012-6122-4. PMID 22710567.
[4] Temporary Class Drug Notice, 5 July 2012. NZ Department of Internal Aairs.
121.1 Pharmacology
Nothing has been published on the pharmacology of
MAM-2201, though it presumably has similar properties
to the closely related AM-2201 and JWH-122, which are
both full agonists and unselectively bind to CB1 and CB2
cannabinoid receptors with low nanomolar anity.
121.1.1
[1] EMCDDAEuropol 2011 Annual Report on the implementation of Council Decision 2005/387/JHA
Pharmacokinetics
Main article: Pharmacokinetic data of JWH-018 is

generally applicable to MAM-2201.
The pharmacokinetics of MAM-2201 has not been studied, but its metabolism likely diers only slightly from
that of JWH-018, with the main metabolic pathway
being hydroxylation at various positions, followed by
glucuronidation of the hydroxylated metabolites. Ndealkylation is also likely to occur, producing uoroalkyl metabolites and ultimately 3-uoropropanoic
acid, though the odd-numbered alkyl chain of MAM2201 would not be expected to produce uoroacetate as
a metabolite. Also metabolism of the related compound
AM-694 has shown hydrolytic deuorination of the alkyl
chain, meaning any uoroalkyl metabolites formed are
likely to be further metabolised themselves.[5]
166
[5] Grigoryev, A.; Kavanagh, P.; Melnik, A. (2012).

The detection of the urinary metabolites of 1-(5uoropentyl)1H-indol-3-yl]-(2-iodophenyl)methanone
(AM-694), a high anity cannabimimetic, by gas
chromatography - mass spectrometry. Drug Testing and
Analysis 5 (2): 1105. doi:10.1002/dta.1336. PMID
22522907.
Chapter 122
MDA-19
MDA-19 is a drug that acts as a potent and selective agonist for the cannabinoid receptor CB2 , with reasonable selectivity over the psychoactive CB1 receptor,
though with some variation between species. In animal
studies it was eective for the treatment of neuropathic
pain, but failed to produce cannabis-like behavioural
eects.[1][2]
122.1 See also

AM-1221
JTE 7-31
JWH-019
JWH-133
122.2 References
[1] Diaz P, et al. Design and synthesis of a novel series of
N-alkyl isatin acylhydrazone derivatives that act as selective cannabinoid receptor 2 agonists for the treatment of
neuropathic pain. Journal of Medicinal Chemistry. 2008
Aug 28;51(16):4932-47. PMID 18666769
[2] Xu JJ, et al. Pharmacological characterization of a novel
cannabinoid ligand, MDA19, for treatment of neuropathic
pain. Anesthesia and Analgesia. 2010 Jul;111(1):99-109.
PMID 20522703
167
Chapter 123
Menabitan
Menabitan (INN; SP-204), or menabitan hydrochloride (USAN), is a synthetic drug which acts as a potent
cannabinoid receptor agonist.[1][2] It is closely related to
natural cannabinoids of the tetrahydrocannabinol (THC)
group, diering mainly by its longer and branched side
chain, and the replacement of the 9-position carbon with
a nitrogen.[1] It was studied as an analgesic in the 1970s
and was found to possess antinociceptive eects in both
humans and animals but was never marketed.[1][3][4]
123.1 See also

A-40174 (SP-1)
Dimethylheptylpyran
123.2 References
[1] Green K, Kim K (February 1977). Acute dose response of intraocular pressure to topical and oral cannabinoids. Proceedings of the Society for Experimental
Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.) 154 (2): 22831.
doi:10.3181/00379727-154-39643. PMID 402656.
[2] David J. Triggle (1996). Dictionary of Pharmacological
Agents. Boca Raton: Chapman & Hall/CRC. p. 1271.
ISBN 978-0-412-46630-4.
[3] Reggio PH (1987). Molecular determinants for cannabinoid activity: renement of a molecular reactivity template. NIDA Research Monograph 79: 8295. PMID
2830539.
[4] Gabriel G. Nahas (5 April 1999). Marihuana and
Medicine. Humana Press. p. 46. ISBN 978-0-89603593-5. Retrieved 9 May 2012.
168
Chapter 124
Methanandamide
Methanandamide (AM-356) is a synthetically created stable chiral analog of anandamide.[1] Its eects
have been observed to act on the cannabinoid receptors
(specically on CB1 receptors, which are part of the
central nervous system) found in dierent organisms such
as mammals, sh, and certain invertebrates (e.g. Hydra).
124.1 References
[1] Abadji, V, et al. (1994). "(R)-methanandamide: A
chiral novel anandamide possessing higher potency and
metabolic stability. Journal of Medical Chemistry 37
(12): 188993. doi:10.1021/jm00038a020. PMID
8021930.
169
Chapter 125
MK-9470
MK-9470 is a synthetic compound, which binds to the
CB1 cannabinoid receptor and functions as an inverse agonist.[1]
125.1 References
[1] Burns HD, Van Laere K, Sanabria-Bohrquez S, Hamill
TG, Bormans G, Eng WS, Gibson R, Ryan C, Connolly B, Patel S, Krause S, Vanko A, Van Hecken A,
Dupont P, De Lepeleire I, Rothenberg P, Stoch SA,
Cote J, Hagmann WK, Jewell JP, Lin LS, Liu P, Goulet
MT, Gottesdiener K, Wagner JA, de Hoon J, Mortelmans L, Fong TM, Hargreaves RJ (2007). "[18 F]MK9470, a positron emission tomography (PET) tracer for
in vivo human PET brain imaging of the cannabinoid1 receptor. Proc. Natl. Acad. Sci. U.S.A.
104 (23): 98005. Bibcode:2007PNAS..104.9800B.
doi:10.1073/pnas.0703472104. PMC 1877985. PMID
17535893.
170
Chapter 126
7-methoxy-1-(2-morpholinoethyl)-N-((1S,4R)1,3,3trimethylbicyclo[2.2.1]heptan-2-yl)1H-indole-3carboxamide (N-[(S)-fenchyl]1-[2-(morpholin-4yl)ethyl]7-methoxyindole-3-carboxamide, UR-12,
MN-25) is a drug invented by Bristol-Myers Squibb,[1]
that acts as a reasonably selective agonist of peripheral
cannabinoid receptors.[2] It has moderate anity for
CB2 receptors with a K of 11nM, but 22x lower
anity for the psychoactive CB1 receptors with a K of
245nM. The indole 2-methyl derivative has the ratio of
anities reversed however, with a K of 8nM at CB1
and 29nM at CB2 ,[3][4] which contrasts with the usual
trend of 2-methyl derivatives having increased selectivity
for CB2 (cf. JWH-018 vs JWH-007, JWH-081 vs
JWH-098).[5][6]
Chemically, it is closely related to another indole-3carboxamide synthetic cannabinoid, Org 28611, but with
a dierent cycloalkyl substitution on the carboxamide, and the cyclohexylmethyl group replaced by morpholinylethyl, as in JWH-200 or A-796,260. Early
compounds such as these have subsequently led to the
development of a large number of related indole-3carboxamide cannabinoid ligands.[7][8][9][10]
126.1 See also

A-834,735
AB-001
AM-1221
2-methyl derivative
126.2 References
JTE 7-31
[1] CANNABINOID
RECEPTOR
MODULATORS,
THEIR PROCESSES OF PREPARATION, AND
USE OF CANNABINOID RECEPTOR MODULATORS IN TREATING RESPIRATORY AND
NON-RESPIRATORY DISEASES. WO 2001/58869
JWH-203
MDA-19
SR-144,528
[2] Rulin Zhao, et al. Improved procedure for the preparation of 7-methoxy-2-methyl-1-(2-morpholinoethyl)1Hindole-3-carboxylic acid, key intermediate in the synthesis
UR-144
171
172
CHAPTER 126. N-(S)-FENCHYL-1-(2-MORPHOLINOETHYL)7-METHOXYINDOLE-3-CARBOXAMIDE
3. Chin CL, et al. (January 2008). Dierential effects of cannabinoid receptor agonists on regional brain
activity using pharmacological MRI. British Journal of
[3] Hynes, J., et al. (2002). C-3 Amido-Indole cannabinoid
Pharmacology 153 (2): 36779. doi :10.1038/ sj.bjp
receptor modulators. Bioorganic & Medicinal Chemistry Letters 12 (17): 2399402. doi:10.1016/S0960- .0707506. PMC 2219521. PMID 17965748
of novel 3-amidoindole and indolopyridone cannabinoid
ligands. ARKIVOC 2010 (vi):89-95.
894X(02)00466-3. PMID 12161142.

[4] Wrobleski, Stephen T., et al. (2003). Rational
Design and Synthesis of an Orally Active Indolopyridone as a Novel Conformationally Constrained Cannabinoid Ligand Possessing Antiinammatory Properties.
doi:10.1021/jm020329q. PMID 12747783.
[5] Human, J. W.; Padgett, L. W. (2005).
Recent Developments in the Medicinal Chemistry of
Cannabimimetic Indoles, Pyrroles and Indenes.
Current Medicinal Chemistry 12 (12): 13951411.
doi:10.2174/0929867054020864. PMID 15974991.
[6] Manera, C.; Tuccinardi, T.; Martinelli, A. (2008). Indoles and Related Compounds as Cannabinoid Ligands.
Mini Reviews in Medicinal Chemistry 8 (4): 370387.
doi:10.2174/138955708783955935. PMID 18473928.
[8] Kiyoi T, et al. (August 2010). Design, synthesis, and structure-activity relationship study of conformationally constrained analogs of indole-3-carboxamides
as novel CB1 cannabinoid receptor agonists. Bioorganic & Medicinal Chemistry Letters 20 (16): 491821.
doi:10.1016/j.bmcl.2010.06.067. PMID 20634067.
[9] Moir EM, et al. (December 2010). Design, synthesis, and structure-activity relationship study of bicyclic piperazine analogs of indole-3-carboxamides as
novel cannabinoid CB1 receptor agonists.
doi:10.1016/j.bmcl.2010.10.061. PMID 21074434.
[10] Blaazer, A. R. et al. (2011). Novel indole and azaindole
(pyrrolopyridine) cannabinoid (CB) receptor agonists:
Design, synthesis, structureactivity relationships, physicochemical properties and biological activity. European
doi:10.1016/j.ejmech.2011.08.021. PMID 21885167.

1. John Hynes., et al. C3 AMIDO-INDOLE CANNABINOID RECEPTOR MODULATORS. Bioorganic and
Medical Chemistry Letters. Volume 12 issue 17, 2
September 2002 pages 2399-2402
2. Frost, J. M., et al. (2010). Indol 3-ylcycloalkyl Ketones: Eects of N1 Substituted Indole Side Chain Variations on CB2 Cannabinoid Receptor Activity. Journal of Medicinal Chemistry 53 (1): 295. doi :10.1021/
jm901214q. PMID 19921781
Chapter 127
Nabazenil
Nabazenil (SP-175) is a synthetic cannabinoid receptor
agonist, which has anticonvulsant properties.[1]
127.1 References
[1] Concise dictionary of pharmacological agents: properties
and synonyms. p188. ISBN 0-7514-0499-3
173
Chapter 128
Nabilone
Main article: Medical cannabis
vealed that patients taking cisplatin chemotherapy preferred metoclopramide, while patients taking carboplatin
chemotherapy preferred nabilone to control nausea and
Nabilone is a synthetic cannabinoid with therapeutic
[5]
use as an antiemetic and as an adjunct analgesic for vomiting.
neuropathic pain. It mimics the main chemical com- One study compared the ecacy and tolerability of
pound of cannabis (THC), the active ingredient found in nabilone with that of dihydrocodeine in the treatment of
naturally occurring Cannabis sativa L.[1]
neuropathic pain.[6] The authors found that nabilone was
In Canada, the United States, the United Kingdom and not as eective as dihydrocodeine in controlling pain, and
Mexico, nabilone is marketed as Cesamet. It was ap- caused a higher incidence of minor adverse drug reactions
proved in 1985 by the U.S. Food and Drug Adminis- than did dihydrocodeine. One critic of the study has sugtration (FDA) for treatment of chemotherapy-induced gested that nabilone might be best suited for the treatment
nausea and vomiting (CINV) that has not responded to of patients suering from central and spasticity-related
conventional antiemetics. Though it was approved by pain, for which there is stronger evidence for the benethe FDA in 1985, the drug only began marketing in the ts of cannabinoid therapy; however, these patients made
United States in 2006. In Austria Nabilone is marketed up only a small fraction of the studys population, and
the study was not designed to identify subgroups which
as Canemes and got its approval for CINV in 2013.[2]
might have responded more favorably to treatment than
Although it doesn't have any indication ocially (except others.[7]
in Mexico), nabilone is widely used as an adjunct therapy for chronic pain management. Numerous trials and A clinical trial performed in Canada reviewed the use
of nabilone to treat nightmares in individuals suering
case studies have demonstrated modest eectiveness for
from post-traumatic stress syndrome.[8] The study found
[3]
[4]
relieving bromyalgia and multiple sclerosis.
that nighttime administration of nabilone reduced the
Nabilone is a racemic mixture consisting of the (S,S) and frequency and/or intensity of nightmares in 34 out of
the (R,R) isomers ("trans").
47 (72%) of patients, with 28 reporting complete cessation of nightmares.[8] This study is limited to the extent that there was no placebo control, but warrants future investigation into the use of cannabinoid therapy
128.1 Medical uses
in the treatment of post-traumatic stress syndrome and
other disorders involving recurrent nightmares. As enNabilone has shown modest eectiveness in relieving docannabinoids play a signicant role in regulating longbromyalgia.[3]
term depression, perhaps downregulating the CB1 sysThe main settings that have seen published clinical tem can help remove the highly potentiated, hippocamtrials of nabilone include movement disorders such pal/amydygalia memories of the fear. At the very least,
as Parkinsons syndrome, chronic pain, dystonia and CB1 agonists make one less likely to remember a dream,
spasticity neurological disorders, multiple sclerosis, and or even make REM sleep happen without signicant inthe nausea of cancer chemotherapy. Nabilone is also ef- volvement of the limbic system.
fective in the treatment of inammatory bowel disease,
especially ulcerative colitis. Medical marijuana patients
report that nabilone is more similar in eect to CBD than 128.2 Adverse eects
THC, indicating that it has more of a therapeutic eect
on the body than a high eect on the mind.
Nabilone can increase, rather than decrease, postA study comparing nabilone with metoclopramide, operative pain; in the treatment of bromyalgia, adconducted before the development of modern 5- verse eects limits the useful dose.[3] Adverse eects of
HT3 antagonist anti-emetics such as ondansetron, re- nabilone include, but are not limited to dizziness/vertigo,
174
128.4. REFERENCES
euphoria, drowsiness, dry mouth, ataxia, sleep disturbance, dysphoria, headache, nausea, disorientation, depersonalization, asthenia and increased appetite.[9]
128.3 See also

Dronabinol
128.4 References
[1] How to use Cesamet. Artek LLC. 2008.
[2] Canemes (nabilone)".
[3] Fine PG, Rosenfeld MJ (2013). The endocannabiRamnoid system, cannabinoids, and pain.
bam Maimonides Med J (Review) 4 (4): e0022.
doi:10.5041/RMMJ.10129. PMC 3820295. PMID
24228165.
[4] Wissel J, et al. (2006). Low dose treatment with
the synthetic cannabinoid Nabilone signicantly reduces
spasticity-related pain : a double-blind placebo-controlled
cross-over trial. J Neurol. (Research article) 253
(10): 133741. doi:10.1007/s00415-006-0218-8. PMID
16988792.
[5] Cunningham D, et al. (1988). A randomized trial of oral
nabilone and prochlorperazine compared to intravenous
metoclopramide and dexamethasone in the treatment of
nausea and vomiting induced by chemotherapy regimens
containing cisplatin or cisplatin analogues. Eur J Cancer
Clin Oncol (Randomized controlled trial) 24 (4): 6859.
doi:10.1016/0277-5379(88)90300-8. PMID 2838294.
[6] Frank B, Serpell MG, Hughes J, Matthews JN, Kapur D
(January 2008). Comparison of analgesic eects and
patient tolerability of nabilone and dihydrocodeine for
chronic neuropathic pain: randomised, crossover, double blind study. BMJ (Randomized controlled trial) 336
(7637): 199201. doi:10.1136/bmj.39429.619653.80.
PMC 2213874. PMID 18182416.
[7] Cohen SP (January 2008). Cannabinoids for chronic
pain. BMJ (Research article) 336 (7637): 167
8. doi:10.1136/bmj.39434.444583.80. PMC 2213791.
PMID 18182415.
[8] Fraser, GA (2009). The Use of a Synthetic Cannabinoid
in the Management of Treatment-Resistant Nightmares
in Posttraumatic Stress Disorder (PTSD)". CNS Neurosci
Ther (Trial report) 15 (1): 8488. doi:10.1111/j.17555949.2008.00071.x. PMID 19228182.
[9] Cesamet (nabilone) Prescribing Information. http://
www.cesamet.com/pdf/Cesamet_PI_50_count.pdf. Meda
Pharmaceuticals Inc. Retrieved 16 July 2014.
175
Chapter 129
Nabitan
Nabitan (Nabutam, Benzopyranoperidine, SP-106,
Abbott 40656) is a synthetic cannabinoid analog
of dronabinol (Marinol).[1] It exhibits antiemetic and
analgesic eects, most likely by binding to and activating the CB1 and CB2 cannabinoid receptors, and reduced
intraocular pressure in animal tests, making it potentially
useful in the treatment of glaucoma.[2]
Nabitan has the advantage of being water soluble unlike most cannabinoid derivatives, and was researched
for potential use as an analgesic or sedative,[3] although
it was never developed for clinical use and is not currently used in medicine, as dronabinol or nabilone were
felt to be more useful. However it is sometimes used
in research into the potential therapeutic applications of
cannabinoids.
129.1 References
[1] Razdan RK. The Total Synthesis of Cannabinoids. WileyInterscience 1980
[2] Razdan RK, Howes JF. Drugs related to tetrahydrocannabinol. Medicinal Research Reviews 1983; 3(2):119146. PMID 6134882
[3] Archer RA. The cannabinoids: therapeutic potentials.
Annual Reports in Medicinal Chemistry 1974; 9: 253-259.
PMID 12307093
176
Chapter 130
Nabiximols
tiate the marketing rights in other countries in European
Union and selected other countries around the world.
In April 2011, GW licensed to Novartis the rights to
commercialise nabiximols in Asia (excluding China and
Japan), Africa and the Middle East (excluding Israel). [3]
130.1 Availability
Canadian packaging of a case of Sativex vials
Nabiximols (USAN,[1] trade name Sativex) is a patented

cannabinoid oromucosal mouth spray developed by
the UK company GW Pharmaceuticals for multiple
sclerosis (MS) patients, who can use it to alleviate
neuropathic pain, spasticity, overactive bladder, and other
symptoms.[2] Nabiximols is distinct from all other pharmaceutically produced cannabinoids currently available
because it is a mixture of compounds derived from
Cannabis plants, rather than a mono-molecular synthetic
product. The drug is a pharmaceutical product standardised in composition, formulation, and dose, although it is
still eectively a tincture of the cannabis plant. Its principal active cannabinoid components are the cannabinoids:
tetrahydrocannabinol (THC) and cannabidiol (CBD).
The product is formulated as an oromucosal spray which
is administered by spraying into the mouth. Each spray
delivers a near 1:1 ratio of CBD to THC, with a xed dose
of 2.7 mg THC and 2.5 mg CBD. Nabiximols is also being developed in Phase III trials as a potential treatment to
alleviate pain due to cancer. It has also been researched
in various models of peripheral and central neuropathic
pain.
In May 2003 GW Pharmaceuticals and Bayer entered into an exclusive marketing agreement for GWs
cannabis-based medicinal extract product, to be marketed under the brand name Sativex. Bayer has obtained
exclusive rights to market Sativex in the UK. In addition,
Bayer has the option for a limited period of time to nego-
In June 2010, the Medicines and Healthcare products

Regulatory Agency of the United Kingdom licensed
nabiximols as a prescription-only medicine for the treatment of spasticity due to multiple sclerosis. This regulatory authorization represents the worlds rst full regulatory approval for the medicine. The spray is being marketed in the UK by Bayer Schering Pharma. Many MS
patients cannot receive nabiximols due to local National
Health Service (NHS) resistance to its funding.[4][5] but,
in August 2014, the NHS in Wales agreed to fund Sativex
for people with multiple sclerosis.[6]
Nabiximols was also approved in Spain for MS spasticity
in the second half of 2010 and was launched in that country in March 2011. It was approved in the Czech Republic in April 2011, in Germany in May 2011, in Denmark
in June 2011 and in Sweden in January 2012 to MS patients who have not responded adequately to other medication for spasticity.[7] It has also been recommended for
approval in Italy and Austria with formal approvals expected in these countries during 2011. In Spain and other
European markets (excluding the UK), nabiximols will be
marketed by Almirall.
In Canada, nabiximols has been approved by Health
Canada for the treatment of MS spasticity. It has also
received a licence with conditions (NOC/c) for two additional uses: as adjunctive treatment for the symptomatic
relief of neuropathic pain in multiple sclerosis,[8] and also
for pain due to cancer.[9][10]
Nabiximols is available in a number of countries as an
unlicensed medicine, which enables doctors to prescribe
the product to individual patients who they consider may
benet. The product has been exported from the UK to a
total of 28 countries to date.
In February 2007, GW and Otsuka Pharmaceutical an-
177
178
nounced an exclusive agreement for Otsuka to develop
and market the drug in the United States. The rst large
scale US Phase IIb trial, Spray Trial, for cancer patients
reported positive results in March 2010. GW and Otsuka have now commenced the Phase III development of
nabiximols in cancer pain.
In 2013, France legalized the use of cannabinoids in
medicine, Sativex is the rst one to be sold under prescription.
130.2 Eectiveness
Of the two preliminary Phase III studies investigating the
treatment of MS patients, one showed a reduction of spasticity of 1.2 points on the 010 points rating scale (versus
0.6 points under placebo), the other showed a reduction
of 1.0 versus 0.8 points. Only the rst study reached statistical signicance. The Phase III approval study consisted of a run-in phase where the response of individuals
to the drug was determined. The responders (42% of patients) showed a signicant eect in the second, placebo
controlled, phase of the trial.[11] A 2009 meta-analysis of
six studies found large variations of eectiveness, with a
statistically non-signicant trend towards a reduction
of spasticity.[12]
130.3 Side eects
CHAPTER 130. NABIXIMOLS

Dronabinol
GW Pharmaceuticals
Hortapharm B.V.
130.6 References
[1] United States Adopted Names Coincil: Statement on a
nonproprietary name
[2] http://www.gwpharm.com/SPC.aspx
[3] GW signs Sativex cannabis-based drug deal with Novartis. The Telegraph. 11 April 2011. Retrieved 12 July
2012.
[4] Ryan, Siobhan (4 June 2011). Sussex MS suerers call
for drug funding. Argus (Sussex,UK). Retrieved 8 June
2011.
[5] Sativex rejected by healthcare provider. Lincolnshire.
20 June 2011. Retrieved 20 June 2011.
[6] Wales NHS to oer MS cannabis drug Sativex. 15 August 2014. Retrieved 18 August 2014.
[7] Sativex (nabiximols), Swedish Medical Products Agency
[8] GW Pharmaceuticals. "Multiple Sclerosis". Accessed 24
July 2011.
[9] GW Pharmaceuticals. "Cancer Pain" Accessed 24 July
2011.
[10] Sativex - Investigational Cannabis-Based Treatment for
Pain and Multiple Sclerosis Drug Development Technology. www.drugdevelopment-technology.com. Retrieved 2008-08-08.
In early clinical trials, nabiximols has generally been well

tolerated.[13][14][15] The most common adverse eects in
Phase III trials were dizziness (25%), drowsiness (8.2%)
and disorientation (4%). 12% of patients stopped taking [11] Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel
the drug because of the side eects. No investigations
2011/2012 (German)
regarding the potential for dependence are available, but
such a potential is unlikely considering the pharmacolog- [12] Lakhan, Shaheen E; Rowland, Marie (2009). Whole
plant cannabis extracts in the treatment of spasticity in
ical properties of the two components.[11]
130.4 Controversy
multiple sclerosis: a systematic review. BMC Neurol

9: 59. doi:10.1186/1471-2377-9-59. PMC 2793241.
PMID 19961570.
[13] Wade D, Makela P, Robson P, House H, Bateman C

(2004). Do cannabis-based medicinal extracts have general or specic eects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled
study on 160 patients. Mult Scler 10 (4): 43441.
doi:10.1191/1352458504ms1082oa. PMID 15327042.
GW Pharmaceuticals were issued a unique license to cultivate cannabis for the manufacturing of Sativex in the
UK, granting them the sole legal right to research in
aerosolized cannabis derived therapeutics, which in April
2013 became commercially viable when the UK Govern[14] Wade D, Makela P, House H, Bateman C, Robson P
ment scheduled the Sativex formulation to part IV of the
(2006). Long-term use of a cannabis-based medicine
UK Drugs Act.[16]
in the treatment of spasticity and other symptoms
in multiple sclerosis. Mult Scler 12 (5): 63945.
doi:10.1177/1352458505070618. PMID 17086911.
130.5 See also

Medical cannabis
Nabilone
[15] Wade D, Robson P, House H, Makela P, Aram J (2003).

A preliminary controlled study to determine whether
whole-plant cannabis extracts can improve intractable
neurogenic symptoms. Clin Rehabil 17 (1): 219.
doi:10.1191/0269215503cr581oa. PMID 12617376.
[16] http://www.gwpharm.com/GW%20Pharmaceuticals%
20cannabinoid-medicine%20Sativex%20moved%
20to%20Schedule%204%20of%20UK%20Drugs%
20Act.aspx

GW Pharmaceuticals Website
179
Chapter 131
Naboctate
Naboctate (SP-325) is a synthetic cannabinoid receptor agonist, which has antiemetic, sedative, anxiolytic and
anti-glaucoma properties.[1]
131.1 References
[1] Concise dictionary of pharmacological agents: properties
and synonyms. p188. ISBN 0-7514-0499-3
180
Chapter 132
NESS-0327
NESS-0327 is a drug used in scientic research which
acts as an extremely potent and selective antagonist of
the cannabinoid receptor CB1 . It is much more potent an
antagonist, and more selective for the CB1 receptor over
CB2 , than the more commonly used ligand rimonabant,
with a K at CB1 of 350fM (i.e. 0.00035nM) and a
selectivity of over 60,000x for CB1 over CB2 .[1] Independently, two other groups have described only modest
nanomolar CB1 anity for this compound (125nM[2] and
18.4nM[3] ). Also unlike rimonabant, NESS-0327 does
not appear to act as an inverse agonist at higher doses, instead being a purely neutral antagonist which blocks the
CB1 receptor but does not produce any physiological effect of its own.[4]
132.1 See also

Discovery and development of Cannabinoid Receptor 1 Antagonists
NESS-040C5
132.2 References
[1] Ruiu S, Pinna GA, Marchese G, Mussinu JM, Saba P,
Tambaro S, Casti P, Vargiu R, Pani L. Synthesis and characterization of NESS 0327: a novel putative antagonist of
the CB1 cannabinoid receptor. Journal of Pharmacology
and Experimental Therapeutics. 2003 Jul;306(1):363-70.
PMID 12663689
[2] A.R. Stoit, J.H.M. Lange, A.P. den Hartog, E. Ronken,
K. Tipker, H.H. van Stuivenberg, J.A.R. Dijksman, H.C.
Wals, C.G. Kruse, Chem. Pharm. Bull. 50 (2002) 11091113
[3] Y. Zhang, J.P. Burgess, M. Brackeen, A. Gilliam, S.W.
Mascarella, K. Page, H.H. Seltzman, B.F. Thomas, J.
Med. Chem. 51 (2008) 3526-3539
[4] Tambaro S, Mongeau R, Dessi C, Pani L, Ruiu S. Modulation of ATP-mediated contractions of the rat vas deferens through presynaptic cannabinoid receptors. European
Journal of Pharmacology. 2005 Nov 21;525(1-3):150-3.
PMID 16271359
181
Chapter 133
NESS-040C5
NESS-040C5 is a potent cannabinoid agonist which was
developed for the treatment of glaucoma.[1] It has reasonable selectivity for the CB2 receptor subtype, having
a CB2 anity of 0.4nM, and 25x selectivity over the related CB1 receptor.[2]
133.1 See also

AB-FUBINACA
NESS-0327
SR-144,528
133.2 References
[1] Paolo Lazzari et al. Pharmaceutical Compounds. US
Patent 8106218
[2] Hanus LO, Mechoulam R. Novel natural and synthetic ligands of the endocannabinoid system. Current Medicinal
Chemistry. 2010;17(14):1341-59. PMID 20166928
182
Chapter 134
NMP-7
NMP-7 is a drug which acts as both a non-selective
agonist of the CB1 and CB2 cannabinoid receptors, and
also as a blocker of T-type calcium channels, the target
of anticonvulsant drugs such as ethosuximide. NMP-7
has an agonist EC50 of 96.9nM at CB1 and 10.5nM at
CB2 , and an IC50 of 1.84M for blocking Cav3.2 T-type
calcium channels. In animal studies it produces potent
analgesic eects in a variety of dierent tests.[1]
134.1 References
[1] You H, Gadotti VM, Petrov RR, Zamponi GW, Diaz P.
Functional characterization and analgesic eects of mixed
cannabinoid receptor/T-type channel ligands. Molecular
Pain. 2011 Nov 17;7:89. PMID 22093952
183
Chapter 135
Nonabine
Nonabine (BRL-4664) is a drug which is a cannabinoid
derivative, which was developed for the prevention of nausea and vomiting associated with cancer
chemotherapy.[1] It has strong antiemetic eects equivalent to those of chlorpromazine, and also produces
some mild sedative eects, along with dry mouth and
EEG changes typical of cannabinoid agonists, but with
minimal changes in mood or perception, suggesting the
abuse potential is likely to be low.[2][3]
135.1 References
[1] Staquet M, Bron D, Rozencweig M, Kenis Y. Clinical
studies with a THC analog (BRL-4664) in the prevention
of cisplatin-induced vomiting. Journal of Clinical Pharmacology. 1981 Aug-Sep;21(8-9 Suppl):60S-63S. PMID
7197692
[2] Archer CB, Amlot PL, Trounce JR. Antiemetic eect
of nonabine in cancer chemotherapy: a double blind
study comparing nonabine and chlorpromazine. British
Medical Journal (Clinical Research Edition). 1983 Jan
29;286(6362):350-1. PMID 6402096
[3] McClelland GR, Sutton JA. Pilot investigation of the
quantitative EEG and clinical eects of ketazolam and
the novel antiemetic nonabine in normal subjects. Psychopharmacology (Berlin). 1985;85(3):306-8. PMID
2860687
184
Chapter 136
11-nor-9-Carboxy-THC
Not to be confused with Tetrahydrocannabinolic acid.
11-nor9-Carboxy-THC, also known as 11-nor9carboxy-delta-9-tetrahydrocannabinol,
11-nor9-carboxy-delta-9-THC, 11-COOH-THC, THCCOOH, and THC-11-oic acid, is the main secondary
metabolite of THC which is formed in the body after
Cannabis is consumed.
11-COOH-THC is formed in the body by oxidation of the
active metabolite 11-Hydroxy-THC (also known as 11OH-THC) by liver enzymes. It is then metabolized further by conjugation with glucuronide,[2] forming a watersoluble congener which can be more easily excreted by
the body.[3]
While 11-COOH-THC does not have any psychoactive eects in its own right, it may still have a
role in the analgesic and antiinammatory eects of
cannabis,[10][11][12] and has also been shown to moderate
the eects of THC itself which may help explain the difference in subjective eects seen between occasional and
regular users of cannabis.[13][14]
136.1 References
11-COOH-THC is not psychoactive itself, but has a long

half-life in the body of up to several days (or even weeks
in very heavy users),[4][5][6] making it the main metabolite tested for when blood or urine testing for cannabis
use. More selective tests are able to distinguish between
11-OH-THC and 11-COOH-THC, which can help determine how recently cannabis was consumed;[7][8] if only
11-COOH-THC is present then the cannabis was used
some time ago and any impairment in cognitive ability
or motor function will have dissipated, whereas if both
11-OH-THC and 11-COOH-THC are present then the
cannabis was consumed more recently and motor impairment may still be present.
Some jurisdictions where cannabis use is decriminalized
or permitted under some circumstances use such tests
when determining whether drivers were legally intoxicated and therefore unt to drive, with the comparative levels of THC, 11-OH-THC and 11-COOH-THC
being used to derive a blood cannabis level analogous to the blood alcohol level used in prosecuting impaired drivers.[9] On the other hand in jurisdictions where
cannabis is completely illegal, any detectable levels of 11COOH-THC may be deemed to constitute driving while
intoxicated, even though this approach has been criticized
as tantamount to prohibition of driving whilst being a
recent user of cannabis regardless of the presence or absence of any actual impairment that might impact on driving performance.
185
[1] http://www.clinchem.org/cgi/content/full/55/12/2180
[2] Skopp, G; Ptsch, L (2002). Stability of 11-nor-delta(9)carboxy-tetrahydrocannabinol glucuronide in plasma and
urine assessed by liquid chromatography-tandem mass
spectrometry. Clinical chemistry 48 (2): 3016. PMID
11805011.
[3] Law, B; Mason, PA; Moat, AC; King, LJ (1984). Conrmation of cannabis use by the analysis of delta 9tetrahydrocannabinol metabolites in blood and urine by
combined HPLC and RIA. Journal of analytical toxicology 8 (1): 1922. doi:10.1093/jat/8.1.19. PMID
6323852.
[4] Huestis, MA; Mitchell, JM; Cone, EJ (1995). Detection
times of marijuana metabolites in urine by immunoassay and GC-MS. Journal of analytical toxicology 19 (6):
4439. doi:10.1093/jat/19.6.443. PMID 8926739.
[5] Pope Jr, HG; Gruber, AJ; Hudson, JI; Huestis,
MA; Yurgelun-Todd, D (2001).
Neuropsychological performance in long-term cannabis users.
Archives of General Psychiatry 58 (10): 90915.
doi:10.1001/archpsyc.58.10.909. PMID 11576028.
[6] Dietz, L; Glaz-Sandberg, A; Nguyen, H; Skopp,
G; Mikus, G; Aderjan, R (2007).
The urinary
disposition of intravenously administered 11-nor-9carboxy-delta-9-tetrahydrocannabinol
in
humans.
Therapeutic drug monitoring 29 (3):
36872.
doi:10.1097/FTD.0b013e31805ba6fd. PMID 17529896.
[7] Huestis, MA; Henningeld, JE; Cone, EJ (1992).
Blood cannabinoids. II. Models for the prediction
of time of marijuana exposure from plasma concentrations of delta 9-tetrahydrocannabinol (THC) and 11-nor9-carboxy-delta 9-tetrahydrocannabinol (THCCOOH)".
186
CHAPTER 136. 11-NOR-9-CARBOXY-THC
Journal of analytical toxicology 16 (5):

doi:10.1093/jat/16.5.283. PMID 1338216.
28390.
[8] Huestis, MA; Elsohly, M; Nebro, W; Barnes, A;

Gustafson, RA; Smith, ML (2006). Estimating time
of last oral ingestion of cannabis from plasma THC and
THCCOOH concentrations. Therapeutic drug monitoring 28 (4): 5404. doi:10.1097/00007691-20060800000009. PMID 16885722.
[9] Mntrey, A; Augsburger, M; Favrat, B; Pin, MA;
Rothuizen, LE; Appenzeller, M; Buclin, T; Mangin, P;
Giroud, C (2005). Assessment of driving capability
through the use of clinical and psychomotor tests in relation to blood cannabinoids levels following oral administration of 20 mg dronabinol or of a cannabis decoction
made with 20 or 60 mg Delta9-THC. Journal of analytical toxicology 29 (5): 32738. doi:10.1093/jat/29.5.327.
PMID 16105257.
[10] Burstein, SH; Hull, K; Hunter, SA; Latham, V (1988).
Cannabinoids and pain responses: a possible role for
prostaglandins. The FASEB journal : ocial publication
of the Federation of American Societies for Experimental
Biology 2 (14): 30226. PMID 2846397.
[11] Doyle, SA; Burstein, SH; Dewey, WL; Welch, SP (1990).
Further studies on the antinociceptive eects of delta 6THC-7-oic acid. Agents and actions 31 (12): 15763.
doi:10.1007/bf02003237. PMID 2178317.
[12] Ujvry, I; Grotenhermen, F (2014). 11-Nor-9-carboxy9-tetrahydrocannabinol a ubiquitous yet underresearched cannabinoid. A review of the literature.
Cannabinoids 9 (1): 18.
[13] Burstein, S; Hunter, SA; Latham, V; Renzulli, L (1987).
A major metabolite of delta 1-tetrahydrocannabinol reduces its cataleptic eect in mice. Experientia 43 (4):
4023. doi:10.1007/BF01940427. PMID 3032669.
[14] Burstein, S; Hunter, SA; Latham, V; Renzulli, L
(1986). Prostaglandins and cannabis--XVI. Antagonism
of delta 1-tetrahydrocannabinol action by its metabolites. Biochemical pharmacology 35 (15): 25538.
doi:10.1016/0006-2952(86)90053-5. PMID 3017356.
Chapter 137
O-1057
O-1057 is an analgesic cannabinoid derivative created
by Organix Inc. for use in scientic research. Unlike
most cannabinoids discovered to date, it is water soluble, which gives it considerable advantages over many related cannabinoids. It has moderate anity for both CB1
and CB2 receptors, with K values of 8.36nM at CB1 and
7.95nM at CB2 .[1]
137.1 See also

AM-2232
O-774
O-1812
O-2694
137.2 References
[1] Pertwee RG, et al. O-1057, a potent water-soluble
cannabinoid receptor agonist with antinociceptive properties.
British Journal of Pharmacology.
2000
Apr;129(8):1577-84. PMID 10780961
187
Chapter 138
O-1125
O-1125
(3-(1,1-dimethylhexyl-6dimethylcarboxamide)-8-tetrahydrocannabinol) is
a drug which is a cannabinoid derivative. It has analgesic
eects and is used in scientic research. It is a potent
CB1 full agonist with a Ki of 1.16nM.[1]
138.1 References
1999 Oct;128(3):684-8.
doi:10.1038/sj.bjp.0702806
PMID 10516649
188
Chapter 139
O-1238
O-1238 is a drug which is a cannabinoid derivative that
is used in scientic research. It is a partial agonist at the
cannabinoid receptor CB1 ,[1] producing a maximal stimulation of 58.3%[2] with a Ki of 8.45nM.[3]
139.1 References
1999 Oct;128(3):684-8.
doi:10.1038/sj.bjp.0702806
PMID 10516649
[2] Grin G, Wray EJ, Rorrer WK, Crocker PJ, Ryan WJ,
Saha B, Razdan RK, Martin BR, Abood ME. An investigation into the structural determinants of cannabinoid receptor ligand ecacy. British Journal of Pharmacology.
1999 Apr;126(7):1575-84. doi:10.1038/sj.bjp.0702469
PMID 10323589
[3] Ross RA, Gibson TM, Stevenson LA, Saha B, Crocker
P, Razdan RK, Pertwee RG. Structural determinants
of the partial agonist-inverse agonist properties of 6'azidohex-2'-yne-delta8-tetrahydrocannabinol at cannabinoid receptors. British Journal of Pharmacology. 1999
Oct;128(3):735-43. PMID 10516656
189
Chapter 140
O-1269
O-1269 is a drug that is a diarylpyrazole derivative,
related to potent cannabinoid antagonist drugs such as
rimonabant and surinabant. However O-1269 and several related drugs were unexpectedly found to act as full
or partial agonists at the cannabinoid receptors rather than
antagonists, and so produce the usual eects expected
of cannabinoid agonists in animal tests, such as sedation
and analgesic eects. The N-heptyl homologue O-1270
and the N-propyl homologue O-1399 also act as cannabinoid agonists with similar potency in vivo, despite weaker
binding anity at cannabinoid receptors compared to the
pentyl homologue O-1269.[1][2][3] Agonist-like and atypical cannabinoid activity has also been observed with a
number of related compounds.[4][5]
140.1 References
[1] Billy R. Martin, Raj K. Razdan, Anu Mahadevan. Pyrazole cannabinoid agonist and antagonists. US Patent
6509367, led Sep 22, 2001, issued Jan 21, 2003.
[2] Shim JY, Welsh WJ, Cartier E, Edwards JL, Howlett AC.
Molecular interaction of the antagonist N-(piperidin1-yl)5-(4-chlorophenyl)1- (2,4-dichlorophenyl)4methyl-1H-pyrazole-3-carboxamide with the CB1
cannabinoid receptor. Journal of Medicinal Chemistry.
2002 Mar 28;45(7):1447-59. PMID 11906286
[3] Francisco ME, Seltzman HH, Gilliam AF, Mitchell RA,
Rider SL, Pertwee RG, Stevenson LA, Thomas BF. Synthesis and structure-activity relationships of amide and
hydrazide analogues of the cannabinoid CB(1) receptor
antagonist N-(piperidinyl)- 5-(4-chlorophenyl)1-(2,4dichlorophenyl)4-methyl-1H-pyrazole-3-carboxamide
(SR141716). Journal of Medicinal Chemistry. 2002 Jun
20;45(13):2708-19. PMID 12061874
[4] Thomas, B. F.; Francisco, M. E. Y.; Seltzman,
H. H.; Thomas, J. B.; Fix, S. E.; Schulz, A. K.;
Gilliam, A. F.; Pertwee, R. G.; Stevenson, L. A.
(2005). Synthesis of long-chain amide analogs of the
cannabinoid CB1 receptor antagonist N-(piperidinyl)5(4-chlorophenyl)1-(2,4-dichlorophenyl)4-methyl1H-pyrazole-3-carboxamide (SR141716) with unique
binding selectivities and pharmacological activities.
Bioorganic & Medicinal Chemistry 13 (18): 54635474.
doi:10.1016/j.bmc.2005.06.005. PMID 15994087.
190
[5] Wiley, J. L.; Selley, D. E.; Wang, P.; Kottani, R.;

Gadthula, S.; Mahadeven, A. (2011). 3-Substituted
Pyrazole Analogs of the Cannabinoid Type 1 (CB1) Receptor Antagonist Rimonabant: Cannabinoid AgonistLike Eects in Mice via Non-CB1, Non-CB2 Mechanism. Journal of Pharmacology and Experimental Therapeutics 340 (2): 433444. doi:10.1124/jpet.111.187815.
PMC 3263966. PMID 22085649.
Chapter 141
O-1602
O-1602 is a synthetic compound most closely related to
abnormal cannabidiol, and more distantly related in structure to cannabinoid drugs such as THC. O-1602 does
not bind to the classical cannabinoid receptors CB1 or
CB2 with any signicant anity, but instead is an agonist at several other receptors which appear to be related to the cannabinoid receptors, particularly GPR18
and GPR55. These previously orphan receptors have
been found to be targets for a number of endogenous and
synthetic cannabinoid compounds, and are thought to be
responsible for most of the non-CB1 , non-CB2 mediated
eects that have become evident in the course of cannabinoid research. O-1602 produces some eects shared with
classical cannabinoid compounds such as analgesic and
antiinammatory eects and appetite stimulation, but it
does not produce sedation or psychoactive eects, and
has several actions in the gut and brain that are not shared
with typical cannabinoid agonists.[1][2][3][4][5][6][7]
141.1 See also

Cannabidiol
17 (8): 16511664. doi:10.1002/ibd.21538.

