Review of the pharmacology of khat
Effects on the central nervous system (CNS)
Effects on noradrenergic neurotransmission in isolated organs
Acute tolerance to the pressor and nictitating membrane effects
Effect on oxygen consumption
Mode of acute pharmacological action
Behavioural pharmacology Food-reinforced responding in rats
Food-reinforced responding in rhesus monkeys
Discriminative stimulus properties
Human pharmacology and dependence
Pharmacological effects in humans
Dependence and abuse
Medical aspects of khat chewing
Social and economic effects
Proposed framework for study of public-health and social problems
Pages: 83 to 93
Creation Date: 1980/01/01
Report of a WHO Advisory Group
This paper is based on the report of a WHO advisory group [ 1] that met 22-24 September 1980 at Geneva to review the international control of psychotropic substances. It describes the efforts made by WHO, with financial assistance from the United Nations Fund for Drug Abuse Control (UNFDAC) to elucidate pharmacological data on khat constituents obtained from the United Nations Narcotics Laboratory [ 1] - [ 3] . The possibility of assessing the public-health and social problems associated with khat chewing are also discussed.
The effects of khat chewing have been reported by Eddy et al. [ 4] , Halbach [ 5] and Hughes [ 6] . The fresh leaves contain a psycho-active substance that is rapidly converted into (+)-norpseudoephedrine. When the fresh leaves are chewed and the juices ingested, the user experiences a stimulant effect.
In 1964, the WHO Committee on Addiction Producing Drugs studied available information on the medical aspects of habitual chewing of khat leaves [ 7] . The Committee was of the opinion that the problems associated with khat and with amphetamines should be considered in the same light. The effects are similar, though with quantitative differences and variations in socio-economic aspects. It was also noted that the problems with khat were confined to only a few countries in one region of the world.
A brief review of the early literature on the chemistry of khat shows that, in spite of repeated efforts and re-examination, much of the earlier work was confused and contradictory, mainly because of the lack of proper technology, but also because information was not available on the degree of freshness of the material used in the investigations.
Through the efforts of the United Nations Narcotics Laboratory, considerable progress has been achieved during recent years in connection with the isolation and characterization of the components of khat [ 8] .
Extensive thin-layer and gas-liquid chromatographic analysis of the extracts prepared from the fresh or freeze-dried plant material revealed the presence of a number of nitrogen-containing compounds, previously unknown in the plant. These compounds were separated into two major groups-the phenylalkylamine derivatives and the weakly basic alkaloids. A study of the phenylalkylamine fraction showed that, in fresh or well-preserved khat material of Kenyan origin, cathine was only a minor component. However, in each khat sample studied, a new compound was found and its chemical structure was established as (-)-α-aminopropiophenone. As this compound had not previously been reported in nature, it was tentatively named "cathinone". Cathi-none base is very unstable and easily undergoes decomposition reactions leading to the formation of a "dimer" (3,6-dimethyl-2,5-diphenylpyrazine) and possibly smaller fragments such as benzaldehyde and ethylamine. Further decomposition may lead to 1-phenyl-1,2-propanedione. Both the "dimer" and the latter compound have been isolated from khat extracts. The absolute configuration of cathinone was established by Schorno and Steinegger in 1978 [ 9] . The Laboratory also synthesized racemic cathinone using the method of Gabriel [ 10] , with some modifications. From this, the optically active isomers and the "dimer" were prepared. Other minor compounds were also identified in the amine fraction. The fraction containing the weakly basic alkaloids was found to have a very complex composition. A number of alkaloids had been detected in khat by thin-layer chromatography. Some of the major components in this group were isolated. Structures were proposed for 11 alkaloids and further structures are being established. With two exceptions, all the alkaloids thus far isolated from khat have had a common hydroxylated sesquiterpene skeleton (euonyminol) esterified with various acids. The common name "cathedulin" was proposed for this class of alkaloids [ 11 ] .
In mice, s. c. administration of a dose of 50 mg/kg of both the (+)- and (-)- cathinone isomers produced excitation, circular movements, slight tremor and piloerection. The symptoms could be observed a few minutes after administration and lasted for several hours. The animals recovered in 24 h. Doses of 50 mg/kg and 100 mg/kg cathine were also administered, producing similar symptoms, with the only difference being that in this case the increase of motor activity occurred only 2-3 h after administration. In rats, administrations of 100 mg/kg of the (+)- and (-)-cathinone isomers and of carbine produced effects similar to those observed in mice and with a similar time course, except that excitation of the cathine-treated animals began 1-2 h after administration [ 12] . In other observations in rats, both the (-)-cathinuone and (±)-cathinone produced exophthalmus, piloerection, and sniffing at doses of 4 mg/kg, s.c., or higher. By comparison, (+)-amphetamine produced such effects at 1 mg/kg, s.c. [ 13] .
