How many mg in 20gm?

I. INTRODUCTION
Ibogaine (12-methoxyibogamine, NIH 10567, Endabuse) will be one of the psychoactive indole
alkaloids found inside the West African shrub, Tabernanthe iboga. Pertaining To over a century,
each extracts associated with T. Iboga and its constituent alkaloids, which includes ibogaine, have
been employed as medicinals (1). Precisely what tends in order to make this alkaloid regarding
particular curiosity to be able to contemporary pharmacology are generally anecdotal observations
indicating in which ibogaine possesses "anti-addictive" properties. Thus, ibogaine (6-25 mg/kg,
throughout humans) continues for you to be claimed to attenuate each dependence as well as
withdrawal signs along with symptoms into a variety of abused drugs such as opiates, alcohol,
nicotine and psychostimulants (2-9). Preclinical studies demonstrating which ibogaine minimizes
self-administration associated with each cocaine as well as morphine, and attenuates the actual the
indicators of morphine-withdrawal, are consistent using these claims [reviewed in (Popik and also
Glick (10)]. This kind of chapter evaluations the particular pharmacological properties of ibogaine
along with associated alkaloids. Since our final comprehensive review (11), a lot more than one
hundred new studies about the pharmacological actions regarding ibogaine and also ibogaine-like
alkaloids have got appeared. Your chemistry of ibogaine continues to be able to be reviewed by
Taylor on this series (12,13).
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II. HISTORICAL OVERVIEW.
Ibogaine is actually derived via Tabernanthe iboga, a new shrub indigenous for you to Central-West
Africa. the iboga shrub, any part of the particular family Apocynaceae (order Contortae), is normally
discovered within the undergrowth involving tropical forests (14). the roots of Tabernanthe iboga
were used inside tribal initiation rites (15,16). Even though the facts of such ceremonies vary, it had
been believed that iboga root enabled initiates to make experience of ancestors in the spirit world.
Ibogaine has also been found in Tabernanthe crassa (17). Nineteenth century reviews via French
and Belgian explorers initial described the actual stimulant along with aphrodisiac results of
consuming Gated Community Chevy Chase MD iboga root (1,16). The really first botanical
description of the plant, ended up being created by Baillon inside 1889 (18).
Dybovsky along with Landrin (19), also as Haller and also Heckel (20), had been the first for you to
isolate the crystalline alkaloid from iboga root, which in turn these people called "ibogaine" or
"ibogine". Within 1901 French pharmacologists discovered ibogaine to get an unusual kind of
excitatory effect within animals (21-23). Phisalix (23) suggested that will ibogaine could produce
hallucinations according to observations of unusual behavior within dogs. The Actual alkaloid ended
up being subsequently tested throughout Western clinical settings, and has been advised as a
stimulant for the remedy of convalescence as well as neurasthenia (24). Regardless of such
recommendations, ibogaine in zero way enjoyed wide clinical use and ended up being neglected by
simply researchers for nearly 30 years. Throughout the 1940's Raymond-Hamet along with
coworkers published the number of papers describing the actual pharmacological properties
involving ibogaine in isolated tissues and the cardiovascular system (25-32).
Lambarene, an extract with the roots with the iboga relative Tabernanthe manii, was bought from
France throughout the 1930's. It contained concerning 8 mg regarding ibogaine, along with ended
up being described as becoming a stimulant. Iperton, yet another ibogaine extract, had been also
employed as being a tonic or even stimulant (33). Ibogaine has been utilized by athletes as being a
performance enhancing drug (34). Throughout many countries, including the particular United
States, ibogaine use can be prohibited, perhaps due in order to the purported hallucinogenic results
(widely publicized within the late 1960's) and its look around the illicit drug market. Inside 1970, the
United States of America food along with Drug Administration classified ibogaine as a schedule I
substance (all non-research use forbidden).
Beginning within 1985, a new number of patents ended up being issued for the use associated with
ibogaine as a rapid method of interrupting addiction to narcotics (morphine as well as heroin) (3),
cocaine and amphetamine (4), alcohol (5), nicotine (6) as well as poly-drug dependency syndrome
(35). These patents claim an oral or perhaps rectal dose regarding ibogaine (4-25 mg/kg) interrupts
your dependence syndrome, permitting patients to be able to maintain a drug-free lifestyle with
regard to a minimum of six months.
Based upon open up clinical studies, it has been claimed (36) that will ibogaine therapy resulted
within 25% regarding patients remaining drug-free with out craving regarding six months. This team
included individuals who were each highly motivated to quit along with had relatively steady home
environments. An Additional 40-50% associated with patients had their particular addictions
interrupted successfully, along with necessary psychotherapy. Twenty to always be able to 30% of
patients had returned to become able to drug use inside a new month subsequent treatment.
Somewhat lower success rates (10-15%) are generally cited simply by Touchette (37).
In your absence of appropriately controlled clinical studies, your efficacy of ibogaine as any possible
anti-addictive agent can't be rigorously assessed at the current time. Nonetheless, curiosity about
ibogaine as becoming a treatment method pertaining to addiction offers increased. Throughout 1985
NDA International, Inc. (Staten Island, NY, USA) began any campaign to persuade your U.S.
government for you to initiate managed clinical trials using ibogaine (38). at the same time, the use
of ibogaine for treating opioid dependence has increased within Europe (39). In present, clinical
trials for you to assess the safety involving ibogaine are usually underway in the College of Miami
and so are planned within New York. Clinical trials to end up being able to test the anti-addictive
efficacy regarding ibogaine are underway in The Particular Netherlands along with Panama (38,40-
44). Based on Ali et al., (45), the particular U.S. food and Drug Administration and the National
Institute with regard to Drug Abuse features approved the utilization regarding ibogaine on the
restricted schedule to end up being able to treat cocaine addiction.
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III. CHEMICAL STRUCTURE AND PROPERTIES.
Figure 1.
Compound R1 R2 R3 R4
Ibogaine CH2CH3 H OCH3 H
O-Desmethylibogaine CH2CH3 H OH H
( )-Ibogamine CH2CH3 H H H
( )-Coronaridine CH2CH3 CO2CH3 H H
Tabernanthine CH2CH3 H H OCH3
O-t-Butyl-O-Desmethylibogaine CH2CH3 H OC(CH3)3 H
Although ibogaine had been first isolated along with identified within 1901, (19-21,46), the
particular composition associated with this and related alkaloids (Fig. 1) had been first established
by simply Taylor in 1957 (47) [see in addition Taylor (12,13)]. Total synthesis via nicotinamide has
been reported utilizing a 13- (48) as well as 14-step (49) sequence. Your 13C NMR spectra of several
iboga alkaloids were published throughout 1976 (50). The Particular synthesis involving tritiated
ibogaine has been lately reported (51,52).
Ibogaine (mol. wt. 310.44) includes a melting point of 153 in 0.01 mm Hg and a pKa regarding 8.1
in 80% methylcellosolve. Your absorption maxima inside methanol tend to be 226 (log e 4.39) and
296 (log e 3.93) nm. Ibogaine crystallizes from alcoholic options into small, reddish prismatic
needles; it's levorotatory [a ]D -53 (in 95% ethanol) and is soluble in ethanol, methanol,
chloroform and acetone, yet insoluble in water. Ibogaine hydrochloride (freezing point 299C, [a ]D
-63 (ethanol), [a ]D -49 (H2O)) can be soluble inside water, ethanol as well as methanol, is
slightly soluble inside acetone along with chloroform, and is practically insoluble in ether (53).
Ibogaine will be heat- as well as light-sensitive (54) and may spontaneously oxidize within solution,
providing iboluteine and also ibochine (16,34). Alkaloids structurally associated to ibogaine include
tabernanthine, ibogamine, iboxigaine, gabonine, iboquine, kisantine and also ibolutenine. Structural
commonalities in between ibogaine along together with other indole alkaloid hallucinogens get also
been reported (55). The Particular synthesis of several ibogaine derivatives has recently been
published by Repke along with coworkers (56).
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IV. PHARMACOKINETICS.
After parenteral administration, ibogaine continues to be identified in the variety of biological
materials, which includes blood along with urine (humans) along with within the liver, kidney and
mind involving laboratory animals (54,57-59). 1 hour after intraperitoneal administration, high
concentrations involving ibogaine had been current within rat liver as well as kidneys (60). Right
After intravenous injection associated with 10 mg/kg in order to mice, maximal mind concentrations
(48 g/g involving wet excess weight [~133 M]) had been achieved inside 10 sec (61).
Recently, Gallagher et al., (62) have got designed a extremely sensitive along with particular method
to quantify ibogaine inside plasma as well as tissues. This kind of approach makes use of organic
extraction, derivatization along with trifluroacetic anhydride, and also detection by gasoline
chromatography-mass spectrometry (GC/MS). Comparable strategies had been developed by Hearn
et al., (63), Alburges et al., (64) and Ley et al., (65). Making Use Of the GC/MS method, Pearl and
also colleagues (66) reported in which 1, 5 and also 19 hours following intraperitoneal
administration associated with 40 mg/kg regarding ibogaine, the whole mind ranges of ibogaine
were 10, 1 and also 0.7 M within female rats and 6, 0.9 and 0.2 M throughout male rats,
respectively. Hough et al., (67) studied your tissue distribution of ibogaine after i.p. and also s.c.
administration in rats. 1 hour after i.p. dosing (40 mg/kg), drug amounts ranged via 106 ng/ml (~ 0.3
M) within plasma to be able to 11,308 ng/g (~ 36 M) inside fat, together with significantly
higher values after s.c. administration associated with the identical dose. Drug amounts had been
10-20 fold lower 12 hrs later. These types of data indicate that will ibogaine will be subject for you to
a substantial "first pass" impact right after i.p. dosing, as well as in which there exists a marked
propensity pertaining to ibogaine being deposited in adipose tissue, reflecting its lipophilicity.
Steady using its lipophilicity, ibogaine ranges throughout adipose tissue were high regarding a
minimal of 12 hours following administration. Based in these data, it was suggested that a new
single dose of ibogaine might give a long-acting, depot-like moment strategy (67).
The reported long-term effects of ibogaine (e.g. (68-70)), have led to the hypothesis this alkaloid may
always be metabolized to an active principle with a extended half existence (71). In present, there is
absolutely no direct evidence to guide this hypothesis. Ibogaine was reported to disappear from your
rat in a price involving ~4% in the administered dose hourly along with ~ 5% with the injected dose
eliminated unchanged within urine. Elimination kinetics via mind yielded any half-life associated
with 60 min throughout rodents (60,61) along with suggest any one-compartment model. Right After
administration regarding ibogaine (10 mg/kg, p.o.) to rabbits, urine concentrations reached the
maximum 4-5 hrs later, then decreased rapidly and disappeared after six hours (54,60). Taken
together, these data claim that ibogaine is actually extensively metabolized. Inspection involving
ibogaine's composition (Fig. 1) led us in order to hypothesize which a new most likely degradation
pathway is O-demethylation from C12. Based about this hypothesis, O-desmethylibogaine (also
referred in order to as noribogaine or 12-hydroxyibogamine), has been synthesized by Dr. C. Bertha
in the National Institutes associated with health inside 1994. at the same time, O-tert-buty-
-O-desmethylibogaine ended up being synthesized in an attempt to produce an ibogaine derivative
resistant to end up being able to O-demethylation (Fig. 1). Thus, the initial compound has been
synthesized to investigate the prospective pharmacological actions of your likely ibogaine
metabolite. Your 2nd compound permitted examination in the pharmacological results of an ibogaine
derivative that would certainly not always be degraded through O-demethylation. The Particular
synthesis of these compounds had been described by simply Layer et al., (72).
Recent studies have indeed demonstrated that ibogaine is metabolized, as well as which O-
desmethylibogaine can be detected within human plasma (73) too as inside the plasma along with
brains of ibogaine-treated rats (66). Behavioral as well as neurochemical studies throughout rodents
get proven that will O-desmethylibogaine will be pharmacologically active (discussed later).
Following an i.p. dose associated with ibogaine (40 mg/kg), Pearl et al., (66) reported brain O-
desmethylibogaine concentrations associated with 20, 10 and also 0.8 M throughout female rats
as well as 13, 7 as well as 0.1 M throughout male rats, respectively, in 1, 5, and 19 hrs after
administration. These information suggest that gender differences in pharmacological responses in
order to ibogaine might be attributed to end up being able to pharmacokinetic, instead of
pharmacodynamic, factors. Whilst the report of one human subject (73) indicated that will O-
desmethylibogaine persisted inside plasma from high amounts pertaining to a minimum of 24 hours
following oral ibogaine administration, it just isn't clear if this pattern is likely to be representative.
There will be evidence indicating that will the various pharmacological effects of ibogaine might end
up being attributable, no less than throughout part, for you to its metabolite(s). for example, your
tremorigenic results of ibogaine dissipate far more rapidly compared to its power to attenuate the
actual morphine withdrawal syndrome within rats (74). This specific obtaining indicates an active
principle(s) responsible for starters action might always be much more rapidly metabolized
compared to compound(s) involved with additional actions. Alternatively, the various
pharmacological results of ibogaine may involve distinct neurotransmitter pathways (discussed
later).