3116968. PMID 21744421.
PMC
[4] Daz-Arteaga, A.; Vzquez, M. J.; Vazquez-Martnez,

R.; Pulido, M. R.; Suarez, J.; Velsquez, D. A.; Lpez,
M.; Ross, R. A.; De Fonseca, F. R.; Bermudez-Silva,
F. J.; Malagn, M. M.; Diguez, C.; Nogueiras, R.
(2012). The atypical cannabinoid O-1602 stimulates
food intake and adiposity in rats. Diabetes, Obesity
and Metabolism 14 (3): 234243. doi:10.1111/j.14631326.2011.01515.x. PMID 21981246.
[5] Kargl, J.; Haybaeck, J.; Stani, A.; Andersen, L.;
Marsche, G.; Heinemann, A.; Schicho, R. (2012). O1602, an atypical cannabinoid, inhibits tumor growth in
colitis-associated colon cancer through multiple mechanisms. Journal of Molecular Medicine 91 (4): 44958.
doi:10.1007/s00109-012-0957-1. PMC 3529923. PMID
22965195.
[6] McHugh, D.; Wager-Miller, J.; Page, J.; Bradshaw, H. B.
(2012). SiRNA knockdown of GPR18 receptors in BV2 microglia attenuates N-arachidonoyl glycine-induced
cell migration. Journal of Molecular Signaling 7 (1): 10.
doi:10.1186/1750-2187-7-10. PMC 3493281. PMID
22834922.
[7] Caldwell, M. D.; Hu, S. S. J.; Viswanathan, S.; Bradshaw, H.; Kelly, M. E.; Straiker, A. (2013). A
GPR18-based signaling system regulates IOP in murine
eye. British Journal of Pharmacology 169 (4): 834
43. doi:10.1111/bph.12136. PMC 3687663. PMID
23461720.
O-1918
141.2 References
[1] Ashton, J. C. (2012). The atypical cannabinoid o-1602:
Targets, actions, and the central nervous system. Central nervous system agents in medicinal chemistry 12 (3):
233239. doi:10.2174/187152412802430156. PMID
22831390.
[2] Schuelert, N.; McDougall, J. J. (2011). The abnormal
cannabidiol analogue O-1602 reduces nociception in a rat
model of acute arthritis via the putative cannabinoid receptor GPR55. Neuroscience Letters 500 (1): 7276.
doi:10.1016/j.neulet.2011.06.004. PMID 21683763.
[3] Schicho, R.; Bashashati, M.; Bawa, M.; McHugh, D.;
Saur, D.; Hu, H. M.; Zimmer, A.; Lutz, B.; MacKie,
K.; Bradshaw, H. B.; McCaerty, D. M.; Sharkey, K.
A.; Storr, M. (2011). The atypical cannabinoid O1602 protects against experimental colitis and inhibits
neutrophil recruitment. Inammatory Bowel Diseases
191
Chapter 142
O-1812
O-1812 is an eicosanoid derivative related to anandamide
that acts as a potent and highly selective agonist for the
cannabinoid receptor CB1 , with a K of 3.4nM at CB1
and 3870nM at CB2 .[1] Unlike most related compounds,
O-1812 is metabolically stable against rapid breakdown
by enzymes, and produces a cannabinoid-like discriminative eect in rats, which is similar but not identical
to that produced by cannabinoid drugs of other chemical
classes.[2][3][4][5]
142.1 See also

AM-1235
AM-2232
AM-2389
Methanandamide
O-774
O-1057
142.2 References
[1] Di Marzo V, et al. (February 2001). Highly selective CB(1) cannabinoid receptor ligands and novel
CB(1)/VR(1) vanilloid receptor hybrid ligands. Biochemical and Biophysical Research Communications 281
(2): 44451. doi:10.1006/bbrc.2001.4354. PMID
11181068.
[2] Baskeld CY, Martin BR, Wiley JL (April 2004).
Dierential eects of delta9-tetrahydrocannabinol and
methanandamide in CB1 knockout and wild-type mice.
The Journal of Pharmacology and Experimental Therapeutics 309 (1): 8691. doi:10.1124/jpet.103.055376.
PMID 14718593.
[3] Wiley JL, et al.
(August 2004).
A comparison of the discriminative stimulus eects of delta(9)tetrahydrocannabinol and O-1812, a potent and metabolically stable anandamide analog, in rats. Experimental and Clinical Psychopharmacology 12 (3): 1739.
doi:10.1037/1064-1297.12.3.173. PMID 15301634.
192
[4] Wiley JL, Smith FL, Razdan RK, Dewey WL (March

2005). Task specicity of cross-tolerance between
Delta9-tetrahydrocannabinol and anandamide analogs in
mice. European Journal of Pharmacology 510 (12): 5968. doi:10.1016/j.ejphar.2005.01.006. PMID
15740725.
[5] Breivogel CS, et al. (July 2008). Sensitivity to delta9tetrahydrocannabinol is selectively enhanced in betaarrestin2 -/- mice. Behavioural Pharmacology 19 (4):
298307. doi:10.1097/FBP.0b013e328308f1e6. PMC
2751575. PMID 18622177.
Chapter 143
O-1871
O-1871 is a potent cannabinoid agonist which was invented by Billy R Martin and Raj K Razdan in 2002.
It has a CB1 receptor anity of 2.0nM and a CB2 receptor anity of 0.3nM.[1] Structurally, O-1871 is a
cyclohexylphenol derivative related to CP 47,497, and
so is illegal in most jurisdictions where CP 47,497
and its derivatives are banned. However the 3,3dimethylcyclohexyl substituent of O-1871 can be replaced by various other groups, producing other potent
compounds such as the cycloheptyl derivative O-1656
and the 2-adamantyl derivative O-1660, as well as the
corresponding 3,5-dichlorophenyl derivative,[2] which are
not cyclohexylphenol derivatives.
143.1 See also

CP 55,940
Cannabidiol
Cannabicyclohexanol
143.2 References
[1] Billy R Martin, Raj K Razdan. CANNABINOIDS. Patent
WO 2003/091189
[2] Xin-Zhong Lai, Dai Lu, Alexandros Makriyannis. Novel
biphenyl and biphenyl-like cannabinoids. Patent US
2004/0087590
193
Chapter 144
O-1918
O-1918 is a synthetic compound related to cannabidiol,
which is an antagonist at two former orphan receptors
GPR18 and GPR55, that appear to be related to the
cannabinoid receptors. O-1918 is used in the study of
these receptors, which have been found to be targets for
a number of endogenous and synthetic cannabinoid compounds, and are thought to be responsible for most of the
non-CB1 , non-CB2 mediated eects that have become
evident in the course of cannabinoid research.[1][2][3][4][5]
144.1 See also

Abnormal cannabidiol
O-1602
144.2 References
[1] Oertler, L.; Mo, F. M.; Btkai, S.; Liu, J.; Begg,
M.; Razdan, R. K.; Martin, B. R.; Bukoski, R. D.;
Kunos, G. (2003). Selective ligands and cellular effectors of a G protein-coupled endothelial cannabinoid
receptor. Molecular Pharmacology 63 (3): 699705.
doi:10.1124/mol.63.3.699. PMID 12606780.
[2] Zakrzeska, A.; Schlicker, E.; Baranowska, M.;
Kozowska, H.; Kwolek, G.; Malinowska, B. (2010). A
cannabinoid receptor, sensitive to O-1918, is involved
in the delayed hypotension induced by anandamide in
anaesthetized rats. British Journal of Pharmacology 160
(3): 574584. doi:10.1111/j.1476-5381.2009.00579.x.
PMC 2931558. PMID 20105178.
[3] Schuelert, N.; McDougall, J. J. (2011). The abnormal
cannabidiol analogue O-1602 reduces nociception in a rat
model of acute arthritis via the putative cannabinoid receptor GPR55. Neuroscience Letters 500 (1): 7276.
doi:10.1016/j.neulet.2011.06.004. PMID 21683763.
[4] Szczesniak, A. M.; Maor, Y.; Robertson, H.; Hung,
O.; Kelly, M. E. M. (2011).
Nonpsychotropic
Cannabinoids, Abnormal Cannabidiol and CanabigerolDimethyl Heptyl, Act at Novel Cannabinoid Receptors to Reduce Intraocular Pressure. Journal of Ocular Pharmacology and Therapeutics 27 (5): 427435.
doi:10.1089/jop.2011.0041. PMID 21770780.
194
[5] Caldwell, M. D.; Hu, S. S. J.; Viswanathan, S.; Bradshaw, H.; Kelly, M. E.; Straiker, A. (2013). A
GPR18-based signaling system regulates IOP in murine
eye. British Journal of Pharmacology 169 (4): 834
43. doi:10.1111/bph.12136. PMC 3687663. PMID
23461720.
Chapter 145
O-2050
O-2050 is a drug that is a classical cannabinoid derivative,
which acts as a silent antagonist for the CB1 receptor.
This gives it an advantage in research over many commonly used cannabinoid antagonists such as rimonabant,
which at higher doses act as inverse agonists at CB1 as
well as showing o-target eects. However while O2050 acts as a silent antagonist in vitro, some tests in vivo
have suggested it may show agonist activity under certain
circumstances.[1][2][3][4][5][6]
145.1 See also

O-2113
145.2 References
[1] Martin B, et al. Agonists and silent antagonists in a series
of cannabinoid sulfonamides. 12th Annual Symposium
on the Cannabinoids, 2002
[2] Martin et al. SULFONAMIDE CANNABINOID AGONISTS AND ANTAGONISTS. US Patent 7279500, Oct
9 2007
[3] Gardner A, Mallet PE. Suppression of feeding, drinking,
and locomotion by a putative cannabinoid receptor 'silent
antagonist'. European Journal of Pharmacology. 2006
Jan 13;530(1-2):103-6. PMID 16380113
[4] Higuchi S, Irie K, Mishima S, Araki M, Ohji M,
Shirakawa A, Akitake Y, Matsuyama K, Mishima K,
Mishima K, Iwasaki K, Fujiwara M. The cannabinoid 1receptor silent antagonist O-2050 attenuates preference
for high-fat diet and activated astrocytes in mice. Journal of Pharmacological Sciences. 2010;112(3):369-72.
PMID 20168044
[5] Higuchi S, Ohji M, Araki M, Furuta R, Katsuki M, Yamaguchi R, Akitake Y, Matsuyama K, Irie K, Mishima
K, Mishima K, Iwasaki K, Fujiwara M. Increment of
hypothalamic 2-arachidonoylglycerol induces the preference for a high-fat diet via activation of cannabinoid
1 receptors. Behavioural Brain Research. 2011 Jan
1;216(1):477-80. PMID 20817042
[6] Wiley JL, Breivogel CS, Mahadevan A, Pertwee RG, Cascio MG, Bolognini D, Human JW, Walentiny DM, Vann
195
RE, Razdan RK, Martin BR. Structural and pharmacological analysis of O-2050, a putative neutral cannabinoid
CB(1) receptor antagonist. European Journal of Pharmacology. 2011 Jan 25;651(1-3):96-105. PMID 21114999
Chapter 146
O-2113
O-2113 is a drug that is a classical cannabinoid derivative,
which acts as a potent agonist for cannabinoid receptors,
producing sedation, hypothermia and analgesia in animal
studies.[1]
146.1 See also

O-2050
O-2372
O-2545
146.2 References
[1] Martin, et al. SULFONAMIDE CANNABINOID AGONISTS AND ANTAGONISTS. US Patent 7279500, Oct
9 2007
196
Chapter 147
O-2372
O-2372 is an analgesic cannabinoid derivative created by
Organix Inc. for use in scientic research. It has high
anity for both CB1 and CB2 receptors, with K values of
1.3nM at CB1 and 0.57nM at CB2 , but is only moderately
soluble in water compared to other related compounds
such as O-2694, which it is a metabolite of.[1]
147.1 See also

O-2113
O-2545
O-2694
147.2 References
[1] Martin BR, et al.
Pharmacological characterization of novel water-soluble cannabinoids. Journal of
Pharmacology and Experimental Therapeutics. 2006
Sep;318(3):1230-9. PMID 16757541
197
Chapter 148
O-2545
O-2545 is an analgesic cannabinoid derivative created
by Organix Inc. for use in scientic research. Unlike
most cannabinoids discovered to date, it is water soluble,
which gives it considerable advantages over many related
cannabinoids. It has high anity for both CB1 and CB2
receptors, with K values of 1.5nM at CB1 and 0.32nM
at CB2 .[1]
148.1 See also

O-2113
O-2372
Tropoxane
148.2 References
Sep;318(3):1230-9. PMID 16757541
198
Chapter 149
O-2694
O-2694 is a drug that is a cannabinoid derivative. It has
analgesic eects and is used in scientic research. Unlike
most cannabinoids discovered to date, it is highly watersoluble, which gives it considerable advantages over many
related drugs. It has high anity for both CB1 and CB2
receptors, with K values of 3.7nM at CB1 and 2.8nM at
CB2 . However, it has complex pharmacokinetics as most
of the administered dose is metabolised by hydrolysis of
the ester link to the water-insoluble compound O-2372,
thus producing a biphasic eects prole that is less suitable for research purposes than the related compound O2545.[1]
149.1 See also

O-1057
O-2372
149.2 References
Sep;318(3):1230-9. PMID 16757541
199
Chapter 150
O-774
O-774 is a classical cannabinoid derivative which acts as
a potent agonist for the cannabinoid receptors, with a K
of 0.6 nM at CB1 , and very potent cannabinoid eects in
animal studies.[1][2]
150.1 See also

AM-2232
O-1057
O-1812
150.2 References
[1] Singer M, et al.
Potent cyano and carboxamido side-chain analogues of 1', 1'-dimethyl-delta8tetrahydrocannabinol. Journal of Medicinal Chemistry.
1998 Oct 22;41(22):4400-7. PMID 9784115
[2] The Cannabinoid Receptors. Part I. Cannabinoid Receptor Ligands and Structure-Activity Relationships. pp 6-9.
Edited by Patricia H Reggio. Humana Press 2009. ISBN
978-1-58829-712-9
200
Chapter 151
O-806
O-806 is a drug which is a cannabinoid derivative that is
used in scientic research. It is described as a mixed agonist/antagonist at the cannabinoid receptor CB1 , meaning
that it acts as an antagonist when co-administered alongside a more potent CB1 agonist, but exhibits weak partial
agonist eects when administered by itself.[1][2]
151.1 References
[1] Grin, G.; Wray, E.; Rorrer, W.; Crocker, P.; Ryan, W.;
Saha, B.; Razdan, R.; Martin, B.; Abood, M. (1999). An
investigation into the structural determinants of cannabinoid receptor ligand ecacy. British Journal of Pharmacology 126 (7): 15751584. doi:10.1038/sj.bjp.0702469.
PMC 1565939. PMID 10323589.
[2] Grin, G.; Wray, E.; Martin, B.; Abood, M.
(1999). Cannabinoid agonists and antagonists discriminated by receptor binding in rat cerebellum.
10516649.
201
Chapter 152
O-823
O-823 is a drug which is a cannabinoid derivative that is
used in scientic research. It is described as a mixed agonist/antagonist at the cannabinoid receptor CB1 , meaning
that it acts as an antagonist when co-administered alongside a more potent CB1 agonist, but exhibits weak partial
agonist eects when administered by itself.[1][2][3]
152.1 References
[1] Pertwee RG, Fernando SR, Grin G, Ryan W,
Razdan RK, Compton DR, Martin BR. Agonistantagonist characterization of 6'-cyanohex-2'-yne-delta
8-tetrahydrocannabinol in two isolated tissue preparations. European Journal of Pharmacology. 1996 Nov
14;315(2):195-201. PMID 8960884
[2] Grin G, Wray EJ, Rorrer WK, Crocker PJ, Ryan WJ,
Saha B, Razdan RK, Martin BR, Abood ME. An investigation into the structural determinants of cannabinoid receptor ligand ecacy. British Journal of Pharmacology.
1999 Apr;126(7):1575-84. doi:10.1038/sj.bjp.0702469
PMID 10323589
1999 Oct;128(3):684-8.
doi:10.1038/sj.bjp.0702806
PMID 10516649
202
Chapter 153
Org 27569
Org 27569 is a drug which acts as a potent and selective
allosteric modulator of the cannabinoid CB1 receptor.
Studies in vitro suggest that it binds to a regulatory site on
the CB1 receptor target, causing a conformational change
that increases the binding anity of CB1 agonists such as
CP 55,940, while decreasing the binding anity of CB1
antagonists or inverse agonists such as rimonabant. However while Org 27569 increases the ability of CB1 agonists to bind to the receptor, it decreases their ecacy at
stimulating second messenger signalling once bound, and
so in practice behaves as an insurmountable antagonist of
CB1 receptor function.[1]
153.1 References
[1] Price MR, Baillie GL, Thomas A, Stevenson LA, Easson M, Goodwin R, McLean A, McIntosh L, Goodwin
G, Walker G, Westwood P, Marrs J, Thomson F, Cowley
P, Christopoulos A, Pertwee RG, Ross RA (November
2005). Allosteric modulation of the cannabinoid CB1
doi:10.1124/mol.105.016162. PMID 16113085.
203
Chapter 154
Org 28312
Org 28312 is a drug developed by Organon International
which acts as a potent cannabinoid receptor full agonist at
both the CB1 and CB2 receptors. It was developed with
the aim of nding a water soluble cannabinoid agonist
suitable for intravenous use as an analgesic, but did not
proceed to human trials, with the related compound Org
28611 chosen instead due to its better penetration into
the brain.[1] The structure-activity relationships of these
compounds have subsequently been investigated further
leading to the development of a number of more potent
analogues, derived by cyclisation around the indole or
piperazine rings.[2][3]
154.1 See also

LBP-1
Org 28611
154.2 References
[2] Kiyoi T, York M, Francis S, Edwards D, Walker G,
Houghton AK, Cottney JE, Baker J, Adam JM (August
2010). Design, synthesis, and structure-activity relationship study of conformationally constrained analogs
of indole-3-carboxamides as novel CB1 cannabinoid receptor agonists. Bioorganic & Medicinal Chemistry Letters 20 (16): 491821. doi:10.1016/j.bmcl.2010.06.067.
PMID 20634067.
[3] Moir EM, Yoshiizumi K, Cairns J, Cowley P, Ferguson
M, Jeremiah F, Kiyoi T, Morphy R, Tierney J, Wishart G,
York M, Baker J, Cottney JE, Houghton AK, McPhail P,
Osprey A, Walker G, Adam JM (December 2010). Design, synthesis, and structure-activity relationship study
of bicyclic piperazine analogs of indole-3-carboxamides
as novel cannabinoid CB1 receptor agonists. Bioorganic & Medicinal Chemistry Letters 20 (24): 732730.
doi:10.1016/j.bmcl.2010.10.061. PMID 21074434.
204
Chapter 155
Org 28611
Org 28611 (SCH-900,111) is a drug developed by
Organon International which acts as a potent cannabinoid
receptor full agonist at both the CB1 and CB2 receptors.
It was developed with the aim of nding a water soluble cannabinoid agonist suitable for intravenous use as an
analgesic,[1] and while it achieved this aim and has progressed as far as Phase II clinical trials in humans as both
a sedative and an analgesic, results against the comparison drugs (midazolam and morphine respectively) were
not particularly favourable in initial testing.[2][3]
155.1 See also

LBP-1
Org 28312
155.2 References
[2] Zuurman L, Passier PC, de Kam M, Kleijn HJ, Cohen
AF, van Gerven JM (August 2009). Pharmacodynamic
and pharmacokinetic eects of the intravenously administered CB1 receptor agonist Org 28611 in healthy male volunteers. Journal of Psychopharmacology (Oxford, England) 23 (6): 63344. doi:10.1177/0269881108091551.
PMID 18635703.
[3] A Comparison of Analgesic Ecacy Between a Single
Dose of ORG 28611, Morphine, and Placebo After Dental Impaction Surgery
205
Chapter 156
Otenabant
Otenabant (CP-945,598) is a drug which acts as a potent and highly selective CB1 antagonist.[1] It was developed by Pzer for the treatment of obesity,[2] but development for this application has been discontinued following
the problems seen during clinical use of the similar drug
rimonabant.[3]
156.1 See also

156.2 References
[1] Kim, M., et al. (2008), Design, chemical synthesis, and biological evaluation of novel triazolyl analogues of taranabant (MK-0364), a cannabinoid-1 receptor inverse agonist, Tetrahedron 64 (48): 1080210809,
doi:10.1016/j.tet.2008.09.057
[2] Woods SC. The endocannabinoid system: novel pathway for cardiometabolic Risk-factor reduction. Journal
of the American Academy of Physician Assistants. 2007
Nov;Suppl Endocannabinoid:7-10. PMID 18047036
[3] http://www.pfizer.com
206
Chapter 157
Parahexyl
Parahexyl (Synhexyl, n-hexyl-3 THC) is a synthetic
homologue of THC, which was invented in 1949 during
attempts to elucidate the structure of 9 -THC, one of the
active components of cannabis. [1][2]
Parahexyl is similar in both structure and activity to THC,
diering only in the position of one double bond, and the
lengthening of the 3-pentyl chain by one CH2 group to
n-hexyl. [3] Parahexyl produces classic cannabis agonist
eects in animals. It has a somewhat higher oral bioavailability than THC itself but is otherwise very similar. [4]
Presumably it acts as a CB1 agonist in the same way as
THC but as there has been no research published using
Parahexyl since the discovery of the CB1 receptor this
has not been denitively conrmed.
157.2 See also

Tetrahydrocannabinol-C4
157.3 References
Parahexyl was made illegal under UN convention in 1982

on the basis of its structural similarity and similar eects
prole to THC, despite never having had any recorded
instances of abuse by humans or illicit sale. Parahexyl was
placed into the most restrictive Schedule 1 as a compound
with no medical use.
157.1 Isomerism

See also: Tetrahydrocannabinol#Isomerism.
207
[1] Adams R, Harfenist M, Loewe S (1949). New Analogs

of Tetrahydrocannabinol. XIX. J. Am. Chem. Soc. 71
(5): 16241628. doi:10.1021/ja01173a023.
[2] Ask Dr. Shulgin Online March 7, 2001
[3] Ono M, Shimamine M, Takahashi K, Inoue T (1974).
"[Studies on hallucinogens. VII Synthesis of parahexyl]".
Eisei Shikenjo hkoku. Bulletin of National Institute of
Hygienic Sciences (in Japanese) 49 (92): 4650. PMID
4477495.
[4] Fairchild MD, Jenden DJ, Mickey MR, Yale C (1980).
EEG eects of hallucinogens and cannabinoids using sleep-waking behavior as baseline. Pharmacol.
Biochem. Behav. 12 (1): 99105. doi:10.1016/00913057(80)90422-0. PMID 6102770.
Chapter 158
UR-144
UR-144 (TMCP-018, KM-X1, MN-001, YX-17) is a
drug invented by Abbott Laboratories,[1] that acts as a selective full agonist of the peripheral cannabinoid receptor
CB2 , but with much lower anity for the psychoactive
CB1 receptor.
drug screens has been developed by Tulip Biolabs, Inc.

An Homogeneous Immunoassay that runs on most Clinical Chemistry Analyzers and detects several UR and
XLR synthetic cannabinoids has been developed and introduced by Immunalysis Inc. Pomona USA.
158.1 Pharmacology
158.4 See also

AB-001
UR-144 has high anity for the CB2 receptor with a K

of 1.8 nM but 83x lower anity for the CB1 receptor with
a K of 150 nM.[2] Although a later study found its CB1
anity to be much higher than previously expected, with
a K of 28.9nM and an EC50 of 1295nM. Chemically it
is closely related to other 2,2,3,3-tetramethylcyclopropyl
synthetic cannabinoids like A-796,260 and A-834,735
but with a dierent substitution on the 1-position of the
indole core, in these compounds its 1-pentyl group is replaced with alkylheterocycles like 1-(2-morpholinoethyl)
and 1-(tetrahydropyran-4-ylmethyl).
AM-1221
4-HTMPIPO
JTE 7-31
JWH-018
XLR-11
158.5 References
158.2 History of use

UR-144 has been detected as an ingredient of synthetic
cannabis smoking blends in New Zealand, and subsequently banned from sale as a temporary class drug on
6 April 2012.[3] It has also been encountered in smoking
blends and subsequently banned in Russia.[4]
The chemical UR-144 has also been banned in the UK in
2013 along with RCS-4 and AM-2201. This is due to two
people in Glasgow being admitted to hospital after taking a legal high with the chemicals in it. Another person
was admitted to Brighton hospital after overdosing on the
drug.
158.3 Detection
A forensic standard of UR-144 is available, and the compound has been posted on the Forendex website of potential drugs of abuse.[5] An ELISA immunoassay technique for detecting UR-144 in urine as part of general
208
[1] WO application 2006069196, Pace JM, Tietje K,

Dart MJ, Meyer MD, 3-Cycloalkylcarbonyl indoles as
cannabinoid receptor ligands, published 2006-06-29, assigned to Abbott Laboratories
[2] Frost JM, Dart MJ, Tietje KR, Garrison TR, Grayson
GK, Daza AV, El-Kouhen OF, Yao BB, Hsieh GC, Pai
M, Zhu CZ, Chandran P, Meyer MD (January 2010).
Indol-3-ylcycloalkyl ketones: eects of N1 substituted
indole side chain variations on CB(2) cannabinoid receptor activity. J. Med. Chem. 53 (1): 295315.
doi:10.1021/jm901214q. PMID 19921781.
[3] Temporary Class Drug Notices. New Zealand Ministry of
Health
[4] Sobolevsky T, Prasolov I, Rodchenkov G (October 2012).
Detection of urinary metabolites of AM-2201 and UR144, two novel synthetic cannabinoids. Drug Test Anal.
doi:10.1002/dta.1418. PMID 23042760.
[5] Southern
Association
of
Forensic
Scientists
http://forendex.southernforensic.org/index.php/detail/
index/1218

Poso A, Human JW (January 2008). Targeting
the cannabinoid CB2 receptor: modelling and
structural determinants of CB2 selective ligands. Br. J. Pharmacol. 153 (2): 33546.
doi:10.1038/sj.bjp.0707567.
PMC 2219524.
PMID 17982473.
Chin CL, Tovcimak AE, Hradil VP, Seifert TR,
Hollingsworth PR, Chandran P, Zhu CZ, Gauvin D,
Pai M, Wetter J, Hsieh GC, Honore P, Frost JM,
Dart MJ, Meyer MD, Yao BB, Cox BF, Fox GB
(January 2008). Dierential eects of cannabinoid receptor agonists on regional brain activity using pharmacological MRI. Br. J. Pharmacol. 153
(2): 36779. doi:10.1038/sj.bjp.0707506. PMC
2219521. PMID 17965748.
Frost JM, Dart MJ, Tietje KR, Garrison TR,
Grayson GK, Daza AV, El-Kouhen OF, Miller
LN, Li L, Yao BB, Hsieh GC, Pai M, Zhu CZ,
Chandran P, Meyer MD (March 2008). Indol3-yl-tetramethylcyclopropyl ketones: eects of indole ring substitution on CB2 cannabinoid receptor activity. J. Med. Chem. 51 (6): 190412.
doi:10.1021/jm7011613. PMID 18311894.
209
Chapter 159
Perrottetinene
Perrottetinene is a naturally occurring cannabinoid compound found in the New Zealand liverwort plant Radula
marginata and other species from the Radula genus,[1]
along with a number of similar compounds. Its chemical structure closely resembles that of THC, the main
active component of marijuana, and it is thought that
perrottetinene may also be an active cannabinoid agonist although detailed pharmacological investigation of
the compound has yet to be reported.[2][3] Stereoselective synthesis of perrottinene has also been carried out to
investigate the activity of its dierent enantiomers.[4]
159.1 References
[1] Cullmann F, Becker H. Prenylated bibenzyls from the liverwort Radula laxiramea. Zeitschrift Fur Naturforschung.
1999; 54(3-4): 147-150. ISSN 09395075
[2] Toyota M, Kinugawa T, Asakawa Y. Bibenzyl Cannabinoid and Bisbibenzyl Derivative from the Liverwort
Radula perrottetii. Phytochemistry 1994; 37(3):859-862.
[3] Toyota M, Shimamura T, Ishii H, Renner M, Braggins
J, Asakawa Y. New bibenzyl cannabinoid from the New
Zealand liverwort Radula marginata. Chemical and Pharmaceutical Bulletin (Tokyo). 2002 Oct;50(10):1390-2.
PMID 12372871
[4] Song Y, Hwang S, Gong P, Kim D, Kim S. Stereoselective total synthesis of (-)-perrottetinene and assignment
of its absolute conguration. Organic Letters. 2008 Jan
17;10(2):269-71. PMID 18085788
210
Chapter 160
PF-03550096
PF-03550096 is a drug that acts as a potent agonist for
the CB2 cannabinoid receptor, with good selectivity over
CB1 having K values of 7nM at CB2 and 1500nM at
CB1 . It was originally developed by Pzer in 2008 as a
medication for irritable bowel syndrome,[1] but has only
progressed to animal studies.[2]
160.1 See also

AB-FUBINACA
AB-PINACA
160.2 References
[1] Ando K et al, BENZIMIDAZOLONE DERIVATIVES.
WO 2008/032164
[2] Kikuchi, A.; Ohashi, K.; Sugie, Y.; Sugimoto, H.;
Omura, H. (2008). Pharmacological evaluation of a
novel cannabinoid 2 (CB2) ligand, PF-03550096, in vitro
and in vivo by using a rat model of visceral hypersensitivity. Journal of pharmacological sciences 106 (2): 219
224. doi:10.1254/jphs.FP0071599. PMID 18270474.
211
Chapter 161
PF-514273
PF-514273 is a drug developed by Pzer, which acts as
an extremely selective antagonist for the CB1 receptor,
with approximately 10,000x selectivity over the closely
related CB2 receptor. This very high selectivity makes
it useful for scientic research into these receptors, as
many commonly used cannabinoid receptor antagonists
also block the CB2 receptor to some extent.[1]
161.1 References
[1] Dow RL, Carpino PA, Hadcock JR, Black SC, Iredale
PA, DaSilva-Jardine P, Schneider SR, Paight ES, Grith
DA, Scott DO, O'Connor RE, Nduaka CI. Discovery
of
2-(2-chlorophenyl)3-(4-chlorophenyl)7(2,2-diuoropropyl)6,7-dihydro-2H-pyrazolo[3,4f][1,4]oxazepin-8(5H)-one (PF-514273), a novel,
bicyclic lactam-based cannabinoid-1 receptor antagonist for the treatment of obesity. Journal of Medicinal
Chemistry. 2009 May 14;52(9):2652-5. PMID 19351113
212
Chapter 162
PipISB
PipISB is a drug used in scientic research which acts as
a potent and selective inverse agonist of the cannabinoid
receptor CB1 . It is highly selective for the CB1 receptor
over CB2 , with a K at CB1 of 1.5nM vs over 7000nM
at CB2 , has good blood-brain barrier penetration, and
can be conveniently radiolabelled with either 11 C or 18 F,
making it useful for mapping the distribution of CB1 receptors in the brain.[1][2]
162.1 References
[1] Donohue, Sean R.; Halldin, Christer; Schou, Magnus; Hong, Jinsoo; Phebus, Lee; Chernet, Eyassu;
Hitchcock, Stephen A.; Gardinier, Kevin M.; Ruley, Kevin M.; Krushinski, Joseph H.; Schaus, John;
Pike, Victor W. (2008). Radiolabeling of a high
potency cannabinoid subtype-1 receptor inverse agonist, N-(4-uoro-benzyl)4-(3-(piperidin-1-yl-indole-1sulfonyl)benzamide (PipISB), with carbon-11 or uorine18. Journal of Labelled Compounds and Radiopharmaceuticals 51 (3): 146. doi:10.1002/jlcr.1491.
[2] Finnema, S. J.; Donohue, S. R.; Zoghbi, S. S.; Brown,
A. K.; Gulys, B. Z.; Innis, R. B.; Halldin, C.; Pike, V.
W. (2009). Evaluation of \11C]PipISB and \18F]PipISB
in monkey as candidate radioligands for imaging brain
cannabinoid type-1 receptors in vivo. Synapse 63 (1):
2230. doi:10.1002/syn.20578. PMC 2587077. PMID
18925657.
213
Chapter 163
Pirnabine
Pirnabine (SP-304) is a synthetic cannabinoid receptor ligand, which was developed for the treatment of
glaucoma.[1]
163.1 References
[1]
214
Chapter 164
PSB-SB-1202
PSB-SB-1202 is a coumarin derivative which is an agonist at the cannabinoid receptors CB1 and CB2 , with a
CB1 Ki of 32nM and a CB2 Ki of 49nM.[1] It is also
a weak antagonist at the related receptor GPR55, with
an IC50 of 6350nM, but has no signicant anity for
GPR18.[2]
164.1 See also

PSB-SB-487
164.2 References
[1] Rempel V, Volz N, Hinz S, Karcz T, Meliciani I,
Nieger M, Wenzel W, Brse S, Mller CE. 7-Alkyl-3benzylcoumarins: a versatile scaold for the development
of potent and selective cannabinoid receptor agonists and
antagonists. Journal of Medicinal Chemistry. 2012 Sep
27;55(18):7967-77. PMID 22916707
[2] Rempel, V.; Volz, N.; Glser, F.; Nieger, M.; Brse,
S.; Mller, C. E. (2013). Antagonists for the orphan
G protein-coupled receptor GPR55 based on a coumarin
scaold. Journal of Medicinal Chemistry 56 (11):
130516144836005. doi:10.1021/jm4005175. PMID
23679955.
215
Chapter 165
PSB-SB-487
PSB-SB-487 is a coumarin derivative which is an antagonist at the former orphan receptor GPR55. Unlike older
GPR55 antagonists such as O-1918, PSB-SB-487 has
good selectivity over the related receptor GPR18, with
an IC50 of 113nM at GPR55 vs 12500nM at GPR18.[1]
However it has poorer selectivity over other related receptors, acting as a weak antagonist at CB1 with a Ki
of 1170nM, and a partial agonist at CB2 with a Ki of
292nM.[2]
165.1 See also

PSB-SB-1202
165.2 References
[1] Rempel, V.; Volz, N.; Glser, F.; Nieger, M.; Brse,
S.; Mller, C. E. (2013). Antagonists for the orphan
G protein-coupled receptor GPR55 based on a coumarin
scaold. Journal of Medicinal Chemistry 56 (11):
130516144836005. doi:10.1021/jm4005175. PMID
23679955.
[2] Rempel V, Volz N, Hinz S, Karcz T, Meliciani I,
Nieger M, Wenzel W, Brse S, Mller CE. 7-Alkyl-3benzylcoumarins: a versatile scaold for the development
of potent and selective cannabinoid receptor agonists and
antagonists. Journal of Medicinal Chemistry. 2012 Sep
27;55(18):7967-77. PMID 22916707
216
Chapter 166
QUCHIC
QUCHIC (BB-22 or 1-(cyclohexylmethyl)1Hindole-3-carboxylic acid 8-quinolinyl ester) is
a designer drug oered by online vendors as a
cannabimimetic agent, and was rst detected being
sold in synthetic cannabis products in Japan in early
2013,[1] and subsequently also in New Zealand.[2] The
structure of QUCHIC appears to utilise an understanding
of structure-activity relationships within the indole class
of cannabimimetics, although its design origins are
unclear. QUCHIC, along with QUPIC, represents a
structurally unique synthetic cannabinoid chemotype
since it contains an ester linker at the indole 3-position
rather than the precedented ketone of JWH-018 and its
analogues, or the amide of SDB-001 and its analogues.
No information regarding the in vitro or in vivo activity
of QUCHIC has been published, and only anecdotal
reports are known of its pharmacology in humans or
other animals.
166.1 See also

5F-PB-22
JWH-018
PB-22
QUPIC
SDB-001
166.2 References
Two new-type
[2] Dunne bans further two substances found in K2. Press
Release: New Zealand Government. Tuesday, 30 April
2013
217
Chapter 167
QUPIC
QUPIC (PB-22 or 1-pentyl-1H-indole-3-carboxylic
acid 8-quinolinyl ester) is a designer drug oered by
online vendors as a cannabimimetic agent, and detected
being sold in synthetic cannabis products in Japan in
2013.[1] The structure of QUPIC appears to use an understanding of structure-activity relationships within the
indole class of cannabimimetics, although its design origins are unclear. QUPIC represents a structurally unique
synthetic cannabinoid chemotype, since it contains an ester linker at the indole 3-position, rather than the precedented ketone of JWH-018 and its analogs, or the amide
of SDB-001 and its analogs. No information regarding
the in vitro activity of QUPIC has been published, however one in vivo study found PB-22 to cause seizures in
humans and dogs.[2] QUPIC is an analog of JWH-018
which diers by having 8-hydroxyquinoline replacing the
naphthalene group of JWH-018. QUPIC is now found in
many herbal incense and potpourri products.
SDB-001
167.4 References
Two new-type
[2] Gugelmann, H; Gerona, R; Li, C; Tsutaoka, B; Olson, KR;
Lung, D (2014). "'Crazy Monkey' Poisons Man and Dog:
Human and canine seizures due to PB-22, a novel synthetic cannabinoid.. Clinical Toxicology 52 (6): 6358.
doi:10.3109/15563650.2014.925562. PMID 24905571.
[3] Forendex entry, Southern Association of Forensic Scientists
167.1 Detection
A forensic standard of PB-22 is available, and the compound has been posted on the Forendex website of potential drugs of abuse.[3]

PMID 24876364.
167.2 Legal status
[5] PB-22 and 5F-PB-22. Drug Enforcement Administration, Oce of Diversion Control.
As of 9 May 2014, PB-22 is no longer legal in New

Zealand.
[6] Jeremy Pelzer (April 17, 2014). Ohio bans two synthetic
marijuana drugs sold as herbal incense"". cleveland.com.
In January 2014, QUPIC was designated as a Schedule I

controlled substance in the United States.[4][5]
[7] Statutes & Constitution :View Statutes : Online Sunshine. Leg.state..us. 1997-05-06. Retrieved 2014-0712.
In Ohio, QUPIC is illegal.[6]

Florida also has banned QUPIC/P-22.[7]
167.3 See also

5F-PB-22
QUCHIC
218
Chapter 168
Rimonabant
Rimonabant (also known as SR141716; trade name
Acomplia) is an anorectic antiobesity drug that has been
withdrawn from the market due to potentially serious side
eects. It was approved for use in Europe and other countries, but never approved in the United States. Rimonabant is an inverse agonist for the cannabinoid receptor
CB1.[3] Its main eect is reduction in appetite.
168.1 History
the anti-obesity treatment for approval.[2] Subsequently,

Sano-Aventis announced it was suspending the new drug
application (NDA) for rimonabant, and that it would resubmit an application at some point in the future.
The EUs approval was not a blanket approval, nor did it
approve Acomplia for nonobesity-related problems, such
as smoking cessation, although o-label use of the drug
was still possible. The approval was, in combination
with diet and exercise, for the treatment of obese patients
(BMI greater than or equal to 30), or overweight patients
(BMI greater than 27) with associated risk factors, such
as type 2 diabetes or dyslipidaemia.
See also: Discovery and development of Cannabinoid

In October 2008, the European Medicines Agency's
Receptor 1 Antagonists
Committee for Medicinal Products for Human Use
(CHMP) had determined that the risks of Acomplia outRimonabant was the rst selective CB1 receptor blocker weighed its benets. The Agency subsequently recomto be approved for use anywhere in the world. In Europe, mended that the product be suspended from the UK marit was indicated for use in conjunction with diet and ex- ket, and that doctors not prescribe the drug due to the risk
ercise for patients with a body mass index (BMI) greater of serious psychiatric problems, and even suicide. Sanothan 30 kg/m, or patients with a BMI greater than 27 Aventis then suspended sale of the drug.[1][6][7] Approval
kg/m with associated risk factors, such as type 2 diabetes of the drug was ocially withdrawn by the European
or dyslipidaemia. In the UK, it was available beginning Medicines Agency on 16 January 2009.[8]
in July 2006. As of 2008, the drug was available in 56
India has prohibited the manufacture and sale of the
countries.
drug.[9]
On 21 June 2006, the European Commission approved
the sale of rimonabant in the then-25-member European
Union. Pharmaceutical company Sano-Aventis, (which
changed its name to Sano in 2011) announced the rst
country in which Acomplia would be sold was the United
Kingdom as a prescription drug. Sales began in July
2006. Sano-Aventis also projected that the drug would 168.2 Uses/potential uses
be sold shortly thereafter in Denmark, Ireland, Germany,
Finland, and Norway. It was expected in Belgium[4] and
Sweden in 2007. Ordinary obesity would, according to 168.2.1 Obesity
ocial medical recommendations, not be enough to acquire the prescription in Sweden; there would be ad- In a 2006 (2 year) study reported in JAMA, Compared
ditional requirements concerning abnormal blood lipid with the placebo group, the 20 mg of rimonabant group
levels.[5]
produced greater mean (SEM) reductions in weight (6.3
Rimonabant was submitted to the Food and Drug Administration (FDA) for approval in the United States. However, in 2007, the FDAs Endocrine and Metabolic Drugs
Advisory Committee (EMDAC) concluded the French
manufacturer Sano-Aventis failed to demonstrate the
safety of rimonabant and voted against recommending
[0.2] kg vs 1.6 [0.2] kg; P<.001), waist circumference

(6.1 [0.2] cm vs 2.5 [0.3] cm; P<.001), and level of
triglycerides (percentage change, 5.3 [1.2] vs 7.9 [2.0];
P<.001) and a greater increase in level of high-density
lipoprotein cholesterol (percentage change, 12.6 [0.5] vs
5.4 [0.7]; P<.001). [10]
219
220
168.2.2
CHAPTER 168. RIMONABANT
Smoking cessation
Rimonabant may also be found to be eective in assisting

some smokers to quit smoking. Sano is currently conducting studies to determine the possible value of rimonabant in smoking-cessation therapy. The Studies with
Rimonabant and Tobacco Use (STRATUS) program involves more than 6,000 subjects. STRATUS is designed
to explore two smoking-related therapies: rst, to use rimonabant directly to aid in smoking cessation; second, to
help prevent weight gain in former smokers. Initial results apparently suggest rimonabant is eective for both
uses. However, the FDA has explicitly stated to Sano
that, without additional studies, rimonabant cannot be approved in the United States for smoking cessation therapy.
According to a Cochrane Collaboration review in 2007,
rimonabant may increase the odds of quitting approximately 11/2-fold.[11]
168.4 Negative side eects

Shortly after market introduction, press reports and independent studies suggested that side eects occurred more
intensely and more commonly than had been found by the
manufacturer in their clinical studies. Reports of severe
depression and suicidal thoughts were frequent.[18] As the
drugs target CB1 receptors are fairly ubiquitous throughout the central nervous system, it is not currently understood where the inverse agonist is acting to cause these
side-eects.
In 2007, it was reported that the committee advising the
U.S. FDA had voted not to recommend the drugs approval because of concerns over suicidality, depression,
and other related side eects associated with use of the
drug.[19]
168.5 Preparation
168.2.3
Addiction behaviors
Rimonabant reduced resumption of cocaine-seeking responses triggered by two of the three most common triggers of relapse in humans: priming and cues. It may also
reduce ethanol- and opiate-seeking behavior.[12]
168.2.4
The chemical synthesis of rimonabant is described as

follows:[20]
Short-term memory
Tetrahydrocannabinol (THC) is known to impair shortterm memory. It was therefore hypothesised that rimonabant may reduce or inhibit the atrophic eects of
cannabinoids. Indeed, in animal studies, it signicantly
improved the ability of rats to encode information into
short-term memory.[13]
168.2.5
Blockage of cannabis eects
Rimonabant blocks the psychoactive and some of the

cardiovascular eects of 9 -tetrahydrocannabinol (THC)
in humans without aecting the pharmacokinetics.[14]
Rimonabant has been described colloquially as reverse marijuana, having a depressing eect on appetite inverse to the increased appetite created by
cannabinoids.[15]
168.3 Other eects

Rimonabant reduces voluntary wheel running in laboratory mice.[16]
Rimonabant signicantly increased human sperm motility and viability in vitro.[17]
168.6 Brand names

Brand names for rimonabant include Acomplia, Bethin,
Monaslim, Remonabent, Riobant, Slimona, and Rimoslim. The proposed brand name if it had been approved for use in the United States was Zimulti.
168.7 References
[1] Anti-obesity drug use suspended. BBC News. 23 October 2008. Retrieved 4 March 2010.
168.7. REFERENCES
[2] Zimulti Acomplia Report - Diet Drug Acomplia / Zimulti Gets Thumbs Down From FDA Panel. Acompliareport.com. 2007-06-13. Retrieved 2010-03-19.
[3] Fong TM, Heymseld SB (September 2009).
Cannabinoid-1 receptor inverse agonists: current
understanding of mechanism of action and unanswered questions. Int J Obes (Lond) 33 (9): 94755.
doi:10.1038/ijo.2009.132. PMID 19597516.
221
[16] Keeney BK, et al. (2008). Dierential response

to a selective cannabinoid receptor antagonist
(SR141716: rimonabant) in female mice from lines
selectively bred for high voluntary wheel-running
behavior. Behavioural Pharmacology 19 (8): 812
820. doi:10.1097/FBP.0b013e32831c3b6b. PMID
19020416.
[4] Auteur: Femke Gebruers. Article from the Belgian

newspaper De Standaard. Standaard.be. Retrieved
2010-03-19.
[17] Aguila S, et al. (2010). Rimonabant (SR141716) induces metabolism and acquisition of fertilizing ability
in human sperm. Br J Pharmacol 159 (4): 83141.
doi:10.1111/j.1476-5381.2009.00570.x. PMC 2829209.
PMID 20067470.
[5] Article from the Swedish TV station TV 4 website.

Tv4.se. 2008-03-06. Retrieved 2010-03-19.
[18] Kassen mssen nicht fr Acomplia zahlen. tagesschau.de. 2006-10-17. Retrieved 2007-06-13.
[6] European Medicines Agency. Ema.europa.eu/ema/.

