Chapter 8

METHCATHINONE, MEPHEDRONE, and METHYLONE

METHCATHIONE
HISTORY
Methcathinone was rst synthesized in Germany and France in the late 1920s as an intermediate in the synthesis of ephedrine. The optical isomers [S()- and R(+)methcathinone] were discovered in the following decade. Parke-Davis Pharmaceuticals obtained the patent for S()-methcathinone in 1957 as an analeptic; however, reports of adverse effects (trembling, seizures, incoordination, spasticity, labored respirations) in animal studies prevented the marketing of this drug.1 Methcathinone was a popular drug of abuse in the former Soviet Union during the 1970s and 1980s with street names of Ephedrone, Jeff, Cosmos, and Jee Cocktail.2 During the early 1990s, the rst reports associating atypical parkinsonism with intravenous (IV) administration of ephedrone (methcathinone) synthesized by the oxidation of ephedrine or pseudoephedrine with potassium permanganate appeared in Russia. Subsequently, similar case reports associated IV methcathinone abuse with persistent movement disorders in Estonia, Georgia, Latvia, Ukraine, and an Azerbaijani resident in Canada.3,4 In 1992, methcathinone was added to the list of controlled substances in the United States,5 followed by cathinone in 1993.

this -keto--methylphenethylamine compound is a more potent stimulant than cathinone based on animal studies.6 Figure 8.1 displays the structural similarities between the optical isomers of methcathinone, methamphetamine, cathinone, and amphetamine. Methcathinone contains an asymmetric carbon; thus, methcathinone is potentially available as a racemic mixture or as enantiomers [S(), R(+)]. In rodent behavioral studies (locomotor stimulation, drug discrimination), the S()-methcathinone enantiomer is about 5 times more potent than the R(+)-enantiomer.7 The World Health Organization includes methcathinone in schedule I (i.e., most controlled substance category as a result of high abuse potential) of the United Nations Convention on Psychotropic Substances. Although some analogs of methcathinone (e.g., N-monoethylcathinone, N-monon-propylcathinone) produce stimulant effects similar to analogs of methamphetamine in animal studies, the potency of structural analogs of methcathinone are not necessarily predicted by structureactivity relationships of similar methamphetamine structural analogs.8 Methcathinone has a distinctive pleasant smell (i.e., likened to pistachio ice cream), bitter taste, and dark color that differentiate this drug from amphetamine and cocaine.1 In addition, methcathinone causes irritation of the mucous membranes in contrast to the anesthetic properties of cocaine.

EXPOSURE
Clandestine laboratories synthesize methcathinone easily by the oxidation of l-ephedrine with household chemicals (sulfuric acid, paint thinner, acetone). Consequently, most illicit methcathinone contains the

IDENTIFYING CHARACTERISTICS
Methcathinone (CAS RN: 5650-44-2, monomethylpropion) is structurally similar to methamphetamine, and

Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants, First Edition. Donald G. Barceloux. 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.

120

METHCATHINONE, MEPHEDRONE, and METHYLONE (+) threo-ephedrine (d-pseudoephedrine), ()-threoephedrine (l-pseudoephedrine), and phenylpropanolamine appear in the urine along with small amounts of phenylpropanolamine.10 Based on 2 trials in a single volunteer, about one-third of this dose appeared in the urine as unchanged methcathinone and about one-half as ephedrine (about 60% l-pseudoephedrine, 40% dpseudoephedrine); phenylpropanolamine was a minor urinary metabolite (<5%). Reports from methcathinone users indicate that cessation of methcathinone use is associated with prolonged sleep, irritability, dysphoria, hyperphagia, and depression similar to the cessation of acute, high-dose amphetamine use.

HISTOPATHOLOGY AND PATHOPHYSIOLOGY

FIGURE 8.1. Structural and stereochemical relationships between the optical isomers of methcathinone, methamphetamine, cathinone, and amphetamine.