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V. GENERAL PHARMACOLOGICAL ACTIONS.
A. Animal Studies
1. Locomotor activity.
Ibogaine generates complex results on locomotor exercise within rodents. Any dose associated with
twenty mg/kg (i.p.) slightly elevated locomotor activity in mice (75) while Sershen et al., (76)
reported that will 40 mg/kg (i.p.) decreased locomotor exercise within male mice in 1, but not 24,
hours right after injection. Your same dose inhibited locomotion in female rats throughout the first
hour right after injection, whereas one week later on locomotor exercise was increased (69).
Recently, Pearl and also colleagues (66) noted gender distinctions within the results of ibogaine on
locomotor activity (40 mg/kg, i.p., 5 or 19 hours before test). in control males along with females the
actual locomotor activity decreased in the program of the second hour involving observation.
Ibogaine treatment in females prevented this decline in locomotor activity. Inside females, although
not males, ibogaine decreased locomotor exercise when offered 19 hrs prior to the test (66). Yet
Another research revealed that in male rats, a new single dose associated with 40 mg/kg inhibited
locomotor activity 4 hours following injection; a dose associated with 80 mg/kg decreased motor
activity a day following injection (77).
Rats injected with doses regarding 20-60 mg/kg regarding ibogaine displayed slower reaction
occasions in sensory along with sensory-motor exams as well as had been in addition impaired in
performing certain motor reflexes at doses involving 40-60 mg/kg. Furthermore, these rats exhibited
any marked reduction inside locomotor activity too as with emotionality from doses including 10- 40
mg/kg. With higher doses (40 mg/kg), rats appeared virtually inactive (78). Throughout various other
studies, at doses above 25 mg/kg, ibogaine produced ataxia, splayed hind limbs, outstretched
forelimbs, Straub tail as well as hyperexcitability (79).
One hour right after O-desmethylibogaine or perhaps 18-methoxy-coronaridine injection (40 mg/kg),
locomotor exercise had been increased during the second hour regarding observation (66,80). Inside
our studies, high doses (120 mg/kg) associated with O-desmethylibogaine along with O-t-buty-
-O-desmethylibogaine produced profound ataxia as well as convulsions (72). Ibogaine, O-
desmethylibogaine, as well as O-t-butyl-O-desmethylibogaine, (80 mg/kg) failed to significantly
influence rotorod performance in mice (72).
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a. Outcomes about locomotor activity induced through other drugs
Ibogaine may be discovered for you to affect the particular motor stimulant properties associated
with amphetamine, cocaine, and also morphine within rodents (hyperlocomotion induced by simply
these drugs is assumed in order to reflect their "psychotomimetic" qualities inside man). Even
though the final results of those studies usually are generally not uniform, throughout general, it has
been found that in female rats this alkaloid potentiates the actual locomotor reaction to
amphetamine along with cocaine, whereas opposite effects were reported throughout male rats
along with mice.
Sershen et al., (81) found that ibogaine (40 mg/ kg i.p., 2 or even 18 hours before amphetamine)
enhanced amphetamine (1 mg/kg) - induced hypermotility within female rats. in some other studies,
an amphetamine-induced rise in locomotor activity had been potentiated in female rats pretreated
with ibogaine (40 mg/kg, i.p.) 19 hours earlier (82). Cocaine-induced hypermotility in female rats has
been in addition potentiated through ibogaine (83,84). Broderick et al., (85,86) reported which
ibogaine (20-40 mg/kg, i.p.) administration to be able to male rats regarding 4 days reduced cocaine
(20 mg/kg) - induced hypermotility. Ibogaine (40 mg/kg, i.p.) administration in addition reduced
cocaine- (25 mg/kg, s.c.) induced hypermotility inside male mice (76), a new finding in agreement
with almost all the amphetamine (1 mg/kg) - ibogaine interaction (81) in this gender along with
species. Current data demonstrate that the outcomes of ibogaine about cocaine (20 mg/kg) -induced
hyperactivity inside female rats tend to be occasion dependent. Thus, given one h before cocaine,
ibogaine and O-desmethylibogaine (40 mg/kg) inhibited cocaine-induced hyperactivity, yet when
provided 19 h before cocaine they produced the opposite effect (80).
Ibogaine pretreatment (40 mg/kg, i.p. 19 hrs just before measurement) decreased as well as blocked
your locomotor stimulation induced simply by morphine (0.5-20 mg/kg) within rats (69,71). Ibogaine
administered 1 week (but not merely one month) prior to morphine (5 mg/kg) reduced the actual
motor stimulant results of this opiate (69). Pearl et al., (87) discovered that ibogaine (5-60 mg/kg) is
a fantastic deal more potent within inhibiting morphine-induced hyperlocomotion in rats pretreated
along with morphine with regard to numerous (1-4) days compared to non-pretreated rats. Doses
associated with ibogaine (5-10 mg/kg) in which on your own own were inactive in drug-naive animals
attenuated morphine-induced hyperactivity in the morphine pretreated rats. the inhibitory outcomes
of ibogaine about morphine-induced hyperlocomotion seem gender related, simply because ibogaine
is a great deal more potent throughout female rats (66). Ibogaine-induced inhibition associated with
morphine - induced hyperlocomotion can be reversed by simply coadministration of your kappa
antagonist (norbinaltorphine, 10 mg/kg) and an NMDA agonist (NMDA, 20 mg/kg). However, neither
norbinaltorphine nor NMDA by yourself blocked this motion of ibogaine (88).
O-Desmethylibogaine (10-40 mg/kg) additionally inhibited morphine-induced hyperlocomotion
throughout female rats. Nevertheless in male rats, the dose involving ten mg/kg potentiated and 40
mg/kg inhibited morphine-induced hyperlocomotion (66,89).
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2. Tremor.
Like the somewhat structurally associated alkaloid harmaline, ibogaine generates tremors.
Throughout mice, ibogaine will be tremorigenic both when provided intracerebrally (ED50 127
nmol/g brain, ~ 46 g/g using a latency in order to tremor regarding about one minute) (90), along
with systemically (ED50 12 mg/kg, s.c.) (61). in rats, ibogaine produced fine tremors, flattening
regarding body posture, and flaccid hind limbs up to 2 hrs after administration associated with 40
mg/kg (i.p.) (91). Low-amplitude whole body tremors appearing within ten min following
administration associated with as little as ten mg/kg regarding ibogaine get additionally been
reported (92). O'Hearn et al., (93) reported in which a higher dose regarding ibogaine (100 mg/kg)
produced ataxia as well as high-frequency tremor in the head along with trunk throughout rats.
Ibogaine-induced tremor preferentially involves the head and upper extremity throughout rats and
mice (94). Ibogaine (20 mg/kg) - induced tremors in mice were blocked more potently through CCK-8
as well as ceruletide compared along along with other reference compounds, which includes prolyl-
leucylglycine amide (MIF), atropine, haloperidol, biperiden, ethopropazine, trihexyphenidyl,
methixene along with clonazepam (95).
Zetler et al., (61) established your tremorigenic structure-activity relationship of countless ibogaine-
like compounds inside descending order of potency: tabernanthine > ibogaline > ibogaine >
iboxygaine > O-desmethylibogaine. Glick et al., (96) found out that at behaviorally successful doses
(2-80 mg/kg) ibogaine, desethylcoronaridine, harmaline and also tabernanthine produced tremors
regarding at least 2-3 hours. Each your R and S enantioners regarding ibogamine and coronaridine
were devoid associated with this action. the ibogaine-like alkaloids, 18-methoxycoronaridine as well
as O-desmethylibogaine had been additionally located to be able to lack tremorigenic outcomes
(89,97).
The tremorigenic properties of ibogaine along with related compounds happen in order to be
attributed to an action in GABAergic pathways (98-100) along with for the blockade associated with
voltage-dependent sodium channels.
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3. Anxiety along with fear.
Schneider and Sigg (101) described the particular behavioral outcomes of ibogaine in cats. The
Particular authors concluded which after intravenous administration involving 2-10 mg/kg, ibogaine
produced fear-like reactions that will persisted for 10-20 minutes having a typical physical
appearance observed 1-2 hours right after injection. The Actual electroencephalographic pattern
obtained after ibogaine administration (2-5 mg/kg) confirmed an average arousal syndrome,
resembling that observed after direct stimulation in the reticular formation. This kind of arousal
syndrome had been inhibited simply by atropine (2 mg/kg) (101). Gershon as well as Lang (102)
described the results of ibogaine throughout dogs, which become more tense and also alert,
interpreted as the appearance involving anxiety. Moreover, these people observed the dogs
exhibited the insufficient recognition involving each his or her standard handlers and environment.
Recently, Benwell et al., (103) reported reductions throughout open up arm entries within the
elevated plus-maze test when rats were tested 22 hours right after pretreatment with ibogaine (40
mg/kg, i.p.). Throughout mice, ibogaine (2.5 mg/kg) exhibited anxiogenic actions, whereas a dose
associated with one mg/kg had anxiolytic effects (104). These are perhaps the most compelling
preclinical data which ibogaine may influence anxiety levels since anxiolytic agents (e.g.
benzodiazepines) increase open arm entries within this test.
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4. Outcomes on self-administration associated with additional drugs.
Ibogaine (40 mg/kg, i.p.) inhibits the actual self-administration associated with cocaine in rodents.
Cappendijk and Dzoljic (105) trained male Wistar rats to always be able to intravenously self-
administer cocaine; a single dose involving ibogaine (40 mg/kg) decreased cocaine consumption by
40-60% with regard to a quantity of days, as well as repeated therapy along with ibogaine in one-
week intervals decreased cocaine self-administration simply by 60-80%. This kind of decrease was
maintained pertaining to numerous weeks. Comparable results were seen in mice that will designed
a choice with regard to cocaine in the drinking water. Thus, ibogaine administration (two weeks
following the beginning of your choice period, 2 doses regarding 40 mg/kg, six hrs apart) diminished
cocaine preference pertaining to five days (70). According to Vocci and also London (106), some
investigators have failed to replicate ibogaine's effect about cocaine self-administration in the rat
(107) and rhesus monkey (108). also Dworkin et al., (109) reported in which neither 40 mg/kg
involving ibogaine provided 60 min prior towards the session, nor 80 mg/kg given round-the-clock
ahead associated with the session, suppressed responding maintained by intravenous cocaine
infusions. in this study, cocaine self-administration has been inhibited by simply pretreatment with
ibogaine (80 mg/kg) both 60 as well as 90 min prior towards the session (109). However, since this
dose associated with ibogaine reduced scheduled meals intake, these latter outcomes of ibogaine
about cocaine self-administration appear to be unspecific.
Glick et al., (96) demonstrated that will ibogaine along with several iboga alkaloids (tabernanthine,
R- and S-coronaridine, R- along with S- ibogamine, desethylcoronaridine, and harmaline) reduced
cocaine self-administration in rats inside a dose-related fashion (2.5-80 mg/kg). With Regard To a
range of alkaloids, these effects were seen the afternoon after injection. O-Desmethylibogaine (40
mg/kg) (89) and also 18-methoxycoronaridine (97) were in addition reported for you to inhibit
cocaine self-administration.
Ibogaine dose dependently (2.5-40 mg/kg) reduced intravenous morphine self-administration
throughout female Sprague-Dawley rats instantly right after injection too as on the overnight (68). In
certain animals, a new reduced morphine consumption has been observed for numerous days; other
rats required a range of doses associated with ibogaine to be able to achieve a prolonged reduction.
similar effects were demonstrated regarding additional ibogaine-like alkaloids which includes O-
desmethylibogaine (89), tabernanthine, R- as well as S-coronaridine, R- and S- ibogamine,
desethylcoronaridine, harmaline (96) as well as 18-methoxycoronaridine (97). However, information
via yet another study revealed somewhat various results. Thus, Dworkin et al., (109) found out that
ibogaine (40 or perhaps 80 mg/kg) diminished heroin self-administration within male Fisher rats
merely around the day it absolutely was administered. Moreover, the same research said that
ibogaine treatment resulted inside a 97% decrease in responding for a food reinforcement schedule,
suggesting that it is effects upon heroin self-administration had been unspecific.
Ibogaine-induced inhibition regarding morphine self-administration has been found being reversed
by simply sequential administration of your kappa antagonist (norbinaltorphine, 10 mg/kg) plus an
NMDA agonist (NMDA, twenty mg/kg). Neither norbinaltorphine nor NMDA on your own own were
effective on this respect (88).
Ibogaine (10-60 mg/kg) reduced alcohol consumption throughout alcohol-preferring Fawn Hooded
rats, without affecting both blood alcohol concentrations or perhaps food intake (110,111). Your
authors concluded which the metabolite could possibly be involved, simply because ibogaine has
been successful in this measure when administered intraperitoneally as well as intragastrically, but
not subcutaneously (112). The current research demonstrated an attenuation of drinking from the
ibogaine congener, 18-methoxycoronaridine in rats (113).
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5. Outcomes upon drug dependence.
Repeated administration of ibogaine (10 or perhaps 40 mg/kg) didn't generate dependence inside
rats as measured utilizing the actual primary Bodily Dependence test (114).