2010-02-15. Retrieved 2010-03-19.
[19] Suicide risk fears over diet pill. BBC News. 15 June
2007. Retrieved 4 March 2010.
[7] Sano-aventis - A diversied healthcare company, focused on patients needs. En.sano-aventis.com. Retrieved 2010-03-19.
[20] Yoshioka, T., et al. (1989). Studies on hindered

phenols and analogs. 1. Hypolipidemic and hypoglycemic agents with ability to inhibit lipid peroxidation. Journal of Medicinal Chemistry 32 (2): 421.
doi:10.1021/jm00122a022. PMID 2913302.
[8] Microsoft Word - Zimulti _Rimonabant_ Public Statement (PDF). Retrieved 2010-03-19.
[9] Drugs banned in India. Central Drugs Standard Control
Organization, Dte.GHS, Ministry of Health and Family
Welfare, Government of India. Retrieved 2013-09-17.
[10] JAMA. 2006 Feb 15;295(7):761-75. Eect of rimonabant, a cannabinoid-1 receptor blocker, on weight and
cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled
trial. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J,
Rosenstock J; RIO-North America Study Group. PMID
16478899
[11] Cahill K, Ussher M (2007).
Cahill, Kate, ed.
Cannabinoid type 1 receptor antagonists (rimonabant) for smoking cessation.
Cochrane database
of systematic reviews (Online) (4):
CD005353.
doi:10.1002/14651858.CD005353.pub3.
PMID
17943852.
[12] Maldonado R, Valverde O, Berrendero F (2006). Involvement of the endocannabinoid system in drug
addiction.
Trends Neurosci.
29 (4): 22532.
doi:10.1016/j.tins.2006.01.008. PMID 16483675.
[13] Deadwyler SA, Goonawardena AV, Hampson RE (2007).
Short-term memory is modulated by the spontaneous release of endocannabinoids: evidence from hippocampal
population codes. Behavioural Pharmacology 18 (56):
57180. doi:10.1097/FBP.0b013e3282ee2adb. PMID
17762525.
[14] Huestis MA, et al. (2001). Blockade of eects of
smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch. Gen. Psychiatry
58 (4): 3228. doi:10.1001/archpsyc.58.4.322. PMID
11296091.
[15] Stephan Guyenet, PhD (9 March 2012) Seduced by Food:
Obesity and the Human Brain Boing Boing
Chapter 169
Rosonabant
Rosonabant (INN; E-6776) is a drug acting as a CB1
receptor antagonist/inverse agonist that was under investigation by Esteve as an appetite suppressant for the treatment of obesity.[1][2] Development of the drug for clinical
use was apparently halted shortly after the related CB1
antagonist rimonabant was discontinued, likely due to
the reports of severe psychiatric adverse eects such as
anxiety, depression, and suicidal ideation associated with
it and with similarly-acting agents.[3][4]
169.1 See also

169.2 References
[1] Janero DR, Makriyannis A (March 2009). Cannabinoid
receptor antagonists: pharmacological opportunities,
clinical experience, and translational prognosis. Expert Opinion on Emerging Drugs 14 (1): 4365.
doi:10.1517/14728210902736568. PMID 19249987.
[2] Tim C. Kirkham; S. J. Cooper (2007). Appetite and Body
Weight: Integrative Systems and the Development of AntiObesity Drugs. Academic Press. p. 325. ISBN 978-0-12370633-1. Retrieved 12 May 2012.
[3] Heal DJ, Gosden J, Smith SL (December 2009).
Regulatory challenges for new drugs to treat obesity and
comorbid metabolic disorders. British Journal of Clinical Pharmacology 68 (6): 86174. doi:10.1111/j.13652125.2009.03549.x. PMC 2810797. PMID 20002080.
[4] Lee HK, Choi EB, Pak CS (2009). The current status and future perspectives of studies of cannabinoid
receptor 1 antagonists as anti-obesity agents. Current Topics in Medicinal Chemistry 9 (6): 482503.
doi:10.2174/156802609788897844. PMID 19689362.
222
Chapter 170
S-444,823
S-444,823 is a drug developed by Shionogi which
is a cannabinoid agonist.[1] It was developed as an
antipruritic, and has moderate selectivity for the CB2
subtype, having a CB2 anity of 18nM, and 32x selectivity over the CB1 receptor. In animal studies it
showed analgesic eects and strongly reduced itching
responses, but without producing side eects such as
sedation and catalepsy that are seen with centrally acting
CB1 agonists.[2]
170.1 See also

JTE 7-31
170.2 References
[1] Arimura A. Novel Use of Cannabinoid Receptor Agonist.
Patent WO 2005/016351
[2] Odan M, et al. Discovery of S-444823, a potent CB1/CB2
dual agonist as an antipruritic agent. Bioorganic and
Medicinal Chemistry Letters. 2012 Apr 15;22(8):2898901. PMID 22421019
223
Chapter 171
SDB-001
This article is about the cannabinoid drug. For the South
Korean girl band, see 2NE1. For the metabotropic
glutamate receptor antagonist, see APICA (drug).
SDB-001 (2NE1, APICA, N-(1-adamantyl)1pentyl-1H-indole-3-carboxamide) is a drug that acts
as a potent agonist for the cannabinoid receptors. It
had never previously been reported in the scientic or
patent literature, and was rst identied by laboratories
in Japan in March 2012 as an ingredient in synthetic
cannabis smoking blends, along with a related compound
APINACA (sold as AKB48).[1] Structurally it closely
resembles cannabinoid compounds from patent WO
2003/035005 but with an indole core instead of indazole,
and a simple pentyl chain on the indole 1-position.
Pharmacological testing determined SDB-001 to have
an IC50 of 175nM at CB1 , only slightly less potent than
JWH-018 which had an IC50 of 169nM, but over four
times more tightly binding than AKB48, which had an
IC50 of 824nM.[2] The rst published synthesis and
pharmacological evaluation of SDB-001 revealed that it
acts as a full agonist at CB1 (EC50 = 34 nM) and CB2
receptors (EC50 = 29 nM).[3] Furthermore, SDB-001
possesses cannabis-like eects in rats, and appears to be
less potent than JWH-018 but more potent than THC.[3]
171.1 See also

AB-001
QUCHIC
JWH-018
SDB-006
STS-135 (drug)
171.2 References
[1] Uchiyama, N.; Kawamura, M.; Kikura-Hanajiri,
R.; Goda, Y. (2012). Identication of two newtype synthetic cannabinoids, N-(1-adamantyl)1pentyl-1H-indole-3-carboxamide (APICA) and N-(1-
224
adamantyl)1-pentyl-1H-indazole-3-carboxamide (APINACA), and detection of ve synthetic cannabinoids,

AM-1220, AM-2233, AM-1241, CB-13 (CRA-13), and
AM-1248, as designer drugs in illegal products. Forensic
Toxicology 30 (2): 114. doi:10.1007/s11419-012-01367.
23063179.
doi:10.1021/cn400035r.
Chapter 172
SDB-006
SDB-006 is a drug that acts as a potent agonist for the
cannabinoid receptors, with an EC50 for CB1 activation
of 19nM, and 7x selectivity for CB1 over CB2 . It was discovered during research into the related compound SDB001 which had been sold illicitly as 2NE1.[1]
172.1 See also

APINACA
SDB-001
STS-135_(drug)
172.2 References
doi:10.1021/cn400035r.
225
Chapter 173
SER-601
SER-601 (COR-167) is a drug which acts as a potent
and selective cannabinoid CB2 receptor agonist, based
on a quinolone3-carboxylic acid core structure, with
190x selectivity for CB2 over the related CB1 receptor. It has analgesic eects in animal studies, as well as
neuroprotective eects,[1] but without cannabis-like behavioural eects due to its low anity for CB1 .[2] A number of related compounds are known, almost all of which
have high selectivity for CB2 .[3]
173.1 See also

A-836,339
CBS-0550
173.2 References
[1] Contartese, A.; Valoti, M.; Corelli, F.; Pasquini, S.; Mugnaini, C.; Pessina, F.; Aldinucci, C.; Sgaragli, G.; Frosini,
M. (2012). A novel CB2 agonist, COR167, potently protects rat brain cortical slices against OGD and reperfusion injury. Pharmacological Research 66 (6): 555563.
doi:10.1016/j.phrs.2012.08.003. PMID 23036353.
[2] Pasquini S,et al. (August 2008). Investigations on
the 4-quinolone-3-carboxylic acid motif. 2. Synthesis
and structure-activity relationship of potent and selective
cannabinoid-2 receptor agonists endowed with analgesic
activity in vivo. Journal of Medicinal Chemistry 51 (16):
507584. doi:10.1021/jm800552f. PMID 18680276.
[3] Pasquini S,et al. (August 2010). Investigations on
the 4-quinolone-3-carboxylic acid motif. 3. Synthesis, structure-anity relationships, and pharmacological characterization of 6-substituted 4-quinolone-3carboxamides as highly selective cannabinoid-2 receptor
ligands. Journal of Medicinal Chemistry 53 (16): 5915
28. doi:10.1021/jm100123x. PMID 20718492.
226
Chapter 174
Serinolamide A
Serinolamide A is a naturally occurring eicosanoid
derivative related to anandamide, which has been isolated
from the marine cyanobacteria Lyngbya majuscula and
related species in the Oscillatoria family. Testing established that serinolamide A is an active cannabinoid agonist with moderate potency, having a Ki of 1300nM at
CB1 and 5x selectivity over the related CB2 receptor.[1]
174.1 See also

Methanandamide
O-1812
Perrottetinene
174.2 References
[1] Gutirrez, M.; Pereira, A. R.; Debonsi, H. M.; Ligresti, A.; Di Marzo, V.; Gerwick, W. H. (2011).
Cannabinomimetic Lipid from a Marine Cyanobacterium. Journal of Natural Products 74 (10): 2313
2317. doi:10.1021/np200610t. PMC 3325759. PMID
21999614.
227
Chapter 175
SR-144,528
SR144528 is a drug that acts as a potent and highly selective CB2 receptor inverse agonist, with a K of 0.6nM
at CB2 and 400nM at the related CB1 receptor.[1][2] It
is used in scientic research for investigating the function of the CB2 receptor,[3][4][5] as well as for studying
the eects of CB1 receptors in isolation, as few CB1 agonists that do not also show signicant activity as CB2 agonists are available.[6][7][8] It has also been found to be an
inhibitor of acyl-coenzymeA:cholesterol acyltransferase,
an eect that appears to be independent from its action
on CB2 receptors.[9]
175.1 See also
74757. doi:10.1016/S0306-4522(03)00126-X. PMID

12809695.
[5] Pldy E, et al. (December 2008). CB(2) cannabinoid receptor antagonist SR144528 decreases mu-opioid receptor expression and activation in mouse brainstem: role
of CB(2) receptor in pain. Neurochemistry International
53 (6-8): 30916. doi:10.1016/j.neuint.2008.08.005.
PMID 18804501.
[6] Lay L, Angus JA, Wright CE (March 2000). Pharmacological characterisation of cannabinoid CB(1) receptors in
the rat and mouse. European Journal of Pharmacology
391 (1-2): 15161. doi:10.1016/S0014-2999(00)000625. PMID 10720647.
[7] German MP, et al. (February 2001). Cannabinoid
CB1-mediated inhibition of stress-induced gastric ulcers
in rats. Naunyn-Schmiedebergs Archives of Pharmacology 363 (2): 2414. doi:10.1007/s002100000360.
PMID 11218077.
NESS-040C5
SR141716
[8] Abalo R, et al. (June 2010). The cannabinoid antagonist SR144528 enhances the acute eect of WIN
55,212-2 on gastrointestinal motility in the rat. Neurogastroenterology and Motility : the Ocial Journal of the
European Gastrointestinal Motility Society 22 (6): 694
e206. doi:10.1111/j.1365-2982.2009.01466.x. PMID
20132133.
175.2 References
[1] Rinaldi-Carmona M, et al. (February 1998). SR
144528, the rst potent and selective antagonist of the
CB2 cannabinoid receptor. The Journal of Pharmacology and Experimental Therapeutics 284 (2): 64450.
PMID 9454810.
[2] Portier M, et al. (February 1999). SR 144528, an antagonist for the peripheral cannabinoid receptor that behaves as an inverse agonist. The Journal of Pharmacology and Experimental Therapeutics 288 (2): 5829.
PMID 9918562.
[3] Gouldson P, et al. (July 2000). Mutational analysis
and molecular modelling of the antagonist SR 144528
binding site on the human cannabinoid CB(2) receptor. European Journal of Pharmacology 401 (1): 1725.
doi:10.1016/S0014-2999(00)00439-8. PMID 10915832.
[4] Nackley AG, Makriyannis A, Hohmann AG (2003). Selective activation of cannabinoid CB(2) receptors suppresses spinal fos protein expression and pain behavior
in a rat model of inammation. Neuroscience 119 (3):
228
[9] Thewke D, et al. (April 2009). AM-251 and SR144528

are acyl CoA:cholesterol acyltransferase inhibitors. Biochemical and Biophysical Research Communications 381
(2): 1816. doi:10.1016/j.bbrc.2009.02.020. PMC
2665256. PMID 19338772.
Chapter 176
Stearoylethanolamide
Stearoylethanolamide (SEA) is an endocannabinoid
neurotransmitter.
176.1 References
Binding, degradation and apoptotic activity
stearoylethanolamide in rat C6 glioma cells
of
229
Chapter 177
STS-135 (drug)
STS-135
(N-(adamantan-1-yl)1-(5uoropentyl)1H-indole-3-carboxamide)
is
a
designer drug oered by online vendors as a
cannabimimetic agent.
The structure of STS-135
appears to utilise an understanding of structure-activity
relationships within the indole class of cannabimimetics,
although its design origins are unclear. STS-135 is
the terminally-uorinated analogue of SDB-001, just
as AM-2201 is the terminally-uorinated analogue of
JWH-018, and XLR-11 is the terminally-uorinated analogue of UR-144. No information regarding the in vitro
or in vivo activity of STS-135 has been published, and
only anecdotal reports are known of its pharmacology in
humans or other animals.
177.1 Detection
A forensic standard of STS-135 is available, and the compound has been posted on the Forendex website of potential drugs of abuse.[1]
177.2 See also

AB-001
APINACA
AM-2201
JWH-018
SDB-001
177.3 References
[1] Southern Association of Forensic Scientists
230
Chapter 178
Surinabant
Surinabant (SR147778) is a cannabinoid receptor type
1 antagonist developed by Sano-Aventis.[1] It is being investigated as a potential treatment for nicotine addiction,
to assist smoking cessation. It may also be developed
as an anorectic drug to assist with weight loss, however there are already several CB1 antagonists or inverse
agonists on the market or under development for this
application,[2] so surinabant is at present mainly being developed as an anti-smoking drug,[3] with possible application in the treatment of other addictive disorders such
as alcoholism.[4][5] Other potential applications such as
treatment of ADHD have also been proposed.[6]
178.1 See also

O-1269
178.2 References
[1] Rinaldi-Carmona M, Barth F, Congy C, Martinez S,
Oustric D, Prio A, Poncelet M, Maruani J, Arnone
M, Finance O, Soubri P, Le Fur G. SR147778
[5-(4-bromophenyl)1-(2,4-dichlorophenyl)4-ethylN-(1-piperidinyl)1H-pyrazole-3-carboxamide], a new
potent and selective antagonist of the CB1 cannabinoid
receptor: biochemical and pharmacological characterization. Journal of Pharmacology and Experimental
Therapeutics. 2004 Sep;310(3):905-14. PMID 15131245
[2] Doggrell SA. Will the new CB1 cannabinoid receptor antagonist SR-147778 have advantages over rimonabant? Expert Opinion on Investigational Drugs. 2005
Mar;14(3):339-42. PMID 15833065
[3] Lamota L, Bermudez-Silva FJ, Marco EM, Llorente R,
Gallego A, Rodrguez de Fonseca F, Viveros MP. Effects of adolescent nicotine and SR 147778 (Surinabant) administration on food intake, somatic growth and
metabolic parameters in rats. Neuropharmacology. 2008
Jan;54(1):194-205. PMID 17720206
[4] Gessa GL, Serra S, Vacca G, Carai MA, Colombo G. Suppressing eect of the cannabinoid CB1 receptor antagonist, SR147778, on alcohol intake and motivational prop-
231
erties of alcohol in alcohol-preferring sP rats. Alcohol and

Alcoholism. 2005 Jan-Feb;40(1):46-53. PMID 15582988
[5] Lallemand F, De Witte P. SR147778, a CB1 cannabinoid receptor antagonist, suppresses ethanol preference
in chronically alcoholized Wistar rats. Alcohol. 2006
Jul;39(3):125-34. PMID 17127132
[6] Louis C, Terranova JP, Decobert M, Bizot JC, Francon D,
Alonso R, Cohen C, Griebel G. Surinabant, a new CB1 receptor antagonist, displays ecacy in animal models of attention decit/hyperactivity disorder. Behavioural Pharmacology 2005; 16:S42.
Chapter 179
Taranabant
Taranabant (codenamed MK-0364) is a cannabinoid
receptor type 1 inverse agonist being investigated as
a potential treatment for obesity due to its anorectic
eects.[1][2] It was discovered by Merck & Co.
In October 2008, Merck has stopped its phase III clinical
trials with the drugs due to high level of central side effects, mainly depression and anxiety.[3][4][5][6]
179.1 See also

179.2 References
[1] Armstrong HE, Galka A, Lin LS, Lanza TJ Jr, Jewell JP,
Shah SK, et al. Substituted acyclic sulfonamides as human cannabinoid-1 receptor inverse agonists. Bioorganic
& Medicinal Chemistry Letters. 2007 Apr 15;17(8):21847. PMID 17293109. doi:10.1016/j.bmcl.2007.01.087
[2] Fong TM, Guan XM, Marsh DJ, Shen CP, Stribling DS, Rosko KM, et al.
Antiobesity ecacy
of a novel cannabinoid-1 receptor inverse agonist,
N-[(1S,2S)3-(4-chlorophenyl)2-(3-cyanophenyl)1methylpropyl]2-methyl-2-[[5-(triuoromethyl)pyridin2-yl]oxy]propanamide (MK-0364),
in rodents.
Journal of Pharmacology and Experimental Therapeutics. 2007 Jun;321(3):1013-22. PMID 17327489.
doi:10.1124/jpet.106.118737
[3] Press release by Merck. Retrieved October 2008.
[4] Aronne LJ, Tonstad S, Moreno M, Gantz I, Erondu N,
Suryawanshi S, Molony C, Sieberts S, Nayee J, Meehan
AG, Shapiro D, Heymseld SB, Kaufman KD, Amatruda
JM (May 2010). A clinical trial assessing the safety
and ecacy of taranabant, a CB1R inverse agonist, in
obese and overweight patients: a high-dose study. International Journal of Obesity (2005) 34 (5): 91935.
doi:10.1038/ijo.2010.21. PMID 20157323.
[5] Kipnes MS, Hollander P, Fujioka K, Gantz I, Seck T,
Erondu N, Shentu Y, Lu K, Suryawanshi S, Chou M,
Johnson-Levonas AO, Heymseld SB, Shapiro D, Kaufman KD, Amatruda JM (June 2010). A one-year study
232
to assess the safety and ecacy of the CB1R inverse agonist taranabant in overweight and obese patients with
type 2 diabetes. Diabetes, Obesity & Metabolism 12 (6):
51731. doi:10.1111/j.1463-1326.2009.01188.x. PMID
20518807.
[6] Proietto J, Rissanen A, Harp JB, Erondu N, Yu Q,
Suryawanshi S, Jones ME, Johnson-Levonas AO, Heymseld SB, Kaufman KD, Amatruda JM (August 2010). A
clinical trial assessing the safety and ecacy of the CB1R
inverse agonist taranabant in obese and overweight patients: low-dose study. International Journal of Obesity (2005) 34 (8): 124354. doi:10.1038/ijo.2010.38.
PMID 20212496.
Chapter 180
Tedalinab
Tedalinab (GRC-10693) is a drug developed by
Glenmark Pharmaceuticals for the treatment of
osteoarthritis and neuropathic pain, which acts as a
potent and selective cannabinoid CB2 receptor agonist.
It has a very high selectivity of 4700x for CB2 over
the related CB1 receptor, has good oral bioavailability
and has shown promising safety results and eective
analgesic and antiinammatory actions in early clinical
trials.[1] A large number of related compounds are
known, most of which also show high CB2 selectivity.[2]
180.1 See also

CBS-0550
SER-601
180.2 References
[1] Glenmarks Molecule for Neuropathic Pain, Osteoarthritis - GRC 10693, Successfully Completes Phase I Trials.
April 13, 2009.
[2] Glenmark Pharmaceuticals. NOVEL CANNABINOID
RECEPTOR LIGANDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND PROCESS
FOR THEIR PREPARATION, Filed June 1st, 2006.
WO 2006/129178.
233
Chapter 181
Tetrad test
The tetrad test is a series of behavioral paradigms in
which rodents treated with cannabinoids such as THC
show eects.[1] It is widely used for screening drugs that
induce cannabinoid receptor-mediated eects in rodents.
The four behavioral components of the tetrad are spontaneous activity, catalepsy, hypothermia, and analgesia.
Common assays for these behavioral paradigms are as follows:
181.1 References
Spontaneous activity (or hypomotility) is determined by an open eld test, in which a mouse is
placed in a cage with perpendicular grid lines, usually spaced by approx. 1 inch. An experimenter
counts the number of line crossings by the mouse
in a given amount of time.
Catalepsy is determined by the bar test. The mouse
is placed on a bar oriented parallel to and approximately 1 inch o of the ground. If the mouse remains immobile on the bar for typically more than
20 seconds, it is considered cataleptic.
Hypothermia is determined by using a rectal probe
to measure the rectal temperature.
Analgesia is usually determined by the hot plate or
tail immersion test. In the hot plate test, the mouse is
placed on a heated plate, typically between 54 and
58C. An experimenter measures the time it takes
for the mouse to jump o of the hot plate. In the
tail immersion test, the mouse is immobilized and its
tail is placed into a warm water bath, typically also
between 54 and 58C. An experimenter measures
the time it takes for the mouse to remove its tail from
the water bath.
Direct CB1 agonists, such as THC (the psychoactive
component of marijuana), or WIN 55,212-2, have effects in all components of the tetrad and induce hypomotility, catalepsy, hypothermia, and analgesia in rodents. Accordingly, all true tetrad eects are not observed following treatment with antagonists of CB1 such
as rimonabant.
234
[1] Little, P.J.; Compton, D.R.; Johnson, M.R.; Melvin, L.S.;

Martin, B.R. (1988). Pharmacology and stereoselectivity
of structurally novel cannabinoids in mice. J Pharmacol
Exp Ther 247: 104651.
Chapter 182
THC redirects here. For other uses, see THC (disam- the periaqueductal gray.[16] Other eects include relaxbiguation).
ation, alteration of visual, auditory, and olfactory senses,
fatigue, and appetite stimulation. THC has marked
antiemetic properties. It may acutely reduce aggression
Tetrahydrocannabinol (THC), or more precisely
and
increase aggression during withdrawal.[17]
9
its main isomer ()-trans- -tetrahydrocannabinol
( (6aR,10aR)-delta-9-tetrahydrocannabinol), is the
principal psychoactive constituent (or cannabinoid) of
the cannabis plant. First isolated in 1964 by Israeli
scientists Raphael Mechoulam and Yechiel Gaoni at the
Weizmann Institute of Science[8][9][10] it is a water-clear
glassy solid when cold, which becomes viscous and
sticky if warmed. A pharmaceutical formulation of
()-trans-9 -tetrahydrocannabinol, known by its INN
dronabinol, is available by prescription in the U.S. and
Canada under the brand name Marinol. An aromatic
terpenoid, THC has a very low solubility in water, but
good solubility in most organic solvents, specically
lipids and alcohols.[7] Along with CBD, CBN, CBC,
CBG and other 80 molecules make up the phytocannabinoid family, found in dierent quantities in Cannabis
Sativa plants.[11]
Due to its partial agonistic activity, THC appears to result in greater downregulation of cannabinoid receptors
than endocannabinoids, further limiting its ecacy over
other cannabinoids. While tolerance may limit the maximal eects of certain drugs, evidence suggests that tolerance develops irregularly for dierent eects with greater
resistance for primary over side-eects, and may actually serve to enhance the drugs therapeutic window.[18]
However, this form of tolerance appears to be irregular throughout mouse brain areas. THC, as well as other
cannabinoids that contain a phenol group, possesses mild
antioxidant activity sucient to protect neurons against
oxidative stress, such as that produced by glutamateinduced excitotoxicity.[19]
Like most pharmacologically-active secondary metabolites of plants, THC in cannabis is assumed to be involved
in self-defense, perhaps against herbivores.[12] THC also
possesses high UV-B (280315 nm) absorption properties, which, it has been speculated, could protect the plant
from harmful UV radiation exposure.[13][14][15]
182.1.1 Appetite and taste
Tetrahydrocannabinol with double bond isomers and their

stereoisomers is one of only three cannabinoids scheduled
by Convention on Psychotropic Substances (the other two
are dimethylheptylpyran and parahexyl). Cannabis as a
plant is scheduled by the Single Convention on Narcotic
Drugs (Schedule I and IV).
182.1 Eects
See also: Eects of cannabis, Long-term eects of
cannabis and Cannabis in pregnancy
THC has mild to moderate analgesic eects, and cannabis
can be used to treat pain by altering transmitter release on dorsal root ganglion of the spinal cord and in
It has long been known that, in humans, cannabis increases appetite and consumption of food. The mechanism for appetite stimulation in subjects is believed to result from activity in the gastro-hypothalamic axis. CB1
activity in the hunger centers in the hypothalamus increases the palatability of food when levels of a hunger
hormone ghrelin increase prior to consuming a meal.
After chyme is passed into the duodenum, signaling
hormones such as cholecystokinin and leptin are released,
causing reduction in gastric emptying and transmission of
satiety signals to the hypothalamus. Cannabinoid activity
is reduced through the satiety signals induced by leptin
release.
A study in mice suggested that based on the connection between palatable food and stimulation of dopamine
(DA) transmission in the shell of the nucleus accumbens
(NAc), cannabis may not only stimulate taste, but possibly the hedonic (pleasure) value of food as well. The
study later demonstrates habitual use of THC lessening
this heightened pleasure response, indicating a possible
similarity in humans.[20] The inconsistency between DA
235
236
CHAPTER 182. TETRAHYDROCANNABINOL
habituation and enduring appetite observed after THC

application suggests that cannabis-induced appetite stimulation is not only mediated by enhanced pleasure from
palatable food, but through THC stimulation of another
appetitive response as well.
182.2 Chemistry
182.2.1
Discovery and structure identication
The discovery of THC by team of researchers from

Hebrew University Pharmacy School was rst described
in Isolation, structure and partial synthesis of an active constituent of hashish, published in the Journal of
the American Chemical Society in 1964.[8] Research
was also published in the academic journal Science, with
Marijuana chemistry by Raphael Mechoulam in June 3D rendering of the THC molecule
1970,[21] In the latter, the team of researchers from Hebrew University and Tel Aviv University experimented
on monkeys to isolate the active compounds in hashish.
Their results provided evidence that, except for tetrahydrocannabinol, no other major active compounds were
present in hashish.
182.2.2
Isomerism
A hybrid Cannabis strain (White Widow) ower coated with

trichomes, which contain more THC than any other part of the
plant

Further reading on cannabanoid isomerism: John C.
Lengwell (May 2003). Chirality & Bioactivity
I.: Pharmacology 3 (1). pp. 1820. Retrieved 12
January 2014.
Closeup of THC-lled trichomes on a Cannabis sativa leaf
182.3 Medical uses

medical marijuana and marijuana-derived products in
In April 2014 the American Academy of Neurology pub- certain neurological disorders.[22] The review identied
lished a systematic review of the ecacy and safety of 34 studies meeting inclusion criteria, of which 8 were
182.4. ADVERSE EFFECTS
237
rated as Class I quality.[22] The study found evidence sup Epilepsy. Data was considered insucient to judge
porting the eectiveness of cannabis extracts and THC in
the utility of cannabis products in reducing seizure
treating certain symptoms of multiple sclerosis, but found
frequency or severity.[22]
insucient evidence to determine the eectiveness of
cannabis products in treating several other neurological
182.3.4 Other studies in humans
diseases.[22]
182.3.1
Multiple sclerosis symptoms
Spasticity. Based on the results of 3 high quality

trials and 5 of lower quality, oral cannabis extract
was rated as eective, and THC as probably eective, for improving patients subjective experience
of spasticity. Oral cannabis extract and THC both
were rated as possibly eective for improving objective measures of spasticity.[22]
Centrally mediated pain and painful spasms. Based
on the results of 4 high quality trials and 4 low quality trials, oral cannabis extract was rated as eective, and THC as probably eective in treating central pain and painful spasms.[22]
Bladder dysfunction. Based on a single high quality study, oral cannabis extract and THC were rated
as probably ineective for controlling bladder complaints in multiple sclerosis[22]
182.3.2
Neurodegenerative disorders
Evidence suggests that THC helps alleviate symptoms

suered both by AIDS patients, and by cancer patients
undergoing chemotherapy, by increasing appetite and decreasing nausea.[24][25][26][27] It has also been shown to assist some glaucoma patients by reducing pressure within
the eye, and is used in the form of cannabis by a number of multiple sclerosis patients, who use it to alleviate
neuropathic pain and spasticity. The National Multiple
Sclerosis Society is currently supporting further research
into these uses.[28] Studies in humans have been limited
by federal and state laws criminalizing marijuana.
In August 2009 a phase IV clinical trial by the Hadassah
Medical Center in Jerusalem, Israel started to investigate
the eects of THC on post-traumatic stress disorders.[29]
Studies have been conducted with spinal injury patients
and THC.[30]
182.4 Adverse eects

182.4.1 Acute toxicity
There has never been a documented human fatality solely

from overdosing on tetrahydrocannabinol or cannabis in
its natural form.[31] However, numerous reports have suggested an association of cannabis smoking with an increased risk of myocardial infarction.[32][33] Information
about the toxicity of THC is primarily based on results
from animal studies. The toxicity depends on the route
Parkinson disease. Based on a single study, oral of administration and the laboratory animal.
cannabis extract was rated probably ineective in
The estimated lethal dose of intravenous dronabinol in
treating levodopa-induced dyskinesia in Parkinson
humans is 30 mg/kg,[34] meaning lethality is unlikely.
disease.[22]
The typical medicinal dosage administered is two 2.5 mg
capsules daily; for an 80 kg man (~170 lb). A lethal dose
Alzheimers disease. A 2011 Cochrane Review for such a person would be 960 of those capsules infused
found insucient evidence to conclude whether intravenously. Non-fatal overdoses have occurred: Sigcannabis products have any utility in the treatment nicant CNS symptoms in antiemetic studies followed
of Alzheimers disease.[23]
oral doses of 0.4 mg/kg (28 mg/70 kg) of dronabinol
capsules.[34]
Huntington disease. No reliable conclusions could
be drawn regarding the eectiveness of THC or oral
cannabis extract in treating the symptoms of Huntington disease as the available trials were too small
to reliably detect any dierence[22]
182.3.3
Other neurological disorders
Tourette syndrome. The available data was determined to be insucient to allow reliable conclusions to be drawn regarding the eectiveness of oral
cannabis extract or THC in controlling tics.[22]
Cervical dystonia. Insucient data was available to
assess the eectiveness of oral cannabis extract of
THC in treating cervical dystonia.[22]
A meta analysis of cannabis and

THC clinical trials conducted by
the American Academy of Neurology found that of 1619 persons
treated with cannabis products (including some treated with smoked
cannabis and nabiximols), 6.9%
discontinued due to side eects,
compared to 2.2% of 1,118 treated
238

with placebo. Detailed information regarding side eects was not
available from all trials, but nausea, increased weakness, behavioral
or mood changes, suicidal ideation,
hallucinations, dizziness, and vasovagal symptoms, fatigue, and feelings of intoxication were each described as side eects in at least
2 trials. There was a single death
rated by the investigator as possibly related to treatment. This person had a seizure followed by aspiration pneumonia. The paper does
not describe whether this was one
of the patients from the epilepsy
trials.[22]
182.4.2
Cognitive eects
cannabis use is associated with a two-fold increase in the

risk of psychosis, but that cannabis use is neither necessary nor sucient to cause psychosis.[41] A French review from 2009 came to a conclusion that cannabis use,
particularly that before age 15, was a factor in the development of schizophrenic disorders.[42]
Some studies have suggested that cannabis users have
a greater risk of developing psychosis than non-users.
This risk is most pronounced in cases with an existing
risk of psychotic disorder.[43][44] A 2005 paper from the
Dunedin study suggested an increased risk in the development of psychosis linked to polymorphisms in the COMT
gene.[45] However, a more recent study cast doubt on the
proposed connection between this gene and the eects of
cannabis on the development of psychosis.[46]
A 2008 German review reported that cannabis was a
causal factor in some cases of schizophrenia and stressed
the need for better education among the public due to increasingly relaxed access to cannabis.[47]
Its status as an illegal drug in most countries can make

research dicult; for instance in the United States where 182.4.4 Other potential long-term eects
the National Institute on Drug Abuse was the only legal
source of cannabis for researchers until it recently became A 2008 National Institutes of Health study of 19 chronic
legalized in Colorado and Washington state.[35]
heavy marijuana users with cardiac and cerebral abnorA 2011 systematic review evaluated published studies of malities (averaging 28 g to 272 g (1 to 9+ oz) weekly)
the acute and long-term cognitive eects of cannabis. and 24 controls found elevated levels of apolipoprotein
[48]
An inTHC intoxication is well established to impair cognitive C-III (apoC-III) in the chronic smokers.
functioning on an acute basis, including eects on the crease in apoC-III levels induces the development of
ability to plan, organize, solve problems, make decisions, hypertriglyceridemia.
and control impulses. The extent of this impact may be
greater in novice users, and paradoxically, those habituated to high level ingestion may have reduced cognition Detection in body uids
during withdrawal. Studies of long-term eects on cognition have provided conicting results, with some studies THC, 11-OH-THC and THC-COOH can be detected and
nding no dierence between long-term abstainers and quantitated in blood, urine, hair, oral uid or sweat usnever-users and others nding long term decits. The dis- ing a combination of immunoassay and chromatographic
crepancies between studies may reect greater long term techniques as part of a drug use testing program or in a
eects among heavier users relative to occasional users, forensic investigation of a trac or other criminal oense
and greater duration of eect among those with heavy or suspicious death.[49][50][51]
use as adolescents compared to later in life.[36] A second systematic review focused on neuroimaging studies
found little evidence supporting an eect of cannabis use
182.4.5 Interactions
on brain structure and function.[37] A 2003 meta analysis
concluded that any long term cognitive eects were relatively modest in magnitude and limited to certain aspects The eects of the drug can be reduced by the CB1 receptor inverse agonist rimonabant (SR141716A) as well
of learning and memory.[38]
as opioid receptor antagonists (opioid blockers) naloxone
and naloxonazine.[20][52] The 7 nicotinic receptor antagonist methyllycaconitine can block self-administration of
182.4.3 Impact on psychosis
THC in rates comparable to the eects of varenicline on
nicotine
administration.[53]
A 2007 meta analysis concluded that cannabis use reduced the average age of onset of psychosis by 2.7 years
relative to non-cannabis use.[39] A 2005 meta analysis
concluded that adolescent use of cannabis increases the
risk of psychosis, and that the risk is dose-related.[40]
A 2004 literature review on the subject concluded that
Cannabidiol, the second most abundant cannabinoid

found in cannabis, is an indirect antagonist against
cannabinoid agonists; thus reducing the eects of
anandamide and THC agonism on the CB1 and CB2 receptors.
182.7. CHEMICAL SYNTHESIS
239
182.5 Mechanism of action

For a review of the mechanisms behind endocannabinoid
synaptic transmission, see Endocannabinoid system.
The pharmacological actions of THC result from its
partial agonist activity at the cannabinoid receptor CB1
(K=10nM[54] ), located mainly in the central nervous system, and the CB2 receptor (K=24nM[54] ), mainly expressed in cells of the immune system.[19] The psychoactive eects of THC are primarily mediated by its activation of CB1 G-protein coupled receptors, which result
in a decrease in the concentration of the second messenger molecule cAMP through inhibition of adenylate cyBiosynthesis of THC
clase.[16]
The presence of these specialized cannabinoid receptors in the brain led researchers to the discovery of endocannabinoids, such as anandamide and 2arachidonoyl glyceride (2-AG). THC targets receptors
in a manner far less selective than endocannabinoid
molecules released during retrograde signaling, as the
drug has a relatively low cannabinoid receptor ecacy
and anity. In populations of low cannabinoid receptor density, THC may act to antagonize endogenous agonists that possess greater receptor ecacy.[18] THC is a
lipophilic molecule[55] and may bind non-specically to a
variety of entities in the brain and body, such as adipose
tissue (fat).[56][57]
is decarboxylated, producing THC. The pathway for

THCA biosynthesis is similar to that which produces the
bitter acid humulone in hops.[62][63]
182.7 Chemical synthesis
Total chemical syntheses largely depend on carefully controlled acid catalyzed condensation of selected
monoterpenes with olivetol. If citral is used as start material only the racemic product is formed. The condensation is acid catalyzed, but 0.0005 N hydrogen chloride
THC, similarly to cannabidiol, albeit less potently, is an only aords a 12% yield. 1% boron triuoride is used
allosteric modulator of the - and -opioid receptors.[58] as the catalyst.
182.5.1
Pharmacokinetics
THC is metabolized mainly to 11-OH-THC by the body.

This metabolite is still psychoactive and is further oxidized to 11-nor-9-carboxy-THC (THC-COOH). In humans and animals, more than 100 metabolites could
be identied, but 11-OH-THC and THC-COOH are
the dominating metabolites. Metabolism occurs mainly
in the liver by cytochrome P450 enzymes CYP2C9,
CYP2C19, and CYP3A4.[59] More than 55% of THC is
excreted in the feces and ~20% in the urine. The main
metabolite in urine is the ester of glucuronic acid and
THC-COOH and free THC-COOH. In the feces, mainly
11-OH-THC was detected.[60]
Since isomerization of 1 THC to virtually inactive

6 THC takes place readily in acid or upon heating, the
cyclizations must be carefully controlled.
Optically active verbenol can be used instead of citral.
Please note the attached citations:[64][65][66]
182.8 Marinol
Dronabinol is the INN for a pure isomer of THC, ()trans-9 -tetrahydrocannabinol,[67] which is the main isomer found in cannabis. It is sold as Marinol (a registered trademark of Solvay Pharmaceuticals). Dronabinol is also marketed, sold, and distributed by PAR Pharmaceutical Companies under the terms of a license and
distribution agreement with SVC pharma LP, an aliate of Rhodes Technologies. Synthesized THC may be
182.6 Biosynthesis
generally referred to as dronabinol. It is available as a
prescription drug (under Marinol[68] ) in several countries
In the cannabis plant, THC occurs mainly as including the United States and Germany. In the United
tetrahydrocannabinolic acid (THCA, 2-COOH-THC). States, Marinol is a Schedule III drug, available by preGeranyl pyrophosphate and olivetolic acid react, catal- scription, considered to be non-narcotic and to have a
ysed by an enzyme to produce cannabigerolic acid,[61] low risk of physical or mental dependence. Eorts to
which is cyclized by the enzyme THC acid synthase get cannabis rescheduled as analogous to Marinol have
to give THCA. Over time, or when heated, THCA not succeeded thus far, though a 2002 petition has been
240
accepted by the DEA. As a result of the rescheduling ics like nabilone.[79]

of Marinol from Schedule II to Schedule III, rells are
now permitted for this substance. Marinol has been approved by the U.S. Food and Drug Administration (FDA)
in the treatment of anorexia in AIDS patients, as well as
for refractory nausea and vomiting of patients undergoing
chemotherapy, which has raised much controversy[69] as
182.9 Regulatory
to why natural THC is still a schedule I drug.[70]
history
An overdose usually presents with lethargy, decreased

motor coordination, slurred speech, and postural hy- For more details on this topic, see Removal of cannabis
potension. The FDA estimates the lethal human dose from Schedule I of the Controlled Substances Act.
of intravenous dronabinol to be 30 mg/kg (2100 mg/ 70
kg).[71]
Since at least 1986, the trend has been for THC in genAn analog of dronabinol, nabilone, is available commer- eral, and especially the Marinol preparation, to be downcially in Canada under the trade name Cesamet, manu- graded to less and less stringently-controlled schedules of
factured by Valeant Pharmaceuticals. Cesamet has also controlled substances, in the U.S. and throughout the rest
received FDA approval and began marketing in the U.S. of the world.
in 2006. Nabilone is a Schedule II drug.[72]
On May 13, 1986, the Drug Enforcement Administration (DEA) issued a Final Rule and Statement of Pol182.8.1 Comparisons with medical mari- icy authorizing the Rescheduling of Synthetic Dronabinol in Sesame Oil and Encapsulated in Soft Gelatin
juana
Capsules From Schedule I to Schedule II (DEA 51 FR
17476-78). This permitted medical use of Marinol, alFurther information: Medical cannabis
beit with the severe restrictions associated with Schedule II status.[80] For instance, rells of Marinol prescripFemale cannabis plants contain more than 60 cannabi- tions were not permitted. At its 1045th meeting, on
noids, including cannabidiol (CBD), thought to be April 29, 1991, the Commission on Narcotic Drugs, in
the major anticonvulsant that helps multiple sclero- accordance with article 2, paragraphs 5 and 6, of the
sis patients;[73] and cannabichromene (CBC), an anti- Convention on Psychotropic Substances, decided that 9 inammatory which may contribute to the pain-killing tetrahydrocannabinol (also referred to as 9 -THC) and
eect of cannabis.[74]
its stereochemical variants should be transferred from
It takes over one hour for Marinol to reach full systemic Schedule I to Schedule II of that Convention. This reeect,[75] compared to seconds or minutes for smoked leased Marinol from the restrictions imposed by Article
or vaporized cannabis.[76] Some patients accustomed to 7 of the Convention (See also United Nations Convention
inhaling just enough cannabis smoke to manage symp- Against Illicit Trac in Narcotic Drugs and Psychotropic
toms have complained of too-intense intoxication from Substances).
Marinols predetermined dosages. Many patients have An article published in the AprilJune 1998 issue of the
said that Marinol produces a more acute psychedelic ef- Journal of Psychoactive Drugs found that Healthcare
fect than cannabis, and it has been speculated that this professionals have detected no indication of scrip-chasing
disparity can be explained by the moderating eect of or doctor-shopping among the patients for whom they
the many non-THC cannabinoids present in cannabis. have prescribed dronabinol. The authors state that MariFor that reason, alternative THC-containing medications nol has a low potential for abuse.[81]
based on botanical extracts of the cannabis plant such
as nabiximols are being developed. Mark Kleiman, di- In 1999, Marinol was rescheduled from Schedule II to III
rector of the Drug Policy Analysis Program at UCLAs of the Controlled Substances Act, reecting a nding that
School of Public Aairs said of Marinol, It wasn't any THC had a potential for abuse less than that of cocaine
fun and made the user feel bad, so it could be approved and heroin. This rescheduling constituted part of the arwithout any fear that it would penetrate the recreational gument for a 2002 petition for removal of cannabis from
market, and then used as a club with which to beat back Schedule I of the Controlled Substances Act, in which pethe advocates of whole cannabis as a medicine.[77] Mr. titioner Jon Gettman noted, Cannabis is a natural source
Kleimans opinion notwithstanding, clinical trials com- of dronabinol (THC), the ingredient of Marinol, a Schedcannabis
paring the use of cannabis extracts with Marinol in the ule III drug. There are no grounds to schedule
[82]
in
a
more
restrictive
schedule
than
Marinol.
treatment of cancer cachexia have demonstrated equal
ecacy and well-being among patients in the two treat- At its 33rd meeting, in 2003, the World Health Organiment arms.[78] United States federal law currently regis- zation Expert Committee on Drug Dependence recomters dronabinol as a Schedule III controlled substance, but mended transferring THC to Schedule IV of the Convenall other cannabinoids remain Schedule I, except synthet- tion, citing its medical uses and low abuse potential.[83]
182.11. REFERENCES
182.10 See also

Anandamide
Cannabis (drug)
Psychoactive drug
Cannabinoids
11-Hydroxy-THC, metabolite of THC
Anandamide, 2-Arachidonoylglycerol, endogenous cannabinoid agonists
Cannabidiol (CBD), an isomer of THC
Cannabinol (CBN), a metabolite of THC
Dimethylheptylpyran
Parahexyl
Tetrahydrocannabinolic acid, the biosynthetic
precursor for THC
HU-210, WIN 55,212-2, JWH-133, synthetic
cannabinoid agonists
Medical cannabis
War on Drugs
Cannabis rescheduling in the United States
Health issues and the eects of cannabis
182.11 References
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245
Chapter 183
Tetrahydrocannabinol-C4, also known as THC-C4 and
butyl-THC, is a homologue of tetrahydrocannabinol
(THC), the active component of cannabis. They are
only dierent by the pentyl side chain being replaced
by a butyl side chain. It is unknown whether THCC4 is an agonist, partial agonist, or antagonist at the
cannabinoid receptors. The propyl analog, THCV, is a
cannabinoid receptor type 1 and cannabinoid receptor
type 2 antagonist,[1] while THC is a CB1 agonist. THCC4 has rarely been isolated from cannabis samples,[2] but
appears to be less commonly present than THC or THCV.
It is metabolised in a similar manner to THC.[3] Similarly
to THC, it has 7 double bond isomers and 30 stereoisomers.
It is not scheduled by Convention on Psychotropic Substances.
183.1 See also

Cannabinoids
Cannabis
Parahexyl
183.2 References
[1] Thomas, Adle; Stevenson, Lesley A; Wease, Kerrie N; Price, Martin R; Baillie, Gemma; Ross, Ruth
A; Pertwee, Roger G (December 2005). Evidence
that the plant cannabinoid 9-tetrahydrocannabivarin
is a cannabinoid CB1 and CB2 receptor antagonist.
doi:10.1038/sj.bjp.0706414. PMID 16205722.
[2] Harvey DJ. Characterization of the butyl homologues of
delta1-tetrahydrocannabinol, cannabinol and cannabidiol
in samples of cannabis by combined gas chromatography
and mass spectrometry. Journal of Pharmacy and Pharmacology. 1976 Apr;28(4):280-5. PMID 6715
[3] Brown NK, Harvey DJ. In vivo metabolism of the n-butylhomologues of delta 9-tetrahydrocannabinol and delta 8tetrahydrocannabinol by the mouse. Xenobiotica. 1988
Apr;18(4):417-27. PMID 2840781
246
Chapter 184
Tetrahydrocannabinolic acid
Not to be confused with 11-nor-9-Carboxy-THC.
3976774,
15190053
Tetrahydrocannabinolic
acid
(THCA,
2COOH-THC), is a biosynthetic precursor of
tetrahydrocannabinol (THC), the active component
of Cannabis.[1][2][3][4] THCA is found in variable quantities in fresh, undried cannabis, but is progressively
decarboxylated to THC with drying, and especially under intense heating such as when cannabis is smoked.[5]
While THCA does not have psychoactive eects
in its own right, it does have antiinammatory and
neuroprotective eects.[6][7] Despite the ready decarboxylation by drying or heating ex vivo, conversion
of THCA to THC in vivo appears to be very limited,
giving it only very slight ecacy as a prodrug for
THC.[8] Consequently it is believed to be important
in less-psychoactive preparations of cannabis used for
medical use, such as cannabis tea.[9] It is also commonly
used as a biomarker in drug testing along with THCV,
to distinguish between prescribed synthetic Delta-9tetrahydrocannabinol, such as Marinol, and cannabis
plant material which may also be used by patients.[10]
184.1 See also
doi:10.1074/jbc.M403693200,
PMID
[3] Moore C, Rana S, Coulter C. (2007-06-01), Simultaneous

identication of 2-carboxy-tetrahydrocannabinol, tetrahydrocannabinol, cannabinol and cannabidiol in oral uid,
J Chromatogr B Analyt Technol Biomed Life Sci. 852 (12): 45964, doi:10.1016/j.jchromb.2007.02.016, PMID
17321807
[4] Taura F. (Jun 2009), Studies on tetrahydrocannabinolic
acid synthase that produces the acidic precursor of tetrahydrocannabinol, the pharmacologically active cannabinoid
in marijuana, Drug Discoveries and Therapeutics 3 (3):
837, PMID 22495534
[5] Dussy FE, Hamberg C, Luginbhl M, Schwerzmann
T, Briellmann TA. (2005-04-20), Isolation of Delta9THCA-A from hemp and analytical aspects concerning the determination of Delta9-THC in cannabis products, Forensic Science International 149 (1): 310,
doi:10.1016/j.forsciint.2004.05.015, PMID 15734104
[6] Ruhaak LR, Felth J, Karlsson PC, Rafter JJ, Verpoorte R, Bohlin L. (2011), Evaluation of the cyclooxygenase inhibiting eects of six major cannabinoids isolated from Cannabis sativa, Biological and Pharmaceutical
Bulletin 34 (5): 7748, doi:10.1248/bpb.34.774, PMID
21532172
[7] Moldzio R, Pacher T, Krewenka C, Kranner B, Novak J, Duvigneau JC, Rausch WD. (2012-05-07), Effects of cannabinoids (9)-tetrahydrocannabinol, (9)tetrahydrocannabinolic acid and cannabidiol in MPP(+)
aected murine mesencephalic cultures, Phytomedicine
19 (8-9): 81924, doi:10.1016/j.phymed.2012.04.002,
PMID 22571976
Cannabinoids
Cannabidiol
184.2 References
[1] Baker PB, Taylor BJ, Gough TA. (Jun 1981), The
tetrahydrocannabinol and tetrahydrocannabinolic acid
content of cannabis products, Journal of Pharmacy and
Pharmacology 33 (6): 36972, doi:10.1111/j.20427158.1981.tb13806.x, PMID 6115009
[2] Sirikantaramas S, Morimoto S, Shoyama Y, Ishikawa
Y, Wada Y, Shoyama Y, Taura F. (2004-09-17), The
gene controlling marijuana psychoactivity: molecular cloning and heterologous expression of Delta1tetrahydrocannabinolic acid synthase from Cannabis
sativa L., Journal of Biological Chemistry 279 (38):
247
[8] Jung J, Meyer MR, Maurer HH, Neusss C, Weinmann W, Auwrter V. (Oct 2009), Studies on the
metabolism of the Delta-9-tetrahydrocannabinol precursor
delta-9-tetrahydrocannabinolic acid A (Delta9-THCA-A)
in rat using LC-MS/MS, LC-QTOF MS and GC-MS techniques, Journal of Mass Spectrometry 44 (10): 142333,
doi:10.1002/jms.1624, PMID 19728318
[9] Hazekamp A, Bastola K, Rashidi H, Bender J, Verpoorte
R. (2007-07-15), Cannabis tea revisited: a systematic
evaluation of the cannabinoid composition of cannabis
tea, Journal of Ethnopharmacology 113 (1): 8590,
doi:10.1016/j.jep.2007.05.019, PMID 17604926
248
[10] Radnz L, Westphal F, Maser E, Rochholz G. (201202-10), THCVA-A - a new additional marker for illegal cannabis consumption, Forensic Science International
215 (1-3): 1714, doi:10.1016/j.forsciint.2011.03.001,
PMID 21454026
CHAPTER 184. TETRAHYDROCANNABINOLIC ACID
Chapter 185
Tetrahydrocannabivarin (THCV, THV) is a
homologue of tetrahydrocannabinol (THC) having
a propyl (3-carbon) side chain. This terpeno-phenolic
compound is found naturally in Cannabis, sometimes in
signicant amounts. The psychoactive eects of THCV
in Cannabis preparations are not well characterized.
185.3 See also

