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Khat Chemistry & Pharmacology Excerpt
by Marcello Spinella
2001
Chemistry #
There are more than 40 alkaloids, glycosides, tannins, and terpenoids in khat (Elmi 1983). Two phenylalkylamines, namely, cathine (norpseudoephedrine) and cathinone [S-(-)-alpha-aminopropiophenone] well account for the CNS stimulant effects (Kalix 1988). The S(-) enantiomer occurs naturally, and the R(+) enantiomer is synthetic (Kalix 1992).

Pharmokinetics #
In its natural form, fresh khat leaves are chewed because the drug is perishable. Young leaves from the tip of the branch are more potent. While the leaves are chewed, the juices are swallowed and the residue is rejected. During a session, one may ingest 100 to 200 grams of leaves.

When khat is chewed, absorption of cathinone is slow, with maximal plasma concentrations occuring at approximately 2 hours (Widler et al 1994; Kalket et al 1995). The terminal elimination half-life is approximately 4.3 hours. Similar effects are achieved with orally administered pure cathinone. Cathinone is the keto-analog of cathine and because it is more lipophilic it penetrates the blood-brain barrier more easily.

The plasma life of cathinone is 1.5 hours. The primary metabolites are norpseudoephedrine, norephedrine, 3,6-dimethyl-2,5-diphenylpyrazine, and 1-phenyl-1,2-propanedione (Szendrei 1980; Brenneisen et al 1986; Guantai and Maita 1983). However, norpseudoephedrine and norephedrine also originate directly from the leaves, as well as being metabolic products (Widler et al 1994). Maximal plasma concentrations of norephedrine and nor pseudoephedrine are reached at about 3.3 and 3.1 hours, respectively. These two drugs have much longer duration of action than cathinone, where terminal half-lives could not be calculated after 10 hours. [erowid note: meaning that the half-lives are substantially longer than 10 hours.]

Animal drug discrimination paradigms show cross-tolerance between cathinone, cathine, and amphetamine (Schechter 1990). S(+)methcathinone is about twice as potent as S(+)amphetamine, and five times as potent as R(+)methcathinone, although both isomers have CNS stimulant effects (Glennon et al 1995).

Mechanisms of Action #
The stimulant effects of khat are mediated through monoamine neurotransmitter systems. Cathinone induces release of monoamines through membrane transporters (Kalix 1984, 1992). It causes release of dopamine in the striatum and nucleus accumbens, with similar potency to amphetamine in low micromolar concentrations (Kalix 1980, 1982; Pehek et al 1990). Consequently, increases are seen in extracellular levels of the metabolite DOPAC in the caudate nucleus, nucleus accumbens, and frontal cortex (Mereu et al. 1983). Norpseudoephedrine also induces release of catecholamines (Kalix 1983).

Cathinone decreases firing of substantia nigra neurons, similar to amphetamine. Animal discrimination of cathinone is dependent on dopamine release, but is independent of 5-HT3 modulation or CA2+ inlux through L-type channels (Schechter 1992. High doses of cathinone result in depletion of dopamine and also have neurotoxic effecs on dopamine neurons (Wagener et al 1982). In contrast, long-term administration of cathinone does not deplete norepinephrine or serotonin (Wagner et al 1982). Cathinone and cathine may also have monoamine oxidase inhibition effects (Nencini et al 1984).

Excerpted from the excellent book "The Psychopharmacology of Herbal Medicine", by Marcello Spinella, 2001.