S()-enantiomer with small amounts of the R(+)enantiomer as a result of spontaneous racemization of the S()-enantiomer during extraction procedures. Abuse of methcathinone involves the use of this drug via the IV, pulmonary, or nasal routes. During a typical episode of methcathinone use, the drug user inhales the drug for 2436 hours until the drug supply is depleted or the drug user is physically exhausted. Desirable effects reported by methcathinone during acute intoxication include intense physical stimulation, sexual arousal, euphoria, and tolerance for alcohol.1 During binges, methcathinone users report the rapid development of strong psychologic craving and tolerance for this drug.2

DOSE EFFECT
The intranasal use (80250 mg) of methcathinone produces euphoria within 10 minutes along with visual illusions and hallucination followed by a 5- to 8-hour period of feeling invincibility and increased libido.2 Undesirable side effects associated with these doses include headache, abdominal pain, diaphoresis, and agitation. In a case series of 13 male opiate addicts developing movement disorders after chronic IV ephedrone (methcathinone) abuse, the reported daily use of ephedrone was 820 mL 16 times daily (mean reported daily use, 42 28 mL).9

TOXICOKINETICS
Following the ingestion of recreational doses (e.g., 30 mg) of methcathinone, unchanged methcathinone,

Rodent studies indicate that methcathinone is a potent CNS stimulant with effects on the dopaminergic and serotonergic receptors.11 These effects are species and enantiomer dependent. In mice, both R(+)and S()-enantiomers produce toxic effects on dopamine neurons based on reduction in dopamine, 3,4-dihydroxyphenylacetic acid (dopamine metabolite), and dopamine uptake in rat brain; the R(+)-enantiomer is more potent than the S()-enantiomer in these studies.12 Neither enantiomer produces serotonin toxicity at intraperitoneal doses ranging from 40 mg/kg every 2 hours for 4 doses to 120 mg/kg every 2 hours for 2 doses, then 2 doses at 4-hour intervals. Both enantiomers produce dopamine depletion in the stratum of rats with the S()-enantiomer slightly greater than the R(+)enantiomer at doses of 25 mg/kg and 50 mg/kg twice daily for 4 days. Only the S()-enantiomer produces serotonin depletion in the hippocampus and neocortex of rats. Following the administration of methcathinone, decreased tyrosine hydroxylase and tryptophan hydroxylase occur along with reductions in dopamine and serotonin in the frontal cortex, neostriatum, and hippocampus. Additionally, methcathinone is a substrate for the dopamine and serotonin transports, resulting in the uptake of methcathinone by dopamine and serotonin neurons.13 The similarity of the movement disorder associated with IV methcathinone abuse and chronic manganism suggest a role for manganese-induced neuropathy as the cause of this movement disorder in ephedrone addicts. The IV administration of ephedrone produced by oxidation of ephedrine or pseudoephedrine with potassium permanganate releases large amounts of manganese into the blood following IV administration. A case series of 3 IV drug users reported the development of similar extrapyramidal disorders and postural instability following the chronic IV use of a solution of potassium permanganate, ephedrine, and acetylsalicylic acid.14 In 121

PART 1

SYNTHETIC and SEMISYNTHETIC CHEMICALS

the 2 addicts recently using this IV solution, their blood manganese concentrations were very high (2,100 ng/mL, 3,176 ng/mL), whereas the addict that did not use the solution for 6 months had a normal blood manganese concentration (2.4 ng/mL; normal <19 ng/ mL). The solution these drug abusers injected did not contain methcathinone, suggesting that the motor disorder does not result from methcathinone.

They were unresponsive to levodopa, and the neurologic abnormalities remained after cessation of methcathinone abuse. Progression of neurologic symptoms after cessation of ephedrone use occurs in up to onethird of these patients. Some patients improve slowly, but complete reversal of neurologic symptoms does not usually occur.

