Drugscom Catha edulis / Khat
Scientific Name(s): Catha edulis Forsk. Family: Celastraceae (moonseed)
Common Name(s): Khat , qut , chaat , chat , kaht , tchat , qaad , jaad , miraa , Kus es Salahin , Tchaad , Tschut , Tohat , Tohai , Gat , Qat
Uses
Khat leaves are chewed for stimulant and euphoriant effects and are used to treat obesity and prevent hunger in areas with meager food supplies. Some users experience dysphoria and sedation. Khat is prohibited in the US, France, Switzerland, and Sweden.
Dosing
A khat preparation was administered at a dose of 0.8 mg/kg cathinone in a pharmacokinetic study. 1
Contraindications
Contraindications have not yet been identified.
Pregnancy/Lactation
Documented adverse effects.
Interactions
Khat chewing interferes with the absorption of amoxicillin and ampicillin.
Adverse Reactions
Constipation is commonly associated with khat use. Other adverse effects include tachycardia, palpitations, increased blood pressure, anorexia, stomatitis, esophagitis, and gastritis. Anaphrodisia is reported frequently by men using khat.
Toxicology
Khat may cause oral and gastric cancer, cerebral hemorrhage, MI, duodenal ulcers, hypertension, testicular degeneration, low birth-weight infants, and a variety of other severe effects including addiction and the attendant ills.
Botany
Khat is a tall plant (2.7 to 3.7 m) with a natural distribution limited to East Africa and the Arabian Peninsula (Kenya, Yemen, and Ethiopia). It grows best at high elevations, and its tender twigs and leaves are harvested almost year-round. Freshly harvested khat is wrapped in leaves and exported by air to neighboring African countries.
History
One of the most common forms of drug use and abuse in many East African nations involves chewing parts of the khat plant. Khat use has increased steadily over the last 50 years and has become a problem of significant social and medical importance. Because of its social acceptability and euphoriant effects, khat chewing often plays a dominant role in celebrations, meetings, marriages, and other gatherings. Khat use even has been prevalent in the Somali military. It has been issued to soldiers in their daily rations with the intention of inhibiting their need for food and sleep, as well as increasing their aggression. 2
The amount of khat chewed per user is 100 to 200 g of leaves and stems over 3 to 4 hours. The tender leaves and stems, which lose their potency 1 day after harvest, are chewed and the juice is swallowed. 2 Khat has a sweet taste and an astringent action. 3 Large amounts of liquids are consumed while chewing because of the dryness induced by the plant.
Khat leaves have been used in traditional medicine for the treatment of depression, fatigue, hunger, obesity, and gastric ulcers.
Chemistry
Studies of the chemical constituents of this plant date to the late 1800s, when European investigators isolated the alkaloid fraction “katin.” It had a stimulating effect on the frog heart and caused dilation of the frog pupil. Katin was later renamed cathine and was identified as (+)-norpseudoephedrine (also designated S(-)-alpha-aminopropiophenone). 4 This amphetamine-like compound has been isolated from the genus Ephedra , the biologic effects of which are, in many respects, similar to those of khat. The cathine content of dried khat leaves ranges from 0.1% to 0.2%. 5 Cathine has approximately 1/ 10 the stimulant activity of d-amphetamine. It decreased food intake and increased locomotor activity in rat studies. The compound has been confused with d,1-norephedrine in the literature, although the 2 compounds differ in pharmacologic properties. 6
Cathinone (alpha-aminopropiophenone) has been isolated in variable quantities from fresh leaves. This compound is a more powerful stimulant than cathine and generally considered to be the most important component; however, it is unstable in the presence of oxygen, and decomposes within a few days of picking or if the plant is dried, 7 making fresh leaves the best source of cathinone. 8 For maximum potency, khat must be picked in the morning and chewed that afternoon. 9 The red variety of khat, considered superior by users, contains more cathinone than the white type. Fresh khat leaves (100 g) contains approximately 36 mg cathinone, 120 mg norpseudoephedrine, and 8 mg norephedrine. 10 More than 30 other minor compounds (eg, cathinine, cathidine, eduline, ephedrine) have been isolated from khat leaves. Khat contains khatamines (phenylpropyl and phenylpentenylamines) in amounts that vary according to the origin, type, and quality of the product. 11 Khat leaves and twigs contain large amounts of tannins (up to 14% of dry weight). One hundred grams of fresh khat contains 36 mg cathinone, 120 mg norpseudoephedrine, and 8 mg norephedrine. 12 After oral administration, 22% to 52% of synthetic cathinone is excreted in 24-hour urine samples, the principal metabolites being aminoalcohols. S-(-)-cathinone is metabolized primarily to R/S-(-)-norephedrine, and R-(+)-cathinone is metabolized primarily to R/R-(-)-norpseudoephedrine. 13
