The newest cathinone derivatives as designer drugs: an analytical and toxicological review

Forensic Toxicol DOI 10.1007/s11419-017-0385-6 REVIEW ARTICLE The newest cathinone derivatives as designer drugs: an analytical and toxicological review Milena Majchrzak1,3 • Rafał Celiński3 • Piotr Kuś2 • Teresa Kowalska1 • Mieczysław Sajewicz1 Received: 30 July 2017 / Accepted: 22 August 2017 Ó The Author(s) 2017. This article is an open access publication Abstract Purpose Currently, among new psychoactive substances, cathinone derivatives constitute the biggest group, which are mainly classified into N-alkylated, 3,4-methylenedioxyN-alkylated, N-pyrrolidinyl, and 3,4-methylenedioxy-Npyrrolidinyl derivatives. These derivatives are actively being subjected to minor modifications at the alkyl chains or the aromatic ring to create new synthetic cathinones with the goal of circumventing laws. In this review, the new synthetic cathinones that have appeared on the illegal drug market during the period 2014–2017 are highlighted, and their characterization by gas chromatography–mass spectrometry and liquid chromatography–tandem mass spectrometry is presented. Methods Various key words were used to conduct an extensive literature search across a number of databases, specifically for synthetic cathinones that emerged between 2014 and 2017. Results More than 30 new cathinone derivatives were discovered. The preexisting parental compounds for the new derivatives are also referenced, and their mass spectral data are compiled in a table to facilitate their identification by forensic toxicologists. & Milena Majchrzak 1 Department of General Chemistry and Chromatography, Institute of Chemistry, University of Silesia, 9 Szkolna Street, 40-006 Katowice, Poland 2 Department of Organic Synthesis, Institute of Chemistry, University of Silesia, 9 Szkolna Street, 40-006 Katowice, Poland 3 Toxicology Laboratory ToxLab, 6 Kossutha Street, 40-844 Katowice, Poland Conclusions To our knowledge, this is the most current review presenting new synthetic cathinones. Political authorities should take measures to implement and enforce generic scheduling (comprehensive system) laws to control the diversely modified synthetic cathinones. Supplementing the existing databases with new findings can greatly facilitate the efforts of forensic toxicologists. Keywords New synthetic cathinones  Designer drugs  NPS  LC–MS  GC–MS  NMR Introduction Cathinone is one of the biologically active alkaloids found in the khat shrub (Catha edulis). Due to its psychoactive properties, khat has been known and utilized for ages by the inhabitants of East Africa and the northeastern parts of Arabian Peninsula. In many regions, chewing of freshly collected khat leaves (thus liberating cathinone, which affects the central nervous system) is considered a matter of culture and local tradition [1–4]. Because of their structural similarity to amphetamine, cathinone and its analogs are often denoted as ‘‘natural amphetamines’’, and the only structural difference between amphetamine and cathinone is the presence of a carbonyl group in the aposition of cathinone’s side chain. Similar to amphetamine, cathinone and its analogs are characterized by stimulating, euphoric, and empathogenic properties [1, 2, 4–6]. Due to their effects on the central nervous system, the first synthetic cathinone derivatives were synthesized for medicinal purposes in the early twentieth century, but they began attracting wider attention around the year 2000. At that time, synthetic cathinones were included in a broader group of psychoactive compounds denoted as 123 Forensic Toxicol ‘‘legal drugs’’ or ‘‘designer drugs’’ [5–8]. Over the course of the past 15 years, cathinone derivatives have gradually become available from so-called smart shops, through the Internet, and from drug paraphernalia stores advertising, for example, ‘‘funny items’’ or ‘‘aromas’’ [9–11]. Synthetic cathinones are most often sold as white or colored crystalline powders, and rather rarely as tablets or capsules. In the past, products containing active ingredients from the cathinone group were advertised as ‘‘plant nutrients’’, ‘‘bath salts’’, or ‘‘research chemicals’’. Nowadays, the same substances are frequently labeled with such names as ‘‘conquerors of leeches’’, ‘‘driver’s charms’’, ‘‘additives to sand’’, and ‘‘bidet refreshers’’. Quite often, these preparations contain a combination of two or more cathinone derivatives, along with other type(s) of new psychoactive substances, caffeine, lidocaine, or benzocaine [12]. Background Synthetic cathinones first made their appearance in the third decade of the twentieth century, solely for medicinal purposes (to treat patients with parkinsonism, obesity, or depression), but at the beginning of the twenty-first century, they began to be consumed recreationally as substitutes for controlled drugs. After the year 2000, two pioneering representatives from this group emerged on the illegal market, namely CAT (methcathinone) and 4-MMC (mephedrone, 4-methylmethcathinone), which were followed by methylone (3,4-methylenedioxy-N-methylcathinone) and MDPV (3,4-methylenedioxypyrovalerone’’) [6, 12, 13]. Immediately after their disclosure, the full chemical and psychoactive characteristics of these compounds were realized; as a consequence, in many countries, they became illegal, and clandestine synthetic chemists began modifying their structures to obtain new analogs. In that way, new cathinones were synthesized as substitute drugs, including butylone, ethylone, buphedrone, and an analog of the latter, pentedrone, which was soon replaced by its constitutional isomer, 4-MEC (4methyl-N-ethylcathinone). About the same time, the chemical structure of mephedrone was modified by introducing new substituents to the aromatic ring; in 2009, 4-FMC (flephedrone, 4-fluoromethcathinone) and its positional isomer 3-FMC (3-fluoromethcathinone) appeared. Along with pentedrone, a second-generation synthetic cathinone, a-PVP (a-pyrrolidinopentiophenone), appeared, which belongs to the same group [5, 6, 12]. 123 Chemistry The structures of the first synthetic cathinones have been continuously modified to this day, so that each year several new derivatives emerge on an illegal designer drug market. Given these circumstances, the identification of these compounds and implementation of a drug library with new structures and their physicochemical and pharmacological characteristics become an analytical challenge equally important for chemists and toxicologists. The structures of all synthetic cathinones are derived from that of natural cathinone, and they can be considered to be phenylalkylamine derivatives, which structurally resemble the molecule of amphetamine with a carbonyl group in the a-position of the side chain adjacent to the aromatic ring. Nowadays, cathinone derivatives can be divided into four groups. Group 1 includes N-alkyl compounds or those with an alkyl or halogen substituent at any possible position of the aromatic ring (Table 1 (...truncated)