Forensic Toxicol DOI 10.1007/s11419-017-0385-6 REVIEW ARTICLE The newest cathinone derivatives as designer drugs: an analytical and toxicological review 1,3 3 2 1 Milena Majchrzak • Rafał Celin´ski • Piotr Kus´ • Teresa Kowalska • Mieczysław Sajewicz1 Received: 30 July 2017 / Accepted: 22 August 2017 Ó The Author(s) 2017. This article is an open access publication Abstract Conclusions To our knowledge, this is the most current Purpose Currently, among new psychoactive substances, review presenting new synthetic cathinones. Political cathinone derivatives constitute the biggest group, which authorities should take measures to implement and enforce are mainly classified into N-alkylated, 3,4-methylenedioxy- generic scheduling (comprehensive system) laws to control N-alkylated, N-pyrrolidinyl, and 3,4-methylenedioxy-N- the diversely modified synthetic cathinones. Supplement- pyrrolidinyl derivatives. These derivatives are actively ing the existing databases with new findings can greatly being subjected to minor modifications at the alkyl chains facilitate the efforts of forensic toxicologists. or the aromatic ring to create new synthetic cathinones with the goal of circumventing laws. In this review, the new Keywords New synthetic cathinones Á Designer drugs Á synthetic cathinones that have appeared on the illegal drug NPS Á LC–MS Á GC–MS Á NMR market during the period 2014–2017 are highlighted, and their characterization by gas chromatography–mass spec- trometry and liquid chromatography–tandem mass spec- Introduction trometry is presented. Methods Various key words were used to conduct an Cathinone is one of the biologically active alkaloids found extensive literature search across a number of databases, in the khat shrub (Catha edulis). Due to its psychoactive specifically for synthetic cathinones that emerged between properties, khat has been known and utilized for ages by 2014 and 2017. the inhabitants of East Africa and the northeastern parts of Results More than 30 new cathinone derivatives were Arabian Peninsula. In many regions, chewing of freshly discovered. The preexisting parental compounds for the collected khat leaves (thus liberating cathinone, which new derivatives are also referenced, and their mass spectral affects the central nervous system) is considered a matter data are compiled in a table to facilitate their identification of culture and local tradition [1–4]. Because of their by forensic toxicologists. structural similarity to amphetamine, cathinone and its analogs are often denoted as ‘‘natural amphetamines’’, and the only structural difference between amphetamine and & Milena Majchrzak cathinone is the presence of a carbonyl group in the a- [email protected] position of cathinone’s side chain. Similar to amphetamine, 1 cathinone and its analogs are characterized by stimulating, Department of General Chemistry and Chromatography, euphoric, and empathogenic properties [1, 2, 4–6]. Institute of Chemistry, University of Silesia, 9 Szkolna Street, 40-006 Katowice, Poland Due to their effects on the central nervous system, the first synthetic cathinone derivatives were synthesized for 2 Department of Organic Synthesis, Institute of Chemistry, University of Silesia, 9 Szkolna Street, 40-006 Katowice, medicinal purposes in the early twentieth century, but Poland they began attracting wider attention around the year 3 Toxicology Laboratory ToxLab, 6 Kossutha Street, 2000. At that time, synthetic cathinones were included in 40-844 Katowice, Poland a broader group of psychoactive compounds denoted as 123 Forensic Toxicol ‘‘legal drugs’’ or ‘‘designer drugs’’ [5–8]. Over the course Chemistry of the past 15 years, cathinone derivatives have gradually become available from so-called smart shops, through the The structures of the first synthetic cathinones have been Internet, and from drug paraphernalia stores advertising, continuously modified to this day, so that each year several for example, ‘‘funny items’’ or ‘‘aromas’’ [9–11]. Syn- new derivatives emerge on an illegal designer drug market. thetic cathinones are most often sold as white or colored Given these circumstances, the identification of these crystalline powders, and rather rarely as tablets or cap- compounds and implementation of a drug library with new sules. In the past, products containing active ingredients structures and their physicochemical and pharmacological from the cathinone group were advertised as ‘‘plant characteristics become an analytical challenge equally nutrients’’, ‘‘bath salts’’, or ‘‘research chemicals’’. Nowa- important for chemists and toxicologists. days, the same substances are frequently labeled with The structures of all synthetic cathinones are derived such names as ‘‘conquerors of leeches’’, ‘‘driver’s from that of