Uses and Pharmacology
The subjective effects of khat include euphoria, intellectual efficiency, and alertness in most subjects, while others report only dysphoria and mild sedation. The expression of these effects appears to be affected by environmental factors. 14
In studies of skeletal muscle, (-)-cathinone and d-norpseudoephedrine antagonized the actions of physostigmine but not those of d-tubocurarine, suggesting that the 2 compounds have a direct action on the neuromuscular junction independent of cholinergic and adrenergic transmission. 15 In the toad heart, a khat extract produced a dose-dependent chronotropic effect and increased the amplitude of the ventricular action potential with acute treatment. Chronic treatment had the opposite effect. These results are related to the catecholamine-releasing effects of the extract. 16
CNS effects
The psychotropic effects of khat are caused by the amphetamine-like compounds, of which cathine is found in highest concentration. The stimulating effects of khat are somewhere between caffeine and amphetamine. Although amphetamine and cathinone act on different regions of the brain, they both share common pharmacologic effects, including an interaction with the dopaminergic pathways. 17
Animal data
D1-type dopamine receptors, studied in rats, have been implicated in mediating the reinforcing effects of cathinone. When studied in rats that self-administer cathinone IV, results show that it was self-administered for its reinforcing properties. 18
Clinical data
Central stimulation by khat is manifested by euphoria, increased alertness, garrulousness, hyperactivity, excitement, aggressiveness, anxiety, elevated blood pressure, and manic behavior, effects that have been verified in a double-blind trial of a single dose of khat. 19 This period of stimulation lasts for approximately 3 hours. 10 A depressive phase, including insomnia, malaise, and a lack of concentration, almost always follows. True psychotic reactions occur with much less frequency than with amphetamines. This is most likely because of the self-limiting dose of khat, which does not permit blood levels of the active compounds to rise high enough for toxic psychosis to occur. However, paranoid (typically persecutory) delusions have been seen. 20
Physical dependence to khat does not occur, and the mental depression, sedation, and social separation that may follow withdrawal are a rebound phenomenon rather than an abstinence syndrome. The psychic dependence that occurs is less than that with amphetamines but still suffices to make daily use of khat the norm. Development of tolerance to the effect of cathinone is more rapid than to that of amphetamine, and there is a cross-tolerance between the effects of cathinone and amphetamine. 4
Endocrine and metabolic effects
Khat has little effect on blood sugar levels.
Animal data
Hypoglycemia has been noted in rabbits after SC injections of khat leaf extracts.
Clinical data
No changes in blood sugar were found in 15 healthy males after khat ingestion. 21 Interviews of 7500 khat users in Somalia 22 did not reveal any beneficial effect of khat in diabetic patients. The overall effect of khat on diabetic patients is deleterious. Its appetite-suppressant effect leads to the omission of meals; the uncooperative khat user is less likely to follow dietary advice, and the consumption of sweetened beverages while using khat aggravates hyperglycemia. 23
Anti-inflammatory effect
Animal data
In experiments with albino rats, a flavonoid fraction isolated from khat at a dosage of 200 mg/kg, reduced paw edema induced by carrageenan and cotton-pellet granuloma. The substance had an anti-inflammatory activity comparable with that of oxyphenbutazone. 24
Clinical data
Research reveals no clinical data regarding the use of khat for anti-inflammatory effects.
