4 12 Review - WHO
MephedroneCritical Review ReportAgenda item 4.12Expert Committee on Drug DependenceThirty‐sixth MeetingGeneva, 16‐20 June 2014
36th ECDD (2014) Agenda item 4.12MephedronePage 2 of 34
36th ECDD (2014) Agenda item 4.12MephedroneAcknowledgementsThis report has been drafted under the responsibility of the WHO Secretariat, EssentialMedicines and Health Products, Policy Access and Rational Use Unit. The WHO Secretariatwould like to thank the following people for their contribution in producing this criticalreview report: Wim Best, the Netherlands (literature review and drafting), Dr CarolineBodenschatz, Switzerland (editing) and Mr David Beran, Switzerland (questionnaire reportdrafting).Page 3 of 34
36th ECDD (2014) Agenda item 4.12MephedronePage 4 of 34
36th ECDD (2014) Agenda item 4.12MephedroneContentsSummary.71.Substance identification .8A.B.C.D.E.F.G.2.International Nonproprietary Name (INN) .8Chemical Abstract Service (CAS) Registry Number .8Other Names .8Trade Names.8Street Names .8Physical properties .8WHO Review History .8Chemistry .8A.B.C.D.E.F.G.Chemical Name .8Chemical Structure .9Stereoisomers .9Synthesis .9Chemical description.9Chemical properties .10Chemical identification .103.Ease of convertibility into controlled substances .104.General pharmacology .104.1. Pharmacodynamics .104.2. Routes of administration and dosage.154.3. Pharmacokinetics .155.Toxicology .176.Adverse reactions in humans .177.Dependence potential .198.Abuse potential .209.Therapeutic applications and extent of therapeutic use and epidemiology of medical use .2210. Listing on the WHO Model List of Essential Medicines .2211. Marketing authorizations (as a medicine) .2212. Industrial use .2213. Non-medical use, abuse and dependence .2214. Nature and magnitude of public health problems related to misuse, abuse and dependence .2415. Licit production, consumption and international trade .2616. Illicit manufacture and traffic and related information .2617. Current international controls and their impact .2618. Current and past national controls .2619. Other medical and scientific matters relevant for a recommendation on the scheduling of thesubstance .26References .27Annex 1: Report on WHO Questionnaire for Review of Psychoactive Substances for the 36th ECDD:Evaluation of Mephedrone.31Page 5 of 34
36th ECDD (2014) Agenda item 4.12MephedronePage 6 of 34
36th ECDD (2014) Agenda item 4.12MephedroneSummaryMephedrone (4-methylmethcathinone) is a synthetic cathinone. Mephedrone has never beenlicensed as a medicine, also no other legitimate uses are known. Although new on the marketof recreational substances the history of mephedrone goes back to 1929 when its synthesiswas published.The product started its way on the market around the time when the availability of 3,4methylenedioxymethylamphetamine decreased. Use of mephedrone was first reported around2007 and since then increasing especially in Europe. This has led to a risk assessment by theEMCDDA in 2010 (EMCDDA, 2011). Meanwhile use/abuse has also been reported fromAustralia and the USA.The effects and the mode of use reported have similarities with (meth)amphetamine, cocaineand 3,4-methylenedioxymethylamphetamine, but its potency is less than (meth)amphetamine.The overall profile shows a molecule with unique pharmacological properties. Not a new kidon the block, nevertheless the study into its pharmacology and toxicology started onlyrecently.Reported toxic effects of mephedrone include soar nose/nosebleeds after snorting,tachycardia, hypertension, agitation, paranoia, hallucinations and insomnia. Some of theseeffects leeding to hospital admissions. A number of analytically confirmed drug-relateddeaths have been reported.Animal studies have indicated that mephedrone possesses an abuse or dependence potentialbut there are no human clinical studies to support this. There are reports to suggest that someindividuals with a particularly high dose and/or frequent use of mephedrone developsignificant ‘cravings’ for it. There is one confirmed report of mephedrone dependence in apatient from Scotland.Page 7 of 34
36th ECDD (2014) Agenda item 4.121.MephedroneSubstance identificationA. International Nonproprietary Name (INN)Not applicable.B. Chemical Abstract Service (CAS) Registry Number1189805-46-6 (base)1189726-22-4 (hydrochloride salt)C. Other NamesMephedrone, 4-methylmethcathinone, ), 4,N-dimethylcathinone,p-methyl-methcathinone, 2-aminomethyl-1-tolyl-propan-1-one.D. Trade NamesNone.E. Street NamesA number of street names for mephedrone can be found in the literature, like:bubbles, blow, Charge , Cristal bath, Crush, Dark , doves, kata, Fisk, Fiskrens,Flower Magic Powder, Flower Power, kati, Ketones, krabba, Kräfta, Lax, mef,Meffe, mefi, Mefko, mefó, mephisto, miaow miaow, meow meow, miaou miaou,Magic, MMC Hammer, moonshine, plant feeder, plant food, Räka, RealEuphoria, Recharge, Rocket fuel. Rush, Special Diamond, Special Gold, SpecialOriginal, Star Dust, Subcoca-1, top cat, Tornado, Torsk, Volt, White Gold, WhiteAroma Crystals, zsuzsi ronzio.F. Physical propertiesThe base is a yellowish liquid at ambient temperature.Mephedrone hydrochloride salt is a white or lightly coloured powder.G. WHO Review HistoryMepehdrone was not previously pre-reviewed or critically reviewed. A directcritical review is proposed based on information brought to WHO’s attention thatMephedrone is clandestinely manufactured, of especially serious risk to publichealth and society, and of no recognized therapeutic use by any party. Preliminarydata collected from literature and different countries indicated that this substancemay cause substantial harm and that it has no medical use.2.ChemistryA. Chemical NameIUPAC Name: A Index Name:MephedronePage 8 of 34