In morphine-dependent rats, the particular opioid antagonist naloxone induces a withdrawal
syndrome, characterized (in rats) by elevated rearing, digging, jumping, salivation as well as "wet-
dog" head shaking. Ibogaine dose-dependently reduced how often regarding many associated with
these withdrawal signs (jumping, rearing, digging, head hiding, chewing, teeth chattering, writhing,
penile licking) right after both intracerebroventricular (4-16 g) (115) as well as i.p. administration
(40 as well as 80 mg/kg) (74,116). However, these effects couldn't be replicated inside additional
studies in both rats (39,117) or mice (118). From least the second failure to become able to replicate
may be attributed to the fact that inside the Frances et al., (118) study, ibogaine had been
administered to animals which designed a full withdrawal syndrome. Throughout morphine-
dependent monkeys, ibogaine (2 and also 8 mg/kg, s.c.) partially suppressed your total variety of
withdrawal signs (114). Our studies (72,119) demonstrate that will ibogaine inhibits the morphine
withdrawal syndrome throughout mice in a dose-related fashion. This effect was reversed by simply
combining ibogaine remedy using glycine. Structure-activity studies said that amongst various
ibogaine-like compounds (including O-desmethylibogaine and also O-t-butyl-O-desmethylibogaine),
simply ibogaine inhibited your intensity involving morphine withdrawal (72). Each the particular
ability of glycine to become able to inhibit this impact regarding ibogaine and furthermore the
failure of additional ibogaine derivatives in order to potently inhibit the actual binding of
noncompetitive NMDA antagonists (e.g., [3H]-N-[1-(2-thienyl)cyclo-hexyl]-3,4-pi... (TCP) and [3H]-
MK-801) shows that the actual NMDA antagonist actions associated with ibogaine are usually
responsible for its anti-withdrawal effects. This particular hypothesis is supported from the
observation in which although O-desmethylibogaine and also O-t-butyl-O-desmethylibogaine had
higher affinities regarding kappa opioid receptors compared to ibogaine did, only ibogaine exhibited
an important affinity with regard to NMDA receptors.
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6. Pain and also analgesia.
Ibogaine didn't mimic the actual analgesic action of morphine in both the actual tail flick (1-40
mg/kg, i.p.) or perhaps hot plate (up to always be able to twenty mg/kg, i.p.) tests, though it
exhibited analgesic activity in the phenylquinone writhing test (ED50 9.7 mg/kg) (114,120,121).
Ibogaine did not exhibit antinociceptive exercise when offered twice a day with regard to 4 times
(122). Ibogaine either increased (120,123) or even failed to affect (114,121) morphine analgesia
within the tail flick test. Similarly, it did not influence analgesia produced simply by either any kappa
opioid agonist (U-50,488H) or even a delta opioid agonist [D-Pen2,D-Pen5]enkephalin (DPDPE)
(121). Ibogaine may be reported to lower analgesia throughout rats when offered 19 hours just
before morphine (123), however another statement signifies ibogaine isn't efficient when offered 4-
24 hours ahead of morphine administration throughout mice (121). Throughout addition, Cao along
with Bhargava (122) demonstrated that ibogaine (40-80 mg/kg) inhibited the development of
analgesia to become able to mu, although not kappa or perhaps delta, agonists within mice.
O-Desmethylibogaine (40 mg/kg) potentiated morphine-induced analgesia inside rats (123) and mice
(121). This kind of effect ended up being no longer apparent 19 hours after its administration (123).
The Particular potentiation involving morphine-induced analgesia could be attributed to the
relatively high affinity involving O-desmethylibogaine with opioid mu (Ki 2.66 0.62 M) and also
kappa (Ki 0.96 0.08 M) receptors (124). However, this interpretation appears unlikely simply
because O-desmethylibogaine pretreatment failed to influence both kappa - or even delta - opioid
agonist - induced antinociception (121).
Ibogaine (10-40 mg/kg) totally blocked the actual antinociceptive effect involving (-)-epibatidine in
rodents, but was ineffective when offered in a dose regarding 40 mg/kg 24 h just before epibatidine.
These information declare that it was an effect of ibogaine rather than that relating to its putative,
long-lasting metabolite (125). This specific blockade in the antinociceptive impact of epibatidine just
isn't surprising, simply because epibatidine-induced analgesia will be mediated by a mechanism
fundamentally various from those of your opioids.
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7. Aggression.
Compared along along with other psychoactive compounds (e.g. psilocybin, JB-336, and also
bufotenine), ibogaine (10 mg/kg) had a negligible impact on the aggressiveness regarding isolated
mice and also muricidal behavior throughout rats (126).
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8. Interoceptive properties.
Animals can easily learn to "recognize" parallels amongst drugs. Such discriminative (interoceptive)
properties could suggest the comparable mechanism regarding action definitely not related for the
construction of your compound.
No generalization among ibogaine along with serotonergic ligands (e.g. fenfluramine, N-(-
-trifluoromethylphenyl)piperazine [TFMPP], 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopr... [DOI],
methyl-enedioxymethamphetamine [MDMA], quipazine as well as LSD) had been seen in drug-
discrimination paradigms (127,128). However, Palumbo as well as Winter (129) do observe the
generalization among ibogaine (15-20 mg/kg) as well as dimethoxymethylamphetamine [DOM] (0.6
mg/kg), as well as among ibogaine along with LSD (0.1 mg/kg) in the two-lever discrimination task.
Since pizotyline (BC-105) blocked DOM-appropriate and also LSD-appropriate responses, an
involvement associated with 5-HT2 or even 5-HT1 receptors inside the stimulus properties of
ibogaine had been suggested. Similarly, zero generalization in between ibogaine and CGS 10476B (a
dopamine release-inhibiting agent) was discovered in the drug-discrimination paradigm (127).
In contrast, ibogaine substituted as a possible interoceptive cue inside mice educated to recognize
MK-801 (dizocilpine) (119), although not in order to [(+)-HA-966] (a reduced efficacy partial agonist
of the glycine site in the NMDA receptor) (130) inside a T-maze drug discrimination paradigm.
Helsley as well as colleagues (131) studied the actual interoceptive cue produced by simply ibogaine
inside male Fisher rats. The Actual occasion span of your ibogaine (10 mg/kg) cue says a new
maximum associated with ibogaine-appropriate responses had been observed with a 60 min
pretreatment time, and, in which at the pretreatment duration of eight hours, zero ibogaine-like
responses were observed. These kinds of findings, together along with observation that O-
desmethylibogaine substituted merely partially towards the ibogaine cue, declare that your
subjective outcomes of ibogaine aren't due in order to this putative metabolite. Your same study
however, revealed that harmaline completely substituted as an ibogaine cue (131). This kind of later
on finding indicates that animals could recognize the particular tremorigenic outcomes of ibogaine.
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9. Reinforcing effects.
Ibogaine will not appear to possess satisfying or even aversive effects as measured inside the
conditioned location preference/aversion test (132), a new preclinical procedure that may predict
abuse potential throughout humans. Nonetheless, exactly the actual same authors reported that
ibogaine (40 mg/kg) might attenuate the particular acquisition, although not expression of morphine
along with amphetamine place-preference throughout male rats (77,132,133). This particular dose of
ibogaine failed to interfere with just about all the acquisition regarding conditioned location aversion
induced by simply both naloxone or lithium chloride (132). Ibogaine (40 mg/kg, 22 hrs prior to the
test) attenuated the actual institution involving lithium- as well as morphine-induced conditioned
taste aversion (134). These results suggest a specific action involving ibogaine on the neurochemical
along with behavioral (both reinforcing as well as aversive) actions involving morphine as opposed to
upon opioid system(s), as the reinforcing results of naloxone were unaffected. Throughout assistance
to these findings, it has been reported in which ibogaine (20 or perhaps 40 mg/kg, 24 h prior for you
to the test) neither decreased the choice for a sweet answer nor attenuated conditioned preference
for any flavor formerly associated using sweet taste (135).
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10. Results upon studying as well as memory.
At any dose utilized inside the majority associated with contemporary behavioral studies inside
rodents (40 mg/kg), ibogaine has been found to end up being able to attenuate the acquisition of
spatial memory, maybe thanks for you to reductions inside locomotor exercise and in detection
regarding sensory details (78). However, in much lower doses (0.25 - 2.5 mg/kg), ibogaine also as O-
desmethylibogaine (but not necessarily O-t-butyl-O-desmethylibogaine) facilitated spatial memory
retrieval (136). Utilizing a spatial memory task, Helsley et al., (92) discovered that: 1) two doses
involving ibogaine (50 mg/kg, spaced by simply eight hours) decreased your response rate, however
did not affect acquisition rate; 2) ibogaine, even in the highest doses associated with 30 and 46
mg/kg given 20 min ahead regarding the mastering trial didn't affect job acquisition; 3) 30 mg/kg
associated with ibogaine administered just following your learning trial facilitated the consolidation
regarding memory trace.
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11. Cardiovascular actions.
Gershon as well as Lang (102) found that ibogaine produced the rise in blood pressure and elevated
heartrate in conscious dogs. These kind of effects were blocked simply by atropine (137). However,
inside anesthetized dogs, ibogaine produced the fall throughout blood pressure and reduced
heartbeat reduction, leading the authors to propose an interaction in between anaesthesia and the
cardiovascular outcomes of ibogaine (102). Schneider along with Rinehart (137) postulated any
centrally mediated stimulatory impact associated with ibogaine. Ibogaine furthermore potentiated
the pressor reaction to each adrenaline and also noradrenaline. more recently, Hajo-Tello et al.,
(138) discovered that tabernanthine (an alkaloid closely associated for you to ibogaine) induced an
adverse inotropic impact throughout electrically stimulated myocardial tissue along with a negative
chronotropic effect in the perfused rat heart. Tabernanthine in addition produced bradycardia as
well as hypotension throughout anesthetized rats along with dogs (139). Binienda et al. (140)
reported that will ibogaine (50 mg/kg) reduced heart rate in rats instantly after injection; this
reduction persisted as significantly as 90 minutes following injection.
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B. Human Studies.
Numerous psychotropic actions regarding ibogaine happen to end up being able to be reported.
These kinds of actions seem to depend upon each dose as well as setting. Throughout addition, the
psychoactive results of iboga extracts (which are likely to contain additional alkaloids and thus are
typically taken inside a ritualistic setting) could differ via those of ibogaine. Thus, users with the
crude extract associated with Tabernanthe iboga taken inside sufficiently higher doses get reported
fantastic visions, feelings regarding excitement, drunkenness, mental confusion as well as
hallucinations when (101). The Actual total extract regarding iboga shrub is certainly a new central
stimulant, as well as in higher doses may result in convulsions, paralysis last although not least
respiratory arrest. The Particular psychotropic actions involving the flower extract include visual
sensations; objects tend to be seen being flanked by specters as well as rainbows. Inside high doses
it might create auditory, olfactory as well as taste synesthesias. The Particular frame involving mind
continues to become able to be reported to vary from profound fear for you to frank euphoria (141).
When offered orally, both ibogaine and the total iboga extract elicits subjective reactions that will
last for approximately six hours. fifty percent associated with topics tend to be reported to encounter
dizziness, incoordination, nausea, as well as vomiting (7,33,142). Typically, the actual drug produced
a situation involving drowsiness in which subjects didn't need to move, open up their eyes, as well as
show up at to the environment. Many topics had been light-sensitive, and covered their eyes as well
as asked that the lights be turned off. Sounds as well as noises were disturbing. Ibogalin (0.1-1.2
mg/kg, p.o.), an alkaloid closely associated to ibogaine and a constituent of the total iboga extract,
failed to create psychotomimetic outcomes within humans (143). Ibogalin additionally differs from
ibogaine inside pharmacokinetics and tremorigenic activity (90).
The psychoactive properties of ibogaine and related compounds had been studied through Naranjo
(33,142) who reported in which patients described the psychic state produced through ibogaine (~
300 mg) as just like a fantasy state with out loss involving consciousness. Ibogaine-induced fantasies
[often described like a "movie run with substantial speed" or even "slide show" (7)] were reported as
rich throughout archetypal contents, involving animals and/or the niche with or even with out some
other individuals. These kind of fantasies had been an easy task to manipulate through both the
themes and additionally the psychotherapist (33,142). at higher doses, ibogaine appears to be able
to create visual along using other hallucinations associated using severe anxiety as well as
apprehension (101,144,145).
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VI. LETHALITY AND NEUROTOXIC EFFECTS.
The LD50 associated with ibogaine has been
established within guinea pig (82 mg/kg, i.p.) and rat
(327 mg/kg, intragastrically as well as 145 mg/kg,
i.p.) (60,146).
No significant pathological modifications in rat liver,
kidney, heart along with brain subsequent chronic
ibogaine remedy (10 mg/kg, regarding thirty days or
perhaps 40 mg/kg, for 12 days, i.p.) had been
reported (60). Sanchez-Ramos and also Mash (42) discovered absolutely no proof of gross pathology
inside African green monkeys provided ibogaine in doses associated with 5-25 mg/kg, p.o. with
regard to 4 consecutive days.
