Khat and Synthetic Cathinones: a Review
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Arch Toxicol DOI 10.1007/s00204-013-1163-9 REVIEW ArtiCLE Khat and synthetic cathinones: a review Maria João Valente · Paula Guedes de Pinho · Maria de Lourdes Bastos · Félix Carvalho · Márcia Carvalho Received: 2 August 2013 / Accepted: 5 November 2013 © Springer-Verlag Berlin Heidelberg 2013 Abstract For centuries, ‘khat sessions’ have played a analogs are introduced into the legal market. Chemically, key role in the social and cultural traditions among sev- these substances are structurally related to amphetamine. eral communities around Saudi Arabia and most East For this reason, cathinone derivatives share with this drug African countries. The identification of cathinone as the both central nervous system stimulating and sympathomi- main psychoactive compound of khat leaves, exhibiting metic features. Reports of intoxication and deaths related amphetamine-like pharmacological properties, resulted in to the use of ‘bath salts’ have been frequently described the synthesis of several derivatives structurally similar to over the last years, and several attempts to apply a leg- this so-called natural amphetamine. Synthetic cathinones islative control on synthetic cathinones have been made. were primarily developed for therapeutic purposes, but However, further research on their pharmacological and promptly started being misused and extensively abused for toxicological properties is fully required in order to access their euphoric effects. In the mid-2000’s, synthetic cathi- the actual potential harm of synthetic cathinones to general nones emerged in the recreational drug markets as legal public health. The present work provides a review on khat alternatives (‘legal highs’) to amphetamine, ‘ecstasyʼ, or and synthetic cathinones, concerning their historical back- cocaine. Currently, they are sold as ‘bath salts’ or ‘plant ground, prevalence, patterns of use, legal status, chem- foodʼ, under ambiguous labels lacking information about istry, pharmacokinetics, pharmacodynamics, and their their true contents. Cathinone derivatives are conveniently physiological and toxicological effects on animals and available online or at ‘smartshops’ and are much more humans. affordable than the traditional illicit drugs. Despite the scarcity of scientific data on these ‘legal highs’, synthetic Keywords Khat · Synthetic cathinones · Bath salts · cathinones use became an increasingly popular practice Pharmacokinetics · Pharmacodynamics · Toxicity worldwide. Additionally, criminalization of these deriva- tives is often useless since for each specific substance that gets legally controlled, one or more structurally modified Introduction Cathinone is the major naturally occurring psychoactive M. J. Valente (*) · P. Guedes de Pinho · M. de Lourdes Bastos · component found in the leaves of the Catha edulis plant, * F. Carvalho · M. Carvalho ( ) commonly known as khat. The first cathinone derivatives REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, were originally synthesized in the beginning of the twenti- Rua Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal eth century for therapeutic purposes, but it was only in the e-mail: [email protected] last decade that the recreational use of these synthetic com- M. Carvalho pounds gained public attention (Balint et al. 2009; Kelly e-mail: [email protected] 2011). Synthetic cathinones are included in a larger group of psychoactive substances generally designated by ‘legal M. Carvalho CEBIMED, Faculdade de Ciências da Saúde, Universidade highs’. They are indiscriminately abused for their cocaine Fernando Pessoa, Porto, Portugal and amphetamine-like pharmacological effects, usually 1 3 Arch Toxicol labeled ‘not for human consumption’, and sold as ‘plant Recently, and following the improvement of the routes food’ or ‘bath salts’ in order to bypass legislative restric- for transportation and distribution, the availability of khat tions in several countries (Bretteville-Jensen et al. 2013; leaves ceased to be exclusive to the native regions, and Fass et al. 2012; Van Hout and Brennan 2011). immigrants spread their use to Western countries (Alem Methcathinone (ephedrone, ‘CAT’) and 4-methylmeth- et al. 1999; Griffiths et al. 2010), although with the limita- cathinone (mephedrone, 4-MMC) were the first cathi- tion that only fresh khat leaves may achieve the aimed psy- none derivatives to be produced. Mephedrone, along with chotropic effects. methylone (3,4-methylenedioxy-N-methylcathinone, βk- The khat plant was first described during an expedition MDMA) and MDPV (3,4-methylenedioxypyrovalerone), to Egypt and Yemen in 1761–1763, by a Swedish botanist rapidly emerged in recreational drug markets as the main named