In mice both the (+)- and (-)-cathinone isomers strongly increased the spontaneous locomotor activity of the mice at a dose range of 30 to 180 mg/kg, s.c. Cathine had a similar effect, with the only difference being in the time course of the effect: While the two optical isomers produced their effects in the first 30 min after administration, the effect of cathine began later, between 90 and 120 min after administration. The effect of cathinone in this test was only moderately antagonized by reserpine [ 12] .
In rats, (±)-cathinone increased the activity level markedly at a dose range of 0.25 - 4 mg/kg, s.c. The potency of the effect was almost comparable to that of (+)-amphetamine. In comparison, (±)-ephedrine did not produce such marked effects at doses up to 16 mg/kg, s.c. [ 13] .
In the hot-plate test in rats, (-)-cathinone, (+)-cathinone and cathine prolonged, like amphetamine, the reaction time at doses of 5-25 mg/kg, s.c. These effects were antagonized by α-methylparatyrosine and were apparently the consequence of over-excitation. None of these compounds was regarded to be a true analgesic, since the analgesics act at lower doses in the writhing test than in the hot plate. Both isomers of cathinone acted only at very high doses in the writhing test [ 12] .
Both isomers of cathinone and cathine markedly inhibited the food intake of rats at intracerebroventricular doses of 300 and 500 μg per animal. Cathine and (-)-cathinone were more potent than amphetamine in this effect [ 12] .
Cross-tolerance to the anorexic effect between (+)-amphetamine and (±)-cathinone was studied in rats by determining the efficacy of the drugs in decreasing the intake of sweetened condensed milk made available for 15 min daily. Both drugs produced a dose-related decrement in milk intake. Inthe first study, (+)-amphetamine was given daily, in the second study, (±)-cathinone. In both studies, tolerance was demonstrated by a diminution in the effect of the chronically administered drug as well as by a shift in the dose-response curve to the right. In the case of (+)-amphetamine, this shift was approximately 2-fold, whereas with (±)-cathinone a much larger shift was obtained (8-12 fold) [ 14] .
Both (+)- and (-)-cathinone inhibited the escape response of rats at doses of 10 mg/kg, s.c., as determined by measuring the latent time for jumping from a heated plate. In addition, at doses of 5 and 10 mg/kg these substances antagonized the inhibitory effect of pre-treatment with reserpine (2.5 mg/kg, s.c.) [ 15] .
The flexor reflex of the hind limb of the spinal rat elicited by hind-paw stimulation was enhanced by intravenous administration of amphetamine at 1 mg/kg. Both isomers of cathinone were found to be as potent as amphetamine in this test, while cathine proved to be less potent than cathinone [ 12] .
In anesthetized rats, both blood pressure and heart rate were increased. At single doses of 1 mg/kg, i.v., the average pressure increases were (mm Hg): (+)-norpseudoephedrine, 24.0 ± 5.8; (-)-cathinone, 15.7 ± 1.4; (±)-cathinone, 11.4 ± 4.1; (±)-ephedrine, 24.8 ± 3.7; (+)-amphetamine, 21.5 ± 1.8. The corresponding heart-rate increases were (beat/min): 49.5 ± 5.1, 50.0 ± 10.1, 41.2 ± 10.1, 55.7 ± 6.4 and 58.7 ± 8.7 [ 13] . In anesthetized cats, the (+)- and (-)-cathinones at 1 mg/kg, i.v., both increased blood pressure temporarily by about 30-35 mm Hg, while sustained contraction of the nictitating membrane was also observed. Amphetamine had the same effect, and cathine acted similarly but was less potent than (-)-cathinone [ 12] .
In isolated guinea pig atria at a bath concentration of 10-5g/ml, positive ionotropic and chronotropic effects were observed with the cathinones. The average increases of the ionotropic effects were (per cent): (-)-cathinone, 83.3 ± 4.8; (+)-norpseudoephedrine, 52.8 ± 10.7; (+)-cathinone, 42.4 ± 7.6; (±)-ephedrine, 36.7 ± 9.6; and (+)-amphetamine, 50.5 ± 9.1 [ 12] .