However, O'Hearn et al., (147,148) and O'Hearn and Molliver, (93) reported that will repeated
administration regarding ibogaine (100 mg/kg, i.p.) for you to rats caused your degeneration of your
subset associated with Purkinje cells inside the cerebellar vermis. This particular degeneration
ended up being accompanied by a loss associated with microtubule-associated protein two (MAP-2)
along with calbindin. Argyrophilic degeneration, astrocytosis and microgliosis were furthermore
observed. the damage seemed to be dependent on the existence associated with an intact inferior
olivary nucleus (149). Ibogaine-induced cerebellar toxicity appear to be independent in its action
from NMDA receptors, because neither MK-801 nor phencyclidine create the identical pattern
involving degeneration (150). the neurotoxic results of substantial doses associated with ibogaine
were confirmed in rats, but not mice, by simply Scallet et al., (151,152) as well as Molinari et al.,
(153), who, additionally discovered that the actual "typical" dose regarding 40 mg/kg failed to
generate significant injury to female rat cerebellum. the not enough neurotoxicity after lower,
behaviorally active doses associated with ibogaine has been additionally demonstrated simply by
showing which chronic administration (60 days) involving 10 mg/kg regarding ibogaine produced
simply no change in the quantity of Purkinje cerebellar cells (154).
In spite of these findings, examination involving cellular markers which tend to become more
sensitive toneurotoxic agents as compared to gross histology shows that ibogaine administration
could produce significant alternation in a excellent many other mind structures. Thus, O'Callaghan
et al., (155,156) reviewed your outcomes of acute and chronic administration regarding ibogaine
upon glial fibrillary acidic protein (GFAP) levels. Acutely, ibogaine elevated GFAP in both sexes;
whereas chronic administration (14 days) produced raises simply throughout females. Ibogaine -
induced changes in GFAP had been dose-related, and, contrary to other studies, observed inside
some other mind structures such as hippocampus, olfactory bulb, brain stem and also striatum.
Inside addition, these authors reported that will throughout females treated chronically using
ibogaine, severe hippocampal damage ended up being existing as measured by simply increases
within the cytoskeletal proteins neurofilament 68 (NF-68) along with beta-tubulin. These types of
latter markers indicate the damage-induced sprouting response (156). Ibogaine administration in
addition produced an increase in c-fos immunostaining in many mind aspects of mice along with
rats; the consequences within rats were observed in all cortical layers although in mice your
response has been restricted to cortical layer 2 (152). Human SK-N-SH neuroblastoma cells cultured
within the existence of 3-30 M ibogaine (but not O-desmethylibogaine or perhaps 18-
methoxycoronaridine) demonstrated concentration- along with time-dependent morphological
changes characterized through the loss involving processes, cell rounding, detachment and also
ultimately cell death (157). Comparable results were observed using primary cultures associated
with rat cerebellar granulae cells. Since within this study merely alkaloids that had marked affinity
at sigma2 websites were neurotoxic, Vilner et al., (157) proposed that sigma2 websites might be
implicated in the neurotoxicity of ibogaine. the neurotoxic results of ibogaine happen in order to be
not too long ago reviewed by Vocci and London (106).
Acute therapy with the ibogaine-like alkaloid, 18-methoxycoronaridine (100 mg/kg) failed to produce
gross pathological changes inside the cerebellum (97). Within contrast, an additional indole alkaloid,
harmaline, produced ibogaine-like degeneration involving Purkinje cells inside the cerebellar vermis
(93).
It may be reported that multiple doses of your non-NMDA antagonist (GYKI 52466) resulted inside a
substantially higher loss involving Purkinje cells along with microglial activation in comparison for
you to ibogaine (50-100 mg/kg) alone (158). Upon one other hand, the actual noncompetitive NMDA
antagonist MK-801 (1 mg/kg) markedly attenuated the amount of Purkinje cell loss caused by
ibogaine (158). This specific later on obtaining strongly sports ths notion in which losing cerebellar
Purkinje cells produced by ibogaine is unrelated to be able to its NMDA antagonist properties (159).
in fact, ibogaine could furthermore exhibit neuroprotective properties, reducing glutamate-induced
neurotoxicity within primary cultures regarding cerebellar granule cell neurons with an EC50
regarding 4-5 M (119). These neuroprotective outcomes of ibogaine have got lately been patented
through Olney (160). Constant having its properties as any possible NMDA antagonist, ibogaine
inhibited NMDA - induced lethality inside mice in the dose-dependent method (161), as well as
protected mice through maximal electroshock seizures (ED50 ~ 31 mg/kg) (162).
Phase I toxicity studies throughout drug-addicted people are in progress at the university of Miami
(42,163).
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VII. EFFECTS ON SPECIFIC NEUROTRANSMITTER SYSTEMS
A. Ibogaine Outcomes about Dopaminergic Systems.
Ibogaine (at concentrations 100 M) doesn't affect radioligand binding for you to dopamine
receptors (D1, D2, D3, D4) (164-166). The Particular affinity involving ibogaine regarding dopamine
transporters as measured by simply inhibition involving [3H]WIN 35,248, [125I]RTI-121 or
[125I]RTI-55 binding had been ~ 1.5 - 4 M (73,76,166,167). However, within an additional study,
ibogaine did not affect binding involving [3H]GBR-12935, the ligand that will furthermore appears
for you to label dopamine transporters (85). Ibogaine inhibited [3H]dopamine uptake in porcine
kidney cells transfected together with dopamine transporter using a Ki ~86 M (168).
The throughout vivo along with ex vivo outcomes of ibogaine on dopamine metabolism throughout
mesolimbic places with the rodent brain (striatum, nucleus accumbens) tend to be controversial and
also highly inconsistent. Throughout an make an effort to reconcile numerous contradictory findings,
one could note the following.
Dopamine concentrations tend to be reduced and also dopamine metabolites dihydroxyphenyl-acetic
acid (DOPAC) as well as homovanilic acid (HVA) tend to be elevated by ibogaine under certain
experimental conditions. for example, when either measurements are usually taken shortly (within
two h) after ibogaine administration or perhaps when relatively substantial concentrations ( 100
M) are employed (69,71,76,81,169-173). Reductions inside extracellular dopamine concentrations
had been furthermore observed right after administration of the number of ibogaine derivatives,
including O-desmethylibogaine (89) as well as 18-methoxycoronaridine (97).
When dopamine will be measured in longer durations right after ibogaine administration (e.g., up to
the week) or perhaps reduced concentrations (e.g., 10 M) are usually applied, brain
concentrations appear unchanged along with metabolite concentrations are usually decreased
(69,71,76,81,82,169,170,172).
The increased ranges regarding extracellular dopamine metabolites collectively together with
decreased or perhaps unchanged levels regarding dopamine suggests that ibogaine increases
dopamine turnover shortly after administration. This particular may end up being adopted with a
reduction in turnover that will could persist for the while after ibogaine administration. French et
al., (91) demonstrated that will doses involving ibogaine (~ 1.5 mg/kg, i.v.), lower when in
comparison to a "typical" dose of 40-80 mg/kg, markedly excited dopaminergic neurons inside the
ventral tegmental region of the rat.
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1. Dopaminergic effects: Pharmacological Specificity.
Administration of the kappa antagonist (norbinaltorphimine, ten mg/kg) and NMDA (10 mg/kg)
(either jointly or perhaps individually) reversed ibogaine (40 mg/kg) induced decreases in striatal
dopamine as well as raises throughout dopamine metabolites (88). Similarly, Reid et al., (172)
observed that the reduction in dopamine ranges produced by ibogaine (100 M ) had been
reversed through either naloxone (1 M) as well as norbinaltorphimine (1-10 M). However,
functionally opposite outcomes had been observed by Sershen et al., (174,175) which reported that
the ability of the kappa opioid agonist (U-62066) to end up being able to inhibit electrical- or
cocaine-induced [3H]dopamine release coming from mouse striatum was attenuated simply by
pretreatment involving mice together with ibogaine (40 mg/kg, i.p., 2 hours prior; or 2 x 40 mg/kg, 6
hours apart, killed 18 hours later) (174,175).
Ibogaine-induced dopamine launch in the isolated mouse striatum may be studied through Harsing
et al., (176). Ibogaine increased basal tritium outflow ([3H]dopamine (DA) along with [3H]DOPAC),
however ended up being without having impact upon electrically stimulated tritium overflow. This
specific dopamine releasing effect was: a) reduced through the dopamine uptake inhibitors cocaine
as well as nomifensine, b) unaltered through omission regarding Ca++ from the perfusion buffer, c)
tetrodotoxin insensitive, d) unaffected through an agonist (quinpirole) or even an antagonist
(sulpiride) with the D2 dopamine receptor, as well as e) unaffected by pretreatment using reserpine.
Throughout this study, ibogaine didn't affect dopamine uptake, whereas Reid et al., (172) found that
both ibogaine as well as harmaline (10 M-1 mM) inhibited it. Since mentioned above, ibogaine
continues to end up being able to be reported in order to inhibit radioligand binding for the
dopamine transporter together with relatively high affinity.
Sershen et al., (177) reported an involvement regarding serotonin receptors inside the regulation of
dopamine launch through ibogaine. Thus, administration regarding ibogaine blocked the ability of
the 5HT1B agonist (CGS-12066A [10 M]) in order to improve [3H]dopamine increase in striatal
slices. Throughout some other studies, a concentration regarding ibogaine (1 M) that was with
out impact in dopamine efflux inhibited each NMDA (25 M) and ( )pentazocine (100 nM) -
induced dopamine release in striatal slices (178).
There are usually couple of studies in the outcomes of ibogaine-like alkaloids about dopamine
metabolism. Such As ibogaine, O-desmethylibogaine acutely decreases dopamine launch within the
rat nucleus accumbens and also striatum (89). Administration in the R- entantiomers associated with
coronaridine along with ibogamine decreased dopamine levels throughout both nucleus accumbens
and also striatum, whereas the S-enantiomers produced zero significant alterations in dopamine
levels either in region (96).
In an make an effort to reconcile several conflicting findings, Staley et al., (167) proposed that
ibogaine might market redistribution of intraneuronal dopamine through vesicular for you to
cytoplasmic pools. Ibogaine displays micromolar affinity for vesicular monoamine transporters
labeled using [125I]-tetrabenazine (167); these sites are really important for that translocation
involving dopamine directly into synaptic vesicles. the inhibitory effect of ibogaine in vesicular
monoamine transporters could result in redistribution involving dopamine in the cytoplasm. Beneath
such conditions, rapid metabolic rate of dopamine by monoamine oxidase would account for the
reduction in tissue dopamine content material as well as the parallel boost in its metabolites.
Multiple transmitter techniques have been proven to modulate dopaminergic function inside the
central nervous system. because ibogaine can easily interact along with many of those systems,
which includes kappa opioid receptors, NMDA receptors, serotonin receptors, and also dopamine
transporters, it is not shocking this alkaloid can create complex (and sometimes apparently opposite)
outcomes on dopaminergic function. Thus, the particular outcomes of ibogaine on dopaminergic
operate described in this section most likely reflect the actual dose (or concentration) involving
alkaloid, preparation employed (e.g., slice versus intact animal), and also mind region studied.
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2. Ibogaine alters the actual results of abused drugs on dopaminergic systems.
In general, ibogaine attenuates your increases within mesolimbic dopamine produced by drugs (e.g,
nicotine, morphine) that seem to behave preferentially with dopaminergic cell bodies. Within the
situation of drugs in which act in terminal regions (e.g., cocaine and also amphetamine), a new
gender distinction has been observed. in female rats, ibogaine enhances stimulant-induced raises
throughout dopamine concentrations, whereas it decreases the actual outcomes of these stimulants
in male rats as well as mice.
Neurochemical studies were performed in male mice provided a pair of doses associated with
ibogaine (40 mg/kg, i.p., 18 hrs apart) followed by amphetamine (5 mg/kg) administered two hours
after the second dose of ibogaine (81). Striatal ranges involving dopamine as well as dopamine
metabolites [DOPAC, HVA and also 3-methoxytyramine (3-MT)] measured one hour following
amphetamine were decreased in mice that will received ibogaine compared to saline-pretreated,
amphetamine-treated controls. In Comparison for you to controls, amounts of DOPAC as well as HVA
had been decreased in the amphetamine along with ibogaine groups, and further decreased within
the team that will received ibogaine along with amphetamine. However, inside female rats,
amphetamine-induced raises inside extracellular dopamine concentrations inside each your striatum
and furthermore the nucleus accumbens had been further potentiated by ibogaine (40 mg/kg, i.p., 19
hours preceding amphetamine) (82). Similarly, Glick et al., (169) found that ibogaine potentiated
amphetamine-induced increases throughout extracellular dopamine concentrations in female rat
nucleus accumbens as well as striatum. Inside this study, however, no impact regarding ibogaine
ended up being seen about amphetamine-induced decreases throughout extracellular concentrations
regarding dopamine metabolites. Similarly, ibogaine potentiated cocaine-induced raises throughout
extracellular dopamine ranges within striatum as well as nucleus accumbens associated with female
rats (84). However, quite opposite data were obtained by simply Broderick et al., (85,86) which
analyzed Gated House Chevy Chase MD dopamine launch within male rats making use of
semiderivative inside vivo voltametry. Within these experiments, ibogaine (40 mg/kg i.p. given
regarding 4 days) reduced the boost in dopamine release coming from nucleus accumbens induced
by simply cocaine (20-40 mg/kg, s.c.). A New presynaptic mechanism for these actions ended up
being suggested. An inhibitory effect of ibogaine about amphetamine metabolic process may be
proposed (179), simply because amphetamine amounts were higher following ibogaine
administration in female rats. However, ibogaine administration had no effect upon mind cocaine
ranges (169).
