4‐Fluoromethcathinone (flephedrone; 4‐FMC). Critical Review Report. Agenda item 4.16. Expert Committee on Drug Dependence. Thirty‐sixth Meeting. Geneva, 16‐20 June 2014 (World Health Organization).

Abstract

(R/S)-1-(4-Fluorophenyl)-2-(methylamino)propan-1-one, also known as flephedrone or 4- FMC, has emerged in recent years as a recreational psychostimulant. Its synthesis was first published in 1952 in order to explore the potential for antithyroidal, antibacterial and bacteriostatic properties. Publications about the detection of 4-FMC obtained from Internet sources and test purchases started to appear from 2009 onwards. The first official notification submitted to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) by a European member state was 2008. Since then, it has been detected across the globe as a reflection of modern forms of trade within a globalised world. As was the case with many other emerging substances with psychoactive properties, commonly used terms include "legal highs", "bath salts" or "new psychoactive substances" (NPS) in the attempt to highlight the fact that many, if not most, did not originally fall under any legislative control and that detailed data on both pre-clinical and clinical levels were normally less well explored. The amount of research data on 4-FMC is comparatively small in comparison with other cathinones such as 4-methyl-N-methylcathinone (mephedrone) or 3,4- methylenedioxypyrolvalerone (MDPV) but the currently available data suggest that the psychoactive and behavioural profile of 4-FMC, for example demonstrated by drug discrimination and in-vitro studies, show similarities to psychomotor stimulants such as cocaine, methcathinone and methamphetamine although it appears that it be less potent. It has been demonstrated that key targets of 4-FMC include monoamine transporters and that it functions as a catecholamine-selective substrate-type releaser of dopamine and norepinephrine. While 4-FMC was a low potency partial agonist at the 5-HT1A receptor, it was found to be an antagonist with very low potency at 5-HT2A and 5-HT2C receptors. 4-FMC was observed to act primarily as a substrate at the human dopamine (hDAT) and human norepinephrine transporter (hNET), with the latter being more pronounced than methamphetamine. In addition, it was observed to display appreciable affinity to the hα1A adrenoceptor and rat trace amine-associated receptor 1. The ability to induce DA release similar to methamphetamine-type substances known to act as hDAT substrates makes it likely that 4-FMC may show abuse potential. It seems conceivable that, especially at high dosage levels, extensive release of NE in combination with hα1A adrenoceptor activation might also contribute to enhanced cardiotoxic effects, in addition to dopamine-mediated stimulation