Cathine and (+)- and (-)-cathinone, as well as amphetamine, markedly enhanced electrically induced contractions of the isolated cat nictitating membrane at a bath concentration as low as 0.2 μg/ml. Cathine seemed to be less potent then (-)-cathinone [ 12] .
The (+)- and (-)-cathinone isomers enhanced electrically stimulated constriction of the perfused rabbit ear artery at a concentration of 0.1 μg/ml. The potencies of their effect were comparable to that of amphetamine, but cathine was found to be less potent. The results obtained in the rabbit pulmonary artery strip were similar [ 12] .
Both (+)- and (-)-cathinone isomers, as well as amphetamine and phenylethylamine, enhanced electrically stimulated constriction of the rat and guinea pig vas deferentia at bath concentrations of 1 and 5 μg/ml, respectively [ 12] .
Development of acute tolerance to the pressor effect in rats and the nictitating membrane effects in in vivo and in vitro studies in cats was observed with some of these khat amines. Acute cross-tolerance to these effects was also developed between these amines and amphetamine [ 12] .
It was observed that (-)-cathinone increased the metabolic rate of anesthetized rats at a subcutaneous dose of 5 mg/kg and at an intracerebroventricular dose of 0.5 mg per animal. The potency of the effect was nearly comparable to that of amphetamine [ 12] .
Based on the above-mentioned findings, the mode of acute pharmacological action of cathine and (-)-cathinone is believed to be the facilitation of noradrenergic neurotransmission by release of the transmitter at the nerve terminals [ 12] .
It was observed that (+)- and (-)-cathinone increased spontaneous activity in mice in doses ranging from 4 - 16 mg/kg, i.p. The (-)-isomer appeared more potent than the (+)-isomer in these activity procedures, and its effects on brain catecholamine turnover were studied further in a different group of mice. The neurochemical effects of (+)-amphetamine were also evaluated using a similar dose range. The (-)-isomer of cathinone was observed to have little effect on norepinephrine (NE) turnover; however, it did significantly increase dopamine (DA) turnover at 8 mg/kg (+32 per cent). In contrast, (+)-amphetamine reduced NE turnover at similar doses but also increased DA turnover (44 per cent) at 4 mg/kg. At higher doses, (±)-cathinone (16 mg/kg) had little effect on DA turnover while (+)-amphetamine produced a 42 per cent reduction. These studies indicated that (±)-cathinone produced CNS stimulant effects and resembled (+)-amphetamine by increasing DA turnover at 8 mg/kg. However, (-)-cathinone in the dose range studied did not appear to be as potent as (+)-amphetamine in altering catecholamine turnover [ 16] .
The operant behavioural effect of (±)-cathinone was tested under a differential reinforcement of low rate (DRL), 20-s schedule for food reinforcement in rats. Like (+)-amphetamine, the drug increased the response rate, decreased the reinforcement rate, and markedly shortened the inter-response time intervals at doses higher than 0.5 mg/kg, s. c. In comparison, (±)-ephedrine had no such effect, except for the decrement of the reinforcement rate which was noted at 16.0 mg/kg, s.c. [ 13] .
After rhesus monkeys had been trained to lever press under a multiple fixed-interval (FI) of 5 min, fixed-ratio (FR) of 30 schedule of food delivery, dose-response curves were obtained for intravenous doses of (+)-amphetamine and (±)-I and (-)-cathinone. All three drugs produced dose-related decreases in responding under both the FI and FR conditions. Both (±)- and (-)-cathinone appeared to be approximately equipotent whereas (+)-amphetamine was twice as potent [ 14] .
Rats were trained to discriminate either (+)-amphetamine (0.9 mg/kg, i.p.) or quipazine, a potent serotonin receptor antagonist (1.0 mg/kg, i.p.), against saline by a two-lever drug discrimination procedure for food reinforcement. The (+)-amphetamine-trained rats generalized to (±)-cathinone at 1.0 mg/kg, i.p. or s.c. The (-)-isomer was found to be equipotent to (±)-cathinone but the potency of the (+)-isomer was about one-half. The quipazine-trained rats partially generalized to (±)-cathinone, which may suggest some possible 5-HT-like effects with this isomer. LSD-trained rats were also used but they did not generalize to (±)-cathinone [ 17] .
In three rhesus monkeys which had been previously trained to lever press under an FR 10 schedule of intravenous cocaine delivery during a 3-h daily session, various doses of (+)-amphetamine, (±)- and (-)-cathinone, as well as saline, were substituted for cocaine during five consecutive sessions. All drugs maintained responding at levels significantly above those seen with saline. Both (±)- and (-)-cathinone maintained rates of responding significantly higher than those generated by cocaine and (+)-amphetamine. In addition, (-)-cathinone appeared to be more potent than either (±)-cathinone or (+)-amphetamine.
