4-Methylethcathinone (4-MEC) Critical Review Report Agenda Item 4.3 Expert Committee on Drug Dependence Thirty-eighth Meeting Geneva, 14-18 November 2016 38th ECDD (2016) Agenda item 4.3 4-MEC Page 2 of 38 38th ECDD (2016) Agenda item 4.3 4-MEC Contents Acknowledgements .......................................................................................................................... 5 Summary .......................................................................................................................................... 6 1. Substance identification .................................................................................................... 7 A. International Nonproprietary Name (INN) ........................................................................ 7 B. Chemical Abstract Service (CAS) Registry Number .......................................................... 7 C. Other Chemical Names ...................................................................................................... 7 D. Trade Names ...................................................................................................................... 7 E. Street Names ...................................................................................................................... 7 F. Physical Appearance .......................................................................................................... 7 G. WHO Review History ......................................................................................................... 7 2. Chemistry ........................................................................................................................... 8 A. Chemical Name .................................................................................................................. 8 B. Chemical Structure ............................................................................................................ 8 C. Stereoisomers ..................................................................................................................... 8 D. Methods and Ease of Illicit Manufacturing ....................................................................... 8 E. Chemical Properties .......................................................................................................... 8 F. Identification and Analysis ................................................................................................. 9 3. Ease of Convertibility Into Controlled Substances .......................................................... 9 4. General Pharmacology ..................................................................................................... 9 A. Routes of administration and dosage ................................................................................. 9 B. Pharmacokinetics ............................................................................................................... 9 C. Pharmacodynamics .......................................................................................................... 10 5. Toxicology ....................................................................................................................... 15 6. Adverse Reactions in Humans ........................................................................................ 15 7. Dependence Potential ...................................................................................................... 17 A. Animal Studies .................................................................................................................. 17 B. Human Studies ................................................................................................................. 17 8. Abuse Potential ................................................................................................................ 17 A. Animal Studies .................................................................................................................. 17 B. Human Studies ................................................................................................................. 18 9. Therapeutic Applications and Extent of Therapeutic Use and Epidemiology of Medical Use ................................................................................................................................... 18 10. Listing on the WHO Model List of Essential Medicines ............................................... 18 11. Marketing Authorizations (as a Medicinal Product) ..................................................... 18 12. Industrial Use .................................................................................................................. 18 Page 3 of 38 38th ECDD (2016) Agenda item 4.3 4-MEC 13. Non-Medical Use, Abuse and Dependence .................................................................... 18 14. Nature and Magnitude of Public Health Problems Related to Misuse, Abuse and Dependence ..................................................................................................................... 19 15. Licit Production, Consumption and International Trade ............................................. 19 16. Illicit Manufacture and Traffic and Related Information ............................................ 19 17. Current International Controls and Their Impact ........................................................ 20 18. Current and Past National Controls............................................................................... 20 19. Other Medical and Scientific Matters Relevant for a Recommendation on the Scheduling of the Substance ........................................................................................... 20 References ...................................................................................................................................... 21 Annex 1: Report on WHO Questionnaire for Review of Psychoactive Substances for the 38th ECDD: Evaluation of 4-MEC ....................................................................................................... 27 Annex 2: Representative examples of studies associated with the detection and chemical analysis of 4-MEC (amongst other substances) published in the scientific literature since the 36th meeting of the WHO Expert Committee on Drug Dependence in June 2014. ................ 30 Page 4 of 38 38th ECDD (2016) Agenda item 4.3 4-MEC Acknowledgements This report has been drafted under the responsibility of the WHO Secretariat, Essential Medicines and Health Products, Policy, Access and Use team. The WHO Secretariat would like to thank the following people for their contribution in producing this critical review report: Dr. Simon Brandt, United Kingdom (literature review and drafting) and Dr. Stephanie Kershaw, Geneva, Switzerland (editing and questionnaire report drafting). The WHO Secretariat would also like to thank the European Monitoring Centre for Drugs and Drug Addiction (EMCCDA) for providing data on 4- MEC collected through the European Union Early Warning System by Reitox National Focal Points in the EU Member States, Turkey and Norway as well as the Europol National Units. The WHO Secretariat would also like to thank Dr. Terence L. Boos (Drug Enforcement Administration) for sharing information obtained from a DEA-NIDA collaboration and to Dr. Justice Tettey (UNODC) for sharing information from the UNODC Early Warning Advisory (EWA) on new psychoactive substances. Page 5 of 38 38th ECDD (2016) Agenda item 4.3 4-MEC Summary 4-Methylethcathinone (2-(ethylamino)-1-(4-methylphenyl)propan-1-one), also known as 4-MEC, has emerged in recent years as a recreational psychostimulant. Its homolog mephedrone (4- methylmethcathinone) is listed as a Schedule II substance under the 1971 United Nations Convention on Psychotropic Substances. The first official notification submitted to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) by a European member state was 2010. Since then it has been detected across the globe and marketed as a “research chemical” although it has also been detected as a constituent in branded products available for purchase via the Internet or brick-and-mortar shops. At the 36th meeting of the WHO Expert Committee on Drug Dependence in June 2014, the Committee discussed a critical review report on 4-MEC and recommended that 4-MEC not be placed under international control at that time due to insufficiency of data regarding dependence, abuse and risks to public health but be kept under surveillance. The majority of literature published since the 36th ECCD meeting deals with methods of chemical analysis but additional data are available from in vitro and in vivo studies. 4-MEC is a psychostimulant with monoamine transporter activity with indications of abuse liability. Some data obtained from the analysis of user reports suggest that 4-MEC produces euphoria, a sense of well being, psychostimulant effects and lack of comedown symptomatology and that these appear to be less intense and short-lived compared to mephedrone. Conflicting information is available related to the urge of redosing, craving and bingeing. Negative effects associated with 4-MEC use include excessive sweating in the armpits, nausea, and vomiting but also jaw clenching, nystagmus, heart palpitations, loss of sight and migraine. The available data so far also suggest that it may also function as a serotonin releasing agent but not dopamine, which would differentiate it from its homolog