Ibogaine (40 mg/kg, i.p. in rats) offered 19 hrs prior to morphine (5 mg/kg) prevented the rise in
extracellular dopamine concentration within the striatum, prefrontal cortex along with nucleus
accumbens typically observed throughout rats (71,83). However, in the ibogaine as well as morphine
group, the particular ranges involving dopamine metabolites were elevated (as has been observed
within the morphine group), suggesting in which ibogaine failed to stop morphine via activating
dopamine neurons. The Actual authors claim that ibogaine therapy might alter the properties
associated with dopaminergic neurons inside this kind of method that dopamine launch is actually
unaffected beneath normal conditions, but altered when stimulated (in this case, by simply
morphine). Nineteen hrs after placebo as well as ibogaine (10 mg/kg, i.p.), female rats responded
similarly along with elevated dopamine launch inside nucleus accumbens subsequent a morphine
challenge (180). However, in rats that will received a pair of doses associated with morphine in your
course of two times preceding the actual experiment, ibogaine pretreatment had inhibitory results
about dopamine reaction into a morphine challenge. Any pharmacokinetic explanation for your
outcomes of ibogaine on morphine-induced actions will be unlikely, since ibogaine (40 mg/kg, i.p. 19
hours prior to measurement) failed to modify brain levels of morphine (10 mg/kg) in rats (71).
Benwell et al., (103) reported that will ibogaine (given 22 hrs prior to nicotine) attenuated the boost
in dopamine overflow within the nucleus accumbens evoked by nicotine administration. similar
results had been demonstrated, when ibogaine was administered 19 hrs just before nicotine infusion
(181).
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B. Opioid Systems
At concentrations regarding up to one hundred M, ibogaine has been reported never to affect
[3H]carfentanil or even [3H]enkephalin binding indicating this alkaloid will not affect mu as well as
delta opioid receptors (124,165). Within contrast, Pearl et al., (124) along with Sweetnam et al.,
(166) demonstrated which ibogaine inhibited radioligand binding in order to mu opioid receptors
together with Ki values ~ 11-20 M. Ex vivo studies demonstrated which ibogaine and also O-
desmethylibogaine enhanced the particular inhibition of adenylyl cyclase activity by a maximally
successful concentration of morphine in the rat frontal cortex, midbrain and striartum (182). This
specific later on impact isn't likely mediated through a new immediate action at opioid receptors
because it was observed in maximally efficient concentration involving morphine.
Ibogaine inhibits (Ki ~2-4 M) [3H]U-69593 binding for you to kappa opioid receptors
(56,72,124,165). This particular binding can be reversible, suggesting that the long-term outcomes
of ibogaine can't be attributed to an irreversible impact only from that site. Recently, Codd (183)
demonstrated that will ibogaine inhibits binding in order to sites labeled by [3H]naloxone
characterized with a two-site model, with Ki values associated with 130 nM as well as 4 M.
O-Desmethylibogaine were built using a higher affinity compared to ibogaine for most of the
particular opioid receptors studied: kappa Ki ~ one M, mu Ki ~ 2.7 M and also delta Ki ~ 24.7
M (124) (a recent research confirmed higher affinity involving O-desmethylibogaine at the mu
receptor; Ki ~ 160 nM (184)). Our perform (72) demonstrated that O-desmethylibogaine were built
together with a 10- in order to 100-fold higher affinity for kappa receptors compared to become able
to ibogaine. The Actual magnitude associated with this potency difference has been species-specific
(e.g., inside rats: IC50 ~ 0.3 M with regard to O-desmethylibogaine as well as IC50 ~30 M for
ibogaine). The Particular same research demonstrated a new reasonable affinity associated with O--
-butyl-O-desmethylibogaine with regard to kappa receptors (IC50 ~17 M in rat forebrain)
suggesting that if any 1 of ibogaine's in vivo actions are produced with kappa receptors, then O--
-butyl-O-desmethylibogaine would be active. Inside this respect, O-t-butyl-O-desmethylibogaine did
not influence the morphine withdrawal syndrome (72) in doses comparable in order to ibogaine.
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C. Serotonergic Systems.
Ibogaine (at concentrations approximately one M) had no impact upon [3H]serotonin binding
(185) along with concentrations associated with up to 3.5 M had zero impact in [3H]LSD binding
(186). A Lot More latest studies using serotonin subtype selective ligands are discrepant. Deecher et
al., (165) reported that will ibogaine didn't displace ligands acting at 5-HT1a, 5-HT1b, 5-HT1c, 5-
HT1d, 5-HT2, or perhaps 5-HT3 receptors. However, Repke et al., (56) reported which ibogaine
inhibited binding of 5-HT1a, 5-HT2a, or even 5-HT3 ligands together with lower affinity (Ki values:
>100, 12.5 as well as >100 M, respectively) along with Sweetnam et al., (166) reported IC50
values regarding ~ 4 M to inhibit radioligand binding to end up being able to both 5-HT2, as well
as 5-HT3 receptors.
Despite these discrepancies, each ex vivo as well as in vivo studies suggest that ibogaine could affect
serotonergic transmission. Ex vivo studies indicate that will ibogaine as well as O-desmethylibogaine
enhance the particular inhibitory outcomes of serotonin on adenylyl cyclase activity inside rat
hippocampus (182). Broderick et al., (86) reported that ibogaine (40 mg/kg, i.p. regarding 4 days)
elevated 5-HT concentrations inside rat nucleus accumbens. Constant with this finding, Ali et al.,
(171) demonstrated that ibogaine elevated 5-HT ranges inside striatum. Sershen et al., (76) reported
which ibogaine (40-50 mg/kg) decreased levels involving the serotonin metabolite 5-hydrox-
-indoleacetic acid [5-HIAA] inside mouse frontal cortex, hippocampus and also olfactory tubercle 2
as well as a day after injection. Ibogaine also decreased 5-HIAA levels throughout rat nucleus
accumbens and striatum (103,171), however elevated 5-HIAA and decreased 5-HT (lasting no less
than 7 days) inside medial prefrontal cortex (103). Lengthy and Lerrin (187) demonstrated which
ibogaine is really a reversible inhibitor with the active transport involving serotonin into blood
platelets, a locating supported by a current observation which ibogaine inhibited serotonin
transporters (in any porcine kidney cell line) using a Ki ~ 10 M (168).
Sershen et al., (177) demonstrated which ibogaine inhibited your ability of the 5-HT1b agonist (CGS-
12066A) in order to boost stimulation-evoked [3H]dopamine release through both rat and also
mouse striatal slices. Additionally, ibogaine increased your ability of a 5-HT3 agonist
(phenylbiguanide) in order to enhance stimulation-evoked [3H]dopamine launch in the mouse
striatal slice (174). in these studies, ibogaine (40 mg/kg, i.p.) has been administered two hours just
before slice preparation. in additional studies, ibogaine (20 mg/kg) enhanced cocaine-induced
reductions throughout serotonin concentration within the nucleus accumbens (rat), an action
attributed to some presynaptic launch mechanism (85,86). However, Sershen et al., (175) reported
which cocaine elevated [3H]serotonin efflux throughout striatal slices which efflux was absent within
mice pretreated using both ibogaine or maybe a 5-HT1b agonist. These kinds of later findings led
Sershen for you to suggest an action involving ibogaine in the HT1b receptor which is likely
unrelated to the capability associated with cocaine to become able to inhibit serotonin reuptake
blockade (188). Your inhibitory effect of the kappa-opioid agonist U-62066 (1M) in [3H]serotonin
release throughout striatal slices could possibly be blocked simply by in vivo ibogaine administration
(175).
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D. Calcium Regulation.
Ibogaine (80 M) non-competitively antagonized calcium-induced contraction associated with rat
aorta along with mesenteric artery (138), which usually was interpreted as an action in intracellular
calcium metabolism. Tabernanthine, an alkaloid related to be able to ibogaine, inhibited
depolarization-stimulated 45Ca influx along with contractions inside the rat aorta (189). Ibogaine
inhibited the binding involving [3H]isradipine (an L-type calcium channel blocker) in the mouse
cerebral cortex with an IC50 associated with ~28 M (11).
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E. Cholinergic Systems.
Ibogaine (at concentrations involving as significantly as 100 M) was reported not to inhibit the
particular binding involving ligands acting with nicotinic or even muscarinic receptors (165).
However, subsequent studies demonstrated in which ibogaine inhibited the particular binding
regarding muscarinic M1, M2 as well as M3 ligands at concentrations involving ~ 31, 50 and also
12.5 M, respectively (56). Sweetnam et al., (166) showed that ibogaine inhibited radioligand
binding in order to M1, and also M2 receptors along with IC50 values of 5-7 M. These kinds of
authors additionally reported that ibogaine didn't inhibit the actual binding regarding [3H]NMCI,
any nonselective ligand in nicotinic receptors. Ex vivo research has demonstrated that neither
ibogaine nor O-desmethylibogaine affect your inhibitory motion in the muscarinic acetylcholine
agonist, carbachol upon adenylyl cyclase exercise in the rat (182).
In a new current study, Badio et al., (125) demonstrated in which ibogaine potently (IC50 ~ twenty
nM) blocked 22NaCl influx by means of nicotinic receptor channels throughout rat
pheochromocytoma cells. This particular effect was seen inside the cells expressing ganglionic,
however, not neuromuscular, nicotinic receptor subtypes. This specific inhibition was
noncompetitive since it had not been overcome simply by growing concentrations regarding agonist.
Moreover, the actual blockade had not really been completely reversible, suggesting in which
ibogaine could use a long-lasting effect. O-Desmethylibogaine and O-t-butyl-O-desmethylibogaine
were 75- and also 20-fold less potent, respectively, than ibogaine in blocking nicotinic receptor-
mediated responses. the identical research demonstrated that will ibogaine, as expected to get a
noncompetitive blocker, stood a relatively lower affinity (Ki ~ 4 M) as a new possible inhibitor in
the binding of an agonist [3H]nicotine. in support about bat roosting findings, Schneider et al., (190)
reported just lately that will ibogaine ( 10 M) had an inhibitory action in nicotinic receptor-
mediated catecholamine release in bovine adrenal chromaffin cells. Constant with the Badio et al.,
(125) study, these inhibitory outcomes appeared being long-lasting.
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F. Gamma-Aminobutyric Acidergic [GABAergic] Systems.
Two impartial studies (165,166) did not locate virtually any impact regarding ibogaine (at
concentrations associated with as significantly as 100 M) in radioreceptor binding to GABAA
receptors. Inside addition, ibogaine didn't influence 36Cl- uptake through GABA-gated channels
(165) as well as GABA-evoked currents throughout rat cultured hippocampal neurons (162).
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G. Voltage-Dependent Sodium Channels.
Ibogaine inhibited (Ki ~ 8.1 M) [3H]batrachotoxin a 20-a-benzoate binding for you to voltage-
dependent sodium channels in depolarized mouse neuronal preparations (165). Ibogaine analogs,
including ibogamine, tabernanthine and also coronaridine, exhibited potencies much like ibogaine in
this assay.
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H. Glutamatergic Systems.
Our studies (159) indicate which ibogaine is a competitive inhibitor associated with [3H]MK-801
binding (Ki ~1 M) to NMDA receptor-coupled ion channels. Within contrast, ibogaine didn't affect
[3H]( )- a new -amino-3-hydroxy-5-methylisoxazole-4-pro... acid ([3H]AMPA), [3H]kainate as well
as [3H]glutamate either to the actual NMDA or perhaps metabotropic receptor sites, binding. These
kinds of findings tend to be constant with a specificity regarding ibogaine with regard to NMDA
receptor-coupled cation channels (159,162,166). The Actual potency involving ibogaine to inhibit
[3H]MK-801 binding was also looked at within 8 distinct brain regions of Sprague-Dawley male rats
along with compared with just about all the dissociation constants with regard to [3H]MK-801
estimated making use of saturation analyses. a high correlation (r=0.976, p=0.0004) has been
obtained between the Ki of ibogaine along with Kd associated with [3H]MK-801 over these mind
regions (119), steady with all the notion in which these compounds reveal the typical binding site.
The Actual capability associated with ibogaine to behave as being a non-competitive NMDA
antagonist can also be demonstrated making use of [3H]1-[1-(2-thienyl)cyclohexyl]piperidin...
([3H]TCP), a new thienyl derivative associated with phencyclidine, resulting inside a Ki ~1.5 M
inside rat forebrain (119).
Structure-activity studies had been performed using a group of ibogaine analogs, such as the
particular putative ibogaine metabolite O-desmethylibogaine, its metabolic rate resistant analog O--
-butyl-O-desmethylibogaine, your iboga alkaloids [( )-ibogamine, ( )-coronaridine,
tabernanthine], harmaline, and also indolotropanes. Ibogaine was the particular strongest inhibitor
of [3H]MK-801 binding (Ki ~ 1.2 M); the particular compounds using the greatest structural
similarity to always be able to ibogaine, O-desmethylibogaine along with O-t-buty-
-O-desmethylibogaine were a smaller sized amount potent (Ki ~ 5.5 along with 179.0 M
respectively) (72). a ~ 5 fold lower affinity of O-desmethylibogaine compared to ibogaine in [3H]MK-
801 binding websites has been furthermore reported by Mash et al., (191).