DIAGNOSTIC TESTING CLINICAL RESPONSE Analytic Methods

Acute intoxication with methcathinone produces clinical features similar to stimulant effects of amphetamine abuse. Reported desirable effects from the IV abuse of methcathinone include rush, feeling happy, and sense of ying within 15 minutes after injection followed by several hours of jocularity and increased alertness. Reported adverse effects of methcathinone use include nausea, abdominal pain, facial erythema, epistaxis, anxiety, irritability, difculty concentrating, agitation, paranoia, tachycardia, insomnia, and muscle cramps. Complications of chronic methcathinone use include paranoid psychosis with auditory hallucinations, weight loss, dehydration, tremor, agitation, personality changes, antisocial behavior, and depression. Case reports associate the development of paranoia with auditory hallucinations, confusion slurred speech, tremor, disorientation, and intermittent anxiety following sustained, IV use of methcathinone.2 These symptoms usually resolve over 2436 hours. Occasionally, transient hypotension and bradycardia may also occur, but these abnormalities usually respond rapidly to supportive care. Case reports associate the IV abuse of methcathinone synthesized by the oxidation of ephedrine or pseudoephedrine by potassium permanganate with levodopa-resistant atypical parkinsonism, profound hypophonia, and gait disturbances.15 In a case series of 13 male opiate addicts developing movement disorders after chronic IV ephedrone (methcathinone) abuse, the mean time between the initiation of ephedrone abuse and the rst neurologic symptoms was 8.5 3.2 months.9 Clinical abnormalities include bradykinesias, dystonia, emotional lability, dysarthria, risus sardonicus, involuntary laughter, and retropulsion with falls backwards.9 These patients did not typically demonstrate olfactory abnormalities or declines in cognitive ability with the exception of mild dysfunction of executive skills and mild depression. These patients had several clinical features distinguishing them from patients with Parkinson disease including particular difculty walking backward, a symmetric motor disorder that resulted in walking on the rst metatarsal-phalangeal joints (cock walk), profoundly soft speech, and lack of a resting tremor. 122 Analytic methods for the quantitation of methcathinone and other amphetamine analogs in biologic samples include gas chromatography,16 high performance liquid chromatography with ultraviolet (UV) detection,17 gas chromatography/mass spectrometry (GC/MS),18 and liquid chromatography/electrospray ionization/tandem mass spectometry.19 The lower limit of quantitation (LLOQ) of methcathinone using the latter method is 10 ng/mL with intermediate precision (<15%). The use of high performance liquid chromatography/atmospheric pressure chemical ionization/mass spectrometry allows the quantitation of methcathinone and other underivatized amphetamines in hair samples with a limit of detection (LOD) in the range of 0.20 ng/mg.20 Commonly available immunoassays do not sufciently screen methcathinone from other amphetamine analogs. In situ derivatization of urine samples by extractive acylation with pentauoropropionic anhydride followed by rapid chromatography on a microbore capillary column and MS in selected-ion mode allows the rapid conrmation of various amphetamine analogs including methcathinone.21 Methcathinone is not a metabolite of phenylpropanolamine or any other over-the-counter medications. Although methcathinone is stable for 3 days in refrigerated samples (24oC/35.639.2F) and in frozen samples (-18oC/-0.4F) for 2 months, urine samples stored at 24oC (35.639.2F) for 3 months lost about 79% of the methcathione.18

Abnormalities
The magnetic resonance images (MRIs) of patients with ephedrine-induced movement disorders demonstrate hyperintensity T1-weighted signals from the globus pallidus, substantia nigra, dentate nucleus, and the pontine tegmentum.22 The whole blood manganese concentration in samples from these patients are typically elevated about 34 times above the upper reference range; whole blood manganese concentrations remain elevated months after cessation of IV methcathinone produced by potassium permanganate oxidation. Both the MRI

METHCATHINONE, MEPHEDRONE, and METHYLONE

and the blood manganese concentration may be normal in the presence of an obvious movement disorder (bradykinesia, postural instability, slowed facial expressions, dysarthria, generalized dystonia).23 Blood manganese concentrations do not correlate well to clinical symptoms.

TREATMENT
The treatment of methcathinone intoxication is supportive, similar to amphetamine intoxication. The movement disorders associated with IV ephedrone (methcathinone) abuse and potassium permanganate oxidation does not usually respond to the drugs (Ldopa, amantadine, bromocriptine, trihexyphenidyl) typically used to treat Parkinson disease. There are inadequate clinical data to determine if chelation of elevated manganese concentrations improves the chronic movement disorder associated with IV ephedrone abuse. Although the use of calcium disodium EDTA is associated with partial improvement in some patients, other patients did not improve and patients did not typically recover completely.22

MEPHEDRONE (4-METHYLMETHCATHINONE)
Mephedrone (2-aminoethyl-1-tolyl-propan-1-one, 4methylmethcathinone) is a -keto amphetamine that is the synthetic 4-methyl aromatic analogue of methcathinone. Figure 8.2 compares the chemical structure, structural formula, and molecular weight of mephedrone and methcathinone. Common names include 4-MMC, Bubbles, Meph, Meow Meow, Miaow, TopCat, MMCAT, and Crab. Limited analytic data on mephedrone samples purchased from the Internet suggest that these sample contain high concentrations of 4-methylmethcathinone