Cannabinoids
Cannabis
Medical marijuana
Similarly to THC, it has 7 double bond isomers and 30

stereoisomers (see: Tetrahydrocannabinol#Isomerism).
It is not scheduled by Convention on Psychotropic Substances.
Rimonabant (synthetic CB1 antagonist)

Parahexyl
185.1 Description
185.4 References
[1] Turner, C.E., Hadley, K.W., and Fetterman, P. 1973.
Constituents of Cannabis Sativa L., VI: Propyl Homologues in Samples of Known Geographical Origin. J.
Pharm. Sci. 62(10):1739-1741
Plants with elevated levels of propyl cannabinoids (including THCV) have been found in populations of
Cannabis sativa L. ssp. indica (= Cannabis indica Lam.)
from China, India, Nepal, Thailand, Afghanistan, and
Pakistan, as well as southern and western Africa. THCV
levels up to 53.7% of total cannabinoids have been reported. [1] [2]
[2] Hillig, Karl W. and Paul G. Mahlberg. 2004. A chemotaxonomic analysis of cannabinoid variation in Cannabis
(Cannabaceae). American Journal of Botany 91(6): 966975.
THCV is a cannabinoid receptor type 1 antagonist and

cannabinoid receptor type 2 partial agonist.[3] 8-THCV
has also been shown to be a CB1 antagonist.[4] Both papers describing the antagonistic properties of THCV were
demonstrated in murine models.
[3] Pertwee, Roger G (September 2007). The diverse CB1

and CB2 receptor pharmacology of three plant cannabinoids: 9-tetrahydrocannabinol, cannabidiol and 9tetrahydrocannabivarin. British Journal of Pharmacology 153 (2): 199215. doi:10.1038/sj.bjp.0707617.
[4] Pertwee RG, Thomas A, Stevenson LA, et al.
2007.
The psychoactive plant cannabinoid, 9tetrahydrocannabinol, is antagonized by 8- and
9-tetrahydrocannabivarin in mice in vivo. Br. J.
Pharmacol. 150(5): 58694.
185.2 Biosynthesis
Unlike THC, cannabidiol (CBD), and cannabichromene
(CBC), THCV doesnt begin as cannabigerolic acid
(CBGA). Instead of combining with olivetolic acid to create CBGA, geranyl pyrophosphate joins with divarinolic
acid, which has 2 less carbon molecules. The result is
cannabigerovarin acid (CBGVA). Once CBGVA is created, the process continues exactly same as it would for
THC. CBGVA is broken down to tetrahydrocannabivarin
carboxylic acid (THCVA) by the enzyme THCV synthase. At that point, THCVA can be decarboxylated with
heat or UV light to create THCV.[5]
[5] MedicalJane. What is Tetrahydrocannabivarin?".
249

www.tetrahydrocannabivarin.com
THCV
Article
on
Chapter 186
THC-O-acetate
THC acetate ester is a derivative of THC which has been
found by the DEA as an apparent controlled substance
analogue of THC. It was apparently made by extracting
and purifying THC from cannabis plant material using
a soxhlet extractor, followed by reaction with acetic anhydride in an analogous manner to how heroin is made
from morphine.[1] A similar case was reported in June
1995 in the UK and THC-O-acetate was ruled to be a
Class A drug.[2] THC acetate was also reported to have
been found by New Zealand police in 1995, again made
by acetylation of puried cannabis extracts with acetic
anhydride.[3] The acetylation of THC does not change the
properties of the compound to the same extent as with
other acetate esters (e.g. morphine vs heroin), as the parent compound is already highly lipophilic, but potency is
nonetheless increased to some extent. This derivative of
THC is interesting as one of the few analogues of THC
to have been encountered as a recreational drug sold and
used in a highly pure smokable form.
THC acetate ester was also investigated as a possible nonlethal incapacitating agent, as part of the Edgewood Arsenal experiments.[4]
186.1 References
[1] Donald A. Cooper. Future Synthetic Drugs of Abuse.
Drug Enforcement Administration, McLean, Virginia
[2] David T. Brown. Cannabis: The Genus Cannabis. p82
ISBN 90-5702-291-5
[3] Valentine MD. 9-THC acetate from acetylation of
cannabis oil. Science and Justice 1995; 36(3):195197.
[4] Possible Long-Term Health Eects of Short-Term Exposure To Chemical Agents, Volume 2: Cholinesterase
Reactivators, Psychochemicals and Irritants and Vesicants (1984) Commission on Life Sciences. The National
Academies Press. pp79-99.
250
Chapter 187
THC-O-phosphate
THC-O-phosphate is a water-soluble phosphate ester
derivative of THC, invented in 1978 in an attempt to get
around the poor water solubility of THC and make it easier to inject for the purposes of animal research into its
pharmacology and mechanism of action. The main disadvantage of THC phosphate ester is the slow rate of hydrolysis of the ester link, resulting in delayed onset of
action and lower potency than the parent drug.
THC phosphate ester is made by reacting THC with
phosphoryl chloride using pyridine as a solvent, following by quenching with water to produce THC phosphate
ester. In the original research the less active but more
stable isomer 8THC was used, but the same reaction
scheme could be used to make the phosphate ester of the
more active isomer 9THC. [1]
187.1 References
[1] Yoshimura H, Watanabe K, Oguri K, Fujiwara M, Ueki S.
Synthesis and pharmacological activity of a phosphate ester of delta8-tetrahydrocannabinol. Journal of Medicinal
Chemistry. 1978 Oct;21(10):1079-81.
251
Chapter 188
Tinabinol
Tinabinol (INN; SP-119) is a synthetic cannabinoid drug
and analogue of dronabinol which was patented as an
antihypertensive but was never marketed.[1][2]
188.1 See also

Dronabinol
Nabitan
188.2 References
[1] David T. Brown (19 November 1998). Cannabis: The
Genus Cannabis. CRC Press. p. 80. ISBN 978-90-5702291-3. Retrieved 27 April 2012.
[2] Martin Negwer (1994). Organic-chemical drugs and their
synonyms: an international survey. Indices. Akad.-Verl.
p. 2242. ISBN 978-3-05-501629-5. Retrieved 27 April
2012.
252
Chapter 189
URB602
URB602 ([1,1'-biphenyl]3-yl-carbamic acid, cyclohexyl ester) is a compound that has been found to inhibit hydrolysis of monoacyl glycerol compounds, such
as 2-arachidonoylglycerol (2-AG) and 2-oleoylglycerol
(2-OG). It was rst described in 2003.[1] A study performed in 2005 found that the compound had specicity for metabolizing 2-AG over anandamide (another
cannabinoid ligand) in rat brain presumably by inhibiting the enzyme monoacylglycerol lipase (MAGL), which
is the primary metabolic enzyme of 2-AG.[2] However,
subsequent studies have shown that URB602 lacks specicity for MAGL inhibition in vitro.[3]
189.1 References
[1] Tarzia, G; Duranti, A; Tontini, A; Piersanti, G; Mor, M;
Rivara, S; Plazzi, PV; Park, C et al. (2003). Design,
synthesis, and structure-activity relationships of alkylcarbamic acid aryl esters, a new class of fatty acid amide hydrolase inhibitors. Journal of Medical Chemistry 46 (12):
235260. doi:10.1021/jm021119g. PMID 12773040.
[2] Hohmann, Andrea G.; Suplita, Richard L.; Bolton,
Nathan M.; Neely, Mark H.; Fegley, Darren; Mangieri, Regina; Krey, Jocelyn F.; Michael Walker,
J. et al.
(2005).
An endocannabinoid mechanism for stress-induced analgesia.
Nature 435
(7045): 110812.
Bibcode:2005Natur.435.1108H.
doi:10.1038/nature03658. PMID 15973410.
[3] Vandevoorde, S; Jonsson, K-O; Labar, G; Persson, E;
Lambert, D M; Fowler, C J (2007). Lack of selectivity of URB602 for 2-oleoylglycerol compared to anandamide hydrolysisin vitro. British Journal of Pharmacology 150 (2): 18691. doi:10.1038/sj.bjp.0706971. PMC
2042901. PMID 17143303.
253
Chapter 190
URB754
URB754 was originally reported by Piomelli et al. to be
a potent, noncompetitive inhibitor of monoacylglycerol
lipase.[1] However, recent studies have shown that
URB754 failed to inhibit recombinant MGL, and brain
FAAH activity was also resistant to URB754.[2] In a later
study by Piomelli et al. showed that the MGL-inhibitory
activity attributed to URB754 is in fact due to a chemical
impurity present in the commercial sample, identied as
bis(methylthio)mercurane.[3]
190.1 References
[1] Makara JK, Mor M, Fegley D, Szab SI, Kathuria S,
Astarita G, Duranti A, Tontini A, Tarzia G, Rivara S,
Freund TF, Piomelli D (2005). Selective inhibition
of 2-AG hydrolysis enhances endocannabinoid signaling
in hippocampus. Nat. Neurosci. 8 (9): 113941.
doi:10.1038/nn1521. PMID 16116451.
[2] Saario SM, Palomki V, Lehtonen M, Nevalainen T,
Jrvinen T, Laitinen JT (2006). URB754 has no effect on the hydrolysis or signaling capacity of 2-AG
in the rat brain. Chem. Biol. 13 (8): 8114.
[3] Tarzia, G; et al. (2007). Identication of a bioactive impurity in a commercial sample of 6-methyl-2-ptolylaminobenzo[d][1,3]oxazin-4-one (URB754.. Ann
Chim. 97 (9): 88794.
254
Chapter 191
VCHSR
VCHSR is a drug used in scientic research which acts
as a selective antagonist of the cannabinoid receptor
CB1 . It is derived from the widely used CB1 antagonist rimonabant, and has similar potency and selectivity
for the CB1 receptor, but has been modied to remove
the hydrogen bonding capability in the C-3 substituent
region, which removes the inverse agonist eect that rimonabant produces at high doses, so that VCHSR instead
acts as a neutral antagonist, blocking the receptor but producing no physiological eect of its own.[1][2]
191.1 References
[1] Hurst, DP; Lynch, DL; Barnett-Norris, J; Hyatt, SM;
Seltzman, HH; Zhong, M; Song, ZH; Nie, J et al. (2002).
N-(piperidin-1-yl)5-(4-chlorophenyl)1-(2,4dichlorophenyl)4-methyl-1H-pyrazole-3-carboxamide
(SR141716A) interaction with LYS 3.28(192) is crucial for its inverse agonism at the cannabinoid CB1
doi:10.1124/mol.62.6.1274. PMID 12435794.
[2] Hurst, D; Umejiego, U; Lynch, D; Seltzman, H; Hyatt, S; Roche, M; McAllister, S; Fleischer, D et al.
(2006). Biarylpyrazole inverse agonists at the cannabinoid CB1 receptor: importance of the C-3 carboxamide
oxygen/lysine3.28(192) interaction. Journal of Medical
Chemistry 49 (20): 596987. doi:10.1021/jm060446b.
PMID 17004712.
255
Chapter 192
VDM-11
VDM-11 is a potent cannabinoid reuptake inhibitor. It
is light-sensitive and therefore must be stored within an
inert gas such as argon, in a dark place and at an ideal
temperature of 20C.[1] This gold-colored substance is
rarely found outside research laboratories.
192.1 See also

AM-404
192.2 References
[1] VDM 11 at Sigma-Aldrich
256
Chapter 193
WIN 54,461
WIN 54,461 (6-Bromopravadoline) is a drug that
acts as a potent and selective inverse agonist for the
cannabinoid receptor CB2 .[1]
193.1 See also

AM-630 (6-Iodopravadoline)
WIN 48,098 (Pravadoline)
WIN 55,212-2
193.2 References
[1] Howlett AC, Berglund B, Melvin LS (October 1995).
Cannabinoid Receptor Agonists and Antagonists. Current Pharmaceutical Design 1 (3): 343352.
257
Chapter 194
WIN 55,212-2
WIN 55,212-2, along with HU-210 and JWH-133, may
prevent the inammation caused by amyloid beta proteins
involved in Alzheimers disease, in addition to preventing
cognitive impairment and loss of neuronal markers. This
anti-inammatory action is induced through agonist action at cannabinoid receptors, which prevents microglial
activation that elicits the inammation. Additionally,
cannabinoids completely abolish neurotoxicity related to
microglial activation in rat models.
WIN 55,212-2 is a full agonist at the CB1 cannabinoid
receptor (K = 1.9 nM) and has much higher anity than
THC (K = 41 nM) for this receptor.[10]
WIN 55,212-2 reduces voluntary wheel running in laboratory mice, but with eects that depend on both genetic
background and sex.[11]
194.1 See also

WIN 48,098
WIN 54,461
WIN 55,225
WIN 56,098
Pancreatic stellate cells. The cells in the lower frame are under
the action of WIN 55,212-2. They are thought to assume a more
"quiescent" phenotype. From Michalski et al., 2008.[1]
194.2 References
WIN 55,212-2 is a chemical described as an

aminoalkylindole derivative, which produces eects similar to those of cannabinoids such as tetrahydrocannabinol
(THC) but has an entirely dierent chemical structure.[2][3][4]
WIN 55,212-2 is a potent cannabinoid receptor agonist[5]
that has been found to be a potent analgesic[6] in a rat
model of neuropathic pain.[7] It activates p42 and p44
MAP kinase via receptor-mediated signaling.[8]
At 5 M WIN 55,212-2 inhibit ATP production in sperm
in a CB1 receptor-dependent fashion.[9]
258
[1] Michalski, C., et al.

(2008).
Gluud, Christian,
ed.
Cannabinoids Reduce Markers of Inammation and Fibrosis in Pancreatic Stellate Cells. PLoS
ONE 3 (2): e1701. Bibcode:2008PLoSO...3.1701M.
PMC 2253501.
PMID 18301776.
[2] Compton DR, et al.
Aminoalkylindole Analogs:
Cannabimimetic Activity of a Class of Compounds Structurally Distinct from 9 -Tetrahydrocannabinol. Journal
of Pharmacology and Experimental Therapeutics. 1992;
263(3):1118-1126.
[3] Ferraro, L.; Tomasini, M. C.; Gessa, G. L.; Bebe, B.
W.; Tanganelli, S.; Antonelli, T. (2001). The Cannabinoid Receptor Agonist WIN 55,212-2 Regulates Glutamate Transmission in Rat Cerebral Cortex: An in Vivo
and in Vitro Study. Cerebral Cortex 11 (8): 728733.

doi:10.1093/cercor/11.8.728. PMID 11459762.
[4] Zhang, Q., et al.
(2002).
In vitro
metabolism
of
R(+)2,3-dihydro-5-methyl-3(morpholinyl)methylpyrrolo 1,2,3-de1,4-benzoxazinyl(1-naphthalenyl) methanone mesylate, a cannabinoid
receptor agonist. Drug metabolism and disposition:
the biological fate of chemicals 30 (10): 10771086.
doi:10.1124/dmd.30.10.1077. PMID 12228183.
[5] Felder, C. C.; Joyce, K. E.; Briley, E. M.; Mansouri, J.;
MacKie, K.; Blond, O.; Lai, Y.; Ma, A. L.; Mitchell, R.
L. (1995). Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2
receptors. Molecular pharmacology 48 (3): 443450.
PMID 7565624.
[6] Meng, I. D.; Manning, B. H.; Martin, W. J.; Fields, H. L.
(1998). An analgesia circuit activated by cannabinoids.
Nature 395 (6700): 381383. doi:10.1038/26481. PMID
9759727.
[7] Herzberg, U.; Eliav, E.; Bennett, G. J.; Kopin, I. J. (1997).
The analgesic eects of R(+)-WIN 55,2122 mesylate,
a high anity cannabinoid agonist, in a rat model of neuropathic pain. Neuroscience Letters 221 (23): 157160.
doi:10.1016/S0304-3940(96)13308-5. PMID 9121688.
[8] Bouaboula, M.; Poinot-Chazel, C.; Bourri, B.; Canat, X.;
Calandra, B.; Rinaldi-Carmona, M.; Le Fur, G.; Casellas,
P. (1995). Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor
CB1. The Biochemical journal. 312 ( Pt 2) (Pt 2): 637
641. PMC 1136308. PMID 8526880.
[9] Morgan, D. J.; Muller, C. H.; Murataeva, N. A.; Davis, B.
J.; MacKie, K. (2012). "9-Tetrahydrocannabinol (9THC) attenuates mouse sperm motility and male fecundity. British Journal of Pharmacology 165 (8): 2575
2583. doi:10.1111/j.1476-5381.2011.01506.x. PMC
3423255. PMID 21615727.
[10] Kuster, J. E., et al. (1993). Aminoalkylindole binding in
rat cerebellum: selective displacement by natural and synthetic cannabinoids. The Journal of Pharmacology and
Experimental Therapeutics 264 (3): 13521363. PMID
8450470.
[11] Keeney BK, et al. (2012). Sex dierences in cannabinoid receptor-1 (CB1) pharmacology in mice selectively
bred for high voluntary wheel-running behavior. Pharmacology, Biochemistry and Behavior 101: 528537.
doi:10.1016/j.pbb.2012.02.017.

Enzo Life Sciences Win 55,212-2 Data Sheet
The cannabinoid WIN 55,212-2 inhibits transient
receptor potential vanilloid 1 (TRPV1) and evokes
peripheral antihyperalgesia via calcineurin. 2006
Jul 18; PubMed 16849427
259
JNeurosci.org Prevention of Alzheimers Disease
Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation
New Scientist: Hope for cannabis-based drug for
Alzheimers
Chapter 195
WIN 56,098
WIN 56,098 is a chemical that is considered to be an
aminoalkylindole derivative. It is a tricyclic aryl derivative that acts as a competitive antagonist at the CB2
cannabinoid receptor. Its activity at CB1 was signicantly
less eective. WIN 56,098 failed to antagonize any of the
in vivo eects of THC.[1]
195.1 See also

WIN 55,212-2
WIN 55,225
195.2 References
[1] Howlett AC, Berglund B, Melvin LS (October 1995).
Cannabinoid Receptor Agonists and Antagonists. Current Pharmaceutical Design 1 (3): 343352.
260
Chapter 196
XLR-11 (drug)
196.4 See also
Not to be confused with Reaction Motors XLR11.

XLR-11 (5"-uoro-UR-144) is a drug that acts as a potent agonist for the cannabinoid receptors CB1 and CB2
with a K of 24.2nM and a EC50 of 359nM at CB1 .
It is a 3-(tetramethylcyclopropylmethanoyl)indole derivative related to compounds such as UR-144, A-796,260
and A-834,735, but it is not specically listed in the
patent or scientic literature alongside these other similar compounds,[2][3] and appears to have not previously
been made by Abbott Laboratories, despite falling within
the claims of patent WO 2006/069196.
JWH-018
STS-135
UR-144
196.5 References
[1] SD HB1024
[2] WO application 2006069196, Pace JM, Tietje K,
Dart MJ, Meyer MD, 3-Cycloalkylcarbonyl indoles as
cannabinoid receptor ligands, published 2006-06-29, assigned to Abbott Laboratories
196.1 Detection
A forensic standard for this compound is available, and
a representative mass spectrum has been posted on
Forendex.[4] An ELISA immunoassay technique for detecting XLR-11 and UR-144 in blood and urine as part
of general drug screens has been developed by Randox
Laboratories and Tulip Biolabs, Inc.[5]
[3] Frost JM, Dart MJ, Tietje KR, Garrison TR, Grayson
GK, Daza AV, El-Kouhen OF, Yao BB, Hsieh GC, Pai
M, Zhu CZ, Chandran P, Meyer MD (January 2010).
Indol-3-ylcycloalkyl ketones: eects of N1 substituted
indole side chain variations on CB(2) cannabinoid receptor activity. J. Med. Chem. 53 (1): 295315.
doi:10.1021/jm901214q. PMID 19921781.
[4] XLR-11. Structural, chemical, and analytical data on
controlled substances. Southern Association of Forensic
Scientists (SAFS).
196.2 Recreational use

XLR-11 was instead rst identied by laboratories in
2012 as an ingredient in synthetic cannabis smoking
blends, and appears to be a novel compound invented
specically for grey-market recreational use. It was
banned in New Zealand by being added to the temporary
class drug schedule, eective from 13 July 2012.[6] It has
also been banned in Florida as of 11 December 2012.[7]
Arizona banned XLR-11 on April 3, 2013.[8]
[5] Randox Toxicology launches ELISA for the detection of

new generation Synthetic Cannabinoids (Spice) drugs UR144 and XLR-11. Press Release. Randox Laboratories
Ltd. 2013-04-29.
[6] CB-13, MAM-2201, AKB48, and XLR11 are classied
as temporary class drugs. Temporary Class Drug Notice. The Department of Internal Aairs: New Zealand
Gazette. 2012-07-05.
[7] News Release - Attorney General Pam Bondi Outlaws
Additional Synthetic Drugs. News Release. State of
Florida. 2012-12-11.
196.3 Toxicity
XLR-11 has been linked to acute kidney injury in some
users,[9] along with AM-2201.[10][11]
261
[8] State of Arizona, Oce of the Governor. azgovernor.gov http://azgovernor.gov/dms/upload/PR_040313_

SyntheticDrugs.pdf |url= missing title (help). Retrieved
2014-08-27.
262
[9] Alphabet Soup, or the newer synthetic cannabinoids....

The Dose Makes The Poison Blog. 11 December 2013.
Retrieved 18 September 2014.
[10] Bhanushali GK, Jain G, Fatima H, Leisch LJ, ThornleyBrown D (April 2013). AKI associated with synthetic
cannabinoids: a case series. Clin J Am Soc Nephrol 8 (4):
5236. doi:10.2215/CJN.05690612. PMID 23243266.
[11] Acute Kidney Injury Associated with Synthetic Cannabinoid Use Multiple States, 2012. Morbidity and Mortality Weekly Report. U.S. Centers for Disease Control and
Prevention (CDC). 2013-92-13. Retrieved 2013-02-15.
Check date values in: |date= (help)
CHAPTER 196. XLR-11 (DRUG)
Chapter 197
AM251
AM-251 is an inverse agonist at the CB1 cannabinoid receptor. AM-251 is structurally very close to SR141716A
(rimonabant); both are biarylpyrazole cannabinoid receptor antagonists. In AM-251 the p-chloro group attached
to the phenyl substituent at C-5 of the pyrazole ring is replaced with a p-iodo group. The resulting compound exhibits slightly better binding anity for the CB1 receptor
(with a K value of 7.5nM) than SR141716A, which has
a K value of 11.5nM, AM-251 is, however, about twofold more selective for the CB1 receptor when compared
to SR141716A.[1]
197.1 See also

Discovery and development of Cannabinoid Receptor 1 Antagonists
197.2 References
[1] Lan, R., Liu, Q., Fan, P., et al. Structure-activity relationships of pyrazole derivatives as cannabinoid receptor
antagonists. J Med Chem 42 769-776 (1999). PubMed
10052983
263
Chapter 198
Aminoalkylindole
Aminoalkylindoles (AAIs) are a family of
cannabinergic compound that act as a cannabinoid
receptor agonist. They were invented by pharmaceutical company Sterling-Winthrop in the early 1990s as
potential non-steroidal anti-inammatory agents.[1]
198.1 Legality
Aminoalkylindole are now commonly found in synthetic
cannabis designer drugs.[2]
In the United States, the DEA added the aminoalkylindole JWH-200 to Schedule I of the Controlled Substances
Act on 1 March 2011 for 12 months.[2][3]
198.2 References
[1] Emmanuel S. Onaivi (2006). Marijuana and Cannabinoid
Research: Methods and Protocols. Springer. pp. 128.
ISBN 978-1-59259-999-8.
[2] Synthetic Cannabinoids. American Association for
Clinical Chemistry. 2013-02-01. Retrieved 2013-11-17.
[3] Schedules of Controlled Substances: Temporary Placement of Five Synthetic Cannabinoids Into Schedule I.
Federal Register. 2011-03-01. Retrieved 2013-11-17.

Aminoalkylindoles, ChEBI
264
Chapter 199
Cannabipiperidiethanone,
(CPE,
or
1(N-methylpiperidin-2-ylmethyl)3-(2methoxyphenylacetyl)indole), is a synthetic cannabinoid that has been found as an ingredient of herbal
synthetic cannabis blends sold in Japan, alongside JWH122 and JWH-081. Its binding anity was measured at
the CB1 and CB2 receptors and it was found to have an
IC50 of 591nM at CB1 and 968nM at CB2 , making it
2.3x and 9.4x weaker than JWH-250 at these two targets
respectively.[1]
199.1 See also

AM-1220
AM-1248
AM-2233
JWH-203
RCS-8
199.2 References
[1] Uchiyama N, Kikura-Hanajiri R, Goda Y (2011). Identication of a novel cannabimimetic phenylacetylindole,
cannabipiperidiethanone, as a designer drug in a herbal
product and its anity for cannabinoid CB and CB receptors. Chemical & Pharmaceutical Bulletin 59 (9):
12035. doi:10.1248/cpb.59.1203. PMID 21881274.
265
Chapter 200
JWH-193
JWH-193 is a drug from the aminoalkylindole family
which acts as a cannabinoid receptor agonist. It was invented by the pharmaceutical company Sano-Winthrop
in the early 1990s. JWH-193 has a binding anity at the
CB1 receptor of 6nM, binding around seven times more
tightly than the parent compound JWH-200,[1] though
with closer to twice the potency of JWH-200 in activity
tests. A structural isomer of JWH-193 with the methyl
group on the indole ring instead of the naphthoyl ring,
was also found to be of similarly increased potency over
JWH-200.[2][3]
JWH-198
200.2 References
12: 1395-1411.
[2] Eissenstat MA, et al. (August 1995). Aminoalkylindoles: structure-activity relationships of novel cannabinoid mimetics. Journal of Medicinal Chemistry 38 (16):
3094105. doi:10.1021/jm00016a013. PMID 7636873.
[3] Shim JY, et al. (November 1998). Three-dimensional
quantitative structure-activity relationship study of the
cannabimimetic (aminoalkyl)indoles using comparative
molecular eld analysis. Journal of Medicinal Chemistry 41 (23): 452132. doi:10.1021/jm980305c. PMID
9804691.
6-Methyl-JWH-200
200.1 See also

JWH-122
266
Chapter 201
JWH-198
JWH-198 is a drug from the aminoalkylindole family
which acts as a cannabinoid receptor agonist. It was invented by the pharmaceutical company Sano-Winthrop
in the early 1990s. JWH-198 has a binding anity at
the CB1 receptor of 10nM, binding around four times
more tightly than the parent compound JWH-200, which
has no substitution on the naphthoyl ring.[1] It has been
used mainly in molecular modelling of the cannabinoid
receptors.[2][3]
201.1 See also

JWH-081
JWH-193
201.2 References
12: 1395-1411.
[2] Eissenstat MA, et al. (August 1995). Aminoalkylindoles: structure-activity relationships of novel cannabinoid mimetics. Journal of Medicinal Chemistry 38 (16):
3094105. doi:10.1021/jm00016a013. PMID 7636873.
[3] Shim JY, et al. (November 1998). Three-dimensional
quantitative structure-activity relationship study of the
cannabimimetic (aminoalkyl)indoles using comparative
molecular eld analysis. Journal of Medicinal Chemistry 41 (23): 452132. doi:10.1021/jm980305c. PMID
9804691.
267
Chapter 202
JWH-200
JWH-200 (WIN 55,225)[1] is an analgesic chemical from the aminoalkylindole family that acts as a
cannabinoid receptor agonist. Its binding anity at
the CB1 receptor is 42nM, around the same as that of
THC,[2] but its analgesic potency in vivo was higher than
that of other analogues with stronger CB1 binding anity in vitro,[3] around 3 times that of THC but with
less sedative eect,[4] most likely reecting favourable
pharmacokinetic characteristics. It was discovered by,
and named after, Dr. John W. Human.
The US DEA temporarily declared JWH-200 a schedule
I controlled substance on 1 March 2011 through 76 FR
11075, and permanently instated the same schedule on 9
July 2012 in the Section 1152 of the Food and Drug Administration Safety and Innovation Act.[5] As of 26 June
2011, the drug is legal in Canada.[6]
202.1 See also

JWH-018
JWH-073
CP-47,497
HU-210
A-796,260
WIN 55,212-2
202.2 References
[1] Dutta, A. K. , E. A. ; Ryan, W.; Thomas, B. F.;
Singer, M.; Compton, D. R.; Martin, B. R.; Razdan,
R. K. (1997). Synthesis, pharmacology, and molecular modeling of novel 4-alkyloxy indole derivatives related to cannabimimetic aminoalkyl indoles (AAIs)".
Bioorganic & Medicinal Chemistry 5 (8): 15911600.
doi:10.1016/S0968-0896(97)00111-9. PMID 9313864.
12: 1395-1411.
268
[3] Bell, MR, et al.. Antinociceptive (aminoalkyl)indoles.

doi:10.1021/jm00107a034. PMID 1900533.
[4] Compton, DR, et al. (1992). Aminoalkylindole analogs:
cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol. Journal of Pharmacology and Experimental Therapeutics 263
(3): 111826. PMID 1335057.
[5] Schedules of Controlled Substances: Temporary Placement of Four Synthetic Cannabinoids Into Schedule I.
DEA Oce of Diversion Control. Retrieved 11 March
2014.
[6] http://laws.justice.gc.ca/en/C-38.8/
Chapter 203
Pravadoline
Pravadoline (WIN 48,098) is an antiinammatory and
analgesic drug with an IC50 of 4.9 M and a K of
2511nM at CB1 , related in structure to non-steroidal
antinammtory drugs (NSAIDs) such as indometacin. It
was developed in the 1980s as a new antiinammatory
and prostaglandin synthesis inhibitor, acting through inhibition of the enzyme cyclooxygenase (COX).
However, pravadoline was found to exhibit unexpectedly strong analgesic eects, which appeared at doses
ten times smaller than the eective anti-inammatory
dose and so could not be explained by its action as a
COX inhibitor. These eects were not blocked by opioid antagonists such as naloxone,[1] and it was eventually discovered that pravadoline represented the rst compound from a novel class of cannabinoid agonists, the
aminoalkylindoles.[2]
Pravadoline was never developed for use as an analgesic,
partly due to toxicity concerns (although these were later
shown to be a result of the salt form that the drug had been
prepared in rather than from the pravadoline itself),[3]
however the discovery of cannabinoid activity in this
structurally novel family of drugs led to the discovery
of several new cannabinoid agonists, including the drug
WIN 55,212-2, which is now widely used in scientic
research.[4][5]
The antinociceptive activity of pravadoline cannot be explained by an opioid mechanism, because pravadolineinduced antinociception was not antagonized by naloxone
(1 mg/kg, s.c.) and pravadoline did not bind to the opioid
receptors at concentrations up to 10M.[1]
203.2 See also

AM-630 (6-iodopravadoline)
WIN 54,461 (6-bromopravadoline)
WIN 55,212-2
RCS-4 (1-pentyl-3-(4-methoxybenzoyl)indole)
203.3 References
[1] Haubrich DR, et al. (1990). Pharmacology of pravadoline: a new analgesic agent. J. Pharmacol. Exp. Ther.
255 (2): 51122. PMID 2243340.
[2] Bell MR, et al.
(1991).
Antinociceptive
(aminoalkyl)indoles. J. Med. Chem. 34 (3): 1099110.
doi:10.1021/jm00107a034. PMID 1900533.
[3] Everett RM, et al. (1993). Nephrotoxicity of pravadoline maleate (WIN 48098-6) in dogs: evidence of maleic
acid-induced acute tubular necrosis. Fundam Appl Toxicol 21 (1): 5965. doi:10.1006/faat.1993.1072. PMID
8365586.
203.1 Animal studies

Administration of pravadoline on rats showed:[1]
Prolonged the response latency induced by tail immersion in hot water at a temperature of 55 degrees
Celsius (minimum eective dose, 100 mg/kg s.c.)
Prevented hyperalgesia in rats with Brewers Yeast
injections during (Randall-Selitto test) (minimum
eective dose, 1 mg/kg, p.o.)
Prevented the nociceptive response induced by paw
exion in the adjuvant-arthritic rat (ED50,41 mg/kg,
p.o.)
Prevented the nociceptive response of bradykinininduced head and forepaw exion (ED50, 78 mg/kg,
p.o.)
269
[4] D'Ambra TE, et al. (1992). Conformationally restrained

analogues of pravadoline: nanomolar potent, enantioselective, (aminoalkyl)indole agonists of the cannabinoid receptor. J. Med. Chem. 35 (1): 12435.
doi:10.1021/jm00079a016. PMID 1732519.
[5] Compton DR, et al. (1992). Aminoalkylindole analogs:
cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol. J.
Pharmacol. Exp. Ther. 263 (3): 111826. PMID
1335057.
Chapter 204
RCS-4
RCS-4, or 1-pentyl-3-(4-methoxybenzoyl)indole, is a
synthetic cannabinoid drug sold under the names SR-19,
BTM-4, or Eric-4 (later shortened to E-4), but originally,
OBT-199.
204.2 See also

AM-630
AM-679
RCS-8
Pravadoline (WIN 48,098)
204.1 Legality
RCS-4 was banned in Sweden on 1 October 2010 as
a hazardous good harmful to health, after being identied as an ingredient in herbal synthetic cannabis
products.[2][3] It was outlawed in Denmark on 11 March
2011.[4] In August 2011, New Zealand added not only
RCS-4 but also its 1-butyl homologue, and the 2methoxybenzoyl isomers of both these compounds, to a
temporary class drug schedule (i.e. equivalent to Class
C but reviewed after 12 months, and with personal possession and use of small amounts decriminalised), which
was newly created under the Misuse of Drugs Amendment Act 2011 passed a week earlier.[5][6][7]
204.3 References
[1] = WDU20111050614 Ustawa z dnia 15 kwietnia 2011 r.
o zmianie ustawy o przeciwdziaaniu narkomanii ( Dz.U.
2011 nr 105 poz. 614 )". Internetowy System Aktw
Prawnych. Retrieved 12 June 2011.
[2] Swedish Code of Statutes Regulation (2010:1086).
[3] Swedish Code of Statutes Regulation (2010:1086). (pdf)
[4] http://laegemiddelstyrelsen.dk/~{}/media/
AC4F04EB48F74523A76BA84DAB9B6067.ashx
[5] Kronic ban passed by Parliament. The New Zealand
Herald. NZPA. 4 August 2011. Retrieved 4 November
2011.
[6] Synthetic cannabis o shelves by Wednesday. The New
Zealand Herald. NZPA. 9 August 2011. Retrieved 4
November 2011.
[7] New Zealand Gazette. Tuesday 9 August 2011. Issue No
122, pp 3365-3366. Departmental Notices. Health. Misuse of Drugs Act 1975. Temporary Class Drug Notice.
RCS-4 and related analogues detected in synthetic cannabis

blends
270
Chapter 205
Anandamide
Anandamide,
also
known
as
Narachidonoylethanolamine or AEA, is an endogenous
cannabinoid neurotransmitter.
The name is taken
from the Sanskrit word (and Hinduistic religious
term) ananda, which means joy, bliss, delight", and
amide.[1][2] It is synthesized from N-arachidonoyl
phosphatidylethanolamine by multiple pathways.[3] It is
degraded primarily by the fatty acid amide hydrolase
(FAAH) enzyme, which converts anandamide into
ethanolamine and arachidonic acid. As such, inhibitors
of FAAH lead to elevated anandamide levels and are
being pursued for therapeutic use.[4][5]
205.1 History
It was isolated and its structure rst described in 1992
by W. A. Devane, Lumr Hanu et al. who were working in a team led by Raphael Mechoulam at the Hebrew
University of Jerusalem.[6]
205.2 Physiological functions

Anandamides eects can be either central, in the brain,
or peripheral, in other parts of the body. These distinct
eects are mediated primarily by CB1 cannabinoid receptors in the central nervous system, and CB2 cannabinoid receptors in the periphery.[7] The latter are mainly
involved in functions of the immune system. Cannabinoid receptors were originally discovered as being sensitive to 9 -tetrahydrocannabinol (9 -THC, commonly
called THC), which is the primary psychoactive cannabinoid found in cannabis. The discovery of anandamide
came from research into CB1 and CB2, as it was inevitable that a naturally occurring (endogenous) chemical
would be found to aect these receptors.
uterus. Therefore cannabinoids such as 9 -THC might

inuence processes during the earliest stages of human pregnancy.[9] Peak plasma anandamide occurs at
ovulation and positively correlates with peak estradiol
and gonadotrophin levels, suggesting that these may
be involved in the regulation of AEA (anandamide)
levels.[10] Subsequently, anandamide has been proposed
as a biomarker of infertility, but so far lacks any predictive
values in order to be used clinically.[11]
Anandamide plays a role in the regulation of feeding
behavior, and the neural generation of motivation and
pleasure. In addition, anandamide injected directly into
the forebrain reward-related brain structure nucleus accumbens enhances the pleasurable responses of rats to
a rewarding sucrose taste, and enhances food intake as
well.[7][12]
A study published in 1998 shows that anandamide inhibits human breast cancer cell proliferation.[13] Some
studies have linked anandamide release as a mechanism
of analgesic eects induced by exercise, particularly by
running.[14]
In 1996, researchers discovered anandamide in chocolate. They also detected the presence of two substances that might mimic the eects of anandamide, Noleoylethanolamine and N-linoleoylethanolamine.[15]
205.3 Synthesis and degradation

The human body synthesizes anandamide from Narachidonoyl phosphatidylethanolamine (NAPE), which
is itself made by transferring arachidonic acid from
lecithin to the free amine of cephalin through an
N-acyltransferase enzyme.[16][17] Anandamide synthesis
from NAPE occurs via multiple pathways and includes
enzymes such as phospholipase A2, phospholipase C and
NAPE-PLD.[3]
Anandamide has been shown to impair working memory

in rats.[8] Studies are under way to explore what role anandamide plays in human behavior, such as eating and sleep
patterns, and pain relief.
Endogenous anandamide is present at very low levels and

has a very short half-life due to the action of the enzyme fatty acid amide hydrolase (FAAH), which breaks it
down into free arachidonic acid and ethanolamine. StudAnandamide is also important for implantation of the ies of piglets show that dietary levels of arachidonic acid
early stage embryo in its blastocyst form into the and other essential fatty acids aect the levels of anan271
272
damide and other endocannabinoids in the brain.[18] High
fat diet feeding in mice increases levels of anandamide in
the liver and increases lipogenesis.[19] This suggests that
anandamide may play a role in the development of obesity, at least in rodents.
Paracetamol (or acetaminophen in the U.S.A.) is
metabolically combined with arachidonic acid by FAAH
to form AM404.[20] This metabolite of paracetamol is a
potent agonist at the TRPV1 vanilloid receptor, a weak
agonist at both CB1 and CB2 receptors, and an inhibitor
of anandamide reuptake. As a result, anandamide levels
in the body and brain are elevated. In this fashion, paracetamol acts as a pro-drug for a cannabimimetic metabolite. This action may be partially or fully responsible for
the analgesic eects of paracetamol.[21][22]
There have been identied transport proteins for anandamide and its sister molecule 2-arachidonoylglycerol.
These include the heat shock proteins (Hsp70s) and fatty
acid binding proteins (FABPs).[23][24]
205.4 Medical benets

The Royal Society of Chemistry have stated that research
indicates that AM1172 could potentially be developed
into a drug that would increase the brains anandamide
levels to help treat anxiety and depression.[25]
205.5 See also

Cannabinoids
Virodhamine
Tetrahydrocannabinol (THC)
Fatty acid amide hydrolase
Raphael Mechoulam
205.6 References
[1] Devane WA et al. (December 1992). Isolation
and structure of a brain constituent that binds to the
cannabinoid receptor. Science 258 (5090): 19469.
doi:10.1126/science.1470919. PMID 1470919. |rst3=
Authors list (help); |rst6= missing |last6= in Authors
list (help); |rst7= missing |last7= in Authors list (help);
|rst8= missing |last8= in Authors list (help); |rst9= missing |last9= in Authors list (help); |rst10= missing |last10=
in Authors list (help)
CHAPTER 205. ANANDAMIDE
[2] Mechoulam R, Fride E (1995). The unpaved road to the

endogenous brain cannabinoid ligands, the anandamides.
In Pertwee RG. Cannabinoid receptors. Boston: Academic Press. pp. 233258. ISBN 0-12-551460-3.
[3] Wang, J.; Ueda, N. (2009).
Biology of endocannabinoid synthesis system.
Prostaglandins
& Other Lipid Mediators 89 (34):
112119.
doi:10.1016/j.prostaglandins.2008.12.002.
PMID
19126434.
[4] Gaetani, S.; Dipasquale, P.; Romano, A.; Righetti, L.;
Cassano, T.; Piomelli, D.; Cuomo, V. (2009). Chapter 5 The Endocannabinoid System as A Target for Novel
Anxiolytic and Antidepressant Drugs. International
Review of Neurobiology - 85. International Review
of Neurobiology 85. pp. 5713. doi:10.1016/S00747742(09)85005-8. ISBN 9780123748935.
[5] Hwang, J.; Adamson, C.; Butler, D.; Janero, D. R.;
Makriyannis, A.; Bahr, B. A. (2009). Enhancement
of endocannabinoid signaling by fatty acid amide
hydrolase inhibition: A neuroprotective therapeutic
Life Sciences 86 (1516): 615623.
modality.
doi:10.1016/j.lfs.2009.06.003. PMC 2848893. PMID
19527737.
[6] Mechoulam, WA; Hanus L; Breuer A; Pertwee RG;
Stevenson LA; Grin G; Gibson D; Mandelbaum
A; Etinger A; Mechoulam R (December 1992).
Isolation and structure of a brain constituent that
binds to the cannabinoid receptor.
Science 258
(5090):
19469.
Bibcode:1992Sci...258.1946D.
doi:10.1126/science.1470919. PMID 1470919.
[7] Pacher P, Batkai S, Kunos G; Btkai; Kunos (2006).
The Endocannabinoid System as an Emerging Target
of Pharmacotherapy. Pharmacol Rev. 58 (3): 389
462. doi:10.1124/pr.58.3.2. PMC 2241751. PMID
16968947.
[8] allet PE, Beninger RJ; Beninger (1996). The endogenous
cannabinoid receptor agonist anandamide impairs memory in rats. Behavioural Pharmacology 7 (3): 276284.
doi:10.1097/00008877-199605000-00008.
[9] Piomelli D (January 2004). THC: moderation during implantation. Nat. Med. 10 (1): 1920.
doi:10.1038/nm0104-19. PMID 14702623.
[10] El-Talatini MR, Taylor AH, Konje JC; Taylor; Konje
(April 2010). The relationship between plasma levels of
the endocannabinoid, anandamide, sex steroids, and gonadotrophins during the menstrual cycle. Fertil. Steril.
93 (6): 198996. doi:10.1016/j.fertnstert.2008.12.033.
PMID 19200965.
[11] Rapino, C.; Battista, N.; Bari, M.; Maccarrone, M.
(2014). Endocannabinoids as biomarkers of human reproduction. Human Reproduction Update 20 (4): 501
516. doi:10.1093/humupd/dmu004. ISSN 1355-4786.
PMID 24516083.
[12] Mahler SV, Smith KS, Berridge KC; Smith; Berridge
(November 2007).
Endocannabinoid hedonic
hotspot for sensory pleasure: anandamide in nucleus accumbens shell enhances 'liking' of a sweet
reward. Neuropsychopharmacology 32 (11): 226778.

doi:10.1038/sj.npp.1301376. PMID 17406653.
[13] De Petrocellis L et al. (July 1998). The endogenous
cannabinoid anandamide inhibits human breast cancer cell
proliferation. Proc. Natl. Acad. Sci. U.S.A. 95 (14):
837580. doi:10.1073/pnas.95.14.8375. PMC 20983.
PMID 9653194. |rst3= missing |last3= in Authors list
(help); |rst4= missing |last4= in Authors list (help);
|rst5= missing |last5= in Authors list (help); |rst6= missing |last6= in Authors list (help); |rst7= missing |last7= in
Authors list (help)
[14] http://www.harford.de/arne/articles/NeuroReport.pdf
[15] di Tomaso E, Beltramo M, Piomelli D.; Beltramo; Piomelli (Aug 1996). Brain cannabinoids in chocolate.
Nature 382 (6593): 6778. doi:10.1038/382677a0.
PMID 8751435.
[16] Natarajan V, Reddy PV, Schmid PC, Schmid HH;
Reddy; Schmid; Schmid (August 1982).
NAcylation of ethanolamine phospholipids in canine
myocardium. Biochim. Biophys. Acta 712 (2): 34255.
doi:10.1016/0005-2760(82)90352-6. PMID 7126608.
[17] Cadas H, di Tomaso E, Piomelli D; Di Tomaso; Piomelli
(February 1997). Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain. J. Neurosci. 17 (4):
122642. PMID 9006968.
[18] Berger A et al. (May 2001). Anandamide and diet:
Inclusion of dietary arachidonate and docosahexaenoate
leads to increased brain levels of the corresponding Nacylethanolamines in piglets. Proc. Natl. Acad. Sci.
U.S.A. 98 (11): 64026. doi:10.1073/pnas.101119098.
PMC 33480. PMID 11353819. |rst3= missing |last3=
in Authors list (help); |rst4= missing |last4= in Authors
|rst6= missing |last6= in Authors list (help)
[19] Osei-Hyiaman D et al. (May 2005). Endocannabinoid
activation at hepatic CB1 receptors stimulates fatty acid
synthesis and contributes to diet-induced obesity. J. Clin.
Invest. 115 (5): 1298305. doi:10.1172/JCI23057. PMC
1087161. PMID 15864349. |rst3= missing |last3= in
|rst6= missing |last6= in Authors list (help); |rst7= missing |last7= in Authors list (help); |rst8= missing |last8=
in Authors list (help); |rst9= missing |last9= in Authors
[20] Hgesttt, E. D.; Jnsson, B. A.; Ermund, A.; Andersson, D. A.; Bjrk, H.; Alexander, J. P.; Cravatt, B. F.;
Basbaum, A. I.; Zygmunt, P. M. (2005). Conversion
of Acetaminophen to the Bioactive N-Acylphenolamine
AM404 via Fatty Acid Amide Hydrolase-dependent
Arachidonic Acid Conjugation in the Nervous System (pdf). Journal of Biological Chemistry 280 (36):
3140531412. doi:10.1074/jbc.M501489200. PMID
15987694.
273
[21] Bertolini A et al. (2006). Paracetamol: new vistas of an old drug. CNS Drug Rev 12 (34): 250
75. doi:10.1111/j.1527-3458.2006.00250.x. PMID
17227290. |rst3= missing |last3= in Authors list (help);
|rst4= missing |last4= in Authors list (help); |rst5= missing |last5= in Authors list (help); |rst6= missing |last6= in
Authors list (help)
[22] Sinning C et al. (December 2008). New analgesics
synthetically derived from the paracetamol metabolite
N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra5,8,11,14-enamide. J. Med. Chem. 51 (24): 78005.
doi:10.1021/jm800807k. PMID 19053765. |rst3=
(15): 63756380. doi:10.1073/pnas.0901515106. PMC
2669397. PMID 19307565.
[24] Oddi, S.; Fezza, F.; Pasquariello, N.; D'Agostino, A.;
Catanzaro, G.; De Simone, C.; Rapino, C.; FinazziAgro, A.; Maccarrone, M. (2009). Molecular identication of albumin and Hsp70 as cytosolic anandamidebinding proteins. Chemistry & Biology 16 (6): 624632.
[25] http://www.rsc.org/chemistryworld/Issues/2004/July/
anandamide.asp

Could anandamide be the missing link to runners
high"? Accessed 2008-10-18
Chapter 206
N-Arachidonoyl dopamine
N-Arachidonoyl
dopamine
(NADA)
is
an
endocannabinoid that acts as an agonist of the CB1
receptor[1] and the transient receptor potential V1
(TRPV1) ion channel. Its discovery was described in
2002 by an academic research group from Italy and the
USA. It was found in the brain of rats, with especially
high concentrations in the hippocampus, cerebellum, and
striatum. It activates the TRPV1 channel with an EC50
of approximately of 50nM. The high potency makes it
the putative endogenous TRPV1 agonist.[2]
206.1 See also

Endocannabinoid
206.2 References
[1] Ralevic V (July 2003). Cannabinoid modulation of
peripheral autonomic and sensory neurotransmission.
doi:10.1016/S0014-2999(03)01813-2. PMID 12860468.
[2] Huang SM, Bisogno T, Trevisani M, Al-Hayani A, De
Petrocellis L, Fezza F, Tognetto M, Petros TJ, Krey JF,
Chu CJ, Miller JD, Davies SN, Geppetti P, Walker JM,
Di Marzo V (June 2002). An endogenous capsaicinlike substance with high potency at recombinant and native vanilloid VR1 receptors. Proceedings of the National Academy of Sciences of the United States of America
99 (12): 84005. doi:10.1073/pnas.122196999. PMC
123079. PMID 12060783.