Peter Forskal, who identified C. edulis as a mem- ingredients of ‘bath salts’, becoming readily accessible on ber of the family Celastraceae. In 1775, Karsten Niebuhr, the Internet and at the so-called ‘head’ or ‘smartshops’. By Forskal’s travelling companion and the only survivor of the the end of 2011, these three compounds were provisionally expedition, named khat as C. edulis Forsk (Al-Motarreb scheduled in the United States of America (USA) under et al. 2002; Dhaifalah and Santavy 2004; Kalix 1984). drug legislation for further analysis of potential harm (Jerry The fresh khat leaves contain over forty compounds, et al. 2012; Kelly 2011; Prosser and Nelson 2012). None- including alkaloids, tannins, flavonoids, terpenoids, ster- theless, legal regulation of synthetic drugs like cathinone ols, glycosides, amino acids, vitamins, and minerals (Balint derivatives is rather difficult to attain success, since they et al. 2009; Cox and Rampes 2003; Halbach 1972; Kalix are easily replaced by novel compounds after minor struc- 1984). In the first attempt to identify the active principle(s) ture modifications. Consequently, for each drug that gets of khat, Fluckiger and Gerock (1887) detected a psychoac- banned, new and more powerful analogs will reach the licit tive compound they named katin, which was later identified drug markets. by Wolfes (1930) as ( )-norpseudoephedrine, an Ephedra + Due to their legal status, users are deceivingly led to alkaloid. For the following three decades, ( )-norpseu- + believe that these drugs are safe to consume. However, doephedrine, commonly known as cathine, was believed several cases of ‘bath salts’-related intoxication and deaths to be the major active component of khat, although some have been reported over the last years (James et al. 2011; evidences showed that cathine stimulant effect was insuf- Kovacs et al. 2012; Murray et al. 2012; Wood et al. 2010a). ficient as the sole responsible for khat pharmacological Despite the scarcity of experimental data on the pharmaco- effects (Halbach 1972; Kalix 1984; Szendrei 1980; Zelger logical and toxicological properties of these ‘legal highs’, et al. 1980). Thus, in 1975, a βk-analog and precursor of based on the structural similarities of cathinone deriva- cathine, the ( )-α-aminopropiophenone, or cathinone, − tives with other amphetamines like MDMA (3,4-methyl- was isolated in the United Nations’ Narcotics Laboratory enedioxymethamphetamine, ‘ecstasy’), identical effects are (United Nations 1975). Early studies showed that cathi- predictable. none is 7- to 10-fold more potent than cathine but degrades The purpose of this work is to provide a thorough report rapidly, thus explaining the need to chew fresh khat leaves on the currently known synthetic cathinone derivatives, and (Cox and Rampes 2003; Kalix and Khan 1984; Kelly to review their chemical, pharmacological, and toxicologi- 2011; Knoll 1979; Nencini and Ahmed 1989). Cathinone cal properties. appeared in the recreational Israeli markets in the early 2000’s, in 200 mg capsules, under the brand name ‘Hagi- gat’, which was sold as a natural psychostimulant and aph- Historical background rodisiac (Bentur et al. 2008). Besides cathine, cathinone can also be metabolized into Khat (Catha edulis) is a flowering evergreen plant that ( )-norephedrine (Brenneisen et al. 1986). These three − grows wild in the Horn of Africa and in the Southwest Ara- alkaloids belong to the khat phenylalkylamine family. bian Peninsula. For centuries, the chewing of fresh khat With the purpose of synthesizing a series of ephedrine leaves, for their gratifying stimulant effects, has been a tra- homologs, Hyde et al. (1928) optimized earlier methods dition in local communities, especially at cultural and reli- and obtained purified α-methylaminopropiophenone, also gious ceremonies, including funerals and weddings. Khat known as methcathinone or ephedrone (EPH). In the fol- chewing is also widely practiced on a daily basis, at the lowing year, Saem de Burnaga Sanchez (1929) described so-called khat sessions, where men gather and chat for sev- a method for the chemical synthesis of 4-methylmethcathi- eral hours, usually after work. These sessions are a major none, generally named mephedrone (MEPH). social and cultural phenomenon in this area, particularly in Due to their central nervous system (CNS) stimu- Yemen (Al-Motarreb et al. 2002; Balint et al. 2009; Car- lant properties, some synthetic cathinone derivatives, valho 2003). such as m-chloro-N-tert-butyl-cathinone (bupropion), 1 3 Arch Toxicol N,N-diethylcathinone (diethylpropion, amfepramone), and (4-methyl-α-pyrrolidinohexiophenone), MPBP (4-methyl- N,N-dimethylcathinone (dimethylpropion, metamfepra- α-pyrrolidinobutiophenone), MOPPP (4-methoxy-α- mone), were primarily developed