Social notes
In his review of the use of khat in Somalia, Elmi 21 warns that “the pleasant stimulation obtained when chewing khat induces many to abuse the drug. This may have damaging effects from a social and economic point of view. Some people may spend a great part of their earnings on khat, thus failing to ensure for themselves and their families important and vital needs. Excess of khat chewing may lead to family disintegration. The chewer often shows irritability and spends much of the time away from home. These facts and the failure of sexual intercourse after chewing may endanger family life. For some countries where khat imports account for the loss of a sizable portion of the national income, there may be a serious economic balance of payments problem.” In an interview with Somalis living in England, up to 90% would rather see their children use khat as opposed to alcohol or cigarettes. 7
A study in Butajira, Ethiopia, where khat usage is legal, showed that 80% of chewers used khat to gain a good level of concentration for prayer, facilitate contact with God, and prevent them from doing bad things. Muslim religion, smoking, and a low income showed strong association with daily khat consumption. 25 , 26
Khat use is tolerated in the Netherlands and Great Britain, but is prohibited in the US, France, Switzerland, and Sweden. 10 , 27 , 28
A study in Scotland of 16 to 25 year olds attending a rave showed that khat is one of the drugs of choice when attending one of these dance events. A marketing leaflet states that khat is said to produce “feelings of euphoria, increased libido, talkativity, excitement, loads of energy, and a big khat smile.” Khat juice is made by blending the plant with water and lemon and filtering the resulting mixture and is sold by the glass or as a tincture (alcohol extracted active ingredients). 29
Methcathinone (also referred to as “cat”), is structurally and pharmacologically related to cathinone and methamphetamine and is a popular drug of abuse in Russia and parts of the US. According to addicts, methcathinone is more potent and addictive than other psychostimulants, with a long-lived intoxicating effect of up to 6 days. 18 , 30
Dosage
A khat preparation was administered at a dose of 0.8 mg/kg cathinone in a pharmacokinetic study. 1
Pregnancy/Lactation
Norpseudoephedrine has been found in breast milk from mothers who use khat and in the urine of at least 1 infant of such a mother. Until research into health hazards is completed, use of khat by lactating mothers is discouraged.
Interactions
The gastrointestinal absorption of the antibiotics amoxicillin and ampicillin may be reduced by khat chewing or ingestion, possibly decreasing the effectiveness of the antibiotics. The effects of khat chewing on the bioavailability of amoxicillin and ampicillin were studied in 8 healthy adult Yemeni volunteers. 31 The percent of dose of unchanged amoxicillin and ampicillin excreted in the urine and the peak excretion were reduce by khat chewing. In addition, the time to reach ampicillin peak concentration was delayed. However, taking amoxicillin or ampicillin 2 hours after chewing khat does not appear to affect the bioavailability of the antibiotics.
Adverse Reactions
Cardiovascular effects
Cardiovascular effects occur within 15 to 30 minutes after ingestion, suggesting absorption of active principles through the oral mucosa. Effects include tachycardia, palpitations, and increased systolic and diastolic blood pressure. These effects can persist up to 4 hours after the onset of chewing. 27
Chronic use of khat has been implicated as a contributing factor to hypertension in young adults; spontaneous improvement follows cessation of use. Other physiological effects include increased respiratory rate, hyperthermia, sweating, pupil dilation, and decreased intraocular pressure.
GI effects
GI side effects are often encountered with khat use. The stomatitis, esophagitis, and gastritis noted in chronic users are most likely because of the presence of the strongly astringent tannins. Two separate studies in healthy volunteers showed that chewing khat slows whole gut transit time, possibly caused by the sympathomimetic action of cathinone. 32 , 33 Daily khat chewing has been found to be associated with a high prevalence of Helicobacter pylori. 34 One report has noted an exceptionally high rate of periodontal disease in Yemeni males who chewed khat. 35 A more recent report states that khat use is associated with some temporomandibular joint dysfunction and keratosis of the buccal mucosa. 36
Constipation is perhaps the most common GI symptom of khat use and is caused by the tannins and the sympathomimetic effects of the alkaloids. The relationship between khat use and constipation is so strong that when a ban was imposed on khat in Aden in 1957, the sales of laxatives decreased 90%but returned to the original levels soon after the ban was lifted. 5 Hemorrhoidal disease has been linked to khat chewing in a study in Yemen. The pathogenesis by which khat induces hemorrhoids includes the following: Chronic constipation, straining during defecation and micturation, and prolonged sitting (during a khat chewing session). Many of these patients with chronic hemorrhoids need to have a hemorrhoidectomy. 37
GU effects
Chewing khat leaves results in reduction in maximum and average urinary flow rates, presumably because of the sympathomimetic action of cathinone on the bladder neck. 38
Anaphrodisia is reported frequently by men during khat use. Although libido initially may be increased, a loss of sexual drive, spermatorrhea, and subsequent impotence soon follow. However, 72% of female users in one survey reported increased sexual desire, followed by an improvement in sexual performance in 78% of the respondents. 21
Anorexia is a socially important effect of khat abuse. The WHO implicates khat in a vicious cycle of khat use, destitution, hunger, anorexia, malnutrition, and digestive troubles.