General information about NADA.
274
Chapter 207
2-Arachidonoylglycerol (2-AG) is an endocannabinoid,
an endogenous agonist of the CB1 receptor.[1][2] It is an
ester formed from the omega-6 fatty acid arachidonic
acid and glycerol. It is present at relatively high levels
in the central nervous system, with cannabinoid neuromodulatory eects. It has been found in maternal bovine
and human milk. The chemical was rst described in
1994-1995, although had been discovered some time
before that. The activities of Phospholipase C (PLC)
and diacylglycerol lipase (DAGL) mediate its formation.
2-AG is synthesized from arachidonic acid-containing
diacylglycerol (DAG).
207.3 Pharmacology
Unlike anandamide, formation of 2-AG is calciumdependent and is mediated by the activities of

phospholipase C (PLC) and diacylglycerol lipase
(DAGL).[2] 2-AG acts as a full agonist at the CB1
receptor.[10] At a concentration of 0.3nM, 2-AG induces
a rapid, transient increase in intracellular free calcium in
NG108-15 neuroblastoma X glioma cells through a CB1
receptor-dependent mechanism.[2] 2-AG is hydrolyzed
in vitro by monoacylglycerol lipase (MAGL), fatty acid
amide hydrolase (FAAH), and the uncharacterized
serine hydrolase enzymes ABHD6 and ABHD12.[11]
The exact contribution of each of these enzymes to
the termination of 2-AG signaling in vivo is unknown,
207.1 Occurrence
though it is estimated that MAGL is responsible for
~85% of this activity in the brain.[12] There have been
2-AG, unlike anandamide (another endocannabinoid), is identied transport proteins for 2-arachidonoylglycerol
present at relatively high levels in the central nervous sys- and anandamide. These include the heat shock proteins
tem; it is the most abundant molecular species of monoa- (Hsp70s) and fatty acid binding proteins (FABPs).[13][14]
cylglycerol found in mouse and rat brain (~5-10 nmol/g
tissue).[2][3] Detection of 2-AG in brain tissue is complicated by the relative ease of its isomerization to 1-AG
207.4 Biosynthesis
during standard lipid extraction conditions. It has been
found in maternal bovine and human milk.[4]
2-Arachidonoylglycerol is synthesized from arachidonic
acid-containing diacylglycerol (DAG), which is derived
from the increase of inositol phospholipid metabolism
by the action of diacylglycerol lipase. The molecule
207.2 Discovery
can also be formed from pathways like the hydrolysis
Shimon Ben-Shabat, of Ben-Gurion University, discov- derived (by diglyceride) from both phosphatidylcholine
ered the chemical.[5] 2-AG was a known chemical com- (PC) and phosphatidic acid (PAs) by the action of DAG
pound but its occurrence in mammals and its anity for lipase and the hydrolysis of arachidonic acid-containing
[15]
the cannabinoid receptors were rst described in 1994- lysophosphatidic acid by the action of a phosphatase.
1995. A research group at Teikyo University reported
the anity of 2-AG for the cannabinoid receptors in
1994-1995,[6][7] but the isolation of 2-AG in the canine
gut was rst reported in 1995 by the research group
of Raphael Mechoulam at the Hebrew University of
Jerusalem, which additionally characterized its pharmacological properties in vivo.[8] 2-Arachidonoylglycerol,
next with Anandamide, was the second endocannabinoid
discovered. The cannabinoid established the existence
of a cannabinoid neuromodulatory system in the nervous
system.[9]
207.5 See also

2-Arachidonoyl glyceryl ether
207.6 References
275
276
207.6.1
CHAPTER 207. 2-ARACHIDONOYLGLYCEROL
Notes
[1] Stella N, Schweitzer P, Piomelli D (August 1997). A

second endogenous cannabinoid that modulates longterm potentiation.
Nature 388 (6644): 7738.
doi:10.1038/42015. PMID 9285589.
[2] Sugiura T, Kodaka T, Nakane S, et al. (January 1999).
Evidence that the cannabinoid CB1 receptor is a 2arachidonoylglycerol receptor. Structure-activity relationship of 2-arachidonoylglycerol, ether-linked analogues,
and related compounds. The Journal of Biological Chemistry 274 (5): 2794801. doi:10.1074/jbc.274.5.2794.
PMID 9915812.
[3] Kondo S, Kondo H, Nakane S, et al. (June 1998). 2Arachidonoylglycerol, an endogenous cannabinoid receptor agonist: identication as one of the major species
of monoacylglycerols in various rat tissues, and evidence for its generation through Ca2+-dependent and independent mechanisms. FEBS Letters 429 (2): 1526.
doi:10.1016/S0014-5793(98)00581-X. PMID 9650580.
[4] Fride E, Bregman T, Kirkham TC. (April 2005).
Endocannabinoids and food intake: newborn suckling
and appetite regulation in adulthood. Experimental Biology and Medicine 230 (4): 225234. PMID 15792943.
[5] Pizzorno, Lara; MDiv; MA; LMT. New Developments
in Cannabinoid-Based Medicine: An Interview with Dr.
Raphael Mechoulam. Longevity Medicine Review. Retrieved 2011-05-26.
[6] Sugiura T, Itoh K, Waku K, Hanahan DJ (1994) Proceedings of Japanese conference on the Biochemistry of
Lipids, 36, 71-74 (in Japanese)
[7] Sugiura T, Kondo S, Sukagawa A, et al. (October 1995).
2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res.
Commun. 215 (1): 8997. doi:10.1006/bbrc.1995.2437.
PMID 7575630. Retrieved 2009-01-27.
[8] Mechoulam R, Ben-Shabat S, Hanu L, et al. (June
1995). Identication of an endogenous 2-monoglyceride,
present in canine gut, that binds to cannabinoid receptors. Biochemical pharmacology 50 (1): 8390.
doi:10.1016/0006-2952(95)00109-D. PMID 7605349.
[9] Marzo, Vincenzo Di (2004). Cannabinoids (Neuroscience
Intelligence Unit) (1st ed.). Georgetown, Texas: Springer.
pp. 99, 181. ISBN 978-0-306-48228-1.
[10] Savinainen JR, Jrvinen T, Laine K, Laitinen JT (October 2001).
Despite substantial degradation, 2arachidonoylglycerol is a potent full ecacy agonist mediating CB(1) receptor-dependent G-protein activation in
rat cerebellar membranes. British Journal of Pharmacology 134 (3): 66472. doi:10.1038/sj.bjp.0704297. PMC
1572991. PMID 11588122.
[11] Blankman JL, Simon GM, Cravatt BF (DecemA comprehensive prole of brain
ber 2007).
enzymes that hydrolyze the endocannabinoid 2arachidonoylglycerol. Chemistry & biology 14 (12):
134756. doi:10.1016/j.chembiol.2007.11.006. PMC
2692834. PMID 18096503.
[12] Savinainen, JR; Saario, SM; Laitinen, JT (2012). The

serine hydrolases MAGL, ABHD6 and ABHD12 as
guardians of 2-arachidonoylglycerol signalling through
cannabinoid receptors.
Acta physiologica (Oxford,
England) 204 (2): 26776.
doi:10.1111/j.17481716.2011.02280.x. PMC 3320662. PMID 21418147.
(15): 63756380. doi:10.1073/pnas.0901515106. PMC
2669397. PMID 19307565.
[14] Oddi, S.; Fezza, F.; Pasquariello, N.; d'Agostino, A.;
Catanzaro, G.; De Simone, C.; Rapino, C.; FinazziAgr, A.; MacCarrone, M. (2009). Molecular identication of albumin and Hsp70 as cytosolic anandamidebinding proteins. Chemistry & Biology 16 (6): 624632.
[15] Kfalvi, Attila (2008). Cannabinoids and the Brain. New
York City: Axel Springer AG. p. 15. ISBN 978-0-38774348-6. 2-Arachidonoylglycerol can be synthesized
from arachidonic acid-containing diacylglycerol derived
from increaded inositol phospholid metabolism by the action of a diacylglycerol lipase. 2-Arachidonoylglycerol
can also be formed via other pathways such as the hydrolysis of the diaclygly derived from PC and phosphatidic
acid by the action of a diacyglycerol lipase and the hydrolysis of arachidonic acid-containing lysophosphatidic
acid by the action of a phosphatase. The relative importance of these pathways may depend on the types of cells
and stimuli.
207.6.2 General references

Dinh TP, Carpenter D, Leslie FM, et al. (August 2002). Brain monoglyceride lipase participating in endocannabinoid inactivation. Proceedings of the National Academy of Sciences of
the United States of America 99 (16): 10819
24. doi:10.1073/pnas.152334899. PMC 125056.
PMID 12136125.
Chapter 208
2-Arachidonyl glyceryl ether

2-Arachidonyl glyceryl ether (2-AGE, Noladin ether)
is a putative endocannabinoid discovered by Lumr Hanu
and colleagues at the Hebrew University of Jerusalem, Israel. Its isolation from porcine brain and its structural
elucidation and synthesis were described in 2001.[1]
208.1 Discovery
receptors.[2]
The presence of 2-AGE in body tissue is disputed.
Although a research group from Teikyo University,
Kanagawa, Japan could not detect it in the brains of
mice, hamsters, guinea-pigs or pigs,[3] two other research
groups successfully detected it in animal tissues.[4][5]
208.3 Pharmacology
Lumr Hanu, Saleh Abu-La, Ester Fride, Aviva Breuer,

Zvi Vogel, Deborah E. Shalev, Irina Kustanovich, and
Raphael Mechoulam found the endogenous agonist of the
cannabinoid receptor type 1 (CB1) in 2000. The discovery was 100 gram of porcine brain, (approximately
a single brain) was added to a mixture of 200 mL of
chloroform and 200 mL of methanol and mixed in a
laboratory blender for 2 minutes. 100 mL of Water was
then added, and the mixing process continued for another minute. After this, the mixture was ltered. Two
layers then formed and the layer of water-methanol was
separated and evaporated when pressure was reduced.
Synaptosomal membranes were prepared from 250g of
the brains of Sabra male rats. A Hewlett Packard G
1800B GCD system that has a HP-5971 GC with electron
ionization detector was used.[1]
2-AGE binds with a K of 21 nM to the CB1 receptor[1]

and 480 nM to the CB2 receptor.[6] It shows agonistic
behaviour on both receptors and is a partial agonist for
the TRPV1 channel.[7] After binding to CB2 receptors
it inhibits adenylate cyclase and stimulates ERK-MAPK
and regulates calcium transients.[8] In comparison to 2arachidonoyl glycerol, noladin is metabolically more stable resulting in a longer half-life.[9] It lowers Intraocular
pressure,[9] increases the uptake of GABA in the globus
pallidus of rats[10] and is neuroprotective by binding to
and activation of PPAR.[11]
208.4 See also

208.2 Production
208.5 References
The production of the endocannabinoid is enhanced in
normal, but not in endothelium-denuded rat aorta on reacting with carbachol, an parasympathomimetic drug. It
potently reduces blood pressure in rats and may represent
an endothelium-derived hypotension factor.[1]
2-Arachidonyl glyceryl ethers structure can be determined by mass spectrometry and Rutherford backscattering spectrometry. It was conrmed by comparison with a
synthetic sample of the endocannabinoid. It binds to the
Cannabinoid receptor type 1 (Ki = 21.2 0.5 nM), which
causes sedation, hypothermia, intestinal immobility, and
mild antinociception in mice.[1] The endocannabinoid exhibits Ki values of 21.2 nM and >3 M at the Cannabinoid receptor type 1 and the peripheral cannabinoid
277
[1] Hanus, L.; Abu-La, S.; Fride, E.; Breuer, A.; Vogel, Z.; Shalev, D.; Kustanovich, I.; Mechoulam, R.
(2001). 2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proceedings of
the National Academy of Sciences 98 (7): 36623665.
doi:10.1073/pnas.061029898. PMC 31108. PMID
11259648.
[2] 2-Arachidonyl Glycerol ether Noladin; 2-AG ether
(CAS 222723-55-9) || Cayman Chemical. Cayman
Chemical. Retrieved 2011-05-29.
[3] Oka S, Tsuchie A, Tokumura A et al.
(2003).
Ether-linked analogue of 2-arachidonoylglycerol (noladin ether) was not detected in the brains of various
278
CHAPTER 208. 2-ARACHIDONYL GLYCERYL ETHER
mammalian species. J. Neurochem. 85 (6): 1374

81. doi:10.1046/j.1471-4159.2003.01804.x. PMID
12787057.
[4] Fezza F, Bisogno T, Minassi A, Appendino G, Mechoulam R, Di Marzo V (2002). Noladin ether, a putative novel endocannabinoid: inactivation mechanisms
and a sensitive method for its quantication in rat tissues. FEBS Lett. 513 (23): 2948. doi:10.1016/S00145793(02)02341-4. PMID 11904167.
[5] Richardson D, Ortori CA, Chapman V, Kendall DA,
Barrett DA (2007). Quantitative proling of endocannabinoids and related compounds in rat brain using liquid chromatography-tandem electrospray ionization mass
spectrometry. Anal. Biochem. 360 (2): 21626.
doi:10.1016/j.ab.2006.10.039. PMID 17141174.
[6] Shoemaker JL, Joseph BK, Ruckle MB, Mayeux PR,
Prather PL (2005). The endocannabinoid noladin ether
acts as a full agonist at human CB2 cannabinoid receptors. J. Pharmacol. Exp. Ther. 314 (2): 86875.
doi:10.1124/jpet.105.085282. PMID 15901805.
[7] Duncan M, Millns P, Smart D, Wright JE, Kendall DA,
Ralevic V (2004). Noladin ether, a putative endocannabinoid, attenuates sensory neurotransmission in the
rat isolated mesenteric arterial bed via a non-CB1/CB2
Gi/o linked receptor. Br. J. Pharmacol. 142 (3): 509
15148262.
[8] Shoemaker JL, Ruckle MB, Mayeux PR, Prather PL
(2005).
Agonist-directed tracking of response
by endocannabinoids acting at CB2 receptors. J.
Pharmacol.
Exp.
Ther.
315 (2): 82838.
doi:10.1124/jpet.105.089474. PMID 16081674.
[9] Laine K, Jrvinen K, Mechoulam R, Breuer A, Jrvinen T (2002). Comparison of the enzymatic stability
and intraocular pressure eects of 2-arachidonylglycerol
and noladin ether, a novel putative endocannabinoid. Invest. Ophthalmol. Vis. Sci. 43 (10): 321622. PMID
12356827.
[10] Venderova K, Brown TM, Brotchie JM (2005). Dierential eects of endocannabinoids on [(3)H]-GABA uptake in the rat globus pallidus. Exp. Neurol. 194 (1):
2847. doi:10.1016/j.expneurol.2005.02.012. PMID
15899265.
[11] Sun Y, Alexander SP, Garle MJ et al.
(2007).
Cannabinoid activation of PPAR; a novel neuroprotective mechanism. Br. J. Pharmacol. 152 (5): 734
17906680.

Commercial supplier of Noladin ether
Chapter 209
Oleamide
Oleamide is an amide of the fatty acid oleic acid. It
is an endogenous substance: it occurs naturally in the
body of animals. It accumulates in the cerebrospinal
uid during sleep deprivation and induces sleep in animals.[4] It is being studied as a potential medical treatment for mood and sleep disorders, and cannabinoidregulated depression.[5][6]
[2] http://www.chemicalbook.com/
ProductChemicalPropertiesCB3238286_EN.htm
[3] http://www.chemspider.com/Chemical-Structure.
4446508.html
[4] Salvador Huitron-Resendiz, Lhys Gombart, Benjamin
F. Cravatt, and Steven J. Henriksen (2001). Eect
of Oleamide on Sleep and Its Relationship to Blood
Pressure, Body Temperature, and Locomotor Activity
in Rats. Experimental Neurology 172 (1): 235243.
doi:10.1006/exnr.2001.7792. PMID 11681856.
The mechanism of action of oleamides sleep inducing eects is an area of current research. It is likely
that oleamide interacts with multiple neurotransmitter
systems.[7] Oleamide is structurally related to the endogenous cannabinoid anandamide, and has the ability to bind
to the CB1 receptor as a full agonist.
[5] Methods of treating anxiety and mood disorders with

oleamide - US Patent 6359010
[6] Raphael Mechoulam, Ester Fride, Lumr Ondej Hanu,
Tzviel Sheskin, Tiziana Bisogno, Vincenzo Di Marzo,
Michael Bayewitch and Zvi Vogel (1997). Anandamide
may mediate sleep induction. Nature 389 (6646): 2526.
doi:10.1038/37891. PMID 9288961.
Synthetically produced oleamide has a variety of industrial uses including as a slip agent, a lubricant, and a corrosion inhibitor.[8]
Oleamide was originally characterized as an endogenous
bioactive substance, isolated from the cerebrospinal uid
of sleep deprived cats. It was characterised in 1995 by
Benjamin Cravatt III and Richard Lerner at The Scripps
Research Institute in La Jolla, CA.[9]
[7] Fedorova I, Hashimoto A, Fecik RA et al. (2001). Behavioral evidence for the interaction of oleamide with
multiple neurotransmitter systems. J. Pharmacol. Exp.
Ther. 299 (1): 33242. PMID 11561096.
Oleamide was found by researchers to be leaking out of

polypropylene plastics used in laboratory experiments,
aecting experimental results.[10] Since polypropylene is
used in a wide number of food containers such as those
for yogurt, the problem is being studied.[11]
[8] Surfactants : Westco Oleamide a Slip Agent In Polyethylene Films

[9] Cravatt BF, et al. (June 1995). Chemical characterization of a family of brain lipids that induce sleep. Science 268 (5216): 15069. doi:10.1126/science.7770779.
PMID 7770779.
A chemical analysis of 44 products containing synthetic

cannabinoid drugs marketed as herbal incense revealed
oleamide in 7 of the products tested.[12]
[10] McDonald, RG. et al. (2008). Bioactive Contaminants
Leach from Disposable Laboratory Plasticware. Science

322 (5903): 917. doi:10.1126/science.1162395. PMID
18988846.
209.1 See also

Anandamide
Fatty acid amide hydrolase
Virodhamine
209.2 References
[11] Mittelstaedt, Martin (6 November 2008). Researchers

Raise Alarm After Chemical Leak Found In Common
Plastic. Globe and Mail. Retrieved 10 June 2013.
[12] Uchiyama, Nahoko; Kikura-Hanajiri, Ruri; Ogata, Jun;
Goda, Yukihiro (2010). Chemical analysis of synthetic cannabinoids as designer drugs in herbal products. Forensic Science International 198 (13): 318.
[1] Oleamide at chemicalland21.com
279
Chapter 210
RVD-Hp
RVD-Hp is an endogenous neuropeptide found in
human and mammalian brain, which was originally
proposed to act as a selective agonist for the CB1
cannabinoid receptor. It is a 12-amino acid polypeptide
having the amino acid sequence Arg-Val-Asp-Pro-ValAsn-Phe-Lys-Leu-Leu-Ser-His and is an N-terminal extended form of hemopressin, a 9-AA polypeptide derived from the 1 subunit of hemoglobin which has previously been shown to act as a CB1 inverse agonist.[1]
All three polypeptides have been isolated from various mammalian species, with RVD-Hp being one of
the more abundant neuropeptides expressed in mouse
brain, and these neuropeptides represent a new avenue for
cannabinoid research distinct from the previously known
endogenous lipid-derived cannabinoid agonists such as
anandamide.[2] Recently it was shown that RVD-Hp
(also called Pepcan-12) is an potent negative allosteric
modulator at CB1 receptors, together with other newly
described N-terminally extended peptides (pepcans) [3]
210.1 References
[1] Heimann, A.; Gomes, I.; Dale, C.; Pagano, R.;
Gupta, A.; De Souza, L.; Luchessi, A.; Castro, L.;
Giorgi, R.; Rioli, V.; Ferro, E. S.; Devi, L. A.
(2007). Hemopressin is an inverse agonist of CB1
cannabinoid receptors. Proceedings of the National
(51): 2058820593. Bibcode:2007PNAS..10420588H.
doi:10.1073/pnas.0706980105. PMC 2154475. PMID
18077343.
[2] Gomes, I.; Grushko, J.; Golebiewska, U.; Hoogendoorn,
S.; Gupta, A.; Heimann, A.; Ferro, E.; Scarlata, S.;
Fricker, L.; Devi, L. A. (2009). Novel endogenous
peptide agonists of cannabinoid receptors. The FASEB
journal : ocial publication of the Federation of American Societies for Experimental Biology 23 (9): 3020
3029. doi:10.1096/fj.09-132142. PMC 2735371. PMID
19380512.
[3] Bauer, M.; Chicca, A.; Tamborrini, M.; Eisen, D.;
Lerner, R.; Lutz, B.; Poetz, O.; Pluschke, G.; Gertsch,
J. (2012). Identication and Quantication of a New
Family of Peptide Endocannabinoids (Pepcans) Showing Negative Allosteric Modulation at CB1 Receptors.
280

doi:10.1074/jbc.M112.382481. PMC 3481297. PMID
22952224.
Chapter 211
Virodhamine
Virodhamine (O-arachidonoyl ethanolamine) is an
endocannabinoid and a nonclassic eicosanoid, derived
from arachidonic acid. O-Arachidonoyl ethanolamine is
arachidonic acid and ethanolamine joined by an ester
linkage, the opposite of the amide linkage found in
anandamide. Based on this opposite orientation, the
molecule was named virodhamine from the Sanskrit word
virodha, which means opposition. It acts as an antagonist
of the CB1 receptor and agonist of the CB2 receptor.
Concentrations of virodhamine in the human hippocampus are similar to those of anandamide, but they are 2to 9-fold higher in peripheral tissues that express CB2 .
Virodhamine lowers body temperature in mice, demonstrating cannabinoid activity in vivo.[1]
211.1 See also

Anandamide
Oleamide
211.2 References
[1] Porter AC, Sauer JM, Knierman MD et al. (2002).
Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J. Pharmacol. Exp. Ther. 301 (3): 1020
4. doi:10.1124/jpet.301.3.1020. PMID 12023533. Retrieved 2007-10-31.
281
Chapter 212
HU-320
HU-320 is a drug related to cannabidiol, which has
strong antiinammatory and immunosuppressive properties while demonstrating no psychoactive eects.[1]
212.1 See also

HU-210
HU-308
HU-331
212.2 References
[1] Sumariwalla PF, et al. (2004). A novel synthetic,
nonpsychoactive cannabinoid acid (HU-320) with antiinammatory properties in murine collagen-induced
arthritis.
Arthritis Rheum.
50 (3): 985998.
doi:10.1002/art.20050. PMID 15022343.
282
Chapter 213
HU-336
HU-336 is a strongly antiangiogenic compound, significantly inhibiting angiogenesis at concentrations as low
as 300nM. It inhibits angiogenesis by directly inducing
apoptosis of vascular endothelial cells without changing
the expression of pro- and antiangiogenic cytokines and
their receptors. HU-336 is highly eective against tumor
xenografts in nude mice.[1]
213.1 See also

HU-210
HU-331
HU-345
213.2 References
[1] Natalya M. Kogan, et al. (2006). A Cannabinoid
Quinone Inhibits Angiogenesis by Targeting Vascular Endothelial Cells. Molecular Pharmacology 70 (1): 5159.
doi:10.1124/mol.105.021089. PMID 16571653.
283
Chapter 214
HU-345
HU-345 (cannabinol quinone) is a drug that is able to
inhibit aortic ring angiogenesis more potently than its parent compound cannabinol.[1][2]
214.1 See also

HU-210
HU-336
214.2 References
[1] Natalya M. Kogan, et al. (2006). A Cannabinoid
Quinone Inhibits Angiogenesis by Targeting Vascular Endothelial Cells. Molecular Pharmacology 70 (1): 5159.
doi:10.1124/mol.105.021089. PMID 16571653.
[2] US patent 0092584, Mechoulam R, Kogan NM, Rabinowitz R, Schlesinger M, Therapeutic Use of Quinonoid
Derivatives of Cannabinoids, granted 2011-04-21
284
Chapter 215
Raphael Mechoulam
Raphael Mechoulam (Hebrew: ( ) born
1930) is an Israeli organic chemist and professor
of Medicinal Chemistry at the Hebrew University
of Jerusalem in Israel. Mechoulam is best known
for his work (together with Y. Gaoni) in the isolation, structure elucidation and total synthesis of
9 -tetrahydrocannabinol, the main active principle of
cannabis and for the isolation and the identication of the
endogenous cannabinoids anandamide from the brain and
2-arachidonoyl glycerol (2-AG) from peripheral organs
together with his students, postdocs and collaborators.
215.2 Research
Raphael Mechoulams major scientic interest is the
chemistry and pharmacology of cannabinoids. He and
his research group succeeded in the total synthesis of
the major plant cannabinoids 9 -tetrahydrocannabinol,
cannabidiol, cannabigerol and various others. Another
research project initiated by him led to the isolation of
the rst described endocannabinoid anandamide which
was isolated and characterized by two of his postdoctoral
researchers, Lumr Ondej Hanu and William Devane.
Another endogenous cannabinoid, 2-AG, was soon discovered by Shimon Ben-Shabat, one of his PhD students.
He published more than 350 scientic articles.
215.1 Biography
215.3 References
Raphael Mechoulam was born in Soa, Bulgaria on
November 5, 1930. His father was a physician and head
of a local hospital, while his mother who had studied in
Berlin, enjoyed the life of a well-to-do Jewish family.
He attended an American Grade School until his parents were forced to leave their hometown because of antisemitic laws and his father was subsequently sent to a concentration camp, from which he survived. After the communist takeover of hitherto pro-German Bulgaria in 1944
he studied chemical engineering, which he disliked. In
1949 his family immigrated to Israel where he later studied chemistry. He gained his rst research experience in
the Israeli Army working on insecticides.[2]
[1] http://www.nndb.com/people/699/000210069/
[2] Conversation with Raphael Mechoulam, Addiction (Wiley) 102 (6), 2007: 887893, doi:10.1111/j.13600443.2007.01795.x, PMID 17523982
[3] Michael
Denman
(2007),
MECHOULAM,
RAPHAEL, Encyclopaedia Judaica 13 (2nd ed.),
Thomson Gale, pp. 711712
215.4 Podcasts
He received his M.Sc. in biochemistry from the Hebrew University of Jerusalem (1952), and his Ph.D. at the
Weizmann Institute, Reovot (1958), with a thesis on the
chemistry of steroids. After postdoctoral studies at the
Rockefeller Institute, New York (195960), he was on
the scientic sta of the Weizmann Institute (196065),
before moving to the Hebrew University of Jerusalem,
where he became professor (1972) and Lionel Jacobson
Professor of Medicinal Chemistry from 1975. He was
rector (197982) and pro-rector (198385). In 1994 he
was elected a member of the Israel Academy of Sciences.
His honors include the Kolthof Prize in chemistry from
the Haifa Technion (1994) and the Israel Prize in chemistry (2000).[3]
285
A podcast (open access) of an interview with

Raphael Mechoulam, recorded by Steve Alexander
for the British Journal of Pharmacology on the occasion of his 80th Birthday in November 2010.
Chapter 216
John W. Human
John William Human (born 1932) is a professor
emeritus of organic chemistry at Clemson University
who rst synthesised many novel cannabinoids.[1] His research, funded by the National Institute on Drug Abuse,
was focused on making a drug to target endocannabinoid
receptors in the body.[2]
216.2 See also

216.3 References
Beginning in 1984, Human and his team of researchers

began developing cannabinoid compounds to aid in research of multiple sclerosis, HIV/AIDS, and chemotherapy. Over the course of twenty years, Human and his
team developed 450 synthetic cannabinoid compounds
which were used to test the eect of cannabinoid receptors in the brain and other organs. Ultimately, the
cannabinoid research provided understanding of diseases
and information for medication development. In the late
2000s, two of Humans cannabinoid compounds began
being sold in Germany as marijuana alternatives known
as K2 and Spice. I gured once it got started in Germany
it was going to spread. I'm concerned that it could hurt
people, Human said. I think this was something that
was more or less inevitable. It bothers me that people are
so stupid as to use this stu. Human may have developed these compounds for scientic research, but now he
gets blamed for its abuse. As JWH-018 is more potent
and easy to make, Human believes it is a more widely
used synthetic cannabinoid of the JWH series.[3]
216.1 Law enforcement

More than half a dozen countries have banned herbal
blends containing synthetic cannabinoids since 2008.
Many countries also consider banning these mixtures. In
the US, the states of Kansas, Georgia, Alabama, Tennessee, Missouri, Louisiana, Mississippi, Arkansas, and
New York banned K2, herbal incense. JWH-018 is currently banned by controlled substances act. [3]
Law enforcement ocials in Canada asked Human to
serve as a consultant and expert witness. He received
numerous media queries and requests for analytical help
from law enforcement ocials.[3]
286
[1] Clemson University :: Department of Chemistry.

Clemson.edu. Retrieved 2010-08-24.
[2] Brownstein, Joseph (March 17, 2010), K2 Giving People
Another Dangerous Way to Get High, ABC News
[3] Wang, Linda (June 28, 2010). C&EN Talks With John
W. Human. Chemical & Engineering News 88 (26): 43.
Retrieved October 8, 2011.
Chapter 217
JWH-007
JWH-007 is an analgesic chemical from the
agonist at both the CB1 and CB2 receptors. It was the
most active of the rst group of N-alkyl naphoylindoles
discovered by the team led by John W Human, several
years after the family was initially described with
the discovery of the N-morpholinylethyl compounds
pravadoline (WIN 48,098), WIN 55,225 (JWH-200)
and WIN 55,212-2 by the Sterling Winthrop group.[1]
Several other N-alkyl substituents were found to be
active by Humans team including the n-butyl, n-hexyl,
2-heptyl and cyclohexylethyl groups,[2] but it was subsequently determined that the 2-methyl group on the
indole ring is not required for CB1 binding, and tends
to increase anity for CB2 instead.[3][4] Consequently
the 2-desmethyl derivative of JWH-007, JWH-018 has
slightly higher binding anity for CB1 , with an optimum
binding of 9.00nM at CB1 and 2.94nM at CB2 , and
JWH-007 displayed optimum binding of 9.50nM at CB1
and 2.94nM at CB2 .[5]
217.3 References
217.1 Law
Sweden: JWH-007 was banned in Sweden on 1 October 2010 as a hazardous good harmful to health, after being identied as an ingredient in herbal synthetic
cannabis products.[6][7] Poland: JWH-007 is illegal in
Poland since 08.06.2010 on the basis of 'Ustawa z dnia
15 kwietnia 2011 r. o zmianie ustawy o przeciwdziaaniu
narkomanii' published in Dz.U. 2011 nr 105 poz. 614[8]
217.2 See also

JWH-015
JWH-018
JWH-019
JWH-073
287
[1] Compton, D. R., et al. (1992). Aminoalkylindole

analogs: cannabimimetic activity of a class of compounds
structurally distinct from delta 9-tetrahydrocannabinol.
The Journal of Pharmacology and Experimental Therapeutics 263 (3): 11181126. PMID 1335057.
[2] Human JW, Dong D. Design, Synthesis and Pharmacology of Cannabimimetic Indoles. Bioorganic and Medicinal Chemistry Letters. 1994;4(4):563-566.
PMID 15582455.
[4] Human, J. W.; Padgett, L. W. (2005). Recent developments in the medicinal chemistry of cannabimimetic indoles, pyrroles and indenes. Current medicinal chemistry
12 (12): 13951411. doi:10.2174/0929867054020864.
PMID 15974991.
[5] Aung, M. M., et al. (2000). Inuence of the N-1 alkyl
chain length of cannabimimetic indoles upon CB(1) and
CB(2) receptor binding. Drug and alcohol dependence
60 (2): 133140. doi:10.1016/S0376-8716(99)00152-0.
PMID 10940540.
[8] Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy o
przeciwdziaaniu narkomanii ( Dz.U. 2011 nr 105 poz.
614 )". ISAP. Retrieved 12 June 2011.
Chapter 218
Naphthoylindole
JWH-018 (1-pentyl-3-(1-naphthoyl)indole) or AM678[1] is an analgesic chemical from the naphthoylindole family that acts as a full agonist at both the CB1
and CB2 cannabinoid receptors, with some selectivity for
CB2 . It produces eects in animals similar to those of
THC, a cannabinoid naturally present in cannabis, leading to its use in synthetic cannabis products such as legal cannabis herbal incense blends which in some countries are sold legally as incense, labeled not for human
consumption.[2][3][4][5][6]
218.2.1 Pharmacokinetics
JWH-018 administered to rats resulted in the excretion
of an indole-N-desalkyl metabolite as well as several hydroxylated metabolites in urine. The highest signals were
observed for the hydroxylated N-desalkyl metabolites.
Hydroxylation took place on the side chain and in both
aromatic systems, the naphthalene and the indole rings,
as could be shown by mass shift of the corresponding
fragments and by MS3 experiments.[13] Human metabolites were similar although most metabolism took place
on the indole ring and pentyl side chain, and the hydroxylated metabolites were extensively conjugated with
glucuronide.[14]
218.1 History
John W. Human, an organic chemist at Clemson University, synthesized analogues and metabolites of 9 tetrahydrocannabinol (THC), the principal active component of cannabis. JWH-018 is one of these analogues,
with studies showing an anity for the cannabinoid (CB1 )
receptor ve times greater than that of THC. Cannabinoid
receptors are found in mammalian brain and spleen tissue; however, the structural details of the active sites are
currently unknown.[7][8]
On December 15, 2008, it was reported by the German
pharmaceutical company THC Pharm that JWH-018 was
found as one of the active components in at least three
versions of the herbal blend Spice, which has been sold
as an incense in a number of countries around the world
since 2002.[9][10][11] An analysis of samples acquired four
weeks after the German prohibition of JWH-018 took
place found that the compound had been replaced with
JWH-073.[12]
218.3 Usage
At least one case of JWH-018 dependence has been reported by the media.[2] The user consumed JWH-018
daily for eight months. Withdrawal symptoms were similar to those experienced as a result of cannabis dependence. JWH-018 has been shown to cause profound
changes in CB1 receptor density following administration, causing desensitization to its eects more rapidly
than related cannabinoids.[6]
On October 15, 2011, Anderson County coroner Greg
Shore attributed the death of a South Carolina college
basketball player to drug toxicity and organ failure
caused by JWH-018.[15] An email dated Nov 4, 2011
concerning the case was nally released by the city of
Anderson S.C. on Dec 16, 2011 under the Freedom of
Information Act after multiple requests by media to see
the information had been denied.[16]
Compared to THC, which is a partial agonist at CB1

receptors, JWH-018 (and many of its analogues) are
full agonists. THC has been shown to inhibit GABA
receptor neurotransmission in the brain via several
pathways.[17][18] JWH-018 may cause intense anxiety, ag218.2 Pharmacology
itation, and, in rare cases (generally with non-regular
JWH users), has been assumed to have been the cause of
JWH-018 is a full agonist of both the CB1 and CB2 seizures and convulsions by inhibiting GABA neurotranscannabinoid receptors, with a reported binding anity of mission more eectively than THC. Cannabinoid recep9.00 5.00 nM at CB1 and 2.94 2.65 nM at CB2 .[3]
tor full agonists may present serious dangers to the user
288
218.6. SYNTHESIS
289
when used to excess.[19]

Various physical and psychological adverse eects have
been reported from JWH-018 use. One study reported psychotic relapses and anxiety symptoms in welltreated patients with mental illness following JWH-018
inhalation.[20] Due to concerns about the potential of
JWH-018 and other synthetic cannabinoids to cause psychosis in vulnerable individuals, it has been recommended that people with risk factors for psychotic ill- Synthesis of JWH-018.[51]
nesses (like a past or family history of psychosis) not use
these substances.[21]
218.6 Synthesis
218.7 See also
218.4 Detection in biological uids

JWH-018 usage is readily detected in urine using spice
screening immunoassays from several manufacturers focused on both the parent drug and its omega-hydroxy and
carboxyl metabolites.[22] JWH-018 will not be detected
by older methods employed for detecting THC and other
cannabis terpenoids. Determination of the parent drug in
serum or its metabolites in urine has been accomplished
by GC-MS or LC-MS. Serum JWH-018 concentrations
are generally in the 110 g/L range during the rst
few hours after recreational usage. The major urinary
metabolite is a compound that is monohydroxylated on
the omega minus one carbon atom of the alkyl side chain.
A lesser metabolite monohydroxylated on the omega (terminal) position was present in the urine of 6 users of the
drug at concentrations of 650 g/L, primarily as a glucuronide conjugate.[23][24][25][26][27][28][29][30][31]
218.5 Legal status
AM-2201
BB-22 (drug)
JWH-073
JWH-250
JWH-200
PB-22
SDB-001
218.8 References
[1] Department of Justice :: Drug Enforcement Administration. 2011-03-01. Retrieved 2011-03-02.
[2] Zimmermann US, Winkelmann PR, Pilhatsch M, Nees
JA, Spanagel R, Schulz K (2009). Withdrawal Phenomena and Dependence Syndrome After the Consumption
of Spice Gold"". Dtsch Arztebl Int 106 (27): 464467.
doi:10.3238/arztebl.2009.0464. PMC 2719097. PMID
19652769.
[3] Aung MM, Grin G, Human JW, Wu M, Keel
C, Yang B, Showalter VM, Abood ME, Martin BR
(2000). Inuence of the N-1 alkyl chain length of
cannabimimetic indoles upon CB1 and CB2 receptor
doi:10.1016/S0376-8716(99)00152-0. PMID 10940540.
[4] US patent 6900236, Alexandros Makriyannis, Hongfeng
Deng, Cannabimimetic indole derivatives, issued 200505-31
JWH-018 powder as it was commonly sold online
[6] Atwood, B.K., et al., JWH018, a common constituent of

'Spice' herbal blends, is a potent and ecacious cannabinoid CB1 receptor agonist. British Journal of Pharmacology, Vol. 160, No. 3. 585-593. 2010.
290
CHAPTER 218. NAPHTHOYLINDOLE

[8] Drugs Forum. Drugs Forum. Retrieved 2010-08-23.
[9] Gefhrlicher Kick mit Spice (German)
[10] Erstmals Bestandteile
nachgewiesen (German)
der
Modedroge
Spice
[11] Spice enthlt chemischen Wirksto (German)

[12] Lindigkeit R, Boehme A, Eiserloh I, Luebbecke M, Wiggermann M, Ernst L, Beuerle T (30 October 2009).
Spice: A never ending story?". Forensic Science International (Forensic Science International) 191 (1): 5863.
[13] T. Kraemer, et al. Studies on the metabolism of JWH018 and of a homologue of CP 47,497, pharmacologically active ingredients of dierent misused incense
(Spice) using GC-MS and LC-MSn techniques (Institute of Legal Medicine, Saarland University, 66421
Homburg, Germany http://www.gtfch.org/cms/images/
stories/media/tk/tk76_2/abstractsvortraege.pdf
[14] Sobolevsky T, Prasolov I, Rodchenkov G (July 2010).
Detection of JWH-018 metabolites in smoking mixture
post-administration urine. Forensic Science International
200 (13): 1417. doi:10.1016/j.forsciint.2010.04.003.
PMID 20430547.
[15] wy4.com, Coroner: Synthetic Pot Killed College Athlete, posted 10/14/11, accessed 12/22/11, http://www.
wyff4.com/news/29497549/detail.html,
[16] Mayo, Nikie, City Releases Email in Lamar Jacks Case,
independentmail.com, posted Dec 16, 2011, accessed
12/22/11, http://www.independentmail.com/news/2011/
dec/16/city-releases-email-lamar-jack-case/
[17] Laaris N, Good CH, Lupica CR (JulyAugust 2010).
"9-tetrahydrocannabinol is a full agonist at CB1 receptors on GABA neuron axon terminals in the hippocampus. Neuropharmacology 59 (12): 121127.
PMID 20417220.
[18] Homan AF, Lupica CR (2000-04-01). Mechanisms of
cannabinoid inhibition of GABAA synaptic transmission
in the hippocampus. The Journal of Neuroscience 20 (7):
24702479. ISSN 0270-6474. PMID 10729327. Retrieved 2011-07-26.
[19] European Monitoring Centre for Drugs and Drug Addiction. Understanding the Spice Phenomenon. 2009.
ISBN 978-92-9168-411-3.
[20] Every-Palmer, S. Synthetic cannabinoid use and psychosis: an explorative study. Journal of Drug and Alcohol
Dependence 2011. [Epub ahead of print].
[21] Every-Palmer S (2010). WARNING: LEGAL SYNTHETIC CANNABINOID-RECEPTOR AGONISTS
SUCH AS JWH-018 MAY PRECIPITATE PSYCHOSIS
IN VULNERABLE INDIVIDUALS. Addiction 105:
doi:10.1111/j.1360-0443.2010.03119.x.
18591860.
PMID 20840203.
[22] See Arntson et al. (2013) http://jat.oxfordjournals.org/

content/37/5/284.abstract, https://www.caymanchem.
com/app/template/Product.vm/catalog/580210;
http://www.randoxtoxicology.com/Products/Elisa-p-50,
http://tulipbiolabs.com/our-product-areas/
synthetic-cannabinoids and others.
[23] Mller I, et al. Screening for the synthetic cannabinoid
JWH-018 and its major metabolites in human doping controls. Drug Test. Anal. Sep 24, 2010. [Epub ahead of
print]
[24] Teske J, et al.
Sensitive and rapid quantication
of the cannabinoid receptor agonist naphthalen-1-yl-(1pentylindol-3-yl)methanone (JWH-018) in human serum
by liquid chromatography-tandem mass spectrometry. J
Chrom. B 878: 2659-2663, 2010.
[25] Auwrter V, Dresen S, Weinmann W, Mller M, Ptz
M, Ferreirs N (2009). "'Spice' and other herbal blends:
harmless incense or cannabinoid designer drugs?". Journal of mass spectrometry : JMS 44 (5): 832837.
JA, Spanagel R, Schulz K (2009). Withdrawal phenomena and dependence syndrome after the consumption
(27): 464467. doi:10.3238/arztebl.2009.0464. PMC
2719097. PMID 19652769.
[27] Sobolevsky T, Prasolov I, Rodchenkov G (2010). Detection of JWH-018 metabolites in smoking mixture postadministration urine. Forensic Science International 200
(13): 141147. doi:10.1016/j.forsciint.2010.04.003.
PMID 20430547.
[28] Beuck S, Mller I, Thomas A, Klose A, Schlrer
N, Schnzer W, Thevis M (August 2011). Structure characterisation of urinary metabolites of the
cannabimimetic JWH-018 using chemically synthesised
reference material for the support of LC-MS/MS-based
drug testing. Anal Bioanal Chem 401 (2): 493505.
doi:10.1007/s00216-011-4931-5. PMID 21455647.
[29] Moran CL, Le VH, Chimalakonda KC, Smedley AL,
Lackey FD, Owen SN, Kennedy PD, Endres GW, Ciske
FL, Kramer JB, Kornilov AM, Bratton LD, Dobrowolski
PJ, Wessinger WD, Fantegrossi WE, Prather PL, James
LP, Radominska-Pandya A, Moran JH (June 2011).
Quantitative measurement of JWH-018 and JWH-073
metabolites excreted in human urine. Anal. Chem.
83 (11): 422836. doi:10.1021/ac2005636. PMID
21506519.
[30] Logan BK, et al. Identication of primary JWH018 and JWH-073 metabolites in human urine.
NMS Labs Technical Bulletin, May 25, 2011.
http://toxwiki.wikispaces.com/file/view/JWH_
metabolites_Technical_Bulletin_Final_v1.1.pdf
[31] R. Baselt, Disposition of Toxic Drugs and Chemicals in
Man, 10th edition, Biomedical Publications, Seal Beach,
CA, 2014, p. 1863.
[32] <http://www.legislation.qld.gov.au/LEGISLTN/
CURRENT/D/DrugsMisuseR87.pdf>
291
[33] Controlled
Drugs
and
Substances
Act.
Laws.justice.gc.ca.
2010-08-16.
Retrieved 201008-23.
[34] *** Tiedote/Valtioneuvoston viestintyksikk: VALTIONEUVOSTON YLEISISTUNTO 1.3.2012 ***
(Finnish)
[35] EMCDDA | Drug prole: Synthetic cannabinoids and
'Spice'". Emcdda.europa.eu. 2010-08-17. Retrieved
2010-08-23.
[36] http://www.afssaps.fr/var/afssaps_site/storage/original/
application/d23d05edc58479d91c803b496017f073.pdf
Januar 2009, S. 4950.
[38] Many head shop products banned - Irish Times.
[39] http://www.politicheantidroga.it/
comunicazione/comunicati/2010/luglio/spice,
-n-joy-e-mefedrone-da-oggi-stupefacenti.aspx (Italian)
[41] http://www.lovdata.no/ltavd1/filer/sf-20111221-1465.
html
[42]
(2 July 2009). 1
5- -
. Retrieved 18 February 2010.
".
[43] http://www.regeringen.se/sb/d/12102/a/130038
(Swedish)
[44] Illicit Drug Report of Turkey 2010. Department of
Anti-smuggling and Organised Crime. Retrieved 201205-03.(Turkish)
[45] Decision of the Council of Ministers, Enactment
2011/1310. General Directorate of Legislation Development and Publication. Retrieved 2012-05-03.(Turkish)
[46] Attachment to Enactment 2012/2861. General Directorate of Legislation Development and Publication. Retrieved 2012-05-03.(Turkish)
[48] Ford, Richard (2009-12-23). Three legal highs banned
after deaths linked to the drugs. The Times (London).
2014.
[50] <http://www.antinarcotics.psd.gov.jo>
[51] Appendino G, Minassi A, Taglialatela-Scafati O (2014).
Recreational drug discovery: natural products as lead
structures for the synthesis of smart drugs. Natural Product Reports 31 (7): 880904. doi:10.1039/c4np00010b.