in a racemic mixture.24 Mephedrone is an uncontrolled cathinone derivative in many countries with sympathomimetic properties (tachycardia, mydriasis, blurred vision, agitation) similar to methcathinone. This compound is a substitute for ecstasy (MDMA) in the club scene. Mephedrone is an illegal drug in Denmark, Finland, Israel, Norway, Sweden, and the United Kingdom. Potential postprohibition mephedrone-like products include the 2-aminopentanophenone compounds.25 These monoamine oxidase inhibitors are marketed as Energy 1 (NRG-1) or naphyrone (naphthylpyrovalerone, O-2482), although these products may contain illicit mephedrone or other cathinones/ adulterants. In a study of 24 products purchased online from 18 UK-based websites within 6 weeks after the ban on mephedrone and other derivatives (3,4-methylenedioxypyrovalerone, butylone), 70% of the NRG-1 and NRG-2 products contained a mixture of banned cathinones.26 Mephedrone is usually sold as a white crystalline or off-whiteyellow powder (hydrochloride salt), frequently from street vendors and less often on the Internet as bath salts.27 The common methods of administration are ingestion, insufation, and rarely by injection with heroin. Biotransformation of mephedrone involves hydroxylation at the 4-methyl group followed by oxidation to the corresponding 4-carboxy metabolite and demethylation of the -keto group to the corresponding alcohol.28 The clinical features of mephedrone overdose reect sympathomimetic toxicity similar to cocaine and methamphetamine intoxication including elevated blood pressure, tachycardia, palpitations, mydriasis, hyperactivity, and agitation as well as anxiety, paresthesias, confusion, vomiting, chest pain, and headache.29 Based on data on 131 telephone enquiries to the UK National Poisons Information Service concerning mephedrone alone or in combination with alcohol, common clinical features reported were as follows: agitation or aggression (n = 32, 24%, 95% CI: 1833%), tachycardia (n = 29, 22%, 95% CI: 1630%), confusion or psychosis (n = 18, 14%, 95% CI: 921%), chest pain (n = 17, 13%, 95% CI: 820%), nausea (n = 15, 11%, 95% CI: 718%), palpitations (n = 14, 11%, 95% CI: 618%), peripheral

FIGURE 8.2. Comparison of chemical structures, structural formulas, and molecular weights of methcathinone, mephedrone (4-methylmethcathinone), and methylone.

123

PART 1

SYNTHETIC and SEMISYNTHETIC CHEMICALS

vasoconstriction (n = 10, 8%, 95% CI: 414%), headache (n = 7, 5%, 95% CI: 211%), and seizures (n = 4, 3%, 95% CI: 18%).30 A 22-year-old man ingested 200 mg mephedrone purchased from an Internet supplier; when he did not develop the desired effects, he injected 3,800 mg intramuscularly into his thighs.31 Shortly thereafter, he developed chest pressure, diaphoresis, blurred tunnel vision, and a feeling of being unwell. At the emergency department (ED), he was agitated, anxious, and hypertensive (blood pressure = 177/111) with mydriasis. His symptoms resolved after 4 hours of observation and 1 mg oral lorazepam. Other complications associated with the use of mephedrone include hypo-osmotic hyponatremia with encephalopathy manifest by altered consciousness, nausea, vomiting, and elevated intracranial pressure.32 Elevation of serum creatine kinase and rarely, hyponatremia may occur. Methods of detection include GC/MS in selective ion monitoring mode using methamphetamine-d14 as an internal standard.33 The LOD and LLOQ with this method are 0.010 mg/L and 0.025 mg/L, respectively, with between-day accuracy ranging from 0.212.4%.

tonin, norepinephrine) in the synaptic cleft by inhibition of the plasma monoamine reuptake transporters with relatively little effect on dopamine concentrations.36 In contrast to MDMA, the effect of methylone on the vesicular monamine transporter is weak. The clinical effects of methylone are similar to MDMA, although the reported euphoric and stimulatory effects of methylone are milder than MDMA. There are few data on the effects of methylone in humans. Expected adverse effects include mydriasis, diaphoresis, nausea, vomiting, agitation, confusion, dysphoria, tachycardia, and hypertension based on structural similarity to MDMA. Methods for the quantitation of methylone include GC/ MS, liquid chromatography/electrospray ionization/ mass spectrometry, and gas chromatography/electron impact mass spectrometry.35,37 Commercial immunoassays for drugs of abuse may be insensitive to the presence of methylone in the urine.38 The use of GC/MS in electron impact mode allows the quantitation of methylone, mephedrone, and butylone in biologic samples.28

