Stimulants belong to a diverse group of psychoactive drugs whose function exerts a constant contribution to hyperactivity and impulse control. From caffeine and nicotine to cocaine and amphetamines, each varies widely in how amply they accelerate body functions, how they are used, and their legal status. Simulants including amphetamines, arylcyclohexylamines, cocaine, phenethylamines, piperazines, and cathinones are among the most widely abused across the US and Europe. However, the popularity of each substance, particularly in party culture settings, is frequently changing. Each has a storied beginning that ultimately led to epidemic abuse and inevitable classification as controlled substances. This article series aims to provide an overview of the history, chemistry, pharmacology, and metabolism of the major classes of stimulants.

Series Part 2: Cathinones

History

Cathinone is a naturally occurring phenylalkylamine alkaloid found in the bitter leaves of khat (Catha edulis), a shrub indigenous to East Africa and the Arabian Peninsula (Figure 1). It is chemically similar to cathine, ephedrine, methamphetamine, and other amphetamines. For thousands of years, fresh khat leaves have been chewed for their stimulant and euphoric effects. Some people have compared the effect of its consumption with drinking strong coffee. The practice is still popular today in geographic regions such as Somalia, Yemen, Kenya, and Ethiopia where the khat shrub grows and its cultivation and trade are legal. Because cathinone begins to decompose shortly after the leaves are harvested, khat chewing at first largely remained limited to the areas where it was grown until increased immigration and expedited shipping capabilities helped the practice to steadily emerge to expatriate communities in other countries.

Figure 1. Khat leaves contain (−)-(S)-cathinone, which is structurally similar to many different stimulants.

The khat shrub was introduced to Europeans in the late eighteenth century by the Swedish botanist Peter Forsskål. Motivated by the discovery of other extract-type remedies originating from plants, attention focused on trying to isolate the active constituents of khat. In 1887, Flückiger and Gerock identified a ‘katin’ alkaloid. This mysterious alkaloid was not isolated and purified until several decades later, when in 1930 the active principle extracted from aged leaves was erroneously shown to have the same chemical structure as cathine (d-norpseudoephedrine). It was not until 1975, when fresher leaves were examined, that the S (−) enantiomer of cathinone was identified as the principal psychoactive component of khat. From 1928-1929 (shortly before cathine was identified in khat leaves) synthetic processes for methcathinone (ephedrone) and 4-methylmethcathinone (mephedrone) were established. The close structural relationship of these substances to amphetamine and its structural analogs led to an interest in developing these compounds for therapeutic purposes. Methcathinone was introduced as an antidepressant in the USSR during the 1930s and 1940s, and later developed by the US pharmaceutical company Parke-Davis as a potential central nervous system stimulant. Amfepramone (diethylpropion) was introduced as an appetite suppressant in the late 1950s. Despite widespread abuse of methcathinone in the USSR starting in the 1970s, bupropion was introduced a decade later as an antidepressant in the 1980s. As abuse potential became more evident, cathinone, cathine, and methcathinone were added to Schedule I of the UN Convention on Psychotropic Substances in the early 1990s. At that time, this designation did not apply to other cathinone derivatives such as methylone, an MDMA (3,4-methylenedioxymethamphetamine) analog, which were still being evaluated for therapeutic potential. Methylone was patented as an antidepressant and anti-Parkinsonian agent in 1996, and though never marketed for these conditions, instead emerged for sale under the trade name ‘Explosion’ around 2004 in headshops in Japan and the Netherlands and on the internet.

Today, there are more than 200 known synthetic cathinone derivatives that have been abused throughout the European Union, Asia, and the United States for their amphetamine-like stimulant effects. This has been fueled by the emergence of unscheduled substituted cathinone products disguised as “research chemicals,” “bath salts,” “plant food or fertilizer,” “jewelry cleaner,” “stain remover,” or “insect repellants.” Labeled “not for human consumption” to evade Food and Drug Administration scrutiny, these products are sold under various names and promoted as legal alternatives to illicit street drugs (mephedrone, methylone, methylenedioxy pyrovalerone (MDPV), cocaine, methamphetamine, and MDMA). Synthetic cathinones are also sold deceptively as ecstasy in powdered form, in single-component tablets and capsules, and in tablets and capsules containing cathinones combined with MDMA or other illicit controlled substances. These are commonly used in the rave, club, and dance festival scenes.

Chemistry

As a phenethylamine derivative, cathinone differs from many other amphetamines by the addition of a ketone functional group at the β-carbon position. Substitutions at various R-group locations of the cathinone molecule produce a variety of derivatives (Figure 2). Variations range from the simple addition of a methyl group to create alkylated cathinones to the incorporation of a cyclic pyridinyl structure at the nitrogen to create pyrrolidine cathinones and/or the fusion of a methylenedioxy group on the phenyl ring to create methylenedioxy cathinones.

Figure 2. Functional group additions to the general structure of cathinone synthesize hundreds of derivatives.