Two monkeys initiated intravenous self-administration by lever presses at FR 1 of (-)-cathinone at a unit dose of 0.06 or 0.25 mg/kg per injection. The self-administration pattern was of the spree type, like cocaine, in which the monkeys took the drug frequently day and night, stopping upon becoming exhausted. Such sprees continued from several hours to two-three days, and during these periods the monkeys manifested extreme restlessness, tremor, mydriasis and anorexia. They relapsed after a period of rest of less than 24 h. This alternation of spree and rest was repeated, but the experiment had to be terminated after less than a month owing to general weakening in one monkey and edema in the other [ 13] .
Three rhesus monkeys were first trained to self-administer cocaine intravenously by lever presses at FR 100, after which progressive ratio tests were conducted at unit doses of 0.25 and 1.0 mg/kg per injection for either cocaine or (-)-cathinone. The final ratios obtained were generally higher with cocaine than with (-)-cathinone, with the ratios for (-)-cathinone (1,350-7,610) being roughly a half of those of cocaine (2,690-12,800) in each monkey [ 18] .
The pharmacological effects of khat in humans include mydriasis, tachy-cardia, extrasystoles, elevated blood pressure, transient facial and conjunctival congestion, headaches, hyperthermia, increased respiration (through central stimulation, bronchodilatation and counter-regulation of hyperthermia), inhibition of micturition, increased diuresis (from intake of large quantities of fluids together with khat) [ 5] .
Khat users seek out the freshest possible plant material, an indication of the rapid degradation of cathine in the plant or, more likely, the existence of a more potent substance, possibly a precursor of cathine. The reinforcing effects of khat include euphoria, logorrhea, improvement of associations, excitement, insomnia. Toxic psychosis occurs very rarely, if at all. This and the absence of tolerance is obviously due to the self-limiting process of ingestion. Symptoms of withdrawal from khat are rebound phenomena rather than the expression of a true physical dependence [ 5] .
The 1971 Convention on Psychotropic Substances requires data on public-health and social problems associated with the use of a psychotropic substance to be considered while weighing its benefit/risk ratio for scheduling. In 1972, Halbach [ 5] prepared a review of the medical aspects of khat chewing based upon literature collected by WHO over a number of years. In that same year a WHO mission was sent to the Yemen Arab Republic to look into the epidemiology of khat. The mission developed a proposal to study the problem but the project could not be immediately funded.
There was still a need for action regarding the availability of the drug in countries where khat chewing was prevalent. Because it was deemed essential to assess the magnitude of the public-health and socio-economic problems associated with khat use, funds have now been obtained from the United Nations Fund for Drug Abuse Control to facilitate the design of a collaborative epidemiological study in at least three countries. Governments of countries in Africa and the Middle East have since been approached to determine their interest in joining a collaborative study co-ordinated by WHO.
Before reviewing the plan for the collaborative study, it may be helpful first to review the medical aspects of khat chewing to help identify some of the public-health problems to be assessed. The review is based on the reports by Halbach [ 5] and Hughes [ 6] . Halbach suggested that the norpseudoephedrine and the tannin in khat account for most of the health disturbances, as follows:
Gastrointestinal tract disturbances are most often described in chronic khat users. The astringent characteristics of the tannins appear to account for reports of periodontal disease, stomatitis, esophagitis and gastritis. Tannins are also believed to delay intestinal absorption and might thereby contribute to some degree of malnutrition. Reports of cirrhosis of the liver may be due to the tannic acid. Constipation, the most common medical complaint of khat users, may be attributed to both tannins and norpseudoephedrine. The anorexia associated with khat chewing is attributed to norpseudoephedrine, as a common side effect of amphetamine-type drugs.
Impairments of the male reproductive system are referred to as a common occurrence among chronic khat chewers. They are believed to have a high frequency of spermatorrhea and, in later stages, impotence. The pharmacological basis for this effect is not understood.
Review of the pharmacology of Khat
Few reports of disturbances of the circulatory system are available, even though norpseudoephedrine is thought to have a greater stimulant effect on this system than does ephedrine. Nevertheless, the drug might conceivably contribute to hypertension, migraine, cerebral hemorrhage, myocardial insufficiency and pulmonary edema.