Toxicology
Severe adverse effects have been associated with khat use: Migraine, cerebral hemorrhage, MI, and pulmonary edema have been described, particularly in older and predisposed individuals. A case report of a 56-year-old patient with diffuse abnormality in the deep white matter of both cerebral hemispheres suggested a rapidly progressive leukoencephalopathy that was likely precipitated by khat use. 39
Khat chewing has been associated with duodenal ulcer. This effect can be because of the stress that follows khat chewing, the amphetamine-like action of cathine, increased presence of H. pylori , or insecticides and chemicals used for growing the khat plant. 24
In vitro studies have demonstrated that a chloroform extract of khat leaves is cytotoxic in cultures of KB, 1BR.3, and XP2B1 mammalian cells. This cytotoxicity appears to be because of inhibition of de novo RNA synthesis affecting all the cell strains tested; KB cells possessed some resistance to the toxicity. 40 The tannins found in khat leaves have been shown to thicken the mucosa of the oropharynx and esophagus and also may be carcinogenic. 41 Oral cancers in certain regions of Saudi Arabia have been found to occur mainly among patients who had been chronic khat chewers. 42 Esophageal and gastric carcinoma have been attributed to khat chewing and water-pipe smoking in men and women in Yemen. 41 Khat-chewing men living in the area of the horn of Africa were studied and were found to have an increased risk of oral carcinoma, especially when accompanied by alcohol and tobacco consumption. 43
Data from Allium cepa root tips suggest that (-)-cathinone is responsible for teratogenic and mutagenic effects of khat because it caused clumping and condensation of chromosomes, sticky metaphases, and anaphasic bridges. 44 Animal studies indicate that cathinone can depress testosterone levels, degenerate testicular tissue, and decrease sperm count and motility. 45 In a study of 65 khat addicts compared with 50 nonkhat addicted subjects, statistically significant differences were detected between the semen parameters of the 2 groups. These parameters included semen volume, motility index, sperm count, sperm motility, and percentage of normal spermatozoa, all of which were lower among the addict group. Long-term addicts also showed severe ultrastructural deformation in comparison with the nonkhat addicted subjects. 46
Studies of full-term human newborns have shown that khat use by the mother is associated with lower birth weight, 47 but no differences in the rates of stillborns or congenital malformations were observed. 48 A study of guinea pigs suggests that (+)-norpseudoephedrine in khat may reduce placental blood flow, impairing fetal growth.
A report of 2 cases has described bilateral optic atrophy in 2 khat users who consumed amounts larger than usual. This may have been an idiosyncratic reaction to khat. 49 Khat-induced anorexia causes a deficient nutritional state that favors infections. Tuberculosis is a particular threat because the chewed residues of the leaves are ejected by spitting and the water pipe is used collectively during a khat session. 10
Hepatic cirrhosis of unknown etiology has been noted in khat users; poor diet and the potentially hepatotoxic effects of khat tannins may be contributing factors. Two case reports of Fasciola hepatica infection have been attributed to contaminated khat chewing. Human fascioliasis usually occurs from ingesting contaminated watercress, water, or liver. Khat grows especially well in moist conditions and could become contaminated with metacercariae, thus leading to fascioliasis. 50 , 51
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