Consistent using these neurochemical studies, ibogaine produced the voltage-dependent block of
NMDA-evoked currents inside hippocampal cultures (119,162). in addition, ibogaine (100 M) as
well as O-desmethylibogaine (1 mM) blocked the capability associated with NMDA (100 M, 5 sec)
to always be able to depolarize frog motoneurons in a non-competitive and also use-dependent
manner (192).
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I. Sigma Receptors.
In our studies (11), ibogaine inhibited [3H]pentazocine (a sigma1 receptor ligand) binding, for you to
high (IC50 ~86 nM) as well as lower (IC50 ~5.6 M) affinity websites inside mouse cerebellum.
Bowen et al., (193) demonstrated that will ibogaine had higher affinity pertaining to sigma2 web
sites (Ki ~ 200 nM) and low affinity regarding sigma1 sites (Ki ~ 8.5 M), a new ~ 43- fold
selectivity pertaining to sigma2 sites. the affinities associated with tabernanthine (13-
methoxyibogamine) and ( )-ibogamine pertaining to sigma2 websites had been just like that
relating to ibogaine. O-Desmethylibogaine, stood a markedly reduced affinity regarding sigma2 web
sites (Ki ~ 5 M) and within addition lacked affinity pertaining to sigma1 sites. The Actual related
alkaloids, ( )-coronaridine [( )-18-carbomethoxyibogamine] as well as harmaline lacked affinity
for both sigma receptor subtypes. O-t-Butyl-O-desmethylibogaine inhibited radioligand binding to
sigma1 sites having a Ki ~ 3.5 M and sigma2 sites using a Ki ~ 346 nM [c.f. Bowen et al, (72)].
The Particular much higher affinity involving ibogaine regarding sigma2 websites compared to
sigma1 websites had been also reported through Mach et al., (194). Bowen et al., (195) examined
your capacity of ibogaine and associated compounds in order to modulate calcium launch from
intracellular shops within indo-1 loaded human SK-N-SH neuroblastoma cells. consistent having its
affinity with sigma2 sites, ibogaine produced any concentration-dependent increase (13-45%) inside
intracellular calcium levels. O-Desmethylibogaine, has been ineffective on this measure in
concentrations as a lot as 100 M. These kind of data claim that the particular shared inside vivo
results of ibogaine and O-desmethylibogaine are nearly all likely not mediated by simply sigma sites.
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J. Miscellaneous Actions regarding Ibogaine.
Deecher et al., (165) reported that will ibogaine (up to one hundred M) did not inhibit radioligand
binding in order to cannabinoid receptors. Ibogaine and O-desmethylibogaine had simply no relation
to basal as well as forskolin-stimulated adenylyl cyclase within the rat frontal cortex, midbrain or
even striatum (182). O-Desmethylibogaine, although not ibogaine, produced concentration -
dependent increases within the generation of [3H]inositol phosphates that will are not altered by
inclusion of tetrodotoxin, cadmium or even omega-conotoxin (196). These kinds of outcomes declare
that the result associated with O-desmethylibogaine upon phosphoinositide hydrolysis was not
secondary for the launch of one as well as much more neurotransmitters. Ali et al., (45) reported
that ibogaine (0.5-250 M) reduced nitric oxide synthase exercise inside mouse brain; similar
effects were noted in the striatum, hippocampus and also cerebellum involving mice handled
parenterally with ibogaine (50 mg/kg). Within radioligand binding studies, no impact of ibogaine
continues for you to be entirely on alpha1, alpha2 or perhaps beta1 adrenergic receptors (165).
Moreover, ibogaine (20 mg/kg) didn't modify cerebral noradrenaline ranges throughout rats (197).
Binienda et al., (140,198) reported in which although ibogaine (50 mg/kg) challenge in rats was
related using a decrease in delta, theta, alpha and also beta power spectra associated with cortical
EEG in the program of the first 30 min, and subsequent recovery of all except delta bands in the
subsequent 15 min, MK-801 (1 mg/kg) treatment had been followed with a reduction in power of all
four frequency bands for that entire duration of recording. Your selective energy reduction in delta
EEG frequency band of the cortical EEG could suggest your activation involving dopamine receptors.
In the anesthetized rat, ibogaine produced any slight hypoglycemia (60). Right After administration
associated with 50 mg/kg regarding ibogaine, elevations regarding corticosterone levels had been
noted 15 - 120 min, however, not a day later on (170,171,173). The Actual same dose of ibogaine
rapidly as well as transiently increased plasma prolactin amounts (171,173). Bunag along with
Walaszek (199) reported that ibogaine antagonized the contractile responses produced in guinea pig
ileum by simply substance P and also angiotensin. Alburges along with Hanson (200) reported which
ibogaine administration produced increases involving neurotensin-like immunoreactivity in striatum,
nucleus accumbens along with substantia nigra and also substance P -like immunoreactivity within
striatum and also substantia nigra. Ibogaine or even harmaline suppressed several (T-cell regulatory
and effector, B-cell, and natural killer cell) immune capabilities within vitro (201). Van Beek et al.,
(17) reported that ibogaine showed exercise against the gram-positive Bacillus subtilis. Ibogaine did
not alter colonic temperature within mice, nor achieved it affect morphine- or even kappa [U-
50,488H]-opioid induced hypothermia (121).
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VIII. CONCLUSIONS.
The renewed curiosity about ibogaine during days gone by decade stems from anecdotal clinical
observations in which ibogaine supplies a novel means of treating drug addictions. Preclinical
studies are, within general, consistent using these claims. Thus, ibogaine decreases self-
administration involving cocaine and morphine, attenuates morphine withdrawal, along with blocks
conditioned location choice produced by simply morphine along with amphetamine. Preclinical
studies also suggest there's absolutely no abuse liability associated with ibogaine. at doses in which
hinder tolerance and dependence phenomena, mind concentrations regarding ibogaine have reached
ranges that will can impact many different neurotransmitter systems. Numerous of those results
(e.g., use dependent block associated with NMDA receptor-coupled cation channels, interactions
together with dopamine transporters as well as kappa opioid receptors) have got previously been
implicated throughout drug seeking phenomena. However, in the current time, the only mechanism
which may be invoked to end up being able to explain ibogaine's results about drug seeking
phenomena with some certainty will be its ability to inhibit naloxone-precipitated jumping by means
of blockade associated with NMDA receptors. Nonetheless, it's even now uncertain if the anti-
addictive properties regarding ibogaine outcome from the single mechanism or are produced at
multiple loci.
The involvement regarding dopaminergic pathways inside drug seeking phenomena can always be
viewed dogma, and also ibogaine undoubtedly affects these pathways. Nonetheless, based on
available data zero distinct picture provides emerged about how this interaction contributes towards
the anti-addictive properties of ibogaine, or perhaps any other anti-addictive medications. Extra
systematic studies are obviously needed. Anecdotal studies claim long term outcomes of ibogaine in
drug seeking next a single administration or perhaps brief course of therapy. This specific claim may
be borne out, a minimal of in part, by simply preclinical studies. Based about these observations, it is
unlikely that ibogaine serves merely as substitution therapy. The idea has been hypothesized that
will a long-lived metabolite is responsible for ibogaine's putative anti-addictive properties,
nevertheless further studies are required on this area.
One in the central concerns regarding the particular molecular mechanisms responsible for the anti-
addictive actions of ibogaine is regardless of whether or not its NMDA antagonist motion is plenty
for you to explain these effects. Thus, there is an established body associated with preclinical data
(and an emerging body of clinical data) demonstrating which NMDA antagonists interrupt drug
seeking phenomena to a variety regarding addictive substances. Although it is now more successful
that ibogaine is a noncompetitive NMDA antagonist (albeit 1000-fold less potent compared to
prototype compound, dizocilpine), with the exception involving its capability to block naloxone
precipitated jumping in morphine-dependent mice, it's uncertain if these outcomes can be attributed
to other mechanisms.
Recent structure exercise studies demonstrate which O-desmethylibogaine, which is much less
potent as compared to ibogaine from NMDA receptors, appears as active as ibogaine within acutely
blocking morphine along with cocaine self-administration. This kind of observation strongly points
too various other mechanisms may become operative. a comparable argument can be designed for
harmaline, which is somewhat structurally associated in order to ibogaine and also shares a few of
its pharmacological actions (e.g., tremor and also neurotoxic effects, reductions within cocaine as
well as morphine self-administration), nevertheless isn't an NMDA antagonist. Even though
inhibition associated with drug self-administration by simply harmaline might be thanks in order to
unspecific results (e.g., general malaise), these findings nonetheless enhance the possibility which
ibogaine's anti-addictive properties might become produced by means of multiple mechanisms. The
Particular involvement of sigma sites over these phenomena appears to become even more obscure
simply because in contrast in order to ibogaine, harmaline features absolutely no appreciable affinity
with sigma web sites whereas O-desmethylibogaine lacks affinity with a sigma2 site, yet all three
block cocaine along with morphine self-administration.
Ibogaine could affect a number of areas of serotonergic transmission with concentrations that are
readily achieved inside the brain next pharmacologically relevant doses [reviewed simply by Sershen
et al., (188)]. Since multiple serotonin receptor subtypes, as well as serotonin reuptake, are usually
modulated by simply ibogaine, it just isn't shocking the results of this alkaloid on steady state
amounts associated with serotonin as well as its metabolites (whether measured throughout situ or
perhaps ex vivo) are complex. Clearly, further studies tend to be required to look at the efficacy of
ibogaine as a new possible anti-addictive agent. Similarly, extra preclinical studies is planning to be
needed to elucidate the actual molecular mechanism(s) accountable for these pharmacological
actions.
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IX. Acknowledgments
The authors thank Dr. H. Sershen with regard to beneficial discussions on the outcomes of ibogaine
upon dopaminergic as well as serotonergic transmission.
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X. REFERENCES
1. A. Lecomte, Arch. Med. Navale 2, 264 (1864).
2. R. Goutarel, O. Gollnhofer, along with R. Sillans, Psychedc Mono. Essays 6, 71 (1993).
3. H.S. Lotsof, U S Patent 4,499,096, (1985).
4. H.S. Lotsof, U S Patent 4,587,243, (1986).
5. H.S. Lotsof, U S Patent 4,857,523, (1989).
6. H.S. Lotsof, U S Patent 5,026,697, (1991).
7. H.S. Lotsof, Bull. MAPS 5, 16 (1995).
8. C.D. Kaplan, E. Ketzer, J. de Jong, along with M. de Vries, Soc. Neurosc. Bull.n 6, six (1993).
9. B. Sisko, Bull. MAPS IV, 15 (1993).
10. P. Popik and also S.D. Glick, Drugs Long Term 21, 1109 (1996).
11. P. Popik, R.T. Layer, and P. Skolnick, Pharmaco. Rev. 47, 235 (1995).
12. W.I. Taylor, within "The Alkaloids. Volume VIII. Chemistry and Physiology" (R.H.F. Manske, ed.),
p. 203, Academic Press, New York, London. 1965.
13. W.I. Taylor, within "The Alkaloids. Volume XI. Chemistry as well as Physiology" (R.H.F. Manske,
ed.), p. 79, Academic Press, New York, London. 1968.
14. R.E. Schultes as well as A. Hofmann, inside "The Botany and also Chemistry associated with
Hallucinogens." (R.E. Schultes as well as A. Hofmann, eds.), p. 235 Charles C. Thomas Publisher,
Sprinfield. 1980.
15. J.W. Fernandez, "Bwiti - an ethnography of religious imagination in Africa.". Princeton Press.,
Princeton, New Jersey, 1982.
16. H.G. Pope, Jr., Econ. Bot. 23, 174 (1969).
17. T.A. Van Beek, C. de Smidt, and also R. Verpoorte, J. Ethnopharmacol. 14, 315 (1985).
18. H. Baillon, Bull. Mens. Soc. Lin. de Paris 1, 782 (1889).
19. J. Dybovsky and also E. Landrin, Acad. Sci. (Paris) 133, 748 (1901).
20. A. Haller and also E. Heckel Compt. Rend. Soc Biol 133, 850 (1901).
21. M. Lambert and also E. Heckel, Compt. Rend. Acad. Sci. 133, 1236 (1901).
22. M. Lambert, Arch. Int. Pharmacodyn. 10, 101 (1902).
23. M.C. Phisalix, Compt. Rend. Soc. Biol. 53, 1077 (1901).
24. G. Pouchet and also J. Chevalier, Bull. Gen. Ther. 149, 211 (1905).
25. E. Rothlin along with M. Raymond-Hamet, Compt. Rend. Soc. Biol. 127, 592 (1938).
26. M. Raymond-Hamet along with E. Rothlin, Arch. Int. Pharmacodyn. Ther. 63, 27 (1939).
27. M. Raymond-Hamet, Compt. Rend. Soc. Biol. 134, 541 (1940).
28. M. Raymond-Hamet, Compt. Rend. Soc. Biol. 133, 426 (1940).
29. M. Raymond-Hamet, Compt. Rend. Soc. Biol. 211, 285 (1940).
30. M. Raymond-Hamet, Compt. Rend. Soc. Biol. 135, 176 (1941).
31. M. Raymond-Hamet, Compt. Rend. Soc. Biol. 212, 768 (1941).
32. M. Raymond-Hamet as well as D. Vincent, Compt. Rend. Soc. Biol. 154, 2223 (1960).
33. C. Naranjo, Clin. Toxicol. 2, 209 (1969).
34. F. De Sio, Medicina Dello Sport 23, 362 (1970).
35. H.S. Lotsof, U S Patent 5,152,994, (1992).
36. L.R. Regan, Justicia September, 1 (1992).
37. N. Touchette, Naturel Med. 1, 288 (1995).
38. FDA Advisory CMTE inside "The NDA Pipeline." (E. Clarke, C. Frederick, as well as K. Balog,
eds.), p. V-76 F-D-C Reports, Inc. Chevy Chase, MD, USA. 1993.