Many of these derivatives have amphetamine counterparts, which are identical in structure except for the β-carbon ketone group. For example, replacing the methylene group with a ketone converts amphetamine → cathinone, methamphetamine → methcathinone, and MDMA → methylone. Accordingly, cathinone acronyms are modeled after their amphetamine counterparts with the addition of the prefix “bk” to indicate the presence of the β-keto substituent (e.g., methylone is abbreviated bk-MDMA). Because of these close structural similarities, similar mass spectral fragmentation, and the potential to undergo a process of cyclization and rearrangement to an isocathinone, analysts have a considerable analytical challenge to precisely identify a particular isomer or metabolite.

Pharmacology

Like other stimulants, substituted cathinones increase synaptic concentrations of dopamine, norepinephrine, and serotonin by stimulating the release of these neurotransmitters from intracellular stores and/or inhibiting specific catecholamine reuptake transporters. For example, mephedrone acts as a dopamine-releasing agent similar to methamphetamine, while MDPV behaves as a dopamine reuptake inhibitor similar to cocaine. These actions on the central dopamine system affect the regulation of behavioral reinforcement, motor coordination, and thermoregulation. Cathinones can also work as partial agonists at serotonin (5-HT)_1A receptors and antagonists at 5-HT_2A and 5-HT_2C receptors, yet they show no affinity towards dopamine receptors. Due to the presence of the β-keto moiety, cathinones are much less lipophilic than amphetamines, and thus, typically require much higher doses in order to produce effects equivalent to the amphetamines. However, the pyrrolidine ring and tertiary amino group additions can improve lipophilicity.

Metabolism

Following absorption, all synthetic cathinones undergo extensive phase I metabolism. Cathinone is metabolized to norephedrine and cathine (norpseudoephedrine) through a reduction of the β-keto moiety to form hydroxyl metabolites. The metabolism of cathinone is stereoselective with the principal metabolite of (−)-(S)-cathinone being (−)-(1R,2S)-norephedrine, whereas (+)-(R)-cathinone is metabolized to the principal metabolite of (−)-(1R,2R)-norpseudoephedrine (Figure 3).

Figure 3. Stereoselective reduction of the β-ketone group of cathinones. Compounds in bold are the more abundant metabolite.

Prior to being reduced to a corresponding secondary alcohol, synthetic cathinones are metabolized to the basic primary amine by either N-dealkylation or demethylation as in Figure 4.

Figure 4. Substituted phenyl ring and alkylated amine metabolism.

For compounds with cyclic amines, metabolism may occur by hydroxylation and dehydrogenation on the ring, whereas metabolism for a cyclic phenyl ring substitution may occur by demethyleneation ring opening and O-methylation (Figure 5).

Figure 5. Cyclic aromatic substitutions and cyclic amine metabolism.

One or more substituents on the phenyl ring may be metabolized by O-demethylation or hydroxylation followed by oxidation (Figure 4). While 4-hydroxylation of the benzene ring is one of the most major metabolic pathways for amphetamines, with non-ring substituted synthetic cathinones this route is almost negligible, indicating the β-ketone substitution alters both the chemical properties and the metabolic profile.

Metabolic phase II pathways include methylation, acetylation, glucuronidation, and/or sulfation. A significant portion of several cathinones is also excreted as an unchanged form in human and rat urine. Phase II metabolites have been identified not only for hydrolyzed- and/or hydroxylated-metabolites but also for these unchanged cathinone derivatives.

Available from Cayman

Cayman offers numerous analytical standards for the identification of cathinones. If you are having trouble identifying or finding a compound of interest, please contact our technical support department. Cayman can also provide assistance in the identification of unknown compounds and provides other tools on our Forensic Science Products page such as our Spectral Library, GC-MS Search Tool, and Literature Library to help chemists identify novel analogs.

Other Articles in this Series

Amphetamines

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Suggested Reading

Bonson, K.R., Dalton, T.P., and Chiapperino, D. Scheduling synthetic cathinone substances under the Controlled Substances Act. Psychopharmacol. (Berl).236(3), 845-860 (2019).

Capriola, M. Synthetic cathinone abuse. Clin. Pharmacol.5, 109-115, (2013).

Kelly, J.P. Cathinone derivatives: A review of their chemistry, pharmacology and toxicology. Drug Test Anal.3(7-8), 439-453 (2011).

Drug Enforcement Administration. 2018 National Drug Threat Assessment. National Drug Threat Assessment. (2018).

Paillet-Loilier, M., Cesbron, A., Le Boisselier, R., et al. Emerging drugs of abuse: Current perspectives on substituted cathinones. Subst. Abuse Rehabil.5, 37-52 (2014).

Zaitsu, K. Metabolism of synthetic cathinones. Synthetic cathinones. Current topics in neurotoxicity. Zawilska, J., editor, vol. 12 Springer, Cham (2018).