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Khat

Scientific Name(s): Catha edulis Forsk.
Common Name(s): Abyssinian tea, Chaat, Chat, Gat, Gomba, Jaad, Jimma, Kaht, Kat, Khat, Kijiti, Kus es Salahin, Miraa, Qaad, Qat, Qut, Tchaad, Tchat, Tea of the Arabs, Tohai, Tohat, Tschut, Veve

Clinical Overview

Use

Khat leaves are chewed mainly for their psychostimulant and euphoric effects. It has traditionally been used to elevate mood and combat fatigue. Khat is also believed to have antiobesity effects due to appetite suppression. However, there are no well-controlled clinical trials to support any of these uses.

Dosing

100 to 300 g of fresh leaves are chewed to form a bolus (called a "quid") that is held against the cheek on one side of the mouth while swallowing its juice; a typical "khat session" lasts for 3 to 4 hours. A khat preparation was administered at a dose of 0.8 mg/kg of cathinone in a pharmacokinetic study.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Avoid use. Documented adverse effects.

Interactions

Khat chewing interferes with the absorption of amoxicillin and ampicillin. Nicotine and caffeine increase the stimulant effects of khat.

Adverse Reactions

Constipation is among the most commonly experienced adverse reaction in khat users. Other serious adverse reactions include cardiovascular, CNS, endocrine, metabolic, GI, dental, cognitive, psychiatric, and respiratory effects.

Toxicology

Khat may cause oral and gastric cancer, cerebral hemorrhage, severe headache, myocardial infarction (MI), duodenal ulcers, hypertension, low-birth-weight infants, and a variety of other severe effects, including addiction and associated sequelae.

Botany

Khat is a natural stimulant native to East Africa and the Arabian Peninsula, with distribution in parts of the Middle East and on the island of Madagascar. It is a tall evergreen shrub (2.7 to 3.7 m in height) that grows best at high elevations (1,500 to 2,000 m above sea level). Its tender twigs and leaves are harvested almost year-round. White leaves are more rare and more expensive than red leaves. Freshly harvested khat has traditionally been wrapped in banana leaves to keep it moist during export to neighboring African countries.Patel 2015

History

The khat plant is believed to be native to Ethiopia and to have been introduced to Yemen between the first and sixth centuries.Mihretu 2017 Though khat has been used historically for medicinal purposes, it is most valued as a stimulant.Al'absi 2013 Chewing parts of the khat plant is one of the most common forms of drug use and abuse in many East African nations, with use increasing steadily in recent years and becoming a problem of social and medical importance. Use is highly prevalent in Yemen, Kenya, Ethiopia, Eretria, Somalia, and Saudi Arabia, and is rapidly growing in Western Europe, Asian countries, North America, and Australia.Al'absi 2013, Al-Maweri 2017 Khat is still legal in some countries in Africa and Europe but is illegal in others, such as Germany.Al'absi 2013, Bongard 2015 Recent bans were established in the Netherlands in 2012 and in the United Kingdom in 2013.Bongard 2015

Given its social and cultural tradition in African and some Middle East societiesAl'absi 2013 and because of its euphoric effects, khat chewing often plays a dominant role in celebrations, meetings, marriages, and other social gatherings. Studies have shown the age at which individuals begin chewing khat is younger than 10 years.Mihretu 2017 A special gathering during which people chew khat is known as a "khat session"; in Ethiopia, people who gather for a khat session are called "jema" or "afosha."Mihretu 2017 Khat sessions typically start in the afternoon and last several hours.Al-Maweri 2017 Khat has a sweet taste and an astringent action.Osol 1955 Large amounts of liquids are often consumed while chewing because of the dryness induced by the plant. Many users reverse the after effects by drinking alcohol.Mihretu 2017

Khat use has also played a role in Somalia's civil conflict; in the Somali military, the leaves have been issued to soldiers in their daily rations with intentions of inhibiting their need for food and sleep, as well as to increase aggression.Randall 1992

Khat leaves have been used in traditional medicine for the treatment of depression and fatigue.Patel 2015 Khat is also traditionally believed to have a role in obesity due to its appetite suppressant effects.Alshagga 2016