39. L.G. Sharpe and J.H. Jaffe, NeuroReport 1, 17 (1990).
40. N. Touchette, J. NIH Res. 5 (November), 50 (1993).
41. J. Buie, Psych. times XI (7), 44 (1994).
42. J. Sanchez-Ramos and D. Mash, Bull. MAPS 4, 11 (1994).
43. S.G. Sheppard, J. Subst. Abuse Treat.11, 379 (1994).
44. B.E. Judd, Ibogaine, psychotherapy, as well as the treatment method involving substance-related
disorders. Your Eighth International Conference upon Drug-related Harm. (1994).
45. S.F. Ali, S.C. Chetty, X.M. Meng, G.D. Newport, along with W. Slikker, J. Neurochem. 65, S172
(1995).
46. A. Landrin, Bull. Sci. Pharmacol. 11, 319 (1905).
47. W.I. Taylor, J. Am. Chem. Soc. 79, 3298 (1957).
48. G. Bchi, D.L. Coffen, K. Kocsis, P.E. Sonnet, as well as F.E. Ziegler, J. Am. Chem. Soc. 88,
3099 (1966).
49. P. Rosenmund, W.H. Haase, J. Bauer, along with R. Frische, Chem. Ber. 180, 1871 (1975).
50. E. Wenkert, D.W. Cochran, H.E. Gottlieb, as well as E.W. Hagaman, Helv. Chim. Acta 59, 2437
(1976).
51. H.H. Seltzman, D.F. Odear, F. Ivy Carroll, along with D. Wyrick, J. Chem. Soc. Chem. Commun.
1757 (1992).
52. H.H. Seltzman, D.F. Odear, as well as C.P. Laudeman, J. Labled. Compds. Radiopharm. 34(4),
367 (1994).
53. S. Budavari, M. O'Neil, A. Smith, P.E. Heckelman, and also J.F. Kinneary, "The Merck Index. An
Encyclopedia associated with Chemicals, Drugs and also Biologicals.". 12th Ed. Merck & Co., Inc.,
Whitehouse Station, N.J., USA, 1996.
54. G.P. Cartoni along with A. Giarusso, J. Chromatogr. 71, 154 (1972).
55. J.M. Kelley along with R.H. Adamson, Pharmacol. 10, 28 (1973).
56. D.B. Repke, D.R. Artis, J.T. Nelson, and E.H. Wong, J. Org. Chem. 59, 2164 (1994).
57. H.I. Dhahir, N.C. Jain, and also R.B. Forney, J. Foren. Sci. 16, 103 (1971).
58. H.I. Dhahir, N.C. Jain, and also J.I. Thornton, J. Foren. Sci. 12, 309 (1972).
59. E. Bertol, F. Mari, along with R. Froldi, J. Chromatogr. 117, 239 (1976).
60. H.I. Dhahir, Diss. Abstr. Int. 32/04-B, 2311 (1971).
61. G. Zetler, G. Singbarth, and also L. Schlosser, Pharmacol. 7, 237 (1972).
62. C.A. Gallagher, L.B. Hough, S.M. Keefner, A. Seyed Mozaffari, S. Archer, as well as S.D. Glick,
Biochem. Pharmacol. 49, 73 (1995).
63. W.L. Hearn, J. Pablo, G.W. Hime, and D.C. Mash, J. Anal. Toxicol. 19, 427 (1995).
64. M.E. Alburges, R.L. Foltz, along with D.E. Moody, J. Anal. Toxicol. 19, 381 (1995).
65. F.R. Ley, A.R. Jeffcoat, and B. Thomas, J. Chromatogr. A New 723, 101 (1996).
66. S.M. Pearl, L.B. Hough, D.L. Boyd, and S.D. Glick, Pharmacol. Biochem. Behav. 57, 809 (1997).
67. L.B. Hough, S.M. Pearl, as well as S.D. Glick, Existence Sci. 58, PL119 (1996).
68. S.D. Glick, K. Rossman, S. Steindorf, I.M. Maisonneuve, as well as J.N. Carlson, Eur. J.
Pharmacol. 195, 341 (1991).
69. I.M. Maisonneuve, K.L. Rossman, R.W. Keller, Jr., as well as S.D. Glick, Mind Res. 575, 69
(1992).
70. H. Sershen, A. Hashim, and A. Lajtha, Pharmacol. Biochem. Behav. 47, 13 (1994).
71. I.M. Maisonneuve, R.W. Keller, and S.D. Glick, Eur. J. Pharmacol. 199, 35 (1991).
72. R.T. Layer, P. Skolnick, C.M. Bertha, M.E. Kuehne, and also P. Popik, Eur. J. Pharmacol. 309, 159
(1996).
73. D. Mash, J.K. Staley, M.H. Baumann, R.B. Rothman, as well as W.L. Hearn, life Sci. 57, PL45
(1995).
74. S.D. Glick, K. Rossman, N.C. Rao, I.M. Maisonneuve, along with J.N. Carlson,
Neuropharmacology 31, 497 (1992).
75. G. Chen and B. Bohner, J. Pharmacol. Exp. Ther. 123, 212 (1958).
76. H. Sershen, A. Hashim, L. Harsing, and also A. Lajtha, Existence Sci. 50, 1079 (1992).
77. T. Luxton, L.A. Parker, and also S. Siegel, Prog. Neuro-Psych. Biol. Psych. 20, 857 (1996).
78. R.P. Kesner, P. Jackson-Smith, C. Henry, as well as K. Amann, Pharmacol. Biochem. Behav. 51,
103 (1995).
79. J.G. Page, L.E. Rodan, D.R. Franell, and J.F. Martin, NIDA Contract report SRI-CBE-94-002-7486,
(1994).
80. I.M. Maisonneuve, K.E. Visker, G.L. Mann, U.K. Bandarage, M.E. Kuehne, as well as S.D. Glick,
Eur. J. Pharmacol. 336, 123 (1997).
81. H. Sershen, L.G. Harsing, Jr., A. Hashim, and A. Lajtha, Lifestyle Sci. 51, 1003 (1992).
82. I.M. Maisonneuve, R.W. Keller, Jr., along with S.D. Glick, Mind Res. 579, 87 (1992).
83. I.M. Maisonneuve, Diss. Abst. Int. 1 (1992).
84. I.M. Maisonneuve as well as S.D. Glick, Eur. .J Pharmacol. 212, 263 (1992).
85. P.A. Broderick, F.T. Phelan, along with S.P. Berger, inside "NIDA Analysis Monograph No. 119.
Problems associated with Drug Dependence" (L. Harris, ed.), p. 285, U.S. Government Printing
Office, Washington, D.C., 1992.
86. P.A. Broderick, F.T. Phelan, F. Eng, and also R.T. Wechsler, Pharmacol. Biochem. Behav. 49, 711
(1994).
87. S.M. Pearl, D.W. Johnson, as well as S.D. Glick, Psychopharmacology 121, 470 (1995).
88. S.D. Glick, I.M. Maisonneuve, and S.M. Pearl, Mind Res. 749, 340 (1997).
89. S.D. Glick, S.M. Pearl, J. Cai, along with I.M. Maisonneuve, Mind Res. 713, 294 (1996).
90. G. Singbarth, G. Zetler, along with L. Schlosser, Neuropharmacology 12, 239 (1973).
91. E.D. French, K. Dillon, and S.F. Ali, Lifestyle Sci. 59, PL199 (1996).
92. S. Helsley, D. Fiorella, R.A. Rabin, as well as J. C. Winter, Pharmacol. Biochem. Behav. 58, 37
(1997).
93. E. O'Hearn and M.E. Molliver, Neuroscience 55, 303 (1993).
94. S.L. Costache "Pharmacological attenuation in the tremorigenic results of ibogaine."
Unpublished M.S. thesis. Albany Healthcare College, Albany, NY, USA, 1995.
95. G. Zetler, Neuropharmacology 22, 757 (1983).
96. S.D. Glick, M.E. Kuehne, J. Raucci, T.E. Wilson, D. Larson, R.W. Keller, as well as J.N. Carlson,
brain Res. 657, 14 (1994).
97. S.D. Glick, M.E. Kuehne, I.M. Maisonneuve, U.K. Bandarage, and H.H. Molinari, brain Res. 719,
29 (1996).
98. S.M. King as well as G. Tunnicliff, Biochem. Int. 20, 821 (1990).
99. E. Roberts, E. Wong, G. Svenneby, as well as P. Degener, Mind Res. 152, 614 (1978).
100. J.H. Trouvin, P. Jacqmin, C. Rouch, M. Lesne, and also C. Jacquot, Eur. J. Pharmacol. 140, 303
(1987).
101. J.A. Schneider and E.B. Sigg, Ann. NY Acad. Sci. 66, 765 (1957).
102. S. Gershon and W.J. Lang, Arch. Int. Pharmacodyn. Ther. 135, 31 (1962).
103. M.E.M. Benwell, P.E. Holtom, R.J. Moran, along with D.J.K. Balfour, Br. J. Pharmacol. 117, 743
(1996).
104. E.S. Onaivi, S.F. Ali, and also A. Chakrabarti, Ann. N. Y. Acad. Sci. in press, (1998).
105. S.L.T. Cappendijk as well as M.R. Dzoljic, Eur. J. Pharmacol. 241, 261 (1993).
106. F.J. Vocci and E.D. London, Ann. N. Y. Acad. Sci. 820, 29 (1996).
107. Anonymous, Offered for the Meals and also Drug Administration's Drug Advisory Committee
#26, (1993).
108. R.S. Mansbach, R.L. Balster, M. Gregory, and E. Soenghen, NIDA Contract Statement SA92.16,
(1992).
109. S.I. Dworkin, S. Gleeson, D. Meloni, T.R. Koves, and also T.J. Martin, Psychopharmacology 117,
257 (1995).
110. Y.W. Lee, A.H. Rezvani, along with D.H. Overstreet, Soc. Neurosci. Abstr. 20, 1608 (1994).
111. A.H. Rezvani, D.H. Overstreet, as well as Y.W. Leef, Pharmacol. Biochem. Behav. 52, 615
(1995).
112. A.H. Rezvani, D. Mash, D.H. Overstreet, W.L. Hearn, and also Y.W. Lee, Alcoholism - Clin. Exp.
Res, 19, 15A (1995).
113. A.H. Rezvani, D.H. Overstreet, Y. Yang, I.M. Maisonneuve, U.K. Bandarage, M.E. Kuehne, and
also S.D. Glick, Pharmacol. Biochem. Behav. 58, 615 (1997).
114. M.D. Aceto, E.R. Bowman, along with L.S. Harris, NIDA. Res. Monogr. 95, 578 (1990).
115. E.D. Dzoljic, C.D. Kaplan, and also M.R. Dzoljic Arch Int Pharmacodyn 294, 64 (1988).
116. S.L.T. Cappendijk, D. Fekkes, along with M.R. Dzoljic, Behav. brain Res. 65, 117 (1994).
117. L.G. Sharpe as well as J.H. Jaffe, NIDA Res.
Monogr. 105, 477 (1991).
118. B. Frances, R. Gout, J. Cros, as well as J.M. Zajac,
Fundam. Clin. Pharmacol. 6, 327 (1992).
119. P. Popik, R.T. Layer, L. Fossom, M. Benveniste, B.
Getter-Douglas, J.M. Witkin, and also P. Skolnick, J.
Pharmacol. Exp. Ther. 275, 753 (1995).
120. J.A. Schneider as well as M. McArthur, Experientia 12, 323 (1956).
121. H.N. Bhargava, Y.J. Cao, along with G.M. Zhao, Brain. Res. 752, 234 (1997).
122. Y.J. Cao and H.N. Bhargava, Mind Res. 752, 250 (1997).
123. A.A. Bagal, L.B. Hough, J.W. Nalwalk, as well as S.D. Glick, Mind Res. 741, 258 (1996).
124. S.M. Pearl, K. Herrickdavis, M. Teitler, along with S.D. Glick, Mind Res. 675, 342 (1995).
125. B. Badio, W.L. Padgett, and also J.W. Daly, Mol. Pharmacol. 51, one (1997).
126. W. Kostowski, W. Rewerski, and also T. Piechocki, Pharmacology 7, 259 (1972).
127. M.D. Schechter and T.L. Gordon, Eur. J. Pharmacol. 249, 79 (1993).
128. M.D. Schechter, Existence Sci. 60, PL83 (1997).
129. P.A. Palumbo and J.C. Winter, Pharmacol. Biochem. Behav. 43, 1221 (1992).
130. J.M. Witkin, S. Brave, D. French, along with B. Geterdouglass, .J Pharmacol. Exp. Ther. 275,
1267 (1995).