natural cathinone, and they can be considered charms’’, ‘‘additives to sand’’, and ‘‘bidet refreshers’’. to be phenylalkylamine derivatives, which structurally Quite often, these preparations contain a combination of resemble the molecule of amphetamine with a carbonyl two or more cathinone derivatives, along with other group in the a-position of the side chain adjacent to the type(s) of new psychoactive substances, caffeine, lido- aromatic ring. Nowadays, cathinone derivatives can be caine, or benzocaine [12]. divided into four groups. Group 1 includes N-alkyl com- pounds or those with an alkyl or halogen substituent at any possible position of the aromatic ring (Table 1). The Background majority of the first synthetic cathinones fall into this group, and they include ethcathinone, ephedrone, mephe- Synthetic cathinones first made their appearance in the drone, flephedrone, buphedrone, and pentedrone. Group 2 third decade of the twentieth century, solely for medicinal includes methylenedioxy-substituted compounds with purposes (to treat patients with parkinsonism, obesity, or substituents at any given position of aromatic ring, such as depression), but at the beginning of the twenty-first cen- methylone, pentylone, and butylone. In terms of their tury, they began to be consumed recreationally as sub- structure and pharmacological effect, these compounds are stitutes for controlled drugs. After the year 2000, two quite similar to 3,4-methylenedioxymethamphetamine pioneering representatives from this group emerged on the (MDMA) (Table 2). Cathinones from group 3 (examples illegal market, namely CAT (methcathinone) and 4-MMC given in Table 3) are analogs of natural cathinone with an (mephedrone, 4-methylmethcathinone), which were fol- N-pyrrolidinyl substituent, and these compounds are cur- lowed by methylone (3,4-methylenedioxy-N-methylcathi- rently the most frequently encountered in the designer drug none) and MDPV (3,4-methylenedioxypyrovalerone’’) market. Compounds which include both methylenedioxyl [6, 12, 13]. Immediately after their disclosure, the full and N-pyrrolidinyl substituents belong to group 4 synthetic chemical and psychoactive characteristics of these com- cathinones (Table 4)[6]. pounds were realized; as a consequence, in many coun- tries, they became illegal, and clandestine synthetic chemists began modifying their structures to obtain new Mechanisms of action and metabolism analogs. In that way, new cathinones were synthesized as substitute drugs, including butylone, ethylone, buphe- In vitro experiments have shown that synthetic cathinones drone, and an analog of the latter, pentedrone, which was easily penetrate the blood-brain barrier (BBB) [13]. soon replaced by its constitutional isomer, 4-MEC (4- Cathinone and its derivatives (denoted as b-keto-am- methyl-N-ethylcathinone). About the same time, the phetamines) exert a stimulating and sympathomimetic chemical structure of mephedrone was modified by effects on the central nervous system due to an increased introducing new substituents to the aromatic ring; in concentrations of catecholamines in the inter-synapse 2009, 4-FMC (flephedrone, 4-fluoromethcathinone) and spaces, and their effects are generally much stronger than its positional isomer 3-FMC (3-fluoromethcathinone) that of amphetamine itself [2, 14–21]. Similar to amphe- appeared. Along with pentedrone, a second-generation tamine, cathinones exist as two stereoisomeric forms, and synthetic cathinone, a-PVP (a-pyrrolidinopentiophenone), each is characterized by different potency [6]. The mech- appeared, which belongs to the same group [5, 6, 12]. anism of action of synthetic cathinones involves the inhi- bition of monoamine transporters such as dopamine transporter (DAT), noradrenaline transporter (NAT), and serotonin transporter (SERT). Depending on the derivative, 123 Forensic Toxicol Table 1 Chemical names, common names, chemical structures, and molecular weights of N-alkylated cathinone derivatives (group 1) Chemical name Common name Chemical structure Molecular weight [Da] [2-(N-Methylamino)-butan-1-onyl]- Buphedrone, a-methylaminobutyrophenone 177.24 benzene [2-(N-Ethylamino)-propan-1- onyl]- Ethcathinone, ETCAT, N-ethylcathinone 177.24 benzene [2-(N-Methylamino)-propan-1-onyl]- Ephedrone, methcathinone, CAT, a- 163.22 benzene methylaminopropiophenone 1-[2-(N-Methylamino)-propan-1- onyl]-4- Flephedrone, 4-FMC, 4-fluoromethcathinone 181.22 fluorobenzene 1-[2-(N-Methylamino)-propan-1- onyl]-4- Mephedrone, 4-MMC, 177.24 methylbenzene 4-methylmethcathinone [2-(N-Methylamino)-pentan-1- onyl]- Pentedrone, a-methylaminovalerophenone 191.27 benzene 1-[2-(N-Methylamino)-propan-1- onyl]- 3,4-DMMC, 3,4-dimethylmethcathinone 191.27 3,4-dimethylbenzene and more precisely, on its chemical structure,