The pharmacology and toxicology of the stimulant khat

Khat chewing, a traditional practice in the Horn of Africa and Yemen, delivers stimulant effects through its active compounds. Fresh khat is rich in cathinone, a potent central nervous system stimulant that acts on dopamine and norepinephrine transporters similarly to amphetamine. Dried khat has reduced cathinone but higher levels of cathine and norephedrine, which act more peripherally. Cathine can match cathinone's cardiovascular toxicity but not its central psychostimulant effects. Switching from fresh to dried khat increases cardiovascular risks relative to central stimulation, while the reverse may cause excessive central stimulation. Awareness of khat's health consequences should be increased.

Study at a glance

Abstract

Khat chewing has a long history in the culture and society of the Horn of Africa and Yemen. Extracts of leaves from khat have similar actions to that of amphetamines and contain the major psychostimulant cathinone, but also the mainly peripherally acting stimulants cathine and norephedrine. Fresh khat is rich in the major stimulant cathinone. In dried khat, cathinone content is greatly reduced, so that the other stimulants, particularly cathine, dominate. Cathinone acts at the dopamine (DA) transporter (DAT) and the norepinephrine (NE) transporter (NET), both as a releaser of monoamines and perhaps also as an antagonist of the transporter. Cathinone has major actions at DAT centrally, and at NET both centrally and peripherally. Although like cathinone, cathine acts potently at DAT to release DA, its stimulant actions are limited by poor central nervous system penetration, and it acts mainly on peripheral NET to release NE in vivo. Norephedrine acts predominantly as a direct agonist at a1-adrenoceptors. Cathine fully substitutes for cathinone in terms of cardiovascular toxicity but not in terms of central psychostimulant actions. The profile of central stimulant actions of cathinone, and to a less extent cathine, differs from that of cocaine or MDMA, and is more similar to that of amphetamine. A change from fresh to dry khat increases potential for cardiovascular toxicity relative to central stimulant actions, and conversely, a change from dry to fresh khat would result in greater and possibly excessive central stimulation. It is important to increase awareness of the health consequences of khat use.