JWH-018 Report Psychonaut Web Mapping Research Project
User of legal high
Chapter 219
JWH-019
naphthoylindole family that acts as a cannabinoid
agonist at both the CB1 and CB2 receptors. It is the
N1-hexyl homologue of the more common synthetic
cannabinoid compound JWH-018. Unlike the butyl
homologue JWH-073, which is several times weaker
than JWH-018, the hexyl homologue is only slightly less
potent, although extending the chain one carbon longer
to the heptyl homologue JWH-020 results in dramatic
loss of activity. These results show that the optimum
side chain length for CB1 binding in the naphthoylindole
series is the ve-carbon pentyl chain, shorter than in the
classical cannabinoids where a seven-carbon heptyl chain
produces the most potent compounds. This dierence
is thought to reect a slightly dierent binding conformation adopted by the naphthoylindole compounds as
compared to the classical cannabinoids, and may be
useful in characterising the active site of the CB1 and
CB2 receptors.[2][3][4]
219.2 See also

JWH-007
JWH-018
JWH-073
JWH-200
219.3 References
219.1 Legal Status

219.1.1
Poland
[4] Ashton JC, Wright JL, McPartland JM, Tyndall JD

(2008). Cannabinoid CB1 and CB2 receptor ligand
specicity and the development of CB2-selective agonists. Current Medicinal Chemistry 15 (14): 142843.
doi:10.2174/092986708784567716. PMID 18537620.
Sweden
JWH-019 is illegal in Sweden
219.1.3
UK
[5] http://crimlaw.blogspot.com/2011/04/
no-more-synthetic-cannabinoid.html
JWH-019 is Class B in the United Kingdom.
219.1.4
[2] Aung MM, et al. (August 2000). Inuence of the

N-1 alkyl chain length of cannabimimetic indoles upon
CB(1) and CB(2) receptor binding. Drug and Alcohol Dependence 60 (2): 13340. doi:10.1016/S03768716(99)00152-0. PMID 10940540.
[3] Poso A, Human JW (January 2008). Targeting
the cannabinoid CB2 receptor:
modelling and
structural determinants of CB2 selective ligands.
17982473.
In Poland, JWH-019 is I-N (Poland)[1]
219.1.2

USA
JWH-019 is not controlled federally in the United States,

however if intended for human consumption, possession
or sales could possibly be prosecuted under the Federal
Analog Act.
JWH-019 is illegal in Virginia.[5]
292
Chapter 220
JWH-030
JWH-030 is a research chemical which is a cannabinoid
receptor agonist.[1] It has analgesic eects and is used in
scientic research.[2] It is a partial agonist at CB1 receptors, with a Ki of 87nM, making it roughly half the potency of THC.[3] It was discovered and named after Dr.
John W. Human.
220.1 See also

JWH-147
220.2 References
[1] Lainton JAH, Human JW, Martin BR, Compton DR.
Tetrahedron Letters. 1995; 36:1401.
[2] Pertwee RG, Grin, G, Lainton JAH, Human JW. European Journal of Pharmacology. 1995; 284:241.
[3] Grin, G.; Atkinson, P. J.; Showalter, V. M.; Martin,
B. R.; Abood, M. E. (1998). Evaluation of cannabinoid
receptor agonists and antagonists using the guanosine-5'O-(3-35Sthio)-triphosphate binding assay in rat cerebellar
membranes. The Journal of Pharmacology and Experimental Therapeutics 285 (2): 553560. PMID 9580597.
293
Chapter 221
JWH-047
JWH-047 is a selective cannabinoid ligand, with a bindining anity of K = 0.9 nM for the CB2 subtype, and
more than 65 times selectivity over the CB1 .[1]
221.1 See also

JWH-015
JWH-018
JWH-019
JWH-073
221.2 References
[1] Aung MM, Grin G, Human JW, Wu M-J, Keel
doi:10.1016/S0376-8716(99)00152-0. PMID 10940540.
294
Chapter 222
JWH-048
JWH-048 is a selective cannabinoid ligand, with a bindining anity of K = 0.5 0.1 nM for the CB2 subtype,
and more than 22 times selectivity over the CB1 .[1]
222.1 See also

JWH-015
JWH-018
JWH-019
JWH-073
222.2 References
[1] Aung MM, Grin G, Human JW, Wu M-J, Keel
doi:10.1016/S0376-8716(99)00152-0. PMID 10940540.
295
Chapter 223
JWH-073
JWH-073 is an analgesic chemical from the synthetic cannabis smoking blends.
naphthoylindole family that acts as a partial agonist
at both the CB1 and CB2 cannabinoid receptors. It is
somewhat selective for the CB1 subtype, with anity at
this subtype approximately 5x the anity at CB2 .[2] The
abbreviation JWH stands for John W. Human, one of
the inventors of the compound.
On 20 April 2009, JWH-073 was claimed by researchers
at the University of Freiburg to have been found in a
fertiliser product called Forest Humus, along with
another synthetic cannabinoid (C8)-CP 47,497.[3] These
claims were conrmed in July 2009 when tests of Spice
product, seized after the legal ban on JWH-018 had gone
into eect in Germany, were shown to contain the unregulated compound JWH-073 instead.[4]
223.1 Pharmacology
JWH-073 has been shown to produce behavioral eects
very similar to THC in animals.[5]
Its eects are produced by binding and acting as an ago4'-Methyl-JWH-073
nist to the CB1 and CB2 cannabinoid receptors. The CB1
receptor is found in the brain. JWH-073 bind to CB1 with
a higher anity than THC, suggesting that taking more
too soon after the initial dose could lead to diminished 223.3 Legal status
eects. CB2 is found outside the brain, mostly in the immune system. The binding with CB2 receptors has been
shown to be similar between JWH-073 and THC.[5]
A search in the literature yielded no published studies of See also: JWH-018
the eects of JWH-073 in humans, but these studies in The US DEA temporarily declared JWH-073 a schedule
animals suggest with high probability that JWH-073 pro- I controlled substance on 1 March 2011 through 76 FR
duces eects very similar to those of THC in humans.[5] 11075, and permanently instated the same schedule on
9 July 2012 in the Section 1152 of the Food and Drug
Administration Safety and Innovation Act.[7]
223.2 Derivatives
The 4'-methyl derivative of JWH-073 has been encountered as an ingredient of synthetic cannabis blends in Germany and several other European countries since 2010.[6]
The 4'-methoxy derivative JWH-080 is also known to be a
potent cannabinoid agonist and has been banned in some
countries, though it is unclear if it has also been used in
223.3.2 Australia
See also: JWH-018
On 8 July 2011 the AUS government banned the sale of
JWH-073.[8]
296
223.5. REFERENCES
297
1 g of JWH-073
223.3.3
New Zealand
On 8 May 2014 the New Zealand government banned the

sale of JWH-073. [9]
223.4 See also

JWH-081
JWH-018
JWH-019
HU-210
223.5 References
[1] http://www.likumi.lv/doc.php?id=201101&from=off
[2] Aung MM, et al. (August 2000). Inuence of the N-1
alkyl chain length of cannabimimetic indoles upon CB(1)
and CB(2) receptor binding. Drug Alcohol Depend
60 (2): 13340. doi:10.1016/S0376-8716(99)00152-0.
PMID 10940540.
[3] Forest Humus - Enthlt synthetische Cannabinoide (in
German)
[4] Lindigkeit R, et al. (July 2009). Spice: A never ending
story?". Forensic Science International 191 (13): 5863.
[5] http://www.deadiversion.usdoj.gov/drugs_concern/
spice/spice_jwh073.html
[6] EMCDDA Annual Report 2010
2014.
[8] http://www.tga.gov.au/pdf/scheduling/
scheduling-decisions-1107-final.pdf
Chapter 224
JWH-081
agonist at both the CB1 and CB2 receptors.[2] With a K
of 1.2nM it is fairly selective for the CB1 subtype, its
anity at this subtype approximately 10x the anity at
CB2 .[3] It was discovered by and named after Dr. John
W. Human.
224.1 See also

JWH-018
JWH-098
JWH-164
JWH-198
JWH-210
224.2 References
[1] Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy
o przeciwdziaaniu narkomanii (Dz.U. 2011 nr 105 poz.
614)". Internetowy System Aktw Prawnych. Retrieved
12 June 2011.
[2] Aung MM, et al. Inuence of the N-1 alkyl chain length
of cannabimimetic indoles upon CB1 and CB2 receptor
binding. Drug and Alcohol Dependence 2000; 60:133140.
[3] Human JW, et al. Structureactivity relationships for 1alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB1 and
CB2 receptors: steric and electronic eects of naphthoyl
substituents. New highly selective CB2 receptor agonists.
Bioorganic and Medicinal Chemistry. 2005; 13:89-112.
298
Chapter 225
JWH-098
JWH-098 is a synthetic cannabinoid receptor agonist
from the naphthoylindole family. It is the indole 2-methyl
derivative of a closely related compound JWH-081, but
has markedly dierent anity for the CB1 and CB2 receptors. While JWH-081 is around 10x selective for CB1
over CB2 , in JWH-098 this is reversed, and it is around
4 times weaker than JWH-081 at CB1 while being six
times more potent at CB2 , giving it a slight selectivity
for CB2 overall. This makes JWH-098 a good example
of how methylation of the indole 2-position in the naphthoylindole series tends to increase CB2 anity, but often
at the expense of CB1 binding.[1] JWH-098 is illegal in
Russia,[2] Sweden,[3] and the UK,[4] although it is unclear
whether it has any history of human use.
225.1 See also

JWH-007
JWH-081
225.2 References
PMID 15582455
[2] " 31 2009 . 1186

,
". Government.ru. Retrieved 2010-09-09.
[3] Svensk frfattningssamling
[4] The Misuse of Drugs Act 1971 (Amendment) Order 2009
299
Chapter 226
JWH-116
JWH-116 is a synthetic cannabinoid receptor ligand from
the naphthoylindole family. It is the indole 2-ethyl derivative of related compound JWH-018. The binding anity
of JWH-116 for the CB1 receptor is reported as K = 52
5 nM.[1]
226.1 See also

JWH-018
JWH-081
226.2 References
[1] Human JW, Mabon R, Wu M-J, Lu J, Hart R, Hurst DP,
Reggio PH, Wiley JL, Martin BR (2003). 3-Indolyl-1naphthylmethanes: new cannabimimetic indoles provide
evidence for aromatic stacking interactions with the CB1
cannabinoid receptor. Bioorg. Med. Chem. 11 (4): 539
549. doi:10.1016/s0968-0896(02)00451-0.
300
Chapter 227
JWH-147
JWH-147 is an analgesic drug used in scientic research,
which acts as a cannabinoid agonist at both the CB1 and
CB2 receptors. It is somewhat selective for the CB2 subtype, with a Ki of 11.0nM at CB1 vs 7.1nM at CB2 .[1]
It was discovered and named after Dr. John W. Human. JWH-147 was banned in Sweden on 1 October
2010 as a hazardous good harmful to health, after being
identied as an ingredient in herbal synthetic cannabis
products.[2][3]
227.1 See also

JWH-030
JWH-307
227.2 References
[1] Human JW, Padgett LW, Isherwood ML, Wiley JL,
Martin BR. 1-Alkyl-2-aryl-4-(1-naphthoyl)pyrroles: New
high anity ligands for the cannabinoid CB1 and CB2 receptors. Bioorganic & Medicinal Chemistry Letters 2006;
16:5432-5435.
301
Chapter 228
JWH-164
JWH-164 is a synthetic cannabinoid receptor agonist
from the naphthoylindole family. It has approximately
equal anity for the CB1 and CB2 receptors, with a K
of 6.6nM at CB1 and 6.9nM at CB2 . JWH-164 is a
positional isomer of the related compound JWH-081, but
with a methoxy group at the 7-position of the naphthyl
ring, rather than the 4-position as in JWH-081. Its potency is intermediate between that of JWH-081 and its
ring unsubstituted derivative JWH-018, demonstrating
that substitution of the naphthyl 7-position can also result
in increased cannabinoid receptor binding anity.[1][2]
228.1 References
PMID 15582455
12: 1395-1411. PMID 15974991
302
Chapter 229
Phenylacetylindole
JWH-167 (1-pentyl-3-(phenylacetyl)indole) is a
synthetic cannabinoid from the phenylacetylindole
family, which acts as a cannabinoid agonist with about
1.75x selectivity for CB1 with a K of 90nM 17 and
159nM 14 at CB2 . Similar to the related 2'-methoxy
compound JWH-250, and the 2'-chloro compound
JWH-203, JWH-167 has a phenylacetyl group in place
of the naphthoyl ring used in most aminoalkylindole
cannabinoid compounds.[1][2]
229.1 References
doi:10.1016/j.bmcl.2005.06.008. PMID 16005223.
[2] Manera, C, Tuccinardi, T, Martinelli, A (2008). Indoles and related compounds as cannabinoid ligands.
doi:10.2174/138955708783955935. PMID 18473928.
303
Chapter 230
JWH-175
JWH-175 is a drug from the naphthylmethylindole family which acts as a cannabinoid receptor agonist. It was
invented by the scientist John W. Human and colleagues
at Clemson University. JWH-175 is closely related to
the widely used cannabinoid designer drug JWH-018, but
with the ketone bridge replaced by a simpler methylene
bridge. It is several times weaker than JWH-018, having
a binding anity at the CB1 receptor of 22nM, though
some derivatives substituted at the 4-position of the naphthyl ring have potency more closely approaching that of
the equivalent naphthoylindoles.[1] This makes JWH-175
considerably less potent than most synthetic cannabinoid
drugs used in synthetic cannabis blends, and it is unclear if
JWH-175 has ever been used for this purpose. However
it has still been explicitly banned in several jurisdictions
including Russia and some Australian states, in order to
stop its potential use as an ingredient in such products.
230.1 See also

JWH-176
JWH-184
JWH-185
230.2 References
12: 1395-1411.
304
Chapter 231
JWH-184
the naphthoylindole family. It is the carbonyl-reduced
derivative of related compound JWH-122. The binding
anity of JWH-184 for the CB1 receptor is reported as
K = 23 6 nM.[1]
231.1 See also

JWH-018
JWH-122
JWH-185
231.2 References
549. doi:10.1016/s0968-0896(02)00451-0.
305
Chapter 232
JWH-185
the naphthoylindole family. It is the carbonyl-reduced
derivative of related compound JWH-081. The binding
anity of JWH-185 for the CB1 receptor is reported as
K = 17 3 nM.[1]
232.1 See also

JWH-081
JWH-184
232.2 References
549. doi:10.1016/s0968-0896(02)00451-0.
306
Chapter 233
JWH-196
the naphthoylindole family. It is the indole 2-methyl
derivative of related compound JWH-175, and the carbonyl reduced analog of JWH-007. The binding anity
of JWH-196 for the CB1 receptor is reported as K = 151
18 nM.[1]
233.1 See also

JWH-007
JWH-175
233.2 References
549. doi:10.1016/s0968-0896(02)00451-0.
307
Chapter 234
JWH-203
JWH-203 (1-pentyl-3-(2-chlorophenylacetyl)indole)
is an analgesic chemical from the phenylacetylindole
family that acts as a cannabinoid agonist with approximately equal anity at both the CB1 and CB2
receptors, having a K of 8.0nM at CB1 and 7.0nM
at CB2 . It was originally discovered by, and named
after, Dr. John W. Human, but has subsequently
been sold without his permission as an ingredient of
synthetic cannabis smoking blends.[2] Similar to the
related 2'-methoxy compound JWH-250, the 2'-bromo
compound JWH-249, and the 2'-methyl compound
cannabinoid compounds, and has the strongest in vitro
binding anity for the cannabinoid receptors of any
compound in the phenylacetyl group.[3][4][5]
Unexpectedly despite its weaker CB1 K in vitro, the 2methylindole derivative JWH-204 is actually more potent
than JWH-203 in animal tests for cannabinoid activity,
though it is still weaker than JWH-249.[6]
234.1 See also

JWH-204
doi:10.2174/138955708783955935. PMID 18473928.
234.2 References
[5] Bononi M, Belgi P, Tateo F (2011). Analytical data for

identication of the Cannabimimetic Phenylacetylindole
JWH-203. Journal of Analytical Toxicology 35 (6): 360
3. doi:10.1093/anatox/35.6.360. PMID 21740693.
[2] Analytical data for identication of the Cannabimimetic

Phenylacetylindole JWH-203. J Anal Toxicol 35 (6):
3603. July 2011. doi:10.1093/anatox/35.6.360. PMID
21740693.
[6] 1-Pentyl-3-phenylacetylindoles and JWH-018 share in

vivo cannabinoid proles in mice. Drug Alcohol Depend.
November 2011. doi:10.1016/j.drugalcdep.2011.11.001.
PMID 22127210.
[3] Human, JW, et al.

(2005).
1-Pentyl-3phenylacetylindoles, a new class of cannabimimetic
indoles. Bioorganic & Medicinal Chemistry Letters 15
(18): 41103. doi:10.1016/j.bmcl.2005.06.008. PMID
16005223.
308
Chapter 235
JWH-210
naphthoylindole family, which acts as a potent
cannabinoid agonist at both the CB1 and CB2 receptors, with K values of 0.46nM at CB1 and 0.69nM at
CB2 . It is one of the most potent 4-substituted naphthoyl
derivatives in the naphthoylindole series, having a higher
binding anity (i.e. lower K) at CB1 than both its
4-methyl and 4-n-propyl homologues JWH-122 (CB1 K
0.69nM) and JWH-182 (CB1 K 0.65nM) respectively,
and than the 4-methoxy compound JWH-081 (CB1
K 1.2nM).[2] It was discovered by and named after
Dr. John W. Human. JWH-210 and JWH-122 were
banned in Sweden on 1 October 2010 as hazardous
goods harmful to health, after being identied as ingredients in herbal synthetic cannabis products.[3][4] The
substances JWH-210, JWH-122 and JWH-203 were
classied as illegal drugs by the Swedish government as
of 1 September 2011.[5]
235.1 See also

JWH-081
JWH-193
JWH-398
235.2 References
[1] Ustawa z dnia 15 kwietnia 2011 r. o zmianie ustawy o
przeciwdziaaniu narkomanii ( Dz.U. 2011 nr 105 poz.
614 )". Internetowy System Aktw Prawnych. Retrieved
12 June 2011.
PMID 15582455.
309
[5] LVFS 2011:8
Chapter 236
JWH-249
JWH-249 (1-pentyl-3-(2-bromophenylacetyl)indole)
is a synthetic cannabinoid from the phenylacetylindole
2.4x selectivity for CB1 with a K of 8.4nM 1.8 and
compound JWH-250, the 2'-chloro compound JWH-203,
and the 2'-methyl compound JWH-251, JWH-249 has a
phenylacetyl group in place of the naphthoyl ring used in
most aminoalkylindole cannabinoid compounds. [1][2]
236.1 See also

AM-679
236.2 References
doi:10.1016/j.bmcl.2005.06.008. PMID 16005223.
doi:10.2174/138955708783955935. PMID 18473928.
310
Chapter 237
JWH-250
JWH-250
or
(1-pentyl-3-(2methoxyphenylacetyl)indole) is an analgesic chemical
from the phenylacetylindole family that acts as a
cannabinoid agonist at both the CB1 and CB2 receptors, with a K of 11nM at CB1 and 33nM at CB2 .
Unlike many of the older JWH series compounds, this
compound does not have a naphthalene ring, instead
occupying this position with a 2'-methoxy-phenylacetyl
group, making JWH-250 a representative member
of a new class of cannabinoid ligands.[2] Other 2'substituted analogues such as the methyl, chloro and
bromo compounds are also active and somewhat more
potent.[3][4]
237.1 History
JWH-250 was discovered by, and named after the researcher Dr. John W. Human. He created JWH250 and a number of other compounds to research the
structure and function of the endocannabinoid system of
mammals. Samples of JWH-250 were rst identied in
May 2009 by the German Federal Criminal Police, as
an ingredient in new generation "herbal smoking blends"
that had been released since the banning of the original
ingredients (C8)-CP 47,497 and JWH-018.[5] An ELISA
immunoassay technique for detecting JWH-250 in urine
has been reported.[6]
237.2 References
[1] Legal article in Latvian (www.likumi.lv)
[2] Human, JW, et al.
(2005).
(18): 41103. doi:10.1016/j.bmcl.2005.06.008. PMID
16005223.
doi:10.2174/138955708783955935. PMID 18473928.
[4] The Cannabinoid Receptors. Edited by Patricia H Reggio.
Humana Press 2009. ISBN 978-1-58829-712-9
311
[5] Understanding the Spice phenomenon. EMCDDA, Lisbon, November 2009

[6] Arntson et al (2013) http://jat.oxfordjournals.org/
content/37/5/284.abstract
Chapter 238
JWH-251
JWH-251 (1-pentyl-3-(2-methylphenylacetyl)indole)
is a synthetic cannabinoid from the phenylacetylindole
5x selectivity for CB1 with a K of 29nM and 146nM
at CB2 .
Similar to the related 2'-methoxy compound JWH-250, the 2'-chloro compound JWH-203,
and the 2'-bromo compound JWH-249, JWH-251 has a
phenylacetyl group in place of the naphthoyl ring used in
most aminoalkylindole cannabinoid compounds. [1][2]
238.1 References
doi:10.1016/j.bmcl.2005.06.008. PMID 16005223.
doi:10.2174/138955708783955935. PMID 18473928.
312
Chapter 239
JWH-302
JWH-302
or
(1-pentyl-3-(3methoxyphenylacetyl)indole) is an analgesic chemical
from the phenylacetylindole family, which acts as a
cannabinoid agonist with moderate anity at both the
CB1 and CB2 receptors. It is a positional isomer of the
more common drug JWH-250, though it is slightly less
potent with a K of 17nM at CB1 , compared to 11nM
for JWH-250.[1][2] Because of their identical molecular
weight and similar fragmentation patterns, JWH-302 and
JWH-250 can be very dicult to distinguish by GC-MS
testing.[3]
239.1 References
[1] Human, JW. et al.
(2005).
(18): 41103. doi:10.1016/j.bmcl.2005.06.008. PMID
16005223.
doi:10.2174/138955708783955935. PMID 18473928.
[3] 'Herbal High' synthetic Cannabinoid composition, released by ESR July 2011
313
Chapter 240
JWH-307
JWH-307 is an analgesic drug used in scientic research,
CB2 receptors. It is somewhat selective for the CB2 subtype, with a Ki of 7.7nM at CB1 vs 3.3nM at CB2 .[1]
It was discovered by, and named after, Dr. John W.
Human. JWH-307 was detected as an ingredient in
synthetic cannabis smoking blends in 2012, initially in
Germany.[2][3]
240.1 See also

JWH-147
240.2 References
[1] Human JW, Padgett LW, Isherwood ML, Wiley JL,
Martin BR. 1-Alkyl-2-aryl-4-(1-naphthoyl)pyrroles: New
high anity ligands for the cannabinoid CB1 and CB2 receptors. Bioorganic & Medicinal Chemistry Letters 2006;
16:5432-5435.
[2] Ernst, L.; Krger, K.; Lindigkeit, R.; Schiebel, H.
M.; Beuerle, T. (2012). Synthetic cannabinoids in
spice-like herbal blends: First appearance of JWH307 and recurrence of JWH-018 on the German market. Forensic Science International 222 (13): 21622.
[3] Kneisel, S.; Auwrter, V. (2012). Analysis of 30 synthetic cannabinoids in serum by liquid chromatographyelectrospray ionization tandem mass spectrometry after
liquid-liquid extraction. Journal of Mass Spectrometry 47
(7): 825835. doi:10.1002/jms.3020. PMID 22791249.
314
Chapter 241
JWH-398
agonist at both the CB1 and CB2 receptors. It has
mild selectivity for CB1 with a K of 2.3nM and 2.8nM
at CB2 .[2] It was identied by the EMCDDA as an
ingredient in three separate "herbal incense" products
purchased from online shops between February to June
2009.[3] It was discovered by, and named after, Dr. John
W. Human.[4]
241.1 See also

JWH-122
JWH-424
241.2 References
[1]
[2] Human JW (2009) Cannabimimetic indoles, pyrroles,
and indenes: structure-activity relationships and receptor
interactions. Cited in: The cannabinoid receptors, Reggio PH (Ed), Humana Press. ISBN 978-1-58829-712-9
doi:10.1007/978-1-59745-503-9
[3] Understanding the Spice phenomenon. EMCDDA, Lisbon, November 2009
[4] John W. Human, et al. STRUCTURE-ACTIVITY
RELATIONSHIPS AT THE CB1 AND CB2 RECEPTORS FOR 1-ALKYL-3-(1-NAPHTHOYL-4 AND 8HALOGEN SUBSTITUTED) INDOLES (2009) 19th
Annual Symposium on the Cannabinoids, Burlington,
Vermont, International Cannabinoid Research Society,
Page 2.
315
Chapter 242
JWH-424
JWH-424 is a drug from the naphthoylindole family,
CB2 receptors, but with moderate selectivity for CB2 ,
having a K of 5.44nM at CB2 vs 20.9nM at CB1 . The
heavier 8-iodo analogue is even more CB2 selective, with
its 2-methyl derivative having 40x selectivity for CB2 .
However the 1-propyl homologues in this series showed
much lower anity at both receptors, reecting a generally reduced anity for the 8-substituted naphthoylindoles overall.[1][2]
242.1 See also

JWH-018
JWH-398
242.2 References
[1] Valerie Smith, John Human, Jenny Wiley and
Billy Martin.
EFFECTS OF HALOGEN SUBSTITUENTS UPON CB1 AND CB2 RECEPTOR
AFFINITIES IN THE SERIES OF N-ALKYL-3-(8HALO-1-NAPTHOYL)INDOLES. (2007) 17th Annual
Symposium on the Cannabinoids, Burlington, Vermont,
International Cannabinoid Research Society, Page 72.
[2] John W. Human, et al. STRUCTURE-ACTIVITY
RELATIONSHIPS AT THE CB1 AND CB2 RECEPTORS FOR 1-ALKYL-3-(1-NAPHTHOYL-4 AND 8HALOGEN SUBSTITUTED) INDOLES (2009) 19th
Annual Symposium on the Cannabinoids, Burlington,
Vermont, International Cannabinoid Research Society,
Page 2.
316
Chapter 243
Naphthoylindole
JWH-018 (1-pentyl-3-(1-naphthoyl)indole) or AM678[1] is an analgesic chemical from the naphthoylindole family that acts as a full agonist at both the CB1
and CB2 cannabinoid receptors, with some selectivity for
CB2 . It produces eects in animals similar to those of
THC, a cannabinoid naturally present in cannabis, leading to its use in synthetic cannabis products such as legal cannabis herbal incense blends which in some countries are sold legally as incense, labeled not for human
consumption.[2][3][4][5][6]
243.2.1 Pharmacokinetics
JWH-018 administered to rats resulted in the excretion
of an indole-N-desalkyl metabolite as well as several hydroxylated metabolites in urine. The highest signals were
observed for the hydroxylated N-desalkyl metabolites.
Hydroxylation took place on the side chain and in both
aromatic systems, the naphthalene and the indole rings,
as could be shown by mass shift of the corresponding
fragments and by MS3 experiments.[13] Human metabolites were similar although most metabolism took place
on the indole ring and pentyl side chain, and the hydroxylated metabolites were extensively conjugated with
glucuronide.[14]
243.1 History
John W. Human, an organic chemist at Clemson University, synthesized analogues and metabolites of 9 tetrahydrocannabinol (THC), the principal active component of cannabis. JWH-018 is one of these analogues,
with studies showing an anity for the cannabinoid (CB1 )
receptor ve times greater than that of THC. Cannabinoid
receptors are found in mammalian brain and spleen tissue; however, the structural details of the active sites are
currently unknown.[7][8]
On December 15, 2008, it was reported by the German
pharmaceutical company THC Pharm that JWH-018 was
found as one of the active components in at least three
versions of the herbal blend Spice, which has been sold
as an incense in a number of countries around the world
since 2002.[9][10][11] An analysis of samples acquired four
weeks after the German prohibition of JWH-018 took
place found that the compound had been replaced with
JWH-073.[12]
243.3 Usage
At least one case of JWH-018 dependence has been reported by the media.[2] The user consumed JWH-018
daily for eight months. Withdrawal symptoms were similar to those experienced as a result of cannabis dependence. JWH-018 has been shown to cause profound
changes in CB1 receptor density following administration, causing desensitization to its eects more rapidly
than related cannabinoids.[6]
On October 15, 2011, Anderson County coroner Greg
Shore attributed the death of a South Carolina college
basketball player to drug toxicity and organ failure
caused by JWH-018.[15] An email dated Nov 4, 2011
concerning the case was nally released by the city of
Anderson S.C. on Dec 16, 2011 under the Freedom of
Information Act after multiple requests by media to see
the information had been denied.[16]
Compared to THC, which is a partial agonist at CB1

receptors, JWH-018 (and many of its analogues) are
full agonists. THC has been shown to inhibit GABA
receptor neurotransmission in the brain via several
pathways.[17][18] JWH-018 may cause intense anxiety, ag243.2 Pharmacology
itation, and, in rare cases (generally with non-regular
JWH users), has been assumed to have been the cause of
JWH-018 is a full agonist of both the CB1 and CB2 seizures and convulsions by inhibiting GABA neurotranscannabinoid receptors, with a reported binding anity of mission more eectively than THC. Cannabinoid recep9.00 5.00 nM at CB1 and 2.94 2.65 nM at CB2 .[3]
tor full agonists may present serious dangers to the user
317
318
when used to excess.[19]

Various physical and psychological adverse eects have
been reported from JWH-018 use. One study reported psychotic relapses and anxiety symptoms in welltreated patients with mental illness following JWH-018
inhalation.[20] Due to concerns about the potential of
JWH-018 and other synthetic cannabinoids to cause psychosis in vulnerable individuals, it has been recommended that people with risk factors for psychotic ill- Synthesis of JWH-018.[51]
nesses (like a past or family history of psychosis) not use
these substances.[21]
243.6 Synthesis
243.7 See also
243.4 Detection in biological uids

JWH-018 usage is readily detected in urine using spice
screening immunoassays from several manufacturers focused on both the parent drug and its omega-hydroxy and
carboxyl metabolites.[22] JWH-018 will not be detected
by older methods employed for detecting THC and other
cannabis terpenoids. Determination of the parent drug in
serum or its metabolites in urine has been accomplished
by GC-MS or LC-MS. Serum JWH-018 concentrations
are generally in the 110 g/L range during the rst
few hours after recreational usage. The major urinary
metabolite is a compound that is monohydroxylated on
the omega minus one carbon atom of the alkyl side chain.
A lesser metabolite monohydroxylated on the omega (terminal) position was present in the urine of 6 users of the
drug at concentrations of 650 g/L, primarily as a glucuronide conjugate.[23][24][25][26][27][28][29][30][31]
243.5 Legal status
AM-2201
BB-22 (drug)
JWH-073
JWH-250
JWH-200
PB-22
SDB-001
243.8 References
[1] Department of Justice :: Drug Enforcement Administration. 2011-03-01. Retrieved 2011-03-02.
JA, Spanagel R, Schulz K (2009). Withdrawal Phenomena and Dependence Syndrome After the Consumption
of Spice Gold"". Dtsch Arztebl Int 106 (27): 464467.
doi:10.3238/arztebl.2009.0464. PMC 2719097. PMID
19652769.
[3] Aung MM, Grin G, Human JW, Wu M, Keel
doi:10.1016/S0376-8716(99)00152-0. PMID 10940540.
JWH-018 powder as it was commonly sold online
[6] Atwood, B.K., et al., JWH018, a common constituent of

'Spice' herbal blends, is a potent and ecacious cannabinoid CB1 receptor agonist. British Journal of Pharmacology, Vol. 160, No. 3. 585-593. 2010.
243.8. REFERENCES
319

[8] Drugs Forum. Drugs Forum. Retrieved 2010-08-23.
[9] Gefhrlicher Kick mit Spice (German)
[10] Erstmals Bestandteile
nachgewiesen (German)
der
Modedroge
Spice
[11] Spice enthlt chemischen Wirksto (German)

[12] Lindigkeit R, Boehme A, Eiserloh I, Luebbecke M, Wiggermann M, Ernst L, Beuerle T (30 October 2009).
Spice: A never ending story?". Forensic Science International (Forensic Science International) 191 (1): 5863.
[13] T. Kraemer, et al. Studies on the metabolism of JWH018 and of a homologue of CP 47,497, pharmacologically active ingredients of dierent misused incense
(Spice) using GC-MS and LC-MSn techniques (Institute of Legal Medicine, Saarland University, 66421
Homburg, Germany http://www.gtfch.org/cms/images/
stories/media/tk/tk76_2/abstractsvortraege.pdf
[14] Sobolevsky T, Prasolov I, Rodchenkov G (July 2010).
Detection of JWH-018 metabolites in smoking mixture
post-administration urine. Forensic Science International
200 (13): 1417. doi:10.1016/j.forsciint.2010.04.003.
PMID 20430547.
[15] wy4.com, Coroner: Synthetic Pot Killed College Athlete, posted 10/14/11, accessed 12/22/11, http://www.
wyff4.com/news/29497549/detail.html,
[16] Mayo, Nikie, City Releases Email in Lamar Jacks Case,
independentmail.com, posted Dec 16, 2011, accessed
12/22/11, http://www.independentmail.com/news/2011/
dec/16/city-releases-email-lamar-jack-case/
[17] Laaris N, Good CH, Lupica CR (JulyAugust 2010).
"9-tetrahydrocannabinol is a full agonist at CB1 receptors on GABA neuron axon terminals in the hippocampus. Neuropharmacology 59 (12): 121127.
PMID 20417220.
[18] Homan AF, Lupica CR (2000-04-01). Mechanisms of
cannabinoid inhibition of GABAA synaptic transmission
in the hippocampus. The Journal of Neuroscience 20 (7):
24702479. ISSN 0270-6474. PMID 10729327. Retrieved 2011-07-26.
[19] European Monitoring Centre for Drugs and Drug Addiction. Understanding the Spice Phenomenon. 2009.
ISBN 978-92-9168-411-3.
[20] Every-Palmer, S. Synthetic cannabinoid use and psychosis: an explorative study. Journal of Drug and Alcohol
Dependence 2011. [Epub ahead of print].
[21] Every-Palmer S (2010). WARNING: LEGAL SYNTHETIC CANNABINOID-RECEPTOR AGONISTS
SUCH AS JWH-018 MAY PRECIPITATE PSYCHOSIS
IN VULNERABLE INDIVIDUALS. Addiction 105:
doi:10.1111/j.1360-0443.2010.03119.x.
18591860.
PMID 20840203.
[22] See Arntson et al. (2013) http://jat.oxfordjournals.org/

content/37/5/284.abstract, https://www.caymanchem.
com/app/template/Product.vm/catalog/580210;
http://www.randoxtoxicology.com/Products/Elisa-p-50,
http://tulipbiolabs.com/our-product-areas/
synthetic-cannabinoids and others.
[23] Mller I, et al. Screening for the synthetic cannabinoid
JWH-018 and its major metabolites in human doping controls. Drug Test. Anal. Sep 24, 2010. [Epub ahead of
print]
[24] Teske J, et al.
Sensitive and rapid quantication
of the cannabinoid receptor agonist naphthalen-1-yl-(1pentylindol-3-yl)methanone (JWH-018) in human serum
by liquid chromatography-tandem mass spectrometry. J
Chrom. B 878: 2659-2663, 2010.
[25] Auwrter V, Dresen S, Weinmann W, Mller M, Ptz
M, Ferreirs N (2009). "'Spice' and other herbal blends:
harmless incense or cannabinoid designer drugs?". Journal of mass spectrometry : JMS 44 (5): 832837.
JA, Spanagel R, Schulz K (2009). Withdrawal phenomena and dependence syndrome after the consumption
(27): 464467. doi:10.3238/arztebl.2009.0464. PMC
2719097. PMID 19652769.
[27] Sobolevsky T, Prasolov I, Rodchenkov G (2010). Detection of JWH-018 metabolites in smoking mixture postadministration urine. Forensic Science International 200
(13): 141147. doi:10.1016/j.forsciint.2010.04.003.
PMID 20430547.
[28] Beuck S, Mller I, Thomas A, Klose A, Schlrer
N, Schnzer W, Thevis M (August 2011). Structure characterisation of urinary metabolites of the
cannabimimetic JWH-018 using chemically synthesised
reference material for the support of LC-MS/MS-based
drug testing. Anal Bioanal Chem 401 (2): 493505.
doi:10.1007/s00216-011-4931-5. PMID 21455647.
[29] Moran CL, Le VH, Chimalakonda KC, Smedley AL,
Lackey FD, Owen SN, Kennedy PD, Endres GW, Ciske
FL, Kramer JB, Kornilov AM, Bratton LD, Dobrowolski
PJ, Wessinger WD, Fantegrossi WE, Prather PL, James
LP, Radominska-Pandya A, Moran JH (June 2011).
Quantitative measurement of JWH-018 and JWH-073
metabolites excreted in human urine. Anal. Chem.
83 (11): 422836. doi:10.1021/ac2005636. PMID
21506519.
[30] Logan BK, et al. Identication of primary JWH018 and JWH-073 metabolites in human urine.
NMS Labs Technical Bulletin, May 25, 2011.
http://toxwiki.wikispaces.com/file/view/JWH_
metabolites_Technical_Bulletin_Final_v1.1.pdf
[31] R. Baselt, Disposition of Toxic Drugs and Chemicals in
Man, 10th edition, Biomedical Publications, Seal Beach,
CA, 2014, p. 1863.
[32] <http://www.legislation.qld.gov.au/LEGISLTN/
CURRENT/D/DrugsMisuseR87.pdf>
320
[33] Controlled
Drugs
and
Substances
Act.
Laws.justice.gc.ca.
2010-08-16.
Retrieved 201008-23.
[34] *** Tiedote/Valtioneuvoston viestintyksikk: VALTIONEUVOSTON YLEISISTUNTO 1.3.2012 ***
(Finnish)
[35] EMCDDA | Drug prole: Synthetic cannabinoids and
'Spice'". Emcdda.europa.eu. 2010-08-17. Retrieved
2010-08-23.
[36] http://www.afssaps.fr/var/afssaps_site/storage/original/
application/d23d05edc58479d91c803b496017f073.pdf
Januar 2009, S. 4950.
[38] Many head shop products banned - Irish Times.
[39] http://www.politicheantidroga.it/
comunicazione/comunicati/2010/luglio/spice,
-n-joy-e-mefedrone-da-oggi-stupefacenti.aspx (Italian)
[41] http://www.lovdata.no/ltavd1/filer/sf-20111221-1465.
html
[42]
(2 July 2009). 1
5- -
. Retrieved 18 February 2010.
".
[43] http://www.regeringen.se/sb/d/12102/a/130038
(Swedish)
[44] Illicit Drug Report of Turkey 2010. Department of
Anti-smuggling and Organised Crime. Retrieved 201205-03.(Turkish)
[46] Attachment to Enactment 2012/2861. General Directorate of Legislation Development and Publication. Retrieved 2012-05-03.(Turkish)
[48] Ford, Richard (2009-12-23). Three legal highs banned
after deaths linked to the drugs. The Times (London).
2014.
[50] <http://www.antinarcotics.psd.gov.jo>
[51] Appendino G, Minassi A, Taglialatela-Scafati O (2014).
Recreational drug discovery: natural products as lead
structures for the synthesis of smart drugs. Natural Product Reports 31 (7): 880904. doi:10.1039/c4np00010b.