References

METHYLONE (3,4METHYLENEDIOXYMETHCATHINONE)
Shulgin et al investigated the psychoactive properties of methylone in the 1970s; he and Jacob patented the drug as an antidepressant and antiparkinson agent in the middle 1990s. Methylone appeared as a designer drug of abuse in Europe and Japan in the middle 2000s.34 Methylone (2-methylamino-1(3,4-methylenedioxyphenyl)propan-1-one, 3,4-methylenedioxymethcathinone) is the -ketone analogue of 3,4-methylenedioxymethamphetamine (MDMA) as displayed in Figure 8.2. Major metabolic pathways for methylone include 1) N-demethylation of the side-chain to methylenedioxycathinone, and 2) demethylenation and O-methylation of the hydroxyl group on the benzene ring to form 4-hydroxy-3-methoxymethcathinone and 3-hydroxy-4-methoxymethcathinone. In rodent studies, the kidney excretes most of the metabolites as conjugates with small amounts (i.e., 3%) appearing in the urine as unchanged methylone.35 The major urinary metabolite of methylone was 4-hydroxy3-methoxymethcathinone. In vitro studies indicate that methylone increases the concentration of monoamine neurotransmitters (sero124

1. Calkins RF, Aktan GB, Hussain KL. Methcathinone: the next illicit stimulant epidemic? J Psychoactive Drugs 1995;27:277285. 2. Emerson TS, Cisek JE. Methcathinone: a Russian designer amphetamine inltrates the rural Midwest. Ann Emerg Med 1993;22;18971903. 3. de Bie RM, Gladstone RM, Strafella AP, Ko J-H, Lang AE. Manganese-induced parkinsonism associated with methcathinone (ephedrone) abuse. Arch Neurol 2007; 64:886889. 4. Sikk K, Taba P, Haldre S, Bergquist J, Nyholm D, Zjablov G, et al. Irreversible motor impairment in young addicts ephedrone, manganism or both? Acta Neurol Scand 2007; 115:385389. 5. Bonner RC. Schedules of controlled substances temporary placement of methcathinone into schedule I. Fed Regist 1992;57:1882418825. 6. Glenon RA, Yousef M, Naiman N, Kalix P. Methcathinone: a new potent amphetamine-like agent. Pharmacol Biochem Behav 1987;26:547551. 7. Glennon RA, Young R, Martin BR, Dal Cason TA. Methcathinone (cat): an enantiomeric potency comparison. Pharmacol Biochem Behav 1995;50:601606. 8. Dal Cason TA, Young R, Glennon RA. Cathinone: an investigation of several N-alkyl and methylenedioxysubstituted analogs. Pharmacol Biochem Behav 1997;58: 11091116. 9. Selikhova M, Fedoryshyn L, Matviyenko Y, Komnatska I, Kyrylchuk M, Krolicki L, et al. Parkinsonism and dystonia caused by the illicit use of ephedronea longitudinal study. Mov Disord 2008;23:22242231.

