Biomedical subjects
Publications and source records attributed to P Kalix.
The chewing of fresh leaves of the khat bush (Catha edulis) is common in certain countries of East Africa and the Arab peninsula, because this material has a stimulating effect. During the last decade, important progress has been made in understanding the pharmacology of this drug. Its actions are mainly due to the alkaloid cathinone, a substance that can be called 'a natural amphetamine'.
OBJECTIVES: To show the subjective and cardiovascular effects of khat leaves having a standardized content of cathinone. BACKGROUND: The main effect of khat is an increase of energy and alertness. This effect is thought to be attributable to the phenylalkylamine cathinone, but no controlled clinical trials have been published. DESIGN: The design was balanced and double blind. Six drug-naïve volunteers received a single dose of khat corresponding to 0.8 mg/kg body weight, as well as alkaloid-free khat as a placebo. Psychologic effects were evaluated by the Addiction Research Center Inventory (ARCI) and visual analog scales. Physiologic measures were systolic blood pressure, diastolic blood pressure, and heart rate. Plasma concentrations of cathinone and its metabolites norephedrine and R,R-(-)norpseudoephedrine were determined by HPLC. RESULTS: Maximal plasma concentrations of cathinone (127 +/- 53 [SD] ng/ml) were attained after 127 +/- 30 minutes. The area under the plasma concentration-time curve from 0 to 9 hours was 415 +/- 207 ng/ml.hr, and the terminal elimination half-life was 260 +/- 102 minutes. An effect of khat was observed in the ARCI scales Abuse Potential (p < 0.01), Motor Stimulation (p < 0.02), Amphetamine-Like Effect (p < 0.005), and Stimulation-Euphoria (p < 0.005), as well as in the visual analog scales Excited-Calm (p < 0.001) and Energetic-Lethargic (p < 0.001). CONCLUSIONS: Our results provide objective evidence for the amphetamine-like stimulatory effects of khat leaves. These effects were closely similar to those observed after cathinone, 0.5 mg/kg body weight, although peak plasma concentrations of cathinone after khat were delayed.
Cathinone is an alkaloid that has been discovered some fifteen years ago in the leaves of the khat bush. This plant grows in East Africa and in southern Arabia, and the inhabitants of these regions frequently chew khat because of its stimulating properties. Cathinone, which is S(-)-alpha-aminopropiophenone, was soon found to have a pharmacological profile closely resembling that of amphetamine; indeed, in a wide variety of in vitro and in vivo experiments it was demonstrated that cathinone shares the action of amphetamine on CNS as well as its sympathomimetic effects; thus, for example, drug-conditioned animals will not distinguish between cathinone and amphetamine. These various observations were confirmed by a clinical experiment showing that cathinone also in humans produces amphetamine-like objective and subjective effects. Finally, it was demonstrated that cathinone operates through the same mechanism as amphetamine, i.e. it acts by releasing catecholamines from presynaptic storage sites. Thus, much experimental evidence indicates that cathinone is the main psychoactive constituent of the khat leaf and that, in fact, this alkaloid is a natural amphetamine.
Because of their stimulating effect, leaves of the khat bush are chewed in several East African countries and in Yemen. Since only fresh leaves are active, this habit is almost unknown outside the regions where the plant grows. Recently, however, khat has made its appearance in the United States and in several European countries, while an import permit has been requested in Switzerland. These are reasons for making the practitioner familiar with the effects of this drug. During the last fifteen years, knowledge of khat and its constituents has made substantial progress. Today, the alkaloid cathinone is regarded as the main active principle of this drug, and this substance is held to be a natural amphetamine. This article summarizes knowledge of the pharmacology of khat.
Ever since the introduction of the alkaloid ephedrine as an anti-asthmatic, the CNS stimulatory effects of this sympathomimetic have been a problem in therapy. Indeed, the use of ephedrine is not only limited by its cardiovascular effects, but also by the occurrence of insomnia, restlessness and anxiety. Exceptionally, ephedrine may even induce toxic psychosis, and the possibility of this side effect has recently received renewed attention. Besides ephedrine, the ephedra plant contains some norpseudoephedrine. This substance is also called cathine, because it is a major alkaloid of Catha edulis or khat, a plant that is widely used as a stimulant in certain countries of East Africa and of the Arab Peninsula. The effects of khat have been explained formerly by those of cathine; some time ago, however, the labile alkaloid cathinone was discovered in khat. This substance is the keto-analog of cathine; it is therefore more lipophilic and penetrates easily to its sites of action in the central nervous system. Indeed, cathinone has been found to be a highly potent CNS stimulant and it is now known to be the main psychoactive constituent of khat; the results of various in vitro and in vivo studies indicate that cathinone must be considered a natural amphetamine. In confirmation of this view, it has recently been demonstrated that cathinone has in humans marked euphorigenic and psychostimulant effects. As the case may be, these findings may lead, together with epidemiological data, to a reconsideration of the use of khat as a stimulant and social drug.
The chewing of the stimulant leaf khat is a habit that is widespread in certain countries of East Africa and the Arabian peninsula. During the last decade, important progress has been made in understanding the pharmacological basis for the effects of khat. It is now known that the CNS action of this drug is due to the presence of the alkaloid cathinone, and the results of various in vitro and in vivo experiments indicate that this substance must be considered a natural amphetamine. It is the purpose of the present review to describe briefly the khat habit and to summarize the pharmacology of khat and of its active constituents.