JWH-018 Report Psychonaut Web Mapping Research Project
User of legal high
Chapter 244
Phenylacetylindole
JWH-167 (1-pentyl-3-(phenylacetyl)indole) is a
synthetic cannabinoid from the phenylacetylindole
1.75x selectivity for CB1 with a K of 90nM 17 and
compound JWH-250, and the 2'-chloro compound
cannabinoid compounds.[1][2]
244.1 References
doi:10.1016/j.bmcl.2005.06.008. PMID 16005223.
doi:10.2174/138955708783955935. PMID 18473928.
321
Chapter 245
RCS-8
RCS-8,
or
1-(2-cyclohexylethyl)3-(2methoxyphenylacetyl)indole, is a synthetic cannabinoid
also known as SR-18 or BTM-8 that has been found as
an ingredient of herbal synthetic cannabis blends. It
can be described as an analogue of JWH-250 with the
1-pentyl group replaced by 1-(2-cyclohexylethyl), and
can be expected to be less potent than JWH-250 (cf.
JWH-007 and its cyclohexylethyl analogue).[1] Despite
not having been reported in the scientic or patent
literature as yet, reputed recreational use of RCS-8 in the
United States has led to it being specically listed in a
proposed 2011 amendment to the Controlled Substances
Act, aiming to add a number of synthetic drugs into
Schedule I.[2]
245.1 See also

JWH-250
RCS-4
245.2 References
[1] Human, J. W.; Dai, D.; Martin, B. R.; Compton,
D. R. (1994). Design, Synthesis and Pharmacology
of Cannabimimetic Indoles. Bioorganic & Medicinal Chemistry Letters 4 (4): 563. doi:10.1016/S0960894X(01)80155-4.
[2] Synthetic Drug Control Act of 2011
322
Chapter 246
Intravenous Marijuana Syndrome

Intravenous Marijuana Syndrome is a distinct shortterm clinical syndrome related to the intravenous injection of boiled cannabis broth, which had been ltered
through a cotton cloth. The syndrome has at least 25
known cases in the English language literature, but all of
them prior to 1983.[1]
It is postulated that contamination, perhaps from the cotton used to strain the liquid of the broth or from particulate plant matter getting through the straining method,
could be cause for the cases of illnesses.[1]
246.1 References
[1] Daniel Brandenburg; Richard Wernick (July 1986).
Intravenous Marijuana Syndrome. wjm 145 (1): 9496.
PMC 1306836. PMID 3489321. Retrieved 2008-06-21.
323
Chapter 247
Mellow Yellow coeeshop

Mellow Yellow is the oldest cannabis coee shop in
Amsterdam. The coee shop was founded in 1972 by
Wernard Bruinin in Weesperzijde, Amsterdam, on the
premises of a former bakery. The shop is named after
"Mellow Yellow", a song by Donovan which describes the
singer trying to become intoxicated through smoking the
peel of banana.[1]
The intent of the shop is to sell cannabis, despite this being illegal at the time of its creation.[1] Sales were originally disguised by drug dealers seated at the bar posing as
customers. Mellow Yellow was unsuccessfully raided by
police several times. Unpackaged cannabis, bought from
wholesalers including drug lord Klaas Bruinsma, was hidden behind secret doors and shutters.
In 1975, the concept was adopted by a shop named Russia
situated on the same street as Mellow Yellow and was followed by another coee shop called The Bulldog. Now
there are 223[2] such coee shops in Amsterdam.
Bruining also runs Stichting Mediwiet (Medi Cannabis
Foundation), a group that supports the legalization of
growing marijuana for medicinal uses.
247.1 Citations
[1] De eerste coeeshop ter wereld (in Dutch). November
2008. Retrieved December 2012.
[2] FAQ Coeeshops in Amsterdam. I Amsterdam. Retrieved 2013-03-24.
247.2 References
Hasj (in Dutch). Geschiedenis 24.
Schoof, Rob (1 May 2008). De achterdeur van de
coeeshop (in Dutch). NRC Handelsblad.
van Schaik, Nol (7 October 2009). Dutch Cannabis
Coeeshop History.
324
Mellow Yellow Lounge

Stichting Mediwiet
Chapter 248
The Night Train Seizure

The Night Train Drug Seizure was a 1978 seizure of 54
tons of marijuana by the United States Coast Guard o
the southeastern coast of Florida which marked the beginning of Operation Stopgap, a United States federal law
enforcement inter-agency drug interdiction operation focusing on interdicting drugs from Colombian cartels and
other illicit Central and South American drug sources.[1]
The Night Train seizure was the largest single drug seizure
in history at the time it occurred, and it remains one of the
largest marijuana seizures made in the territorial waters
of the United States.[2]
List of United States Coast Guard cutters
Operation Stopgap was one of the rst inter-agency law

enforcement eorts focused on the interdiction of illegal
drugs from Central and South America, and it featured
personnel of the Coast Guard, DEA and US Federal Marshals Service working together,[3] as well as the resources
of the Intelligence Section of the Drug Enforcement Administration and Coast Guard Intelligence (CGI).[4]
United States Coast Guard Legal Division
The Night Train was a 189 foot coastal cargo vessel that
had become legendary in the law enforcement community and smuggling circles due to its repeated ability to
elude US law enforcement for almost two years before
they were nally captured o of West Palm Beach as the
rst seizure of Stopgap. Operation Stopgap was but the
rst of a number of highly successful inter-agency intelligence and interdiction operations[5] that led to a large
number of successful seizures and prosecutions in the late
1970s and early 1980s, garnering the U.S. Coast Guard
considerable press coverage during this period as seizure
records continued to be broken.[6] Stopgap was also one
of the earliest interdiction operations to eectively use
satellite technology in the pursuit and interdiction of drug
smugglers.[7]
List of United States Coast Guard stations

Maritime Law Enforcement Academy
MARSEC
National Data Buoy Center
National Ice Center
Patrol Forces Southwest Asia
United States Coast Guard ocer rank insignia

United States Coast Guard Research & Development Center
248.2 References
[1] Name Of Pot-Laden Ship Sounded Familiar To Coast
Guard Miami News, December 11, 1977
[2] Marijuana Seizure Was Largest Haul On Record Lakeland
(Florida) Ledger, April 20, 1978
[3] The Battle Against Drugs Takes to the Seas: High Seas
Drama When the Night Train was Seized by the Coast
Guard. U.S. News and World Report LXXXIV (Mar 27,
1978), pp. 6971.
[4] DEA and Coast Guard Could Almost Track Drug Ship By
The Smell St. Petersburg Times, July 11, 1978
[5] Operation Stopgap The Spokesman Review, September
16, 1978
[6] Operation Stopgap Nails The Legendary Night Train, St.
Petersburg Times, July 11, 1978
248.1 See also
[7] Satellites Aiding In Pot Seizures Sarasota Herald-Tribune,

July 11, 1978
Coast Guard Investigative Service

Go-fast boat
Joint Maritime Training Center
List of active United States military aircraft
325
Chapter 249
PSN-375,963
PSN-375,963 is a selective ligand for the suggested novel
249.1 See also

AR-231,453
PSN-632,408
249.2 References
[1] Overton HA, Babbs AJ, Doel SM, Fyfe MC, Gardner
LS, Grin G, Jackson HC, Procter MJ, Rasamison
CM, Tang-Christensen M, Widdowson PS, Williams
GM, Reynet C. (2006). Deorphanization of a G
protein-coupled receptor for oleoylethanolamide
and its use in the discovery of small-molecule hypophagic agents.. Cell Metab. 3 (3): 167175.
doi:10.1016/j.cmet.2006.02.004. PMID 16517404.
326
Chapter 250
PSN-632,408
PSN-632,408 is a selective ligand for the suggested novel
250.1 See also

AR-231,453
PSN-375,963
250.2 References
[1] Overton HA, Babbs AJ, Doel SM, Fyfe MC, Gardner
LS, Grin G, Jackson HC, Procter MJ, Rasamison
CM, Tang-Christensen M, Widdowson PS, Williams
GM, Reynet C. (2006). Deorphanization of a G
protein-coupled receptor for oleoylethanolamide
and its use in the discovery of small-molecule hypophagic agents.. Cell Metab. 3 (3): 167175.
doi:10.1016/j.cmet.2006.02.004. PMID 16517404.
327
Chapter 251
Soma Seeds
Soma Seeds (also known as Somas Sacred Seeds) is
an Amsterdam based medical cannabis seed company
owned by Soma. The company became internationally
famous after winning the 1999 High Times Cannabis
Cup with Somas 'Reclining Buddha' strain in the Indica
category;[1] in 2001, 2002, 2003 and 2004 with 'NYC
Diesel' strain in the Sativa category,[2] in 2002 with 'Buddhas Sister' strain in the Indica category [3] in 2004 with
'Amnesia Haze' in the best strain category [4] and in 2005
with 'Lavender' strain in the Indica category.[5]
251.1 References
[1] Cannabis Cup winners 1999.

http://www.somaseeds.nl/
328
Chapter 252
TM-38837
TM38837 is a new small molecule inverse agonist/antagonist of the CB1 cannabinoid receptor. It is being developed for the treatment of obesity and metabolic
disorders by 7TM Pharma.[1] The company has announced phase I clinical trials.
TM38837 is among the rst of a new generation of
cannabinoid receptor antagonist designed to avoid the
central nervous system liabilities of the rst generation
CB1 receptor antagonists, for example rimonabant.[2]
252.1 See also

AM-6545
252.2 References
[1] http://www.7tm.com
[2] Hung, M. S.; Chang, C. P.; Li, T. C.; Yeh, T. K.; Song,
J. S.; Lin, Y.; Wu, C. H.; Kuo, P. C.; Amancha, P. K.;
Wong, Y. C.; Hsiao, W. C.; Chao, Y. S.; Shia, K. S.
(2010). Discovery of 1-(2,4-Dichlorophenyl)4-ethyl5-(5-(2-(4-(triuoromethyl)phenyl)ethynyl)thiophen2-yl)-N-(piperidin-1-yl)1H-pyrazole-3-carboxamide
as a Potential Peripheral Cannabinoid-1 Receptor
Inverse Agonist. ChemMedChem 5 (9): 14391443.
doi:10.1002/cmdc.201000246. PMID 20652930.

www.7tm.com
Experimental obesity drug avoids brain eects that
troubled predecessors
329
330
CHAPTER 252. TM-38837
252.4 Text and image sources, contributors, and licenses

252.4.1
Text
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JWSchmidt, Nnh, AnthonyQBachler, Hadal, Fuelbottle, Centrx, Karn, Bensaccount, Jfdwol, St3vo, Eequor, Christopherlin, OldakQuill,
Ferre, Mearlon, Lazypplunite, Freakofnurture, Rich Farmbrough, Cacycle, Kwamikagami, Tgeller, Renice, Arcadian, Kaf, Alansohn,
Eric Kvaalen, Howrealisreal, Axl, Mrholybrain, Ombudsman, Gene Nygaard, Natalya, Bobrayner, Qnonsense, Mpj17, WadeSimMiser,
Mandarax, SqueakBox, BD2412, Mendaliv, Zachjones4, Rjwilmsi, HappyCamper, Fred Bradstadt, X1987x, Avocado, FlaBot, Margosbot, Jrtayloriv, Nosforit, Fborgnia, YurikBot, Mushin, Chris Capoccia, Gaius Cornelius, Zwobot, S. Neuman, Jeh, Ochiwar, Smaines,
Saric, Itub, SmackBot, Unyoyega, Jrockley, Antrophica, Timotheus Canens, Jpvinall, Edgar181, David.Throop, Chris the speller, Bluebot, Droll, Deli nk, Ioscius, Roadnottaken, Radagast83, Drphilharmonic, J306, Provider uk, Ilyse Kazar, Rhetth, CmdrObot, Scoticus,
ShelfSkewed, Meodipt, Kupirijo, Dougweller, Thijs!bot, Barticus88, RobArmstrong, Bendroz, Luke poa, Gharmon, Subvertc, Headbomb,
Java13690, E. Ripley, Big Bird, Smartse, Astavats, Dougher, Ph.eyes, MudPhud, Probios, PhilKnight, Iownutopia, Cannabis, Hiplibrarianship, CliC, Leyo, Lumir, J.delanoy, Pharaoh of the Wizards, Extransit, Nonantum, Jeepday, Mikael Hggstrm, Tanevala, Enix150,
Funandtrvl, MenasimBot, Benrr101, LeaveSleaves, GeorgeLTirebiter, Glaman7, Carinabean1, Sapphic, Doc James, Ohiostandard, Nonsomniac, Scarian, Bradgon, Delighted eyes, ClueBot, Andrew Nutter, Drmies, Niceguyedc, Anon lynx, Phil Ian Manning, Vivio Testarossa,
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Wormantson, Jameskirby, Tide rolls, OlEnglish, Teles, Jarble, Gaberdine2, Luckas-bot, Yobot, Themfromspace, Clarechenoweth, Dmarquard, AnomieBOT, Gtz, Rjanag, JackieBot, Materialscientist, Flaminhaz, Citation bot, Xqbot, Dagrun, GrouchoBot, Slowart, Ajax151,
Shadowjams, Custoo, FrescoBot, Lothar von Richthofen, Maria mdv, Biker Biker, Pinethicket, CCIC, Abductive, Tea with toast, Trainwreckwebb, David Hedlund, Minimac, Algarcia85, RjwilmsiBot, Mungox, Alph Bot, EmausBot, Eekerz, SalviaFan, Nuujinn, Beeshoney,
Zane Russell,, Tommy2010, Dcirovic, Doddy Wuid, Subtropical-man, MajorVariola, WickedSpice, Wayne Slam, Duncan169, DASHBotAV, Frozen Wind, ClueBot NG, Horoporo, Osterluzei, Mesoderm, HenryScow, Helpful Pixie Bot, BG19bot, Lewisly, Petrarchan47, Nikos
1993, Veried72, Drpainless, Viridis Veritas, Seannyboy219, Papier K, Kingofoviedo, Shisha-Tom, TheBaur, Stark1987, 32cllou, Mogism,
Makecat-bot, Cerabot, Aachaos, Eyesnore, Wicked licks, Dymethylated, Meteor sandwich yum, Farmkid1958, Monkbot, Bosch1ltd rc development, Crazykatchic, Medgirl131, Jameshelsing, JuggaloICP, SP1977 and Anonymous: 218
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Katana0182, Furrykef, Dale Arnett, Alan Liefting, DocWatson42, Everyking, St3vo, Neilc, Chowbok, Gadum, Beland, Jokestress,
Oknazevad, Cacycle, Cyclopia, Mr2001, Alansohn, Eleland, Ynhockey, Sciurin, BDD, KevinOKeee, SqueakBox, Rjwilmsi, XLerate, Krzysiu, Wgfcrafty, Diza, Therefore, Wavelength, Jimp, RadioFan, Grafen, Alpha 4615, BorgQueen, Fram, JDspeeder1, Paul Erik,
SmackBot, KAtremer, Kintetsubualo, Edgar181, Ohnoitsjamie, Hmains, Cs-wolves, Chris the speller, Myxsoma, Thumperward, Cybercobra, Derek R Bullamore, Drphilharmonic, Salamurai, Curly Turkey, Ohconfucius, AThing, John, Minna Sora no Shita, IronGargoyle,
SandyGeorgia, Skinsmoke, G patkar, MrDolomite, Valoem, Winston Spencer, J Milburn, JForget, Edward Vielmetti, CBM, Nczempin,
Meodipt, Funnyfarmofdoom, Doctormatt, Crossmr, Kotiwalo, DumbBOT, FG Fox, Qwyrxian, N5iln, Turkeyphant, Matthew Proctor,
Pfranson, Ssr, Shirt58, Smartse, DuncanHill, Adjwilley, Jheiv, Zendu, Umeboshi, Hiplibrarianship, BatteryIncluded, Esteroth12, Andytuba, Leyo, Edgeweyes, 2012Olympian, Malkuth1, Carolfrog, Danwoodard, AngryEoin, DadaNeem, Themoodyblue, Pdcook, 360aerial,
Speciate, VolkovBot, Dave Andrew, Trex21, Philip Trueman, TXiKiBoT, Philaweb, Fxhomie, Clarince63, Ownthink, Smb1138, Anarchangel, Falcon8765, Living under a rock, Caltas, Psilonautika, Sokari, Soporaeternus, Sfan00 IMG, Tmtung, ClueBot, The Thing That
Should Not Be, Drmies, PixelBot, John Nevard, Coinmanj, Lnelsonmd, Buckethed, XLinkBot, Psych0-007, Richard-of-Earth, WikiDao, MystBot, Addbot, Alex.mccarthy, MartinezMD, Debresser, Favonian, Exor674, 5 albert square, Tide rolls, Teles, MuZemike, Hartz,
Hxck, Luckas-bot, Yobot, Preppysob99, Guy1890, AnomieBOT, Metalhead94, Gtz, MovieImage, Csigabi, GB fan, ArthurBot, LilHelpa,
Ryanjca, NFD9001, Tyrol5, Mlpearc, Ragityman, User931, GrouchoBot, Clark candace, Jezhotwells, A45b22chp, Antitak, Epiftw, Shadowjams, FrescoBot, Wikicool11, Mu Mind, Moloch09, Ttg53, Louperibot, Nirmos, SpacemanSpi, Pinethicket, Elockid, HRoestBot,
Calmer Waters, MastiBot, Theodore.Miller3, Tim1357, PiRSquared17, Tolvic, Benbullen, David Hedlund, Reaper Eternal, Seahorseruler,
Diannaa, Phunlee, Fastilysock, Tbhotch, Tzores, RjwilmsiBot, Bento00, Surentity, DASHBot, WikitanvirBot, Nuujinn, Asred, Psychonaut2010, Minimacs Clone, RenamedUser01302013, Tisane, Tommy2010, White Trillium, GreatSuccess101, OregonIronCo, Elektrik
Shoos, AcidBurn211, Bxj, BGinOC, WickedSpice, Wayne Slam, Glennconti, Astara85, Voxcarnage, Norsci, KazekageTR, L Kensington, Mr. SpiceMan, Deathwishh, Akakeillo34, Lgarcia024, Killerprey23, Dominic Ragbottom, Joshgolf81, Sailsbystars, Tobeprecise,
DeirdreNocturne, Limelitespice, Orange Suede Sofa, Stacks19, Keeper0fdahoes, Lagato123, Marioja1, Joey kandewit, Bentway, EdoBot,
Quagamee, AJ12Gamer, E. Fokker, Teaktl17, Redpanda44, ClueBot NG, SpikeTorontoRCP, Munda8163, Bkane16, AznBurger, Mr.
Berty, Dchrguy, Kylesnage, Names are hard to think of, Helpful Pixie Bot, BG19bot, Oliveralbq, Justthinking25, Thirdeye616, Bodhisvaha5, BattyBot, Dereistic, BaeyerDrewson, ComfyKem, Yo222, Schenka, Exesop, Anrnusna, Monkbot, Medgirl131, Amanda Smalls and
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ADBICA Source: http://en.wikipedia.org/wiki/ADBICA?oldid=595202165 Contributors: Meodipt, Yosefxp, Anypodetos, AnomieBOT,
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Enix150, SamChem7, Addbot, C6541, CheMoBot, Lapuchca, BogBot, Yunshui, Dcirovic, Skoot13, Shisha-Tom, Monkbot and Anonymous: 1
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Beetstra, Meodipt, Enix150, CheMoBot, , BogBot, Addihockey10 (automated) and Monkbot
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Panoramix303, CheMoBot, , BogBot, Skoot13 and Anonymous: 1
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Chemgirl131, CheMoBot, , Citation bot 1, Nirmos, Tea with toast, BogBot, RjwilmsiBot and PotatoBot
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Rjwilmsi, Edgar181, Beetstra, CheMoBot, Citation bot, Tea with toast, The chemistds and Skoot13
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bot, Trappist the monk, BG19bot, BattyBot, Kjkokesh, Anne Delong, Sanganik, HasteurBot, Monkbot, Medgirl131 and Anonymous: 2
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CheMoBot, Hazard-SJ, The chemistds and Monkbot
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Meodipt, ChemNerd, Enix150, Addbot, CheMoBot, Citation bot, , Citation bot 1, BogBot, Dcirovic, MikeyMouse10, The
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SmackBot, Edgar181, Jon513, Chrylis, Beetstra, VolkovBot, MenasimBot, Benrr101, Chem-awb, Mild Bill Hiccup, Plasmic Physics,
Addbot, LaaknorBot, CheMoBot, Metalhead94, Citation bot, , Custoo, A8UDI, RjwilmsiBot, EmausBot, Dcirovic, The
chemistds, Louisajb, Nikos 1993, NotWith, Oneultralamewhiteboy and Anonymous: 1
Cannabicyclohexanol Source: http://en.wikipedia.org/wiki/Cannabicyclohexanol?oldid=618475852 Contributors: Rich Farmbrough,
EncMstr, Meodipt, Bobber0001, Boing! said Zebedee, Addbot, MartinezMD, CheMoBot, Biker Biker, BogBot, Dcirovic, ZroBot, The
chemistds, ClueBot NG, Diogenes2000, Skoot13, Robcrowl, Nikos 1993, Veried72, Monkbot, Medgirl131 and Anonymous: 4
Cannabicyclol Source: http://en.wikipedia.org/wiki/Cannabicyclol?oldid=562446736 Contributors: Cheyinka, JIP, Pumeleon, Pegship,
SmackBot, Edgar181, Beetstra, Leyo, Secretservgy, Panoramix303, Chemgirl131, Addbot, Mai-tai-guy, CheMoBot, Anypodetos,
, BenzolBot, Mcrosenstein, BogBot, Nikos 1993 and Anonymous: 5
333
Cannabidiol Source: http://en.wikipedia.org/wiki/Cannabidiol?oldid=630847328 Contributors: Bryan Derksen, MadSurgeon, Andrevan,

Selket, Phil Boswell, Robbot, St3vo, Vanished user 1234567890, Ary29, Alexrexpvt, Rich Farmbrough, Cacycle, Zaslav, Kwamikagami,
Causa sui, Tgeller, Renice, Viriditas, Eric Kvaalen, Benjah-bmm27, Howrealisreal, Thoric, Animated Cascade, Ceyockey, Lofor, Rjwilmsi,
Heah, FlaBot, A scientist, Margosbot, SouthernNights, Shao, Physchim62, WriterHound, ThunderPeel2001, Nick, Revaaron, ASmartKid,
SmackBot, Alex Ex, Ohnoitsjamie, HartzR, Elixir0219, Zachorious, Frantik, Ioscius, BullRangifer, Drphilharmonic, DMacks, Acdx,
Fireemblem555, Gobonobo, Ckatz, Smith609, Beetstra, SandyGeorgia, DeLarge, MessedRobot, ShelfSkewed, Meodipt, Linuxrocks123,
Cydebot, Supposed, Mrt50, DumbBOT, Alaibot, Thijs!bot, CopperKettle, Subvertc, Headbomb, Nashmaximus, SummerPhD, Smartse,
18hands, Badgerbear, NLuchs, Noobeditor, Cadsuane Melaidhrin, ChemNerd, Fconaway, Enix150, Funandtrvl, Meiskam, Sergivs-en,
MenasimBot, Wikieditor12, Benrr101, LetTheSunshineIn, Cheryladay, Gamesguru2, Vvevo, Yintan, Alexbrn, Danelo, Eplebel, Literaturegeek, Leodmacleod, Panoramix303, Chemgirl131, Dthomsen8, Addbot, C6541, DOI bot, Hermgenes Teixeira Pinto Filho, SamatBot,
Pigoutultra, Lightbot, Yobot, CheMoBot, Anypodetos, AnomieBOT, Gtz, Royote, Jtmorgan, Citation bot, LilHelpa, Zad68,
, Harbinary, O0Alea0o, P-kun80, Custoo, Citation bot 1, Nirmos, DrM!KEY, A8UDI, Codwiki, Sucrase, Tea with toast, Oldmaneinstein, BogBot, David Hedlund, Gtziavelis, Reach Out to the Truth, RjwilmsiBot, Dustin 3choes, Kermonger, Dcirovic, AManWithNoPlan,
Eagleye54321, Allethrin, Ehsan soltani, Bayhemp, Rachman321, Louisajb, ClueBot NG, Vjiced, BakuninGoldmanKropotkin, Osterluzei,
Soleil mouse, TeXnocrat, Redmitrow, Shabadahabada, Eeroth, Helpful Pixie Bot, Badmusician, BG19bot, Petrarchan47, Nikos 1993,
Exercisephys, MrBill3, NotWith, 123957a, Fuse809, BattyBot, TheBaur, ChrisGualtieri, Qxukhgiels, FoCuSandLeArN, Webclient101,
Will Sandberg, Steinsplitter, UseTheCommandLine, ComfyKem, ScoutKnot, Youtalkfunny, Tentinator, ArmbrustBot, Mer, Tired canadian, Tankbank420, Dave Underbridge, HeyItsAedan, JaconaFrere, Zouloum, MissSpade602, Logan Lynn Roberts, C.o.young, Monkbot,
Mattdavid22, Silent Singularitarian, Wendywhatnot, Daveyboy9999, Jakens84, JackDemarco 420, Medgirl131, Tristonlarsen, Rowanbiggs,
Aethyta, Shirt0ripper0, DystoniaPatient and Anonymous: 156
Cannabidivarin Source: http://en.wikipedia.org/wiki/Cannabidivarin?oldid=599332824 Contributors: RedWolf, Jorge Stol, Foobar, Cacycle, Ceyockey, PoccilScript, BD2412, Fred Bradstadt, FlaBot, Physchim62, Pegship, Frantik, Beetstra, Alaibot, Benrr101,
GeorgeLTirebiter, Panoramix303, DumZiBoT, Chemgirl131, Addbot, CheMoBot, Anypodetos, Casforty, , Nirmos,
MastiBot, BogBot, EmausBot, Davesynth, Nikos 1993, NotWith, BattyBot and Anonymous: 2
Cannabigerol Source: http://en.wikipedia.org/wiki/Cannabigerol?oldid=618473245 Contributors: Renice, Cheyinka, Rjwilmsi, Pegship,
Edgar181, Beetstra, ChemNerd, Benrr101, Secretservgy, Chem-awb, Panoramix303, Chemgirl131, Addbot, Tide rolls, CheMoBot, Anypodetos, Metalhead94, Citation bot, , Custoo, Nirmos, MastiBot, Tea with toast, BogBot, PotatoBot, Louisajb, MerlIwBot,
Nikos 1993, NotWith, Shisha-Tom, Sedind, Monkbot, Medgirl131 and Anonymous: 3
Cannabinoidergic Source: http://en.wikipedia.org/wiki/Cannabinoidergic?oldid=630539739 Contributors: Rjwilmsi, Bhny, Fram, Wilhelmina Will, Addbot, The Elves Of Dunsimore, Sunilaggarwal7, CitationCleanerBot, Monkbot and Medgirl131
Cannabinol Source: http://en.wikipedia.org/wiki/Cannabinol?oldid=618473196 Contributors: Robbot, Cacycle, Pacula, Howrealisreal,
Ceyockey, Rjwilmsi, FlaBot, Physchim62, Pegship, SmackBot, Eskimbot, Frymaster, Edgar181, Lieutenant Colonel Frank Slade, Beetstra,
Saxbryn, Cydebot, Rieman 82, Absentis, Alaibot, Subvertc, VolkovBot, MenasimBot, THC Loadee, Benrr101, Chem-awb, Anthonyvidal,
Eeekster, Panoramix303, Stevem848, Chemgirl131, Addbot, DOI bot, LaaknorBot, Wormantson, Luckas-bot, Ptbotgourou, Fraggle81,
CheMoBot, Anypodetos, Gtz, , P-kun80, Custoo, Micasta, Citation bot 1, A8UDI, RedBot, MastiBot, BogBot, PotatoBot,
Peryeat, Osterluzei, Jonfarrimond, Bemopa, Nikos 1993, NotWith, ArmbrustBot, MissSpade602, Monkbot, Sentaloc, Medgirl131 and
Anonymous: 15
Cannabivarin Source: http://en.wikipedia.org/wiki/Cannabivarin?oldid=599333620 Contributors: Jorge Stol, Cacycle, Aude, Ceyockey,
PoccilScript, BD2412, Fred Bradstadt, FlaBot, Physchim62, Pegship, Beetstra, Saxbryn, Alaibot, Benrr101, Chem-awb, Panoramix303,
Addbot, CheMoBot, Casforty, , FrescoBot, EmausBot, Dcirovic, HiW-Bot, Nikos 1993 and Anonymous: 1
Caryophyllene Source: http://en.wikipedia.org/wiki/Caryophyllene?oldid=622304553 Contributors: Mboverload, Rich Farmbrough,
Kwamikagami, Mendaliv, Rjwilmsi, WriterHound, Chris Capoccia, SmackBot, Edgar181, Sesquis, Mwtoews, DMacks, Beetstra, Timothykinney, Meodipt, Cydebot, Calvero JP, Deective, NEUROtiker, ChemNerd, Arsenal1508, TimofKingsland, Chem-awb, Sensonet,
Alexbot, Panoramix303, Addbot, DOI bot, Fothergill Volkensni IV, LaaknorBot, Luckas-bot, Yobot, CheMoBot, Citation bot, Xqbot,
, Itineranttrader, Andromeas, Custoo, FrescoBot, Citation bot 1, Sorneguer, EmausBot, Dcirovic, NotWith, Bcary, DarafshBot, Mogism, ArmbrustBot, Monkbot, RohdeN and Anonymous: 14
CB-13 Source: http://en.wikipedia.org/wiki/CB-13?oldid=590870232 Contributors: Meodipt, Enix150, Yobot, CheMoBot,
, BogBot, Hazard-SJ, BaeyerDrewson, Monkbot and Anonymous: 1
CBS-0550 Source: http://en.wikipedia.org/wiki/CBS-0550?oldid=570619983 Contributors: Meodipt, The chemistds and Skoot13
CP 47,497 Source: http://en.wikipedia.org/wiki/CP_47,497?oldid=610061328 Contributors: Cacycle, Alansohn, Poul818, Pegship, Cybercobra, Valenciano, Beetstra, Meodipt, Cydebot, Thijs!bot, Smartse, Enix150, Funandtrvl, TXiKiBoT, ClueBot, Addbot, C6541, MartinezMD, Ryanjca, , Custoo, DrilBot, Biker Biker, BogBot, Akerans, LoverOfTheWord, Louisajb, ClueBot NG, Skoot13,
Nikos 1993, Veried72, Woo 24, Monkbot and Anonymous: 26
CP 55,244 Source: http://en.wikipedia.org/wiki/CP_55,244?oldid=561022757 Contributors: Rjwilmsi, Pegship, Edgar181, Meodipt,
Rhadamante, Enix150, Funandtrvl, CheMoBot, , BogBot and Anonymous: 1
CP 55,940 Source: http://en.wikipedia.org/wiki/CP_55,940?oldid=618472345 Contributors: DropDeadGorgias, Ktotam, St3vo, Sam Hocevar, Cacycle, Flying Hamster, Ceyockey, Galaxiaad, Pol098, Rjwilmsi, Heah, Physchim62, Muijzo, Kajerm, SmackBot, GoldenXuniversity, Hmains, Tsca.bot, Simonster, Rory096, Saxbryn, Ccroberts, Meodipt, Cydebot, CDrecche, Alaibot, MattTweedell, Astavats, Floateruss, Tanevala, Enix150, Funandtrvl, Jonakimmen, Psych0-007, Wertyg, Modern Shaman, Addbot, C6541, Chempedia, AnomieBOT,
Citation bot, , Harbinary, Custoo, FrescoBot, BogBot, RjwilmsiBot, PotatoBot, Louisajb, Skoot13, Yukileoo, Delphine
Psychoyos, Medgirl131 and Anonymous: 27
Dexanabinol Source: http://en.wikipedia.org/wiki/Dexanabinol?oldid=602665690 Contributors: Drphilharmonic, Beetstra, Meodipt,
Rod57, Enix150, Panoramix303, Addbot, CheMoBot, Anypodetos, , Citation bot 1, HRoestBot, Tea with toast, BogBot, The chemistds, ClueBot NG, Skoot13, Monkbot, Madtay and Anonymous: 3
Dimethylheptylpyran Source: http://en.wikipedia.org/wiki/Dimethylheptylpyran?oldid=629287274 Contributors: Bkell, St3vo, GregorB,
Rjwilmsi, Pegship, Chris the speller, Beetstra, Meodipt, Astavats, Funandtrvl, Wikieditor12, Panoramix303, Chemgirl131, C6541,
CheMoBot, Anypodetos, Rifter0x0000, Metalhead94, Materialscientist, Citation bot, , Harbinary, BogBot, Lotje,
Dcirovic, K kisses, Daviesje, Nikos 1993, Testem, ChrisGualtieri, Medgirl131 and Anonymous: 7
334
Docosatetraenoylethanolamide Source: http://en.wikipedia.org/wiki/Docosatetraenoylethanolamide?oldid=479428373 Contributors:

Edgar181, Beetstra, Cydebot, CheMoBot, Citation bot, Erik9bot, Kpstewart, Citation bot 1, Tea with toast, The chemistds and Anonymous:
1
Drinabant Source: http://en.wikipedia.org/wiki/Drinabant?oldid=608365837 Contributors: Woohookitty, Rjwilmsi, Edgar181, Meodipt,
Chemgirl131, Yobot, A412 and Anonymous: 1
EAM-2201 Source: http://en.wikipedia.org/wiki/EAM-2201?oldid=602234811 Contributors: Dl2000, Meodipt, Magioladitis, Destruktor5000, D42kn355 and Anonymous: 3
Endocannabinoid reuptake inhibitor Source: http://en.wikipedia.org/wiki/Endocannabinoid_reuptake_inhibitor?oldid=630847750
Contributors: Firsfron, De728631, Mild Bill Hiccup, SchreiberBike, Custoo, Rideer13, AvicAWB, SaetaSolea, Beedublu, Jpgunner13,
Sbuinformation, Medgirl131 and Anonymous: 3
Endocannabinoid system Source: http://en.wikipedia.org/wiki/Endocannabinoid_system?oldid=630033669 Contributors: Nagelfar, Rich
Farmbrough, Lycurgus, Jpgordon, C4 Diesel, Rjwilmsi, Chris Capoccia, Tavilis, Trovatore, Pb30, Winter Light, Banus, SmackBot, Roadnottaken, Mini-Geek, Clicketyclack, Gobonobo, Kimdonndenman, Rhetth, Darthelmo, Inferiority, CopperKettle, Headbomb, Leon7, Nick
Number, MarshBot, Thibbs, Marcuj, Nono64, Boghog, Colincbn, Tanevala, Enix150, DragonBot, BDov777, ZuluPapa5, Wnt, DumZiBoT, Chemgirl131, Mjpresson, Ost316, Vojtch Dostl, Addbot, JayGSXR750, Yobot, Bunnyhop11, Jzlong, Wrightmj, AnomieBOT,
Materialscientist, Citation bot, Drilnoth, The myoclonic jerk, Lothar von Richthofen, Citation bot 1, I dream of horses, Tea with toast,
David Hedlund, Gtziavelis, Uploadvirus, Lucas Thoms, Jlb92, ClueBot NG, Vjiced, Osterluzei, SaetaSolea, Bibcode Bot, Snow Blizzard,
Glacialfox, Wyliea, BattyBot, Hoodjuice, Ramizein, Meteor sandwich yum, Monkbot, Medgirl131, Mrokiestar and Anonymous: 59
Endocannabinoid transporters Source: http://en.wikipedia.org/wiki/Endocannabinoid_transporters?oldid=625857200 Contributors:
Rjwilmsi, Wavelength, Vigyani, Yobot, Citation bot, Alvin Seville, GoingBatty, Sbuinformation, Anaen21, Medgirl131 and Anonymous:
1
GW-405,833 Source: http://en.wikipedia.org/wiki/GW-405,833?oldid=610061444 Contributors: Rjwilmsi, Drphilharmonic, Meodipt,
Cydebot, Enix150, Addbot, CheMoBot, , Harbinary, Custoo, BogBot, Dcirovic and Louisajb
GW-842,166X Source: http://en.wikipedia.org/wiki/GW-842,166X?oldid=591559628 Contributors: Meodipt, CheMoBot, BogBot, The
chemistds, Louisajb and Monkbot
Hemopressin Source: http://en.wikipedia.org/wiki/Hemopressin?oldid=619651829 Contributors: Kielsky, Arcadian, Rjwilmsi, Meodipt,
Boghog, Enix150, Ronhjones, CheMoBot, ScottMHoward, Jesse V., RjwilmsiBot, The chemistds, Monkbot, Medgirl131 and Anonymous:
5
HU-210 Source: http://en.wikipedia.org/wiki/HU-210?oldid=618472397 Contributors: Fnielsen, Rich Farmbrough, Cacycle, ZayZayEM,
SqueakBox, Heah, Margosbot, Physchim62, Fourdee, WriterHound, YurikBot, Gaius Cornelius, Daemon8666, Pegship, SmackBot,
C.Lser, GoldenXuniversity, Edgar181, Nuklear, Cybercobra, Drphilharmonic, Ourai, Beetstra, Ccroberts, CmdrObot, Meodipt, Alaibot,
Gharmon, Turkeyphant, Smartse, Homeier, ThinkBlue, Enix150, Funandtrvl, VolkovBot, Fences and windows, Altzinn, SPECVLVMSINCERVS, Panoramix303, Addbot, DOI bot, Tide rolls, Ale66, Luckas-bot, Yobot, CheMoBot, Metalhead94, Gtz, Codc,
, Harbinary, FrescoBot, StrawberryCube, Biker Biker, Snazzra, Calmer Waters, JKChandler, BogBot, Gould363, SalviaFan, Nuujinn,
RenamedUser01302013, Daviesje, Phenomenologyx, Louisajb, Doctorarcane, RealMortimir, Skoot13, SubDural12, Veried72, Hmainsbot1, Monkbot, Cbmacewan, Medgirl131 and Anonymous: 51
HU-243 Source: http://en.wikipedia.org/wiki/HU-243?oldid=536294331 Contributors: Meodipt
HU-308 Source: http://en.wikipedia.org/wiki/HU-308?oldid=610213643 Contributors: St3vo, Wimvandorst, FlaBot, Pegship, Nuklear,
Drphilharmonic, Beetstra, Meodipt, Cydebot, Enix150, Panoramix303, Addbot, C6541, CheMoBot, , Custoo, BogBot,
Dcirovic, JimJoiner and Anonymous: 2
HU-331 Source: http://en.wikipedia.org/wiki/HU-331?oldid=613064375 Contributors: BD2412, Drphilharmonic, Meodipt, R'n'B,
Enix150, SchreiberBike, Addbot, CheMoBot, Anypodetos, KamikazeBot, MALLUS, The chemistds, Skoot13, NotWith and ChrisGualtieri
11-Hydroxy-THC Source: http://en.wikipedia.org/wiki/11-Hydroxy-THC?oldid=620143359 Contributors: Yidele, Cacycle, Rjwilmsi,
Derek.cashman, Edgar181, Beetstra, Suboptimal Username, Meodipt, Isilanes, Equazcion, DorganBot, Danelo, Alexbot, Panoramix303,
MystBot, Addbot, Yobot, CheMoBot, KamikazeBot, Citation bot, , Harbinary, Citation bot 1, BogBot, Jynto, Medgirl131
and Anonymous: 3
9-nor-9-Hydroxyhexahydrocannabinol Source:
http://en.wikipedia.org/wiki/9-nor-9-Hydroxyhexahydrocannabinol?oldid=
517509498 Contributors: Rjwilmsi, Edgar181, Meodipt, Enix150, Yobot, Citation bot, , Skoot13 and Anonymous: 1
Ibipinabant Source: http://en.wikipedia.org/wiki/Ibipinabant?oldid=618474939 Contributors: Rjwilmsi, Pegship, SmackBot, Meodipt,
Enix150, Chemgirl131, CheMoBot, Anypodetos, Rjanag, Citation bot, , BogBot, Peryeat, The chemistds, Louisajb,
Pashihiko, Vaccinationist, Medgirl131 and Anonymous: 2
IDFP Source: http://en.wikipedia.org/wiki/IDFP?oldid=576656123 Contributors: Meodipt
2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4-nonylphenyl)cyclohex-1-ene
Source:
http://en.wikipedia.org/wiki/
Cacycle, Deyyaz, Peg2-Isopropyl-5-methyl-1-(2,6-dihydroxy-4-nonylphenyl)cyclohex-1-ene?oldid=545325142 Contributors:
ship, Edgar181, Meodipt, Nono64, Enix150, Addbot, CheMoBot, Citation bot, , Citation bot 1, BogBot, EmausBot and
Anonymous: 1
JTE 7-31 Source: http://en.wikipedia.org/wiki/JTE_7-31?oldid=546233677 Contributors: Meodipt, Enix150, Addbot, CheMoBot, RevelationDirect, Skoot13 and AvocatoBot
JTE-907 Source: http://en.wikipedia.org/wiki/JTE-907?oldid=606454861 Contributors: Rjwilmsi, Pegship, Drphilharmonic, Meodipt,
Smartse, Enix150, Addbot, CheMoBot, Citation bot, , Citation bot 1, BogBot, EmausBot, Skoot13, Stark1987, WildCation
and Anonymous: 1
JWH-015 Source: http://en.wikipedia.org/wiki/JWH-015?oldid=616440152 Contributors: Rjwilmsi, Pegship, Drphilharmonic, Meodipt,
Cydebot, Headbomb, Boghog, Enix150, Addbot, C6541, Queenmomcat, CheMoBot, Citation bot, , Lapuchca, Custoo,
Jonesey95, BogBot, Tisane, Dcirovic, Skoot13, Monkbot, WildCation and Anonymous: 3
JWH-051 Source: http://en.wikipedia.org/wiki/JWH-051?oldid=606457301 Contributors: Rjwilmsi, Pegship, Meodipt, Enix150,
CheMoBot, Citation bot, , Citation bot 1, BogBot, Tisane, WildCation and Anonymous: 1
335
JWH-057 Source: http://en.wikipedia.org/wiki/JWH-057?oldid=606458240 Contributors: Bgwhite, Meodipt, Magioladitis, AnomieBOT,

BaeyerDrewson and WildCation
JWH-120 Source: http://en.wikipedia.org/wiki/JWH-120?oldid=606478716 Contributors: Meodipt, BaeyerDrewson and WildCation
JWH-122 Source: http://en.wikipedia.org/wiki/JWH-122?oldid=560783506 Contributors: Bearcat, Edgar181, Beetstra, Meodipt,
Katharineamy, Enix150, Cvf-ps, Addbot, C6541, Yobot, CheMoBot, A412, Diogenes2000, Skoot13, Snotbot, JamietwBot and Anonymous: 2
JWH-133 Source: http://en.wikipedia.org/wiki/JWH-133?oldid=618472603 Contributors: St3vo, Arcadian, SmackBot, Zaphraud, Beetstra, Saxbryn, Ccroberts, CmdrObot, Meodipt, Cydebot, NewEnglandYankee, Tanevala, Enix150, Altzinn, Addbot, CheMoBot,
, Harbinary, Anonabyss, Custoo, BogBot, Tisane, Dcirovic, Frozen Wind, Rich Smith, Managermerrill, AwamerT, Drblizz,
JWH-148 Source: http://en.wikipedia.org/wiki/JWH-148?oldid=606481972 Contributors: Meodipt, BaeyerDrewson and WildCation
JWH-149 Source: http://en.wikipedia.org/wiki/JWH-149?oldid=606483315 Contributors: Meodipt, C6541, BaeyerDrewson and WildCation
JWH-161 Source: http://en.wikipedia.org/wiki/JWH-161?oldid=606483553 Contributors: Rjwilmsi, Edgar181, Meodipt, Enix150,
CheMoBot, , FrescoBot, BogBot and WildCation
JWH-176 Source: http://en.wikipedia.org/wiki/JWH-176?oldid=606485810 Contributors: Pegship, Meodipt, Enix150, CheMoBot,
, BogBot, Tisane, Deathhell77 and WildCation
JWH-359 Source: http://en.wikipedia.org/wiki/JWH-359?oldid=502194790 Contributors: Rjwilmsi, Nuklear, Meodipt, Headbomb,
Nono64, Enix150, CheMoBot, Grim23, , FrescoBot, BogBot, Tisane, Rich Smith, Managermerrill and Anonymous:
4
JZL184 Source: http://en.wikipedia.org/wiki/JZL184?oldid=591975737 Contributors: Wimvandorst, Roadnottaken, Beetstra, Meodipt,
Enix150, Chem-awb, Addbot, CheMoBot, Anypodetos, Jzlong, , P-kun80, Citation bot 1, Nirmos, EmausBot, PotatoBot,
Monkbot and Anonymous: 3
JZL195 Source: http://en.wikipedia.org/wiki/JZL195?oldid=546258079 Contributors: Enix150, Addbot, The Blade of the Northern Lights
and Rezabot
KM-233 Source: http://en.wikipedia.org/wiki/KM-233?oldid=624180345 Contributors: BD2412, Meodipt, Dthomsen8, Yobot, Skoot13
and WildCation
L-759,633 Source: http://en.wikipedia.org/wiki/L-759,633?oldid=610061479 Contributors: Rjwilmsi, Pegship, Drphilharmonic, Meodipt,
Cydebot, Enix150, Addbot, CheMoBot, Citation bot, , Custoo, Citation bot 1, BogBot, Dcirovic, Louisajb and Shisha-Tom
L-759,656 Source: http://en.wikipedia.org/wiki/L-759,656?oldid=545322433 Contributors: Pegship, Nuklear, Drphilharmonic, Meodipt,
Enix150, ClueBot, Addbot, CheMoBot, , BogBot, Dcirovic, Louisajb and Anonymous: 1
LASSBio-881 Source: http://en.wikipedia.org/wiki/LASSBio-881?oldid=489676335 Contributors: Meodipt
LBP-1 (drug) Source: http://en.wikipedia.org/wiki/LBP-1_(drug)?oldid=587855670 Contributors: Meodipt, Hazard-SJ and ChrisGualtieri
Leelamine Source: http://en.wikipedia.org/wiki/Leelamine?oldid=618475826 Contributors: Magioladitis, Eeekster, Sekio and Medgirl131
Levonantradol Source: http://en.wikipedia.org/wiki/Levonantradol?oldid=618472637 Contributors: Howrealisreal, Wouterstomp,
Rjwilmsi, FlaBot, Pegship, Edgar181, Beetstra, Meodipt, Cydebot, Enix150, Funandtrvl, Sam Blacketer, Addbot, CheMoBot, Anypodetos,
, Harbinary, Custoo, BogBot, ZroBot, Peryeat, Skoot13, BattyBot, Najenager, Monkbot, Medgirl131 and Anonymous:
1
List of AM cannabinoids Source: http://en.wikipedia.org/wiki/List_of_AM_cannabinoids?oldid=604703358 Contributors: Bearcat,
Chris the speller, Meodipt, Enix150, Citation bot, BattyBot, Monkbot and Anonymous: 5
List of JWH cannabinoids Source: http://en.wikipedia.org/wiki/List_of_JWH_cannabinoids?oldid=607385076 Contributors: Rjwilmsi,
Meodipt, Uruiamme, Enix150, The Thing That Should Not Be, Ironholds, Quebec99, RjwilmsiBot, Tisane, 4321acb, BG19bot, BaeyerDrewson and Anonymous: 3
LY-2183240 Source: http://en.wikipedia.org/wiki/LY-2183240?oldid=630847383 Contributors: Meodipt, Addbot, Rezabot, Fylbecatulous, WildCation, Medgirl131 and Anonymous: 3
LY-320,135 Source: http://en.wikipedia.org/wiki/LY-320,135?oldid=525861108 Contributors: Pegship, Meodipt, RXPhd, Yobot,
CheMoBot, , BogBot and Anonymous: 1
MAM-2201 Source: http://en.wikipedia.org/wiki/MAM-2201?oldid=615014022 Contributors: Dl2000, Meodipt, C6541, AnomieBOT,
Harbinary and WildCation
MDA-19 Source: http://en.wikipedia.org/wiki/MDA-19?oldid=517576564 Contributors: Drphilharmonic, Beetstra, Meodipt, CheMoBot
and Skoot13
Menabitan Source: http://en.wikipedia.org/wiki/Menabitan?oldid=621328559 Contributors: Rjwilmsi, Edgar181, Meodipt, Chemgirl131,
Anypodetos, Braincricket, Monkbot and Medgirl131
Methanandamide Source: http://en.wikipedia.org/wiki/Methanandamide?oldid=544106189 Contributors: Bearcat, St3vo, Wimvandorst,
Stemonitis, Rjwilmsi, SmackBot, Edgar181, Bluebot, Beetstra, Cytocon, Waacstats, STBot, Nono64, Enix150, Plasmic Physics, Addbot,
CheMoBot, Anypodetos, Citation bot, , Erik9bot, Tea with toast, Skoot13, Amolbot and Anonymous: 4
MK-9470 Source: http://en.wikipedia.org/wiki/MK-9470?oldid=612370825 Contributors: Rjwilmsi, Pegship, Edgar181, DMacks, CmdrObot, Meodipt, MSBOT, Boghog, Chem-awb, Addbot, CheMoBot, Citation bot, , Citation bot 1, RedBot, Dcirovic and
WildCation
N-(S)-Fenchyl-1-(2-morpholinoethyl)7-methoxyindole-3-carboxamide
Source:
http://en.wikipedia.org/wiki/N-(S)
Edgar181, A5b, Meodipt,
-Fenchyl-1-(2-morpholinoethyl)$-$7-methoxyindole-3-carboxamide?oldid=592608780 Contributors:
Smartse, Ben MacDui, Enix150, Denisarona, Addbot, CheMoBot, AnomieBOT, Citation bot, Xqbot, SDPatrolBot, Dcirovic, The
chemistds, Skoot13, ScottSteiner, Vasiliy 100, Vasiliy 101, ChrisGualtieri, Monkbot and Anonymous: 1
336
Nabazenil Source: http://en.wikipedia.org/wiki/Nabazenil?oldid=628470027 Contributors: Meodipt, ChemNerd, CheMoBot,

