Mechanism of action
Cathinone, the active principle of Catha edulis (khat), shows long-lasting analgesic effects when the tail-flick test is used in rats. The involvement of monoamines, endogenous opioids and stress in this analgesic effect was tested. Both early (30 min) and late (24 hr) analgesic effects of cathinone were prevented by reserpine or p-chlorophenylalanine, which deplete catecholamines or serotonin, respectively, and by nomifensine, which prevents neuronal uptake of biogenic amines and amphetamines. The same inhibitory effect was obtained with a high dose (4 mg/kg) of naloxone. However, rats made tolerant to morphine retained both early and late analgesic response to cathinone. The increase in plasma ACTH induced by the tail-flick test at 30 min and 24 hr was significantly enhanced by cathinone, in a naloxone-reversible way. However, the analgesic responses shown at these times were not prevented by either dexamethasone or adrenalectomy. ... The prolonged analgesia induced by cathinone is primarily due to an amphetamine-like activation of monoaminergic pathways, but requires the integrity of non-mu-opioid mechanisms. The involvement of the adrenohypophyseal axis in this cathinone effect is less probable.
Infusion of khat leaves is an African traditional remedy used to treat airway diseases. The beneficial effects of khat are thought to be due to the activity of its main active component, cathinone. Cathinone inhibited electric field stimulation-induced acetylcholine release and the contractions of smooth muscle, which could be responsible for the beneficial effects seen in airway disease. The mechanism of action of this natural product appears to be via the activation of both pre-junctional alpha(2) adrenergic and 5-hydroxytryptamine 7 receptors. The present novel study describes how cathinone modulates airway tone, and may go some way to explaining the traditional use of khat as a remedy for the alleviation of respiratory disease symptoms.
The alkaloid (-)-cathinone, which accounts for the stimulating properties of khat leaves, has a pharmacological profile closely resembling that of (+)-amphetamine. Since amphetamine is known to induce release at CNS serotonin storage sites, experiments were performed to determine whether (-)-cathinone also displays this aspect of amphetamine action. When the effects of (-)-cathinone and (+)-amphetamine on the release of radioactivity from rat striatal tissue prelabelled with 3H-serotonin were compared, it was found that (-)-cathinone had a releasing effect similar to that of (+)-amphetamine, although it was only one third as potent. Thus, the khat alkaloid (-)-cathinone appears to share an important effect of (+)-amphetamine on serotoninergic neurotransmission.
The effects of (-)cathinone, the primary psychoactive alkaloid of the Khat plant, were compared to those of (+)amphetamine in the anterior caudate-putamen and the nucleus accumbens. In vivo microdialysis was used to measure extracellular levels of dopamine and metabolites in both regions of the brain simultaneously, after intraperitoneal administration of 0.8, 1.6 or 3.2 mg/kg of either drug (doses expressed as the salts). Both drugs increased levels of dopamine but decreased levels of metabolites in a dose-dependent manner. However, the relative magnitude of these effects depended upon the specific drug, the dose and area of the brain examined. At the largest dose used, amphetamine had a relatively greater effect than cathinone on dopamine in both caudate and accumbens. However, among smaller doses, this difference was only observed in the nucleus accumbens after administration of 1.6 mg/kg. The results also demonstrated a differential regional effect of both drugs at 3.2 mg/kg, in that both had a greater effect on dopamine in the caudate, as opposed to the accumbens. These findings demonstrate a functional heterogeneity of the striatum of the rat, that may be relevant to the understanding of both normal brain function and the neural responses to psychoactive drugs.
For more Mechanism of Action (Complete) data for Cathinone (6 total), please visit the HSDB record page.
Pharmacokinetics
Half-life
The elimination half-life of cathinone is 1.5 +/- 0.8 hours
The elimination half life of cathinone (given as khat) is approximately 4 hours.
Six drug-naive volunteers received a single dose of khat corresponding to 0.8 mg/kg body weight ... . The terminal elimination half-life was 260 +/- 102 minutes.
Absorption
The active components of khat are absorbed orally by chewing the leaves. The peak plasma concentration of cathinone, cathine, and norephedrine are reached in 127 minutes, 183 minutes, and 200 minutes, respectively.
Four volunteers chewed khat leaves in an amount equivalent to one-quarter of that used in a typical khat session. Blood samples were collected up to 80 hr and the alkaloids were assayed using gas chromatography-mass spectrometry. The data were evaluated using computerized pharmacokinetic compartmental analysis. The plasma concentration-time data for the alkaloids could be described using a two-compartment model with two-segment absorption. The mucosa of the oral cavity is considered to be the first absorption segment, where the major proportion of the alkaloids is absorbed (mean +/- SD 59 +/- 21% for cathinone and 84 +/- 6% for cathine). The extraction of the alkaloids from the leaves by chewing was very effective with only 9.1 +/- 4.2% remaining as a residue. Cathinone was eliminated from the central compartment with a mean half-life of 1.5 +/- 0.8 hr. The half-life of cathine was 5.2 +/- 3.4 hr. The metabolism of cathinone to norephedrine had a substantial influence on its plasma concentration profile. Psychophysical functions were essentially unaffected by the chewing of khat.
Peak plasma levels of cathinone are obtained 1.5 to 3.5 hours after the onset of chewing. The mean plasma level may reach 100 ng/mL after chewing 60 g fresh khat for one hour. Cathinone is barely detectable in blood after eight hours. ... Only 2 % of cathinone is excreted unchanged in the urine.
A small amount of cathinone is excreted by thekidney unchanged (0.6% to 3.3%).
Metabolism
Cathinone is metabolized by keto-reduction to norephedrine and norpseudoephedrine at an approximate ratio of 9:1. ... Up to 52% of oral doses of cathinone isomers are recovered in 24 hour urine samples as aminoalcohol metabolites. Cathine is also primarily excreted in the urine: 40% of an oral dose within 6 hours and 84.6% within 24 hours.
... After oral administration of synthesized cathinone (isomers, racemate), 22-52% was recovered in 24 hr urine samples mainly as aminoalcohol metabolites. With GC/MS, HPLC and CD, the main metabolite of S-(-)-cathinone was identified as R/S-(-)-norephedrine and the main metabolite of R-(+)-cathinone as R/R-(-)-norpseudoephedrine. Both aminoalcohols are formed by a stereospecific keto reduction.
First-pass metabolism of cathinone in the liver leads to the formation of norephedrine.
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.