METHCATHINONE, MEPHEDRONE, and METHYLONE

10. Markantonis SL, Kyroudis A, Beckett AH. The stereoselective metabolism of dimethylpropion and monomethylpropion. Biochem Pharmacol 1986;35:529532. 11. Young R, Glennon RA. Discriminative stimulus effects of S()-methcathinone (CAT): a potent stimulant drug of abuse. Psychopharmacology 1998;140:250256. 12. Sparago M, Wlos J, Yuan J, Hatzidimitriou G, Tolliver J, Dal Cason TA. Neurotoxic and pharmacologic studies on enantiomers of the N-methylated analog of cathinone (methcathinone): a new drug of abuse. J Pharmacol Exp Ther 1996;279:10431052. 13. Cozzi NV, Foley KF. Methcathinone is a substrate for the serotonin uptake transporter. Pharmacol Toxicol 2003;93:219225. 14. Varlibas F, Delipoyraz I, Yuksel G, Filiz G, Tireli H, Gecim NO. Neurotoxicity following chronic intravenous use of Russian cocktail. Clin Toxicol 2009;47:157160. 15. Stepens A, Logina I, Liguts V, Aldins P, Iksteina I, Platkajis A, et al. A parkinsonian syndrome in methcathinone users and the role of manganese. N Engl J Med 2008;358: 10091017. 16. Soriano C, Muoz-Guerra J, Carreras D, Rodrguez C, Rodrguez AF, Corts R. Automated analysis of drugs in urine. J Chromatogr B Biomed Appl 1996;687:183187. 17. Belhadj-Tahar H, Sadeg N. Methcathinone: a new postindustrial drug. Forensic Sci Int 2005;153:99101. 18. Paul BD, Cole KA. Cathinone (khat) and methcathinone (CAT) in urine specimens: a gas chromatographic-mass spectrometric detection procedure. J Anal Toxicol 2001;25: 525530. 19. Beyer J, Peters FT, Kraemer T, Maurer HH. Detection and validated quantication of nine herbal phenalkylamines and methcathinone in human blood plasma by LC-MS/MS with electrospray ionization. J Mass Spectrom 2007;42: 150160. 20. Stanaszek R, Piekoszewski W. Simultaneous determination of eight underivatized amphetamines in hair by highperformance liquid chromatography-atmospheric pressure chemical ionization mass spectrometry (HPLC-APCIMS). J Anal Toxicol 2004;28:7785. 21. Marais AA, Laurens JB. Rapid GC-MS conrmation of amphetamines in urine by extractive acylation. Forensic Sci Int 2009;183:7886. 22. Sanotsky Y, Lesyk R, Fedoryshyn L, Komnatska I., Matviyenko Y, Fahn S. Manganic encephalopathy due to ephedrine abuse. Mov Disord 2007;22:13371343. 23. Varlibas F, Delipoyraz I, Yuksel G, Filiz G, Tireli H, Gecim NO. Neurotoxicity following chronic intravenous use of Russian cocktail. Clin Toxicol 2009;47:157160. 24. Gibbons S, Zloh M. An analysis of the legal high mephedrone. Bioorg Med Chem Lett 2010;20:41354139. 25. Meltzer PC, Butler D, Deschamps JR, Madras BK. 1 - (4 - Methylphenyl) - 2 - pyrrolidin - 1 - yl - pentan - 1 - one

26.

27.

28.

29.

30.

31.

32. 33.

34.

35.

36.

37.

38.

(Pyrovalerone) analogues: a promising class of monoamine uptake inhibitors. J Med Chem 2006;49: 14201432. Brandt SD, Sumnall HR, Measham F, Cole J. Analyses of second-generation legal highs in the UK: initial ndings. Drug Test Anal 2010;2:377382. Dargan PI, Albert S, Wood DM. Mephedrone use and associated adverse effects in school and college/university students before the UK legislation change. QJM 2010;103: 875879. Meyer MR, Wilhelm J, Peters FT, Maurer HH. Beta-keto amphetamines: studies on the metabolism of the designer drug mephedrone and toxicological detection of mephedrone, butylone, and methylone in urine using gas chromatography-mass spectrometry. Anal Bioanal Chem 2010;397:12251233. Regan L, Mitchelson M, Macdonald C. Mephedrone toxicity in a Scottish emergency department. Emerg Med J 2011;28:10551058. James D, Adams RD, Spears R, Cooper G, Lupton DJ, Thompson JP, Thomas SH. Clinical characteristics of mephedrone toxicity reported to the UK National Poisons Information Service. Emerg Med J 2011;28:686689. Wood DM, Davies S, Puchnarewica M, Button J, Archer R, Ovaska H, et al. Recreation use of mephedrone (4-methylmethcathinone, 4-MMC) with associated sympathomimetic toxicity. J Med Toxicol 2010;6;327330. Sammler EM, Foley PL, Lauder GD, Wilson SJ, Goudie AR, ORiordan JI. A harmless high? Lancet 2010;376:742. Dickson AJ, Vorce SP, Levine B, Past MR. Multipledrug toxicity caused by the coadministration of 4-methylmethcathinone (mephedrone) and heroin. J Anal Toxicol 2010;34:162168. Bossong MG, van Dijk JP, Niesink RJ. Methylone and mCPP, two new drugs of abuse? Addict Biol 2005;10: 321323. Kamata HT, Shima N, Zaitsu K, Kamata T, Miki A, Nishikawa M, et al. Metabolism of the recently encountered designer drug, methylone, in humans and rats. Xenobiotica 2006;36:709723. Nagai F, Nonaka R, Satoh Hisashi Kamimura K. The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain. Eur J Pharmacol 2007;559:132137. Kikura-Hanajiri R, Kawamura M, Saisho K, Kodama Y, Goda Y. The disposition into hair of new designer drugs; methylone, MBDB and methcathinone. J Chromatogr B 2007;855:121126. Shimizu E, Watanabe H, Kojima T, Hagiwara H, Fujisaki M, Miyatake R, et al. combined intoxication with methylone and 5-MeO-MIPT. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:288291.

125