, BogBot, Peryeat, Helpful Pixie Bot, WildCation and Medgirl131
Nabilone Source: http://en.wikipedia.org/wiki/Nabilone?oldid=627639158 Contributors: Selket, IceKarma, St3vo, Cacycle, Arcadian,
Kjkolb, E=MC^2, Rad Racer, Rjwilmsi, Heah, FlaBot, Ground Zero, Kerowyn, Bgwhite, Asacarny, Pegship, JRey, Andrew73, SmackBot,
Edgar181, Zachorious, Cybercobra, Beetstra, CmdrObot, Meodipt, Guitarmankev1, Anthonyhcole, Alaibot, Tins128, Amontgomery, Gwern, AliaGemma, ChemNerd, Gojo002, Floateruss, Enix150, Funandtrvl, McM.bot, Dr.michael.benjamin, Flyer22, Alexbrn, Atdavies,
Mlas, Zhile, Dr. Anymouse, Chemgirl131, Addbot, DOI bot, Earthguy69, Yobot, CheMoBot, Yngvadottir, AnomieBOT, Metalhead94,
Citation bot, J, , Harbinary, Apteekkarin poika, Citation bot 1, Tea with toast, BogBot, RjwilmsiBot, ZroBot, Peteb4,
Louisajb, ClueBot NG, Skoot13, Petrarchan47, PhnomPencil, Scopolaminemethylnitrate, Fuse809, Crocodile100100, Monkbot, Medgirl131, SP1977 and Anonymous: 27
Nabitan Source: http://en.wikipedia.org/wiki/Nabitan?oldid=618475710 Contributors: St3vo, Pegship, Edgar181, Beetstra, Meodipt, Leftfoot69, Funandtrvl, Addbot, Yobot, CheMoBot, Anypodetos, , BogBot, Snubcube, NotWith and Medgirl131
Nabiximols Source: http://en.wikipedia.org/wiki/Nabiximols?oldid=625135113 Contributors: Pfrishauf, Arm, Jfdwol, Trevor MacInnis,
Tribble, Pacula, Eleland, Oasisbob, GJeery, SidP, Galaxiaad, Urod, Tokek, SqueakBox, Vegaswikian, Aspro, WriterHound, YurikBot,
Shalmoo, Andrew73, Anarchist42, Poldavo, Uthbrian, Cybercobra, Beetstra, L'uf, Yaris678, Anthonyhcole, Psilocin, Path2k6, DB1986,
Jamieliz, McM.bot, Martha p, VVVBot, Fibo1123581321, Toddst1, Dala11a, Denisarona, Morton12, Maxxx55, Mjpresson, Addbot,
C6541, DOI bot, Armyyo, Luckas-bot, Yobot, CheMoBot, Anypodetos, GrouchoBot, Fuz2y, Dpf90, The myoclonic jerk, RedBot, Tea
with toast, EmausBot, ZroBot, Norsci, Satellizer, Vjiced, TheNoBrainer, Fuse809, Ellomo, Sedind, Medgirl131 and Anonymous: 49
Naboctate Source: http://en.wikipedia.org/wiki/Naboctate?oldid=618475582 Contributors: Meodipt, Kupirijo, ChemNerd, CheMoBot,
, BogBot, Peryeat, Helpful Pixie Bot and Medgirl131
NESS-0327 Source: http://en.wikipedia.org/wiki/NESS-0327?oldid=557658516 Contributors: Pegship, SmackBot, Edgar181, Meodipt,
Tanevala, Enix150, Yobot, CheMoBot, Rjanag, and BogBot
NESS-040C5 Source: http://en.wikipedia.org/wiki/NESS-040C5?oldid=581293179 Contributors: Meodipt and Mrbenzhao
NMP-7 Source: http://en.wikipedia.org/wiki/NMP-7?oldid=574549912 Contributors: Meodipt and The chemistds
Nonabine Source: http://en.wikipedia.org/wiki/Nonabine?oldid=618472034 Contributors: Wimvandorst, Pegship, Edgar181, Beetstra,
Meodipt, CheMoBot, Anypodetos, , BogBot, PotatoBot, Peryeat, NotWith, Medgirl131 and Anonymous: 1
11-nor-9-Carboxy-THC Source: http://en.wikipedia.org/wiki/11-nor-9-Carboxy-THC?oldid=626249075 Contributors: Cacycle,
Rjwilmsi, Edgar181, Beetstra, Meodipt, ChemNerd, Bobber0001, Addbot, Luckas-bot, Legobot II, CheMoBot, Citation bot,
, Harbinary, Custoo, Citation bot 1, A8UDI, BogBot, 564dude, Jynto, EmausBot, Shisha-Tom, Igramudi, Medgirl131 and Anonymous: 10
O-1057 Source: http://en.wikipedia.org/wiki/O-1057?oldid=608378294 Contributors: Pegship, Closedmouth, Meodipt, Enix150,
Panoramix303, CheMoBot, , BogBot, Gunnanmon, Skoot13 and WildCation
O-1125 Source: http://en.wikipedia.org/wiki/O-1125?oldid=608380315 Contributors: Rjwilmsi, Pegship, Meodipt, Enix150, CheMoBot,
, BogBot and WildCation
O-1238 Source: http://en.wikipedia.org/wiki/O-1238?oldid=513487985 Contributors: Shoey, Rjwilmsi, Pegship, Meodipt, Enix150,
CheMoBot, , BogBot and Shisha-Tom
O-1269 Source: http://en.wikipedia.org/wiki/O-1269?oldid=538765444 Contributors: Meodipt
O-1812 Source: http://en.wikipedia.org/wiki/O-1812?oldid=607130796 Contributors: Drphilharmonic, Meodipt, Enix150, Plasmic
Physics, CheMoBot, BogBot, Skoot13 and Monkbot
O-2113 Source: http://en.wikipedia.org/wiki/O-2113?oldid=517511788 Contributors: Meodipt, The chemistds and Skoot13
O-2372 Source: http://en.wikipedia.org/wiki/O-2372?oldid=591901705 Contributors: Edgar181, Drphilharmonic, Meodipt, Enix150,
CheMoBot, BogBot, Skoot13 and Anonymous: 1
O-2545 Source: http://en.wikipedia.org/wiki/O-2545?oldid=517511924 Contributors: Pegship, Meodipt, Enix150, CheMoBot,
, BogBot, Gunnanmon, Skoot13 and Anonymous: 3
O-2694 Source: http://en.wikipedia.org/wiki/O-2694?oldid=517511601 Contributors: Pegship, Drphilharmonic, Meodipt, Enix150,
CheMoBot, , BogBot and Skoot13
O-774 Source: http://en.wikipedia.org/wiki/O-774?oldid=607131131 Contributors: Meodipt, Enix150, Anypodetos, The chemistds and
Skoot13
O-806 Source: http://en.wikipedia.org/wiki/O-806?oldid=448105477 Contributors: Pegship, Nuklear, Meodipt, Marek69, Enix150,
CheMoBot, , BogBot and The chemistds
O-823 Source: http://en.wikipedia.org/wiki/O-823?oldid=513577948 Contributors: Rjwilmsi, Pegship, Meodipt, Enix150, CheMoBot,
, BogBot, The chemistds and Shisha-Tom
Org 27569 Source: http://en.wikipedia.org/wiki/Org_27569?oldid=592717766 Contributors: Meodipt, Addbot, CheMoBot, BogBot,
Dcirovic, The chemistds and Monkbot
Org 28312 Source: http://en.wikipedia.org/wiki/Org_28312?oldid=592716560 Contributors: Beetstra, Meodipt, Enix150, CheMoBot,
BogBot, The chemistds and Monkbot
Org 28611 Source: http://en.wikipedia.org/wiki/Org_28611?oldid=592716578 Contributors: Beetstra, Meodipt, Enix150, CheMoBot,
BogBot, The chemistds and Monkbot
337
Otenabant Source: http://en.wikipedia.org/wiki/Otenabant?oldid=618474885 Contributors: Pegship, SmackBot, Meodipt, Chemgirl131,

CheMoBot, Anypodetos, Rjanag, , Harbinary, Custoo, Citation bot 1, Jonesey95, BogBot, RjwilmsiBot, Peryeat, Louisajb,
Pashihiko, Skoot13, WildCation and Medgirl131
Parahexyl Source: http://en.wikipedia.org/wiki/Parahexyl?oldid=618474777 Contributors: SqueakBox, Pegship, Beetstra, Meodipt, JaGa,
Funandtrvl, Panoramix303, DumZiBoT, Addbot, DOI bot, CheMoBot, Anypodetos, Citation bot, , BogBot, Nikos 1993,
UR-144 Source: http://en.wikipedia.org/wiki/UR-144?oldid=627620534 Contributors: Discospinster, Wainblatrobert, MZMcBride, Vegaswikian, Edgar181, Myxsoma, Beetstra, Meodipt, Smartse, JamesBWatson, ChemNerd, Boghog, Reedy Bot, Enix150, Yikrazuul, Carriearchdale, C6541, Download, CheMoBot, AnomieBOT, SDPatrolBot, AManWithNoPlan, ClueBot NG, Skoot13, Frietjes, O.Koslowski,
Ieponumos, Dipankan001, Vasiliy 100, Stark1987, ChrisGualtieri, BaeyerDrewson, Luxemoxie, Yougotwarsh, Rebrewind, Monkbot, Rusty
Lugnuts and Anonymous: 22
Perrottetinene Source: http://en.wikipedia.org/wiki/Perrottetinene?oldid=518915209 Contributors: Meodipt, Benrr101, CheMoBot,
Anypodetos, , BogBot and Anonymous: 2
PF-03550096 Source: http://en.wikipedia.org/wiki/PF-03550096?oldid=618824275 Contributors: Meodipt, FreddysFun and WildCation
PF-514273 Source: http://en.wikipedia.org/wiki/PF-514273?oldid=583222914 Contributors: Meodipt, Anypodetos and The chemistds
PipISB Source: http://en.wikipedia.org/wiki/PipISB?oldid=538846629 Contributors: Meodipt
Pirnabine Source: http://en.wikipedia.org/wiki/Pirnabine?oldid=618818792 Contributors: Beetstra, Meodipt, CheMoBot,
, BogBot, WildCation and Medgirl131
PSB-SB-1202 Source: http://en.wikipedia.org/wiki/PSB-SB-1202?oldid=575732178 Contributors: Meodipt, Fraggle81 and Mrbenzhao
PSB-SB-487 Source: http://en.wikipedia.org/wiki/PSB-SB-487?oldid=557656947 Contributors: Meodipt
QUCHIC Source: http://en.wikipedia.org/wiki/QUCHIC?oldid=617182468 Contributors: Meodipt, Yobot, SciRambar, The chemistds,
BaeyerDrewson, Yougotwarsh and Anonymous: 7
QUPIC Source: http://en.wikipedia.org/wiki/QUPIC?oldid=619859946 Contributors: Velella, Rjwilmsi, Meodipt, Enix150, Earcanal,
Yobot, AnomieBOT, SciRambar, AManWithNoPlan, The chemistds, BG19bot, BaeyerDrewson, Dr J.Rozen, Yougotwarsh and Anonymous: 12
Rimonabant Source: http://en.wikipedia.org/wiki/Rimonabant?oldid=628033220 Contributors: Kpjas, MadSurgeon, David spector, Tpbradbury, Francs2000, Schutz, ZimZalaBim, Obli, Fjarlq, St3vo, Geni, BozMo, Beland, Nowster, M1ss1ontomars2k4, Monkeyman,
Rich Farmbrough, Cacycle, Peak Freak, Jtact, Remuel, Arcadian, Pacula, Wouterstomp, Malo, Versageek, Siafu, Scjessey, Eras-mus,
SDC, Rjwilmsi, Darguz Parsilvan, Miserlou, Margosbot, Stevenfruitsmaak, Hydrargyrum, Janke, Semperf, Syldaril, Smaines, Yonidebest,
Bdell555, Zzuuzz, Closedmouth, Colin, Kajerm, Jereymcmanus, SmackBot, Edgar181, Gilliam, Amatulic, Deli nk, Cormagh, JanesDaddy, Oltsw, KaiserbBot, Roadnottaken, JonHarder, Apexprim8, JHeuser, Cybercobra, Drphilharmonic, Lobster101, Simonster, Beetstra, Bwalters, Az1568, Linkspamremover, Fvasconcellos, DoctorFuQang, Cytocon, DrPiotroski, Give Peace A Chance, Ward3001,
Thijs!bot, Sacxnz, Adjespers, Link Spam Remover, Mcscmd, AntiVandalBot, Yupik, Dextrovert, Joo Carvalho, Postlewaight, Astavats, Kgbveg, Rkwwkr, Krunalc, It2media, DietGurl, .anacondabot, OM, MaxPont, Jackboogie, Mtiany71, Crazy-Chemist, Rettetast, Kkeane, Boghog, Mikael Hggstrm, Tanevala, Enix150, Danbearsea, TXiKiBoT, Celtus, Mikeaubert, GPryce, Nadsozinc, Eve
Teschlemacher, Poterala, Oreiser, Le feu, Vcare, Lightmouse, Phillymutt, Sabne, Rimonabant, Sisalgs, ClueBot, Schaea, Osm agha, Carlo
Banez, Panoramix303, Pharmankur, BlackHoleSon, DumZiBoT, Chemgirl131, Gazimo, Addbot, DOI bot, SpBot, Shankkark, Nizil
Shah, TALKO, CheMoBot, Anypodetos, AnomieBOT, Casforty, Rjanag, LilHelpa, Dagrun, Gigemag76, , Custoo, Citation bot 1, Teenmd, Tea with toast, BogBot, David Hedlund, Peacedance, RjwilmsiBot, Yid, Dcirovic, ZroBot, H3llBot, Timetraveler3.14,
Peryeat, Skoot13, BG19bot, BattyBot, Vaccinationist, Monkbot, Medgirl131 and Anonymous: 108
Rosonabant Source: http://en.wikipedia.org/wiki/Rosonabant?oldid=618474987 Contributors: Rjwilmsi, Edgar181, Chemgirl131, Anypodetos, BG19bot, Monkbot and Medgirl131
S-444,823 Source: http://en.wikipedia.org/wiki/S-444,823?oldid=628622349 Contributors: Meodipt, Skoot13 and WildCation
SDB-001 Source: http://en.wikipedia.org/wiki/SDB-001?oldid=557806974 Contributors: Meodipt, Magioladitis, C6541, BaeyerDrewson
and Anonymous: 2
SDB-006 Source: http://en.wikipedia.org/wiki/SDB-006?oldid=585445393 Contributors: Meodipt, BaeyerDrewson, Mrbenzhao and
Anonymous: 2
SER-601 Source: http://en.wikipedia.org/wiki/SER-601?oldid=607679714 Contributors: Beetstra, Meodipt, Enix150, Davecrosby uk,
CheMoBot, BogBot, The chemistds, Skoot13, Monkbot and Anonymous: 1
Serinolamide A Source: http://en.wikipedia.org/wiki/Serinolamide_A?oldid=579444765 Contributors: Edgar181, Meodipt, John of
Reading and RichardsonsRSC
SR-144,528 Source: http://en.wikipedia.org/wiki/SR-144,528?oldid=618472544 Contributors: Rjwilmsi, Drphilharmonic, Meodipt,
Enix150, Addbot, CheMoBot, BogBot, Dcirovic, Louisajb, Skoot13, Monkbot and Medgirl131
Stearoylethanolamide Source: http://en.wikipedia.org/wiki/Stearoylethanolamide?oldid=630989213 Contributors: Bearcat, Malcolma,
Jatlas and Medgirl131
STS-135 (drug) Source: http://en.wikipedia.org/wiki/STS-135_(drug)?oldid=628883259 Contributors: Edgar181, Meodipt, Jim1138,
SciRambar, BaeyerDrewson, Yougotwarsh and Anonymous: 3
Surinabant Source: http://en.wikipedia.org/wiki/Surinabant?oldid=618475012 Contributors: Edward, St3vo, Pegship, Beetstra, Meodipt,
R'n'B, Enix150, Carlo Banez, Chemgirl131, CheMoBot, Anypodetos, Rjanag, Dagrun, , BogBot, PotatoBot, Peryeat,
ChrisGualtieri and Medgirl131
Taranabant Source: http://en.wikipedia.org/wiki/Taranabant?oldid=618475039 Contributors: St3vo, Woohookitty, OrphanBot, Meodipt,
Magioladitis, ChemNerd, Enix150, Kizly, Carlo Banez, Panoramix303, Chemgirl131, Yobot, CheMoBot, Rjanag, Dagrun,
, P-kun80, BogBot, PotatoBot, Peryeat, Monkbot, Medgirl131 and Anonymous: 2
Tedalinab Source: http://en.wikipedia.org/wiki/Tedalinab?oldid=491266810 Contributors: Meodipt
338
Tetrad test Source: http://en.wikipedia.org/wiki/Tetrad_test?oldid=443471240 Contributors: Chick Bowen, Roadnottaken, Jzlong, AloysiusLiliusBot, Aaron Kauppi and Anonymous: 1
Tetrahydrocannabinol Source: http://en.wikipedia.org/wiki/Tetrahydrocannabinol?oldid=630780019 Contributors: Damian Yerrick, AxelBoldt, Kpjas, Bryan Derksen, The Anome, Tarquin, Malcolm Farmer, SimonP, Pit, Gabbe, Chinju, Paul A, MichaelJanich, Mkweise,
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Andycjp, Geus, Sonjaaa, Ferre, Antandrus, HistoryBA, AlexanderWinston, OwenBlacker, Gene s, Bk0, Rlcantwell, Joyous!, Mearlon,
Gerrit, Tonik, Idolcrash, Lynto008, Adashiel, Porges, Stevenmattern, Discospinster, Rich Farmbrough, Guanabot, Cacycle, Pie4all88,
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von Richthofen, StaticVision, Vishnu2011, Ryan.rota, La able, Citation bot 1, Izzardthegizzard, Pinethicket, Jrew86, A8UDI, Jschnur,
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Snow Blizzard, NotWith, Zujua, Wyliea, Zmbonvallat, Fuse809, TheBaur, LegacyWeapon, Indirectantagonist, EuroCarGT, 14jay69,
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Formerly 98, A915, Joshuabumbarger, Santavy2014, JoPhoenix, Fuzznerdees, Medgirl131, Amc98, GP10698 and Anonymous: 949
Tetrahydrocannabinol-C4 Source: http://en.wikipedia.org/wiki/Tetrahydrocannabinol-C4?oldid=618601612 Contributors: Cacycle, Natalya, BD2412, Pegship, Meodipt, Astavats, Benrr101, Mild Bill Hiccup, Phil Ian Manning, Chemgirl131, Yobot, CheMoBot,
, ZackRegit, BogBot, Nikos 1993, NotWith, Monkbot and Jakenowatzke
Tetrahydrocannabinolic acid Source: http://en.wikipedia.org/wiki/Tetrahydrocannabinolic_acid?oldid=614212282 Contributors:
Rjwilmsi, Meodipt, Wikieditor12, Benrr101, Gtz, Jim1138, Monkbot and Anonymous: 4
Tetrahydrocannabivarin Source: http://en.wikipedia.org/wiki/Tetrahydrocannabivarin?oldid=630568385 Contributors: William Avery,
St3vo, Rich Farmbrough, Cacycle, Ceyockey, Amire80, Fred Bradstadt, Physchim62, WriterHound, YurikBot, Gaius Cornelius, Pegship,
Edgar181, Naturalsol, Chris the speller, Fireemblem555, Smith609, Beetstra, Meodipt, Alaibot, Probios, VolkovBot, GeorgeLTirebiter,
Chem-awb, Panoramix303, Burner0718, Chemgirl131, MystBot, Addbot, DOI bot, Wormantson, CheMoBot, Casforty, Obersachsebot,
, Custoo, Citation bot 1, UFO Reporter, MastiBot, BogBot, CrowzRSA, Jynto, ClueBot NG, Nikos 1993, NotWith,
Sfgiants1995, Jakenowatzke, Medgirl131, Mplanine and Anonymous: 20
THC-O-acetate Source: http://en.wikipedia.org/wiki/THC-O-acetate?oldid=586788432 Contributors: Cacycle, Pegship, SmackBot,
Edgar181, Afasmit, Beetstra, Meodipt, JaGa, CheMoBot, , BogBot, Helpful Pixie Bot, ChrisGualtieri and Anonymous: 1
339
THC-O-phosphate Source: http://en.wikipedia.org/wiki/THC-O-phosphate?oldid=447734263 Contributors: Koavf, Pegship, Edgar181,

Beetstra, Meodipt, Alaibot, Mojo Hand, Greatmajor55, CheMoBot, and BogBot
Tinabinol Source: http://en.wikipedia.org/wiki/Tinabinol?oldid=618475536 Contributors: Meodipt, OrenBochman, Chemgirl131, Anypodetos, Braincricket, BG19bot and Medgirl131
URB602 Source: http://en.wikipedia.org/wiki/URB602?oldid=600974517 Contributors: Rjwilmsi, Edgar181, Beetstra, Smartse, MSBOT,
Addbot, Yobot, CheMoBot, Citation bot, Tea with toast, The chemistds and Stark1987
URB754 Source: http://en.wikipedia.org/wiki/URB754?oldid=618360159 Contributors: Arcadian, Fred Bradstadt, Itub, SmackBot, Bluebot, Roadnottaken, Bwduca, Beetstra, Smartse, Isilanes, Tanevala, Danelo, Chem-awb, Panoramix303, DOI bot, CheMoBot,
, P-kun80, RjwilmsiBot, GoingBatty, PotatoBot, Stark1987, Vaccinationist, Monkbot and Anonymous: 4
VCHSR Source: http://en.wikipedia.org/wiki/VCHSR?oldid=600803681 Contributors: Rjwilmsi, Pegship, Meodipt, Enix150, CheMoBot,
Citation bot, , Citation bot 1, BogBot and Anonymous: 1
VDM-11 Source: http://en.wikipedia.org/wiki/VDM-11?oldid=630848440 Contributors: RussBot, Edgar181, CommonsDelinker,
Enix150, Auntof6, Addbot, Yobot, CheMoBot, Rideer13, The chemistds, AvocatoBot, Medgirl131 and Anonymous: 2
WIN 54,461 Source: http://en.wikipedia.org/wiki/WIN_54,461?oldid=593323168 Contributors: Drphilharmonic, Enix150, Anypodetos,
BogBot, Skoot13 and Monkbot
WIN 55,212-2 Source: http://en.wikipedia.org/wiki/WIN_55,212-2?oldid=618472575 Contributors: GTBacchus, Howrealisreal, ^demon,
Mandarax, Zachjones4, Fred Bradstadt, WriterHound, Pegship, SmackBot, Edgar181, Bluebot, Mirshae, Phaedriel, Nuklear, Drphilharmonic, Saxbryn, Iridescent, Ccroberts, Meodipt, Cydebot, RelentlessRecusant, D666D, CopperKettle, Sony 1, Tanevala, Enix150, Funandtrvl, Altzinn, Panoramix303, Yuhong wang, Addbot, Maclia, Yobot, CheMoBot, , Harbinary, Lapuchca, Custoo,
FrescoBot, BogBot, RjwilmsiBot, Gould363, DASHBot, ZroBot, Louisajb, Skoot13, Je.keyser, Fuse809, Testem, Gareth CHEBI, Medgirl131 and Anonymous: 12
WIN 56,098 Source: http://en.wikipedia.org/wiki/WIN_56,098?oldid=605489228 Contributors: Enix150, Anypodetos, SwisterTwister,
BogBot, Snotbot, Crosstemplejay, BattyBot and Monkbot
XLR-11 (drug) Source: http://en.wikipedia.org/wiki/XLR-11_(drug)?oldid=626107904 Contributors: Wainblatrobert, Dl2000, Meodipt,
Boghog, Enix150, Balst32, CMBJ, Yobot, AnomieBOT, SciRambar, The chemistds, Skoot13, BattyBot, Testem, ChrisGualtieri, BaeyerDrewson, Epicgenius, KMAnomalocaris, Rebrewind, Monkbot and Anonymous: 5
AM251 Source: http://en.wikipedia.org/wiki/AM251?oldid=544204589 Contributors: Bearcat, Circeus, Vanky, BorisTM, Rjwilmsi, Laminado, Beetstra, Ccroberts, Meodipt, Calvero JP, Astavats, Cgingold, Tanevala, Enix150, Panoramix303, Addbot, CheMoBot, Gongshow,
Rjanag, , BogBot, PotatoBot and Anonymous: 3
Aminoalkylindole Source: http://en.wikipedia.org/wiki/Aminoalkylindole?oldid=582043905 Contributors: John Vandenberg, Smartse
and AnomieBOT
Cannabipiperidiethanone Source: http://en.wikipedia.org/wiki/Cannabipiperidiethanone?oldid=618475932 Contributors: Rjwilmsi, Drphilharmonic, Meodipt, Addbot, Dcirovic, The chemistds, BaeyerDrewson, Medgirl131 and Anonymous: 1
JWH-193 Source: http://en.wikipedia.org/wiki/JWH-193?oldid=606478297 Contributors:
CheMoBot, BogBot, Skoot13, Monkbot and WildCation
Rjwilmsi, Meodipt, Enix150, C6541,
JWH-198 Source: http://en.wikipedia.org/wiki/JWH-198?oldid=606597688 Contributors:

CheMoBot, BogBot, Skoot13, Monkbot and WildCation
Rjwilmsi, Meodipt, Enix150, C6541,
JWH-200 Source: http://en.wikipedia.org/wiki/JWH-200?oldid=606475531 Contributors: Rich Farmbrough, John Vandenberg, Velella,

Rjwilmsi, Pegship, Edgar181, Drphilharmonic, Meodipt, Smartse, Enix150, Funandtrvl, Addbot, C6541, Favonian, CheMoBot,
AnomieBOT, Citation bot, Grim23, , BogBot, Unceasing, Tisane, HarDNox, SmokingNewton, Frozen Wind, Caponex,
Silver Harshy, Managermerrill, Skoot13, Exercisephys, Fuse809, WildCation and Anonymous: 15
Pravadoline Source: http://en.wikipedia.org/wiki/Pravadoline?oldid=607406644 Contributors: Rich Farmbrough, Wimvandorst, Natalya,
Pegship, Drphilharmonic, Beetstra, Hu12, Meodipt, Enix150, Lamro, Panoramix303, CheMoBot, Anypodetos, Citation bot,
, Citation bot 1, Jonesey95, BogBot, Peryeat, S1lv3rblad3, Skoot13, Snotbot, Yukileoo, ChrisGualtieri and Anonymous: 2
RCS-4 Source: http://en.wikipedia.org/wiki/RCS-4?oldid=525171484 Contributors: Aardark, XLerate, SmackBot, Shoy, Beetstra,
Meodipt, Bobber0001, Enix150, C6541, CheMoBot, AnomieBOT, BogBot, RenamedUser01302013, The chemistds, ClueBot NG,
Bped1985, VeiledReference, Pan Czy Pani and Anonymous: 2
Anandamide Source: http://en.wikipedia.org/wiki/Anandamide?oldid=629335365 Contributors: MadSurgeon, Olivier, MartinHarper,
Sugarsh, Robbot, Sanders muc, Fuelbottle, Unfree, Giftlite, SoCal, Mearlon, Rich Farmbrough, Cacycle, Van Flamm, Mjpieters, Bitplane, Mykhal, El C, Arcadian, Eritain, M7, Max rspct, Reaverdrop, Mahanga, Josh Parris, Rjwilmsi, Fred Bradstadt, FlaBot, Doc glasgow, RexNL, WriterHound, YurikBot, RobotE, Tavilis, El Cazangero, A314268, Joncolvin, Gamerider, Laminado, SmackBot, Saravask,
AlexNordeen, Edgar181, Lennert B, Colonies Chris, Oatmeal batman, Roadnottaken, Drphilharmonic, Beetstra, Saxbryn, Chirality, Fvasconcellos, Mellery, Icek, Cydebot, Bendroz, Dream Focus, Trapezoidal, Belizefan3000, Lumir, .Jos, Boghog, Mikael Hggstrm, Pmallet, Tanevala, Enix150, DorganBot, VolkovBot, Chango369w, Cotard, Hertz1888, Djadvance, Chem-awb, Orbitalcombustion, ClueBot,
Plastikspork, Redspades, Ltnemo2000, Nettacog, Yonskii, Chemgirl131, Dthomsen8, Addbot, DOI bot, Chempedia, Lightbot, Jarble,
Gaberdine2, Yobot, Legobot II, CheMoBot, Gtz, Citation bot, , Jyeh, GrouchoBot, Xasodfuih, Custoo, FrescoBot,
Akshatrathi294, Tea with toast, BogBot, 564dude, RjwilmsiBot, Dcirovic, Tomsdearg92, Ronhirzmd, ClueBot NG, Gilderien, Vjiced,
Skoot13, BG19bot, Lifeformnoho, Enomai, Valera123, Vjiced1, Anaen21, JaconaFrere, Monkbot, Medgirl131 and Anonymous: 76
N-Arachidonoyl dopamine Source: http://en.wikipedia.org/wiki/N-Arachidonoyl_dopamine?oldid=618471241 Contributors: St3vo,
Rich Farmbrough, Rjwilmsi, Edgar181, Beetstra, Rhetth, Cydebot, ChemNerd, Enix150, Benrr101, Accounting4Taste, PookeyMaster,
Chem-awb, Panoramix303, Chemgirl131, Addbot, DOI bot, CheMoBot, , Custoo, Nirmos, Tea with toast, ZroBot, The
chemistds, Brainiacal, Monkbot, Medgirl131 and Anonymous: 3
2-Arachidonoylglycerol Source: http://en.wikipedia.org/wiki/2-Arachidonoylglycerol?oldid=618471104 Contributors: Rich Farmbrough,
Rjwilmsi, WriterHound, Shaddack, El Cazangero, SmackBot, Edgar181, Roadnottaken, Beetstra, Rhetth, Cydebot, Astavats, Kilrothi,
ChemNerd, Tanevala, Enix150, Michal George, SieBot, Chem-awb, Drmies, Panoramix303, ChemSpiderMan, Chemgirl131, Addbot,
K-MUS, DOI bot, Ginosbot, Yobot, CheMoBot, Jzlong, Citation bot, Xasodfuih, Custoo, Citation bot 1, RedBot, BogBot, CrowzRSA,
564dude, Dcirovic, ZroBot, Helpful Pixie Bot, Shisha-Tom, Cotedesneiges, Austinpk, Jianhui67, Anaen21, Monkbot, Medgirl131 and
Anonymous: 15
340
2-Arachidonyl glyceryl ether Source: http://en.wikipedia.org/wiki/2-Arachidonyl_glyceryl_ether?oldid=618471126 Contributors: St3vo,

Rich Farmbrough, Physchim62, WriterHound, Slashme, Edgar181, Beetstra, Cydebot, Benrr101, Chem-awb, Panoramix303, ChemSpiderMan, Chemgirl131, Addbot, CheMoBot, Citation bot, Custoo, Citation bot 1, Tea with toast, CrowzRSA, Dcirovic, Cimmerian praetor,
ChrisGualtieri, Gareth CHEBI, Medgirl131 and Anonymous: 5
Oleamide Source: http://en.wikipedia.org/wiki/Oleamide?oldid=618471264 Contributors: AxelBoldt, Richard Taytor, Henrik, Rjwilmsi,
WriterHound, SmackBot, Edgar181, Roadnottaken, Beetstra, Meodipt, Scouse123, ChemNerd, Ejhoekstra, TXiKiBoT, Benrr101, Living
under a rock, Chem-awb, Yikrazuul, DumZiBoT, Chemgirl131, Addbot, DOI bot, CheMoBot, Neoligand, Citation bot, Custoo, Citation
bot 1, Abductive, Tea with toast, BogBot, ZroBot, Cimmerian praetor, Skoot13, Rezabot, Drpainless, Makecat-bot, Monkbot, Medgirl131
and Anonymous: 15
RVD-Hp Source: http://en.wikipedia.org/wiki/RVD-Hp?oldid=618471413 Contributors: Meodipt, Magioladitis, Boghog, Yobot, Custoo, BG19bot, Medgirl131 and Anonymous: 1
Virodhamine Source: http://en.wikipedia.org/wiki/Virodhamine?oldid=618471494 Contributors: Rich Farmbrough, Arcadian, Natalya,
WriterHound, BlueZenith, Edgar181, David.Throop, Drphilharmonic, Beetstra, Rhetth, Cydebot, Enix150, Benrr101, Chem-awb, Plasmic
Physics, Chemgirl131, Addbot, Luckas-bot, CheMoBot, Citation bot, Custoo, Citation bot 1, Tea with toast, ZroBot, Medgirl131 and
Anonymous: 1
HU-320 Source: http://en.wikipedia.org/wiki/HU-320?oldid=517594060 Contributors: Rjwilmsi, Meodipt, Enix150, CheMoBot, Anypodetos, RjwilmsiBot and Skoot13
HU-336 Source: http://en.wikipedia.org/wiki/HU-336?oldid=580010784 Contributors: Rjwilmsi, Enix150, CheMoBot, Anypodetos,
RjwilmsiBot and Skoot13
HU-345 Source: http://en.wikipedia.org/wiki/HU-345?oldid=580010824 Contributors: Rjwilmsi, Drphilharmonic, Beetstra, Meodipt,
Enix150, CheMoBot, Anypodetos, RjwilmsiBot and Skoot13
Raphael Mechoulam Source: http://en.wikipedia.org/wiki/Raphael_Mechoulam?oldid=621871273 Contributors: GreatWhiteNortherner,
Andycjp, WadeSimMiser, SqueakBox, Rjwilmsi, Bgwhite, RussBot, El Cazangero, Shuki, Mqzspa, Meodipt, Cydebot, Dougweller,
J.delanoy, Enix150, Juliancolton, Tzahy, Panoramix303, Qwfp, Addbot, Lightbot, 55, Luckas-bot, Yobot, Amirobot, Davshul, Almabot,
FrescoBot, Anti-Nationalist, ZroBot, Cimmerian praetor, Vjiced, Drkup(IMJ), Cyberbot II, Jethro B, Reverend Mick man34, VIAFbot,
Looppushh, Monkbot, Jonarnold1985 and Anonymous: 15
John W. Human Source: http://en.wikipedia.org/wiki/John_W._Huffman?oldid=604651417 Contributors: Delirium, Wdfarmer, Dismas, Patken4, Stormbay, KGasso, SmackBot, Meodipt, Lugnuts, Spyder Monkey, Smartse, Trusilver, NewEnglandYankee, KudzuVine,
Jackfork, Panoramix303, Addbot, Yobot, AVB, AnomieBOT, OlYeller21, Grim23, Sgravn, Gunnanmon, Tisane, ZroBot, Andyman1125,
Dagko, Allethrin, Frozen Wind, ClueBot NG, Skoot13, 4321acb, Nickt0963, Wiki magnet, Touchhole97 and Anonymous: 19
JWH-007 Source: http://en.wikipedia.org/wiki/JWH-007?oldid=606455199 Contributors: Meodipt, Enix150, Ziggy Sawdust, C6541,
CheMoBot, , FrescoBot, BogBot, John of Reading, Tisane, Kabutop, Pan Czy Pani, D42kn355, NotWith and WildCation
JWH-018 Source: http://en.wikipedia.org/wiki/JWH-018?oldid=628920223 Contributors: Deisenbe, Topbanana, St3vo, Utcursch,
Kevin143, Jcorgan, Discospinster, Cacycle, Bender235, Surachit, Alansohn, Hadlock, Zntrip, Damicatz, Rjwilmsi, Poul818, Windchaser,
Tedder, WriterHound, Therefore, Grafen, Poobread, Pegship, Josh3580, BorgQueen, SmackBot, Shoy, Edgar181, Nuklear, Drphilharmonic, DMacks, Gobonobo, Joshua Scott, Beetstra, BSI, Iridescent, TwistOfCain, CmdrObot, Meodipt, Cydebot, Crossmr, DumbBOT,
Nirigihimu, Turkeyphant, Zeel, Smartse, Theguy0000, MER-C, Grimelab, Iownutopia, JamesBWatson, Monosodious, Bradgib, ChemNerd, Leyo, Boghog, Malkuth1, Gutterkitty, Enix150, Pdcook, CardinalDan, Funandtrvl, Msrbl49, Fbifriday, Philip Trueman, Flux12n21,
Flopster2, Wikieditor12, Jpaliano, Guldenat, Falcon8765, Living under a rock, Pjoef, Dlfreem, Dhusereau, Hobartimus, ClueBot, GorillaWarfare, Tomas e, Drmies, Yuubi, Auntof6, Ktr101, Alexbot, Dr.Koljan, Panoramix303, Sun Creator, Christopherbrian, XLinkBot,
Fastily, ErgoSum88, ESO Fan, PurrfectPeach, Addbot, C6541, MartinezMD, Fieldday-sunday, Fluernutter, LaaknorBot, DFS454, Favonian, Tide rolls, Wax025, Ben Ben, Legobot, Luckas-bot, Yobot, Legobot II, CheMoBot, Daddyrob81, Anypodetos, AnomieBOT, XLocal,
Vinyl Ketone, Piano non troppo, Citation bot, GB fan, Intelati, OlYeller21, , Ponticalibus, Nasnema, Rhoodey, ,
Harbinary, Shirik, Amaury, Psychonaught, Shadowjams, Custoo, FrescoBot, Nageh, RicHard-59, Metallica3790, Borguebabe, Weetoddid,
Boylechem, Citation bot 1, Biker Biker, Calmer Waters, MastiBot, Sw1ngOnTheSp1ral, BogBot, CrowzRSA, Clickpop, David Hedlund,
Tbhotch, RjwilmsiBot, Dustin 3choes, Jwh018, Rsharpe28, John of Reading, Gunnanmon, Katherine, Tisane, Clayman1976, Atropinesulfate, Tommy2010, Sraab2, Wikipelli, White Trillium, F, Josve05a, James.dynamite, Hereforhomework2, H3llBot, Darkwire89, Drhjort,
ALANON54, Wayne Slam, Ocaasi, OnePt618, Scema, PeterGrinJK, Akacypress, Demetrius259, Corei7Maniac, Del nerius, Lagato123,
Tjiseclipsed, ClamDip, HaydenBeck, W5NLbrian, Handsum53, DASHBotAV, Hetoi, Abnorml1, Louisajb, Mikhail Ryazanov, ClueBot
NG, Agents of The Free, Easyzeh, Dualdj1, Tesacrynheart, EnvyCo, Diogenes2000, Skoot13, 4321acb, Jacobso4, Murraysymes, 1989Exley1989, Exercisephys, Veried72, Snow Blizzard, Boobs4fun, Justthinking25, Shisha-Tom, Fuse809, PhoenixPie, Kid squid, BattyBot,
BaeyerDrewson, Rawrfaceace, KMAnomalocaris, Rebrewind, Monkbot, Cbmacewan, Medgirl131 and Anonymous: 417
JWH-019 Source: http://en.wikipedia.org/wiki/JWH-019?oldid=606455993 Contributors: Drphilharmonic, Meodipt, Leyo, Enix150,
Alexbot, Addbot, C6541, CheMoBot, Citation bot, , Citation bot 1, Biker Biker, BogBot, Skoot13, Pan Czy Pani, Veried72, Shisha-Tom, Monkbot, WildCation and Anonymous: 2
JWH-030 Source: http://en.wikipedia.org/wiki/JWH-030?oldid=628060353 Contributors: Wimvandorst, Pegship, Nuklear, Beetstra,
Meodipt, Enix150, Funandtrvl, CheMoBot, , BogBot, Tisane, Louisajb, WildCation and Anonymous: 4
JWH-047 Source: http://en.wikipedia.org/wiki/JWH-047?oldid=540030725 Contributors: Rjwilmsi, RjwilmsiBot and BaeyerDrewson
JWH-048 Source: http://en.wikipedia.org/wiki/JWH-048?oldid=606457011 Contributors: Rjwilmsi, Wikieditor12, C6541, RjwilmsiBot,
BaeyerDrewson and WildCation
JWH-073 Source: http://en.wikipedia.org/wiki/JWH-073?oldid=618472305 Contributors: Rich Farmbrough, Cacycle, LindsayH, Blaxthos, Grafen, Pegship, SmackBot, Cybercobra, Drphilharmonic, Meodipt, Cydebot, Marek69, Turkeyphant, Theguy0000, Iownutopia,
Leyo, Enix150, Funandtrvl, X!, Krakaet, ClueBot, Panoramix303, Alibobar, Yoman82, ErgoSum88, Addbot, C6541, MartinezMD,
Luckas-bot, Yobot, CheMoBot, XLocal, Piano non troppo, Addihockey10, OlYeller21, Grim23, , Custoo, Weetoddid,
Citation bot 1, Biker Biker, BogBot, Noraft, Tisane, Ocaasi, PeterGrinJK, Darksp000n, Caponex, ClueBot NG, Dvsbmx, Skoot13,
Exercisephys, Veried72, Cerabot, Woo 24, Monkbot, WildCation, Cbmacewan, Medgirl131 and Anonymous: 36
341
JWH-081 Source: http://en.wikipedia.org/wiki/JWH-081?oldid=627566683 Contributors: Pegship, Beetstra, Meodipt, Turkeyphant, Terrek, Enix150, TopGun, Funandtrvl, Svick, Micha Sobkowski, Addbot, C6541, CheMoBot, Grim23, , Biker Biker, BogBot, Tisane, ZroBot, Frozen Wind, Caponex, ClueBot NG, Skoot13, Pan Czy Pani, Veried72, WildCation and Anonymous: 10
JWH-098 Source: http://en.wikipedia.org/wiki/JWH-098?oldid=606459363 Contributors: Meodipt, Enix150, C6541, CheMoBot,
, BogBot, Skoot13 and WildCation
JWH-116 Source: http://en.wikipedia.org/wiki/JWH-116?oldid=608540716 Contributors: Rjwilmsi, C6541, BaeyerDrewson and WildCation
JWH-147 Source: http://en.wikipedia.org/wiki/JWH-147?oldid=606479371 Contributors: Pegship, Meodipt, Enix150, Yobot,
CheMoBot, , BogBot, Tisane, Destruktor5000, WildCation and Anonymous: 1
JWH-164 Source: http://en.wikipedia.org/wiki/JWH-164?oldid=606483862 Contributors: Meodipt, Enix150, CheMoBot,
, FrescoBot, BogBot, Skoot13 and WildCation
JWH-167 Source: http://en.wikipedia.org/wiki/JWH-167?oldid=600826360 Contributors: Stephen, Rjwilmsi, Shoy, Beetstra, Boghog,
Enix150, Jsfouche, C6541, Ben Ben, CheMoBot, Citation bot, EmausBot, The chemistds, Rezabot and Anonymous: 1
JWH-175 Source: http://en.wikipedia.org/wiki/JWH-175?oldid=607110954 Contributors: Jorge Stol, Meodipt, Enix150, CheMoBot and
WildCation
JWH-184 Source: http://en.wikipedia.org/wiki/JWH-184?oldid=608540728 Contributors: Rjwilmsi, Meodipt and BaeyerDrewson
JWH-203 Source: http://en.wikipedia.org/wiki/JWH-203?oldid=607451648 Contributors: Rich Farmbrough, Rjwilmsi, Bazonka, Drphilharmonic, Meodipt, Enix150, C6541, CheMoBot, Citation bot, Grim23, , BogBot, Gunnanmon, Tisane, Caponex,
Skoot13, Pan Czy Pani, Monkbot, WildCation and Anonymous: 3
JWH-210 Source: http://en.wikipedia.org/wiki/JWH-210?oldid=625525612 Contributors: Mike Rosoft, KGasso, Edgar181, Meodipt,
Christian75, DumbBOT, MER-C, Enix150, Addbot, C6541, Luckas-bot, CheMoBot, Anypodetos, Mdog228, Grim23, ,
FrescoBot, BogBot, NotAnonymous0, Tisane, ZroBot, DASHBotAV, Caponex, Tryptamines, Pan Czy Pani, WildCation and Anonymous:
16
JWH-249 Source: http://en.wikipedia.org/wiki/JWH-249?oldid=600743349 Contributors: Rjwilmsi, Shoy, Beetstra, Meodipt, Enix150,
Squids and Chips, Ben Ben, CheMoBot, Citation bot, BogBot and The chemistds
JWH-250 Source: http://en.wikipedia.org/wiki/JWH-250?oldid=606791115 Contributors: Mike Rosoft, Blaxthos, Rjwilmsi, WriterHound, KGasso, Edgar181, Drphilharmonic, Meodipt, Smartse, Salih, Enix150, Panoramix303, Chemgirl131, Addbot, C6541, Yobot,
CheMoBot, Sarrus, XLocal, Citation bot, ArthurBot, OlYeller21, Grim23, , Harbinary, Citation bot 1, BogBot, Tbhotch,
EmausBot, Tisane, PotatoBot, Joseph3311, IGeMiNix, ChuispastonBot, DASHBotAV, Caponex, Louisajb, MelbourneStar, Skoot13,
Names are hard to think of, Purple Blanket, Rebrewind, WildCation and Anonymous: 17
JWH-251 Source: http://en.wikipedia.org/wiki/JWH-251?oldid=600909501 Contributors: Rjwilmsi, Bazonka, Beetstra, Meodipt,
Enix150, Addbot, C6541, CheMoBot, Citation bot, The chemistds and AvocatoBot
JWH-302 Source: http://en.wikipedia.org/wiki/JWH-302?oldid=517587317 Contributors: Rjwilmsi, Beetstra, Meodipt, CheMoBot, BogBot, The chemistds and Skoot13
JWH-307 Source: http://en.wikipedia.org/wiki/JWH-307?oldid=606472694 Contributors: Cacycle, NawlinWiki, Pegship, KGasso,
Edgar181, Meodipt, Smartse, MER-C, Enix150, Addbot, CheMoBot, Sarrus, Grim23, , Biker Biker, BogBot, Dinamikbot, Tbhotch, Tisane, Somerwind, Caponex, ClueBot NG, Veried72, WildCation and Anonymous: 14
JWH-398 Source: http://en.wikipedia.org/wiki/JWH-398?oldid=622353964 Contributors: Rjwilmsi, Meodipt, Enix150, C6541,
CheMoBot, Grim23, , Harbinary, BogBot, Tisane, Skoot13, WildCation and Anonymous: 1
JWH-424 Source: http://en.wikipedia.org/wiki/JWH-424?oldid=606469047 Contributors: Meodipt, Enix150, C6541, CheMoBot, Gongshow, FrescoBot, BogBot, Skoot13, BaeyerDrewson and WildCation
Naphthoylindole Source: http://en.wikipedia.org/wiki/JWH-018?oldid=628920223 Contributors: Deisenbe, Topbanana, St3vo, Utcursch,
Kevin143, Jcorgan, Discospinster, Cacycle, Bender235, Surachit, Alansohn, Hadlock, Zntrip, Damicatz, Rjwilmsi, Poul818, Windchaser,
Tedder, WriterHound, Therefore, Grafen, Poobread, Pegship, Josh3580, BorgQueen, SmackBot, Shoy, Edgar181, Nuklear, Drphilharmonic, DMacks, Gobonobo, Joshua Scott, Beetstra, BSI, Iridescent, TwistOfCain, CmdrObot, Meodipt, Cydebot, Crossmr, DumbBOT,
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Contents

Cannabinoid receptor type 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Cannabinoid receptor type 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Cannabinoids from other plants

Cannabis plant prole

Types of endocannabinoid ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Table of natural cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Cannabinoid research organizations

11.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

21.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

22.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

24.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25.1 Eects in bone cancer model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

26.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

27.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28.4 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

29.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

30.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

31.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

32.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

35.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

36.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

40.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

41.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

42.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

43.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

48.2 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

49.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

52.2.1 Eects on the nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

52.2.2 Eects on the immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

52.2.3 Cell migration

52.2.4 Other targets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

53.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

57.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

58.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

59.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

60.1 Medical uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

61.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62.2 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63.1 Clinical applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63.1.1 Antimicrobial actions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63.1.2 Neurological eects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63.1.3 Psychotropic eect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63.1.4 Dravet syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63.2 CBD-enhanced cannabis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63.3 Industrial hemp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63.4.2 Pharmacokinetic interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63.4.3 Pharmaceutical preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63.7 Legal status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

64.3 External links . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

65.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

66.1 See also . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .