Dr. Gordon Alles managed to obtain samples of the dried plant in the 1930s; (+)-
-norephedrine (1)
(also called pseudonorephedrine, norpseudoephidrine, and cathine) was isolated from the samples and was reported to be the active constituent of khat. This agent was synthesized in large quantities, and subsequent pharmacological evaluation demonstrated that the -norephidrine, like its isomer norephidrine posesses modest central stimulant properties. End of story? Not quite.
In the mid 1970s, on of our research projects focussed on determining what structural features of phenylisopropylamines impart central stimulant (i.e., amphetamine-like) properties, and what features are responsible for producing other psychoactive effects. It was also of interest to determine whether other, clinically useful phenylisopropylamines (e.g. cardiovascular agents, anorexic agents) possess any abuse liability. In the course of our work, we synthesized and evaluated a number of structural analogs of phenylisopropylamines. One of our findings was that many simple phenylisopropylamines lack amphetamine-like stimulant activity[1]. However, we identified one agent (one of very few agents) that retatins the stimulant potency of amphetamine. This compound, which we called benzylketoamphetamine (2), is simply amphetamine with a carbonyl group at the benzylic postion.
In the late 1970s, while we were working with benzylketoamphetamine, the World Health Organization planned a meeting in Madagascar to discuss the khat problem. This served to renew scientific interest in khat. One of the findings to emerge from this meeting was that although -norephidrine was one of the major constituents of dried khat, a different substance seemed responsible for the stimulant activity of fresh khat. This substance, which degrades as the leaves age, accounting for its previous lack of detection in dried khat samples) was identified as (-)cathinone [(-)2]. It was subsequently demonstrated that (-)cathinone is the major psychoactive constituent of khat. Interestingly, (-)cathinone is one of the two optical isomers of benzylketoamphetamine. Thus we found ourselves in possession of some of the first pharmacological data on what represented the racemate of the active component of khat. In the early 1980s, there was considerable interest in identifying the properties and mechaninsm of action of cathinone. However, some of the literature of this period is rather comnfusing. The term cathinone was originally applied to the (-)enentiomer (shown), with the (+)isomer being refered to as (+)cathinone. When racemic cathinone became available to the scientific community, some referred to the racemate as cathinone whereas others continued to use the name in reference to the (-)isomer. Thus, studies with cathinone must be cautiously interpreted. To avoid confusion, the naturally occuring (-)isomer is now referred to, by most, as (-)cathinone.
During this time, cathinone was viewed by pharmacologists as an exotic new substance. We argued on structural, stereochemical, and structure-activity grounds, that cathinone was essentially a naturally occuring amphetamine analog. Others were disturbed that although the (+)isomer of amphetamine is more potent that its (-)enantiomer, (-)cathinone is more potent than (+)cathinone. We emphasized that in both cases, however, the absolute stereochemistry was identical; that is, (+)amphetamine and (-)cathinone both posess the S absolute configuration. As mentioned above, very few analogs of amphetamine retain its potent central stimulant actions; one such analog is the N-methyl derivative of amphetamine, or methamphetamine. We hypothesized that if methamphetamine is more potent than amphetamine, and if cathinone is acting as an amphetamine-like agent, then the N-methyl analog of cathinone should be more potent than cathinone. We synthesized this compound and termed it methcathinone. Indeed, it was shown to be a rather potent amphetamine-like analog[2].
Cathinone was scheduled (Schedule I of the Controlled Substances Act) in the 1980s. Although work continued with cathinone, and although we continued our studies with cathinone and methcathinone, research in this area seemed to lose its sense of urgency. With the fall of the Soviet empire came a loosening of communication. In early 1992, I received a letter from a Russian scientist who had finnaly obtained a copy of our 1987 publication on methcathinone. He stated that our paper was the only published reference he could find on methcathinone and was surprised by the lack of interest in this substance in the West. He further wrote that methcathinone was widely abused in the Soveit Union but that formal public disclosure of the methcathinone problem had been withheld by Soviet authorities for "political motives". Evidently, methcathinone has been abused since the late 1970s; its use has incereased by ten-fold from 1984 to 1988 alone. Apparently, this substance is less costly than alcohol and has "even [won over] subjects with opium dependence". In Russia, methcathinone is termed ephedrone and is known on the street as JEFF. Together with alcohol, it may be considered the greatest drug abuse problem in Russia today.
Later that same year, the DEA informed me that methcathinone was appearing in this country (under the street name CAT) and that they had just raided several clandestine methcathinone labs. They also confirmed the use of methcathinone in Russia. Methcathinone was emergency scheduled (Schedule I) in 1992[3].
Today, neither cathinone nor methcathinone constitutes a major drug abuse problem in the West. This likely accounts for the relative lack interest in, and research on, these agents. But, we can draw some parallels with another drug that was once a minor abuse problem - cocaine. Certain South American Indians chew coca leaf, a practice that has continued for centuries. Coca chewing may be a social event, but is often practiced to ward off fatigue. It was not until the active constituent, cocaine, was isolated, identified, and used in its pure form, that it became a significant abuse problem. Is this the harbringer of things to come? Will history repeat itself? Another parallel can be drawn. In a recent manuscript[4], we describe teh results of a study using animals trained in a behavioral paradigm to discriminate cocaine from vehicle; we have found that methcathinone substitutes for cocaine. Indeed, it is more potent than cocaine. Cathinone, the active constituent of khat, also substitues for cocaine. All three agents substitute for amphetamine in animals trained to discriminate (+)amphetamine from vehicle.
Chronic administration of high doses of amphetamine can lead to symptoms that are indistinguishable from those of acute paranoid psychosis. A similar effect has been reported for cocaine. Now, descriptions of khat psychosis have appeared in the literature. Methamphetamine and amphetamine are the most widely clandestinely-synthesized drugs in the world. Cocaine, the active constituent of coca leaf, is currently one of our greatest drug abuse problems. Will cathinone, the active constituent of khat leaf, and derivatives of cathinone such as methcathinone, become a future problem?
1. Glennon, R.A.; Showalter, D. The effest of cathinone and several related derivatives on locomoter activity. Res. Commun. Subst. Abuse 1981, 2, 186-191.
2. Glennon, R.A.; Yousif, M.; Naiman, N.; Kalix, P. Methcathinone: A new and potent amphetamine-like agent. Pharmacol. Biochem. Behav. 1987, 26, 547-551.
3. Bonner, R.C. Schedules of controlled substances: Temporary placement of methcathinone into Schedule I. Federal Register 1992, 57, 18824-18825.
4. Young, R.; Glennon, R.A. Cocaine stimulus generalization to two new designer drugs: Methcathinone and 4-Methylaminorex. Pharmacol. Biochem. Behav. 1993, ?, ?.