36th ECDD (2014) Agenda item 4.12MephedroneB. Chemical StructureFree base:Molecular Formula:Molecular Weight:Melting point:Boiling point:C11H15NO177.242 g/mol66.61 C269.51 CC. StereoisomersMephedrone contains a chiral centre at the C-2 carbon of the propane sidechain,so that two enantiomers exist: R-mephedrone and S-mephedrone.Due to the similarity with cathinone the S form is thought to be more potent thanthe R form.D. SynthesisThe synthesis of mephedrone, mentioned as ‘toluyl-alpha-monomethylaminoethylcetone’, was first described by Saem de Burnaga Sanchez (1929). Themain synthetic route involves α-bromination of 4-methylpropiophenone followedby reaction of the resulting compound (4-methyl-2-bromopropiophenone) withmethylamine hydrochloride and triethylamine in an acidic scavenger to produce 4methylmethcathinone. The reaction is then quenched with gaseous or aqueoushydrogen chloride providing the hydrochloride salt that needs to be recrystallised.The resulting product is always racemic.There is the potential for other synthetic routes including oxidation of thesubstituted ephedrine analogue (4-methylephedrine) with potassium permanganateor potassium dichromate in a solution of diluted sulphuric acid. The precursor canbe obtained in a specific enantiomeric form, ensuring that the synthesis is stereoselective.Alternative synthetic methods, though more cumbersome, have been described inthe literature such as the Hartung-Munch procedure.E. Chemical descriptionMephedrone (4-methylmethcathinone) is a beta-keto-amphetamine related tocathinone and methcathinone.Page 9 of 34
36th ECDD (2014) Agenda item 4.12MephedroneF. Chemical propertiesThe base is a yellowish liquid at ambient temperature.Mephedrone hydrochloride salt is a white or lightly coloured powder. The powderis readily soluble in water and therefore can be dissolved prior to oral/ rectal useor injection.G. Chemical identificationGas-chromatography mass-spectrometry (GC-MS) and liquid chromatographywith mass spectrometry-mass spectrometry (LC-MS/MS) techniques have beendeveloped for the detection of mephedrone (Camilleri et al., 2010, Meyer et al.,2010, Gibbons and Zloh, 2010). The mass-spectrometry technique does notdistinguish between the various methyl-methcathinone isomers. However, nuclearmagnetic resonance spectroscopy allow the isomers to be differentiated.Mass spectral data for mephedrone (m/z): 58 (base peak, 100 %).Mephedrone does not give a colour reaction with the Marquis test.3.Ease of convertibility into controlled substancesMephedrone is not converted into controlled substances.4.General pharmacologyIn 2014 mephedrone will celebrate its 85th anniversary. But its pharmacology andtoxicologyhaveonlyrecentlybeen investigated. Mephedrone (4methylmethcathinone) is a β-ketoamphetamine stimulant drug of abuse with structuraland mechanistic similarities to methamphetamine.4.1.PharmacodynamicsBiochemical effectsMartínez-Clemente et al., (2012) were one of the first to start investigations into thepharmacological targets of mephedrone in rats to establish the basis of the mechanismof action of this drug. They performed several in vitro experiments studying the effectof mephedrone on monoamine uptake and the displacement of several specificradioligands. In isolated synaptosomes from rat cortex or striatum, mephedroneinhibited the uptake of serotonin (5-HT) with an IC50 value lower than that ofdopamine (DA) uptake (IC50 0.31 0.08 and 0.97 0.0 5μM, respectively). Moreover,mephedrone displaced competitively both [³H]paroxetine and [³H]WIN35428 bindingin a concentration-dependent manner (Ki values of 17.55 0.78μM and 1.53 0.47 μM,respectively), indicating a greater affinity for DA than for 5-HT membranetransporters. The affinity profile of mephedrone for the 5-HT2 and D2 receptors wasassessed by studying [³H]ketanserin and [³H] raclopride binding in rat membranes.Mephedrone showed a greater affinity for the 5-HT2 than for the D2 receptors.In vitro studies using recombinant human monoamine transporters point in the samedirection (Eshleman et al., 2013). Mephedrone and methylone had higher inhibitorypotency at uptake compared to binding and generally induced release of preloadedPage 10 of 34