The most common adverse psychological effects mimic those of amphetamines, that is, insomnia and (when the drug effect wears off) reactive depression. The insomnia at night and the reactive depression and irritability the following morning may explain reports of lateness for work and diminished work performance among chronic users. Toxic psychosis and aggressive behaviour are reported with high doses of amphetamines, but are rarely, if ever, seen among khat users.
A poorly understood psychic dependence or "khat addiction" is said to cause "khat addicts" to spend a large portion of their salaries on the habit, even when it causes considerable hardship to their families. There appears to be no evidence that khat produces physical dependence in humans. While no tolerance to khat chewing is reported, this could be due to the physical limits on the amount that can be chewed rather than to an inherent property.
The literature on social and economic effects of khat use suggests that it contributes to family instability because of the economic drain on family resources and the absence of the father from participation in family life. Work productivity is said to be reduced as a result of absenteeism, tardiness and the depressed mood of khat chewers. Finally, there may be a serious economic balance-of-payments problem in those countries where khat imports account for the loss of a sizeable portion of the national income.
The following elements of a research plan are proposed:
A sample survey in several regions of the country to determine the patterns and distribution of khat chewing in the general population, as well as an overview of its effects on the society at large;
An intensive case-control study of a matched sample of moderate and heavy khat-chewing users and non-user controls. The three groups would be compared to identify a possible dose-effect relationship based on data collected in interviews and in physician and laboratory examinations. Mental status examinations would be performed if feasible in both the drug-free and intoxicated states. Interviews would be carried out with family members to assess the presence of family and social problems and particularly the economic effects of khat chewing;
Observation of a small number of khat-chewing subjects, in a hospital, if feasible, to look for evidence of an abstinence syndrome.
The research plan should be co-ordinated by an experienced investigator with sufficient resources for an intensive study in one country. A brief description of the general approach follows.
The first step would be to send a consultant or consultant team to interested countries to determine the feasibility of a study, make preliminary assessments on the nature and extent of the problems associated with khat use in that particular setting, make a preliminary examination of existing data that might be easily collected, identify collaborating investigators and institutions, prepare a preliminary study design, and, if possible, carry out pilot feasibility work by testing a data-collecting instrument on user and non-user subjects.
Following the experience in other collaborative studies on drug abuse, the work would be initially focused on the essential information to be collected. An effort would first be made to analyze existing data in order to define the types and distribution of public-health and social problems, including production, import, and consumption statistics on both the amount and cost of khat in each participating country. Then a case-control study would be designed. It would be desirable if a common data-collecting instrument could be used, with centralized analysis of data. If possible, subjects would be selected from specific occupational groups in order to obtain employer ratings on work performance. Families would also be interviewed.
If local expertise and resources permitted, more ambitious sub-studies in categories (a), (b) and (c) above could then be carried out.1
The members of the group were Dr. Pierre Chanoit, lnstitut Marcel Rivière, France; Dr. H. Halbach, Honorary Professor, University of Munich, Federal Republic of Germany; Dr. D. Jasinski, Director, Addiction Research Center, National Institute on Drug Abuse, United States; Dr. J. Knoll, Head, Department of Pharmacology, University of Semmelweis, Hungary; Dr. V. Navaratnum. Director, National Drug Dependence Research Centre, Malaysia; Dr. O. O. Ogunremi, Professor and Head of the Department of Behavioural Sciences, University of Ilorin, Nigeria; Major General Doctor Muhammed Shuaib, Consultant Psychiatrist, Pakistan Army, Pakistan Narcotics Control Board, Pakistan; Dr. Charles Schuster, Department of Psychiatry, University of Chicago, United States; Dr. K. Setyonegoro, University of Indonesia, Directorate of Mental Health, Ministry of Health, Indonesia; Dr. T. Yanagita, Director, Preclinical Research Laboratories, Central Institute for Experimental Animals, Japan; representing the United Nations: Dr. George M. Ling, Director, Division of Narcotic Drugs, and P. IC Bailey, Division of Narcotic Drugs; representing the International Narcotics Control Board: Dr. T. L. Chrusciel, Deputy Director, Institute for Drugs, Research and Control, Poland; representing the International Criminal Police Organization: G. Atkinson, Drugs Sub-Division. The secretariat of the group consisted of Dr. Inayat Khan, Senior Medical Officer, Division of Mental Health, WHO (Secretary); Dr. P. Hughes, formerly Senior Medical Officer, Division of Mental Health, WHO, who co-operated in the development of the epidemiology part of this paper; and Dr. P. Kalix, Department of Pharmacology, School of Medicine, Geneva.
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