1. The chewing of khat leaves as a stimulant is common in certain countries, and the effects of this material are supposed to be due to the phenylalkylamine alkaloid cathinone. In order to determine the effects of this substance in humans, a single oral dose of cathinone or placebo was administered to six healthy male volunteers in a double-blind, random order crossover study. 2. Cathinone produced increases in blood pressure and in heart rate, and these changes were concomitant with the presence of cathinone in blood plasma. 3. The physical and mental changes that the subjects reported during the experiment indicated that cathinone has in humans euphorigenic and psychostimulant effects. 4. These observations support the assumption that cathinone is the constituent mainly responsible for the effects of khat, and they show that this alkaloid has also in humans amphetamine-like effects.
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The chewing of leaves of the khat shrub is common in certain countries of East Africa and the Arabian peninsula, and some khat users are subject to psychic dependence on this stimulant. Recently, important progress has been made in understanding the pharmacological basis for the effects of khat. It is now known that the CNS stimulation is mainly due to the presence of the alkaloid cathinone in the leaves, and the results of various in vitro and in vivo experiments indicate that this substance must be considered a "natural amphetamine." In recent years, several cases of khat intoxication observed in the USA and in Great Britain have been described in the literature. In view of these developments, the khat habit and its health effects are described, and the possibilities for the treatment of acute khat intoxication are discussed.
The purpose of the present investigation was to examine the effect of N-monomethylation of phenylisopropylamine derivatives on amphetamine-like activity. In tests of stimulus generalization using rats trained to discriminate 1.0 mg/kg of (+)-amphetamine from saline, the N-monomethyl derivatives of 1-(X-phenyl)-2-aminopropane, where X = 2,4-dimethoxy (2,4-DMA), 3,4-dimethoxy (3,4-DMA), 2,4,5-trimethoxy (2,4,5,-TMA), and 2-methoxy-4,5-methylenedioxy (MMDA-2), did not produce amphetamine-appropriate responding at the doses evaluated. However, the N-monomethyl derivative of cathinone (i.e., methcathinone), like cathinone, resulted in stimulus generalization. Further studies with this agent revealed that (a) in the amphetamine-trained animals, methcathinone (ED50 = 0.37 mg/kg) is more potent than racemic cathinone or racemic amphetamine (ED50 = 0.71 mg/kg in both cases), (b) methcathinone is capable of inducing release of radioactivity from [3H]dopamine-prelabeled tissue of rat caudate nucleus in a manner similar to that observed with cathinone, amphetamine, and methamphetamine, and (c) methcathinone is more potent than cathinone as a locomotor stimulant in mice as determined by their effect on spontaneous activity. The results of the present study provide evidence for a structural analogy between the prototypic psychostimulants amphetamine/methamphetamine and cathinone/methcathinone, and lend further support to the concept that amphetamine and cathinone correspond in their pharmacological effects.
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The CNS-stimulating properties of leaves of the khat shrub (Catha edulis, Celastraceae) are presumed to be due mainly to (-)-cathinone, a phenylpropylamine alkaloid that has been shown to have an amphetamine-like releasing effect at physiological catecholamine storage sites. Recently, several phenylpentenylamine alkaloids have been identified in khat leaves, and these have been evaluated, in-vitro, in the present study for their ability to induce release of radioactivity from [3H]dopamine-prelabelled rat striatal tissue. It was found that the phenylpentenylamines have a weak releasing effect, and are therefore considered unlikely to play an important role in the stimulating properties of khat leaves.
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The alkaloid (-)cathinone is a potent stimulant with pharmacological properties closely resembling those of (+)amphetamine. Since (-)cathinone is capable of inducing release at physiological catecholamine storage sites, it has been suggested that (-)cathinone and (+)amphetamine have the same mechanism of action. In the present study, the potency of (-)cathinone in inducing the release of radioactivity from 3H-dopamine prelabelled tissue of the rat caudate nucleus was compared to that of several structural analogs, i.e. to that of four other aminophenones. (-)Cathinone was found to be the most potent of the compounds under investigation, and among these only demethylcathinone had an effect that was within the same order of magnitude as that of (-)cathinone. Furthermore, (-)cathinone and two of its analogs were evaluated in behavioral experiments with regard to their ability to substitute for (+)amphetamine in rats trained to discriminate between (+)amphetamine and saline. It was found that, unlike the other aminophenones, (-)cathinone is capable of producing (+)amphetamine-like stimulus effects, and these can be antagonized by haloperidol in a dose-related manner. Taken together, these findings support the hypothesis that (+)amphetamine and (-)cathinone produce their central stimulant effect via the same dopaminergic mechanism.
The alkaloid (-)cathinone is known to have an amphetamine-like releasing effect on physiological storage sites for catecholamines. The present study was performed in order to determine whether the synthetic enantiomer (+)cathinone would have a comparable effect. This was done by measuring the release of radioactivity in response to the cathinone isomers, from tissue slices taken from different areas of the nervous system of the rat and prelabelled with tritiated catecholamines ([3H]dopamine: nucleus accumbens and nucleus caudatus; [3H]noradrenaline: atrium and vas deferens). The two isomers of cathinone were found to be approximately equipotent in inducing release at peripheral noradrenergic nerve endings, but the (-)isomer was about three times more potent than the (+)isomer at dopamine terminals in the CNS. Thus, the releasing effect of the cathinones is characterized by a certain degree of stereoselectivity with regard to dopamine storage sites in the CNS, but not with regard to peripheral noradrenergic nerve endings.
In order to evaluate a series of phenethylamines with regard to their capacity to induce release from presynaptic catecholamine stores, their effect on the efflux of radioactivity from 3H-dopamine-prelabelled rat caudate nucleus tissue was determined. All of the phenethylamines studied were found to enhance the release of radioactivity from this preparation. However, marked differences were observed between the individual compounds with regard to potency and dose dependence of the effect.
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