131. S. Helsley, R.A. Rabin, as well as J.C. Winter, Existence Sci. 60, PL147 (1997).
132. L.A. Parker, S. Siegel, and T. Luxton, Exp. Clin, Psychopharm. 3, 344 (1995).
133. I. Moroz, L.A. Parker, and also S. Siegel, Exp. Clin. Psychopharm. 5, 119 (1997).
134. L.A. Parker as well as S. Siegel, Learn. Motiv. 27, 170 (1996).
135. J.R. Blackburn along with K.K. Szumlinski, Soc. Neurosci. Abstr. 21, 1467 (1995).
136. P. Popik, life Sci. 59, PL379 (1996).
137. J.A. Schneider along with R.K. Rinehart, Arch. Int. Pharmacodyn. Ther. CX, 92 (1957).
138. N. Hajo-Tello, C. Dupont, J. Wepierre, Y. Cohen, R. Miller, as well as T. Godfraind, Arch. Int.
Pharmacodyn. Ther. 276, 35 (1985).
139. N. Hajo, C. Dupont, along with J. Wepierre, J. Pharmacol. 12, 441 (1981).
140. Z. Binienda, M.A. Beaudoin, B.T. Thorn, D.R. Prapurna, J.R. Johnson, C.M. Fogle, W. Slikker,
and also S.F. Ali, Ann. NY Acad. Sci. within press, (1998).
141. E.L. Mandrile and G.M. Bongiorno de Pfirter, Acta. Farm. Bonaerense 4, 49 (1985).
142. C. Naranjo, "The healing journey. New approaches for you to consciousness". N.Y.
Pantheon.New York, 1973.
143. P.B. Von Schmid, Arzneim.-Forsch. 17, 485 (1967).
144. R.S. Sloviter, E.G. Drust, B.P. Damiano, along with J.D. Connor, J. Pharmacol. Exp. Ther. 214,
231 (1980).
145. N.R. Farnsworth, Science 162, 1086 (1968).
146. J. Delourme-Houde, Ann. Pharm. Fr. 4, 30 (1946).
147. E. O'Hearn, D.B. Long, and also M.E. Molliver, NeuroReport 4, 299 (1993).
148. E. O'Hearn, P. Zhang, and also M.E. Molliver, NeuroReport 6, 1611 (1995).
149. E. O'Hearn along with M.E. Molliver, J. Neurosci. 17, 8828 (1997).
150. E. O'Hearn as well as M.E. Molliver, Soc. Neurosci. Abstr. 23, 2308 (1997).
151. A.C. Scallet, X. Ye, R. Rountree, P. Nony, along with S.F. Ali, Ann. NY Acad. Sci. 801, 217
(1996).
152. A.C. Scallet, X. Ye, and also S.F. Ali, Ann. NY Acad. Sci. 801, 227 (1996).
153. H.H. Molinari, I.M. Maisonneuve, as well as S.D. Glick, brain Res. 737, 255 (1996).
154. S. Helsley, C.A. Dlugos, R.J. Pentney, R.A. Rabin, as well as J.C. Winter, Mind Res. 759, 306
(1997).
155. J.P. O'Callaghan, L.E. Rodman, T.S. Roggers, J.B. Terril, and J.G. Page, Soc. Neurosci. Abstr. 20,
1650 (1994).
156. J.P. O'Callaghan, T.S. Rogers, L.E. Rodman, as well as J.G. Page, Ann. NY Acad. Sci. 801, 205
(1996).
157. B.J. Vilner, U.K. Bandarage, M.E. Kuehne, C.M. Bertha, and also W.D. Bowen, in "Problems
associated with Drug Dependence. Proceedings with the 59th Annual Scientific Meeting, NIDA Res.
Monograph." (L.S. Harris, ed.), U.S. Government Printing Office, Washington, D.C. 1997.
158. E. O'Hearn along with M.E. Molliver, Soc. Neurosci. Abstr. 21, 1340 (1995).
159. P. Popik, R.T. Layer, as well as P. Skolnick, Psychopharmacology 114, 672 (1994).
160. J.W. Olney, U S Patent 5,629,307, (1997).
161. K. Chen, T.G. Kokate, S. Yamagishi, F.I. Carroll, and also M.A. Rogawski, Soc. Neurosci. Abstr.
21, 1105 (1995).
162. K. Chen, T.G. Kokate, S.D. Donevan, F.I. Carroll, as well as M.A. Rogawski, Neuropharmacology
35, 423 (1996).
163. D.C. Mash, R. Douyon, W.L. Hearn, N.C. Sambol, as well as J. Sanchezramos, Biol. Psychiat. 37,
652 (1995).
164. P.M. Whitaker and also P. Seeman, J. Pharm. Pharmacol. 29, 506 (1977).
165. D.C. Deecher, M. Teitler, D.M. Soderlund, W.G. Bornmann, M.E. Kuehne, as well as S.D. Glick,
Mind Res. 571, 242 (1992).
166. P.M. Sweetnam, J. Lancaster, A. Snowman, J. Collins, S. Perschke, C. Bauer, and also J.
Ferkany, Psychopharmacology 118, 369 (1995).
167. J.K. Staley, Q. Ouyang, J. Pablo, W.L. Hearn, D.D. Flynn, R.B. Rothman, K.C. Rice, along with
D.C. Mash, Psychopharmacology 127, 10 (1996).
168. C. Messer along with G. Rudnick, Soc. Neurosci. Abstr. 21, 1383 (1995).
169. S.D. Glick, K. Rossman, S. Wang, N. Dong, and R.W. Keller, Jr., brain Res. 628, 201 (1993).
170. S.F. Ali, G.D. Newport, W. Slikker, R.B. Rothman, and also M.H. Baumann, Soc. Neurosci.
Abstr. 21, 2107 (1995).
171. S.F. Ali, G.D. Newport, W. Slikker, Jr., R.B. Rothman, and also M.H. Baumann, Mind Res. 737,
215 (1996).
172. M.S. Reid, K. Hsu, K.H. Souza, P.A. Broderick, and also S.P. Berger, J. Neural. Transm. 103,
967 (1996).
173. M.H. Baumann, R.B. Rothman, and S.F. Ali, Ann. NY Acad. Sci. inside press, (1998).
174. H. Sershen, A. Hashim, as well as A. Lajtha, brain Res. Bull. 36, 587 (1995).
175. H. Sershen, A. Hashim, along with A. Lajtha, Pharmacol. Biochem. Behav. 53, 863 (1996).
176. L.G. Harsing, H. Sershen, and also A. Lajtha, J. Neur. Trans. 96(3), 215 (1994).
177. H. Sershen, A. Hashim, as well as A. Lajtha, Neurochem. Res. 19, 1463 (1994).
178. H. Sershen, A. Hashim, and A. Lajtha, brain Res. Bull. 40, 63 (1996).
179. S.D. Glick, C.A. Gallagher, L.B. Hough, K.L. Rossman, along with I.M. Maisonneuve, brain Res.
588, 173 (1992).
180. S.M. Pearl, I.M. Maisonneuve, and also S.D. Glick, Neuropharmacology 35, 1779 (1996).
181. I.M. Maisonneuve, G.L. Mann, C.R. Deibel, along with S.D. Glick, Psychopharmacology (Berlin)
129, 249 (1997).
182. R.A. Rabin and J. C. Winter, Eur. J. Pharmacol. 316, 343 (1996).
183. E.E. Codd, Existence Sci. 57, PL315 (1995).
184. J.P. Pablo and also D.C. Mash, NeuroReport, within press, (1998).
185. P.M. Whitaker as well as P. Seeman, Psychopharmacology 59, 1 (1978).
186. P.M. Whitaker and also P. Seeman, Proc. Nat. Acad. Sci. USA 75, 5783 (1978).
187. R.F. Lengthy along with A.W. Lessin, Biochem. J. 82, 4P (1962).
188. H. Sershen, A. Hashim, and also A. Lajtha, Mind Res. Bull. 42, 161 (1997).
189. R.C. Miller and also T. Godfraind, Eur. J. Pharmacol. 96, 251 (1983).
190. A.S. Schneider, J.E. Nagel, and also S.J. Mah, Eur. J. Pharmacol. 317, R1 (1996).
191. D. Mash, J.K. Staley, J.P. Pablo, A.M. Holohean, J.C. Hackman, and R.A. Davidoff, Neurosc. Lett.
192, 53 (1995).
192. J. Pablo, J.K. Staley, A.M. Holohean, J.C. Hackman, R.A. Davidoff, as well as D.C. Mash, Soc.
Neurosci. Abstr. 21, 1264 (1995).
193. W.D. Bowen, B.J. Vilner, W. Williams, C.M. Bertha, M.E. Kuehne, as well as A.E. Jacobson, Eur.
J. Pharmacol. 279, R1 (1995).
194. R.H. Mach, C.R. Smith, along with S.R. Childers, Existence Sci. 57, PL57 (1995).
195. W.D. Bowen, B.J. Vilner, U.K. Bandarage, as well as M.E. Kuehne, Soc. Neurosci. Abstr. 22,
2006 (1996).
196. R.A. Rabin as well as J.C. Winter, brain Res. 731, 226 (1996).
197. E. Cretet, M. Prioux-Guyonneau, C. Jacquot, H. Sentenac, and also J. Wepierre, Arch.
Pharmacol. 313, 119 (1980).
198. Z. Binienda, J. Johnson, B. Thorn, as well as S.F. Ali, Soc. Neurosci. Abstr. 23, 1227 (1997).
199. R.D. Bunag along with E.J. Walaszek, Ann. NY Acad. Sci. 104, 437 (1968).
200. M.E. Alburges and G.R. Hanson, Soc. Neurosci. Abstr. 23, 2408 (1997).
201. R.V. House, P.T. Thomas, as well as H.N. Bhargava, Pharmacology 51, 56 (1995).
202. Y. Itzhak along with S.F. Ali, Soc. Neurosci. Abstr. 21, 2108 (1995).
TOP
XI. Table 1. Interactions of ibogaine along with neurotransmitter systems: radioligand binding
studies.
Receptor system Ligand Ki or even IC50+ [ M] Reference
Alpha-adrenergic1 prazosin 7.2 3.0+ 166
Dopamine transporter WIN 35,248 1.5+ 76
Dopamine transporter WIN 35,248 3.5 0.6+ 166
Dopamine transporter RTI-121 2.0 73
Dopamine transporter RTI-55 4.11 0.45+ 167
Monoamine transporter (vesicular) tetrabenazine 2.23 0.22+ 167
Muscarinic M1 pirenzepine 7.6 0.7+ 166
Muscarinic M2 AF-DX384 5.9 1.4+ 166
Nicotinic nicotine 4.0 0.6 125
Nicotinic noncompetitive carbamylcholine-induced 22NaCl influx 0.02 0.007+ 125
NMDA ion channel MK-801 1.0 0.1 159
NMDA ion channel MK-801 1.1 0.03 72
NMDA ion channel MK-801 5.6 0.8+ 166
NMDA ion channel MK-801 4-10 191
NMDA ion channel MK-801 or TCP 0.01-0.05 and also 2-4 202
NMDA ion channel TCP 1.5 0.3 119
Opioid naloxone 0.13 0.03 183
Opioid (kappa) U69,593 2.1 0.2 165
Opioid (kappa) U69,593 29.8 8.3+ (rat)
13.8 0.6+ (mouse)
21.0 1.1+ (giunea-pig)
72
Opioid (kappa) U69,593 5.5 56
Opioid (kappa) U69,593 3.77 0.81 124
Serotonin2 ketanserin 4.8 1.4+ 166
Serotonin3 GR-75558 3.9 1.1+ 166
Serotonin transporter RTI-55 0.55 0.03 73
Serotonin transporter RTI-55 10 168
Serotonin transporter RTI-55 0.59 0.09+ 167
Serotonin transporter paroxetine 9.30 1.70+ 167
Sigma haloperidol 0.003+ 164
Sigma pentazocine 0.086+ 11
Sigma1 pentazocine 9.3 0.63 194
Sigma1 pentazocine 8.6 1.1 193
Sigma1 pentazocine 1.5-3 202
Sigma2 DTG 0.0904 0.0101 194
Sigma2 DTG 0.201 0.023 193
Sigma2 DTG 1.5-3 202
Voltage-dependent sodium channels batrachotoxin Any 20-a- benzoate 8.1 1.3 165
LEGEND TO TABLE 1. presented are generally Ki or IC50 (+) values for assorted neurotransmitter
methods affected by ibogaine together with affinities higher than 10 M. the affinities regarding
O-desmethylibogaine for your corresponding receptors are presented within footnotes.
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