36th ECDD (2014) Agenda item 4.12Mephedrone[³H]neurotransmitter from human dopamine (hDAT), serotonin (hSERT) andnorepinephrine (hNET) transporters (highest potency at hNET), and thus nd3,4methylenedioxymetamphetamine. In general these substituted methcathinones hadlow uptake inhibitory potency and low efficacy at inducing release via humanvesicular monoamine transporters (hVMAT2). Furthermore these compounds werelow potency h5-HT(1A) receptor partial agonists, h5-HT(2A) receptor antagonists,weak h5-HT(2C) receptor antagonists and have no affinity for dopamine receptors.The primary mechanisms of action may be as inhibitors or substrates of DAT, SERTand NET.Also in vivo methods employed by Baumann et al., (2012) showed similar results.Due to its numerous mechanistic overlaps with methamphetamine and the cathinonederivatives Angoa-Pérez et al., (2012) decided to start a study into the neurotoxicity ofmephedrone. They treated mice with a binge-like regimen of mephedrone (4 20 or40 mg/kg) and examined the striatum for evidence of neurotoxicity 2 or 7 days aftertreatment. Although mephedrone caused hyperthermia and locomotor stimulation, itdid not lower striatal levels of dopamine, tyrosine hydroxylase or the dopaminetransporter under any of the treatment conditions used. Furthermore, mephedrone didnot cause microglial activation in striatum nor did it increase glial fibrillary acidicprotein levels. These results strongly suggest that mephedrone does not causeneurotoxicity to dopamine nerve endings of the striatum.One of the most powerful actions associated with mephedrone is the ability tostimulate dopamine (DA) release and block its re-uptake through its interaction withthe dopamine transporter (DAT). Although mephedrone does not cause toxicity to DAnerve endings, its ability to serve as a DAT blocker could provide protection againstmethamphetamine-induced neurotoxicity like other DAT inhibitors.To test this possibility, Angoa-Pérez et al., (2013a) treated mice with mephedrone (10,20, or 40 mg/kg) prior to each injection of a neurotoxic regimen of methamphetamine(four injections of 2.5 or 5.0 mg/kg at 2 h intervals). The integrity of DA nerveendings of the striatum was assessed through measures of DA, DAT, and tyrosinehydroxylase levels. The moderate to severe DA toxicity associated with the differentdoses of methamphetamine was not prevented by any dose of mephedrone but wassignificantly enhanced. Mephedrone also enhanced the neurotoxic effects ofamphetamine and 3,4-methylenedioxymethamphetamine on DA nerve endings. Incontrast, nomifensine protected against methamphetamine-induced neurotoxicity. Asmephedrone increases methamphetamine neurotoxicity, the present results suggest thatit interacts with the DAT in a manner unlike that of other typical DAT inhibitors.The effects of mephedrone on serotonin (5HT) nerve endings are not fully understood,with some investigators reporting damage while others conclude it does not. ThereforAngoa-Pérez et al., (2013b) performed another study to investigate if mephedronegiven alone or with methamphetamine or MDMA damages 5HT nerve endings of thehippocampus.The status of 5HT nerve endings in the hippocampus of female C57BL mice wasassessed through measures of 5HT, serotonin transporter (SERT) and tryptophanhydroxylase 2 (TPH2). Mephedrone alone did not cause persistent reductions in thePage 11 of 34
36th ECDD (2014) Agenda item 4.12Mephedronelevels of 5HT, SERT or TPH2. Methamphetamine and MDMA alone caused mildreductions in 5HT but did not change SERT and TPH2 levels. Combined treatmentwith mephedrone and methamphetamine or MDMA did not change the status of 5HTnerve endings to an extent that was different from either drug alone. Mephedrone doesnot cause toxicity to 5HT nerve endings of the hippocampus. When co-administeredwith methamphetamine or MDMA toxicity is not increased as is the case for dopaminenerve endings when these drugs are taken together.To summarize: mephedrone is a stimulant of dopamine release and blocks its reuptake through an its interaction with the dopamine transporter (DAT).Furthermore it has some affinity for various serotonin receptor subtypes. And althoughexpected mephedrone does not have a neurotoxic effect on the dopamine or serotoninsystem when given alone.Functional effectsThe cardiovascular effects of mephedrone were characterized in rats by Varner et al.(2013). A group of 12 rats received radio telemetry probes which were used tomeasure the changes in mean arterial pressure (MAP) and heart rate (HR).Mephedrone was compared with metamphetamine. Mephedrone (0.01-9 mg/kg, i.v.)elicited increases in MAP and HR that were very similar to those elicited bymethamphetamine (0.01-9 mg/kg, i.v.). The tachycardia and pressor responses tomephedrone (3 mg/kg) were blocked by the β-blocker atenolol (1 mg/kg, i.v.) and theα1, α
Alternative synthetic methods, though more cumbersome, have been described in the literature such as the Hartung-Munch procedure. E. Chemical description Mephedrone (4-methylmethcathinone) is a beta-keto-amphetamine related to cathinone and methcathinone.
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