Chemistry

Khat is a psychostimulant; the major pharmacologically active constituent is cathinone, an amphetamine-like sympathomimetic amine.Al'absi 2013 The chief active ingredients are cathinone, cathine, and norephedrine.Shujaa 2013 Studies of the chemical constituents of the 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).Kalix 1992 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%.Halbach 1972 Cathine has approximately one-tenth the stimulant activity of d-amphetamine. The compound has been confused with d,1-norephedrine in the literature; despite identical structural formulas, the 2 compounds differ significantly in pharmacologic properties.Eisenberg 1987 Cathinone (alpha-aminopropiophenone) has been isolated in variable quantities from fresh khat leaves, with content varying depending on the country of origin.Patel 2015 Cathinone increases dopamine and norepinephrine through actions on their transporter functions, and is associated with sympathetic activity.Al'absi 2013, Berihu 2017 Cathinone may be responsible for sleep disturbances; the release of cathinone in the bloodstream stimulates the CNS, promoting release of dopamine, serotonin, and noradrenaline, resulting in inhibition of the sleep pathways.Robinson 2013 The cathinone compound is a more powerful stimulant than cathine and is considered to be the most important component of khat; however, it is unstable in the presence of oxygen and decomposes within a few days of picking or when the plant is dried,Griffiths 1997 making fresh leaves the best source of cathinone.Balint 1994 For maximum potency, khat must be chewed fresh.Baron 1999 The red variety of khat, considered superior by users, contains more cathinone than the white type. Fresh khat leaves (100 g) contain approximately 36 mg of cathinone, 120 mg of norpseudoephedrine, and 8 mg of norephedrine.Kalix 1996 Khat includes more than 40 alkaloids, glycosides, tannins, amino acids, vitamins, and minerals; khat also contains 62 types of cathedulins.Patel 2015 It contains khatamines (phenylpropyl and phenylpentenylamines) in varying amounts depending on origin, type, and quality of the product.Geisshusler 1987 The leaves and twigs contain large amounts of tannins (up to 14% of dry weight); the astringent tannins may be responsible for gastritis in some khat users due to irritation of the gastric mucosa leading to inflammation.Nigussie 2013 The tannin content may also be responsible for frequent reports of constipation in khat users.Patel 2015 Alternatively, constipation may be due to the sympathomimetic effect of cathinone; sympathetic stimulation inhibits colon motility and increases sphincter tone, which in turn leads to excess water absorption by the intestinal epithelium, resulting in hardened stools.Nigussie 2013 Cathinone and cathine are extracted by the action of enzymes in saliva.Mihretu 2017 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.Brenneisen 1986

Uses and Pharmacology

Leaves of khat are chewed fresh for their psychostimulant properties.Al'absi 2013 The acute psychostimulant effects of khat include enhanced mood and alertness, euphoria, increased flow of ideas while studying, feelings of optimism, elation, a general sense of well-being, enhanced concentration, friendliness, contentment, ability to think more clearly, confidence, and improved vigilance.Al'absi 2013, Berihu 2017, Bongard 2015, Nakajima 2016, Nakajima 2017, Patel 2015 Also similar to amphetamine, cathinone, the active ingredient in khat, suppresses appetite, which explains the belief that khat may have antiobesity effects.Al'absi 2013, Alshagga 2016 It has been used to prevent fatigue, and is thought to improve memory and alleviate pain.Berihu 2017, Mihretu 2017 In placebo-controlled trials, khat was found to increase motor activity, euphoria, and a sense of excitement and activation.Al'absi 2013

When chewing khat, cathinone is released within 15 to 45 minutes, with peak plasma levels of cathinone obtained 1.5 to 3.5 h after the onset of chewing. Cathinone is detectable in plasma for up to 24 hours after consumption.El-Sayed 2012

Dosing

100 to 300 g of fresh leaves are chewed to form a bolus that is held in the buccal sulcus against the cheek of the mouth while swallowing the juice it produces; chewing sessions typically last 3 to 4 hours.Al-Maweri 2017, Patel 2015 In Scotland, khat has been blended and filtered to be served as a drink called "Herbal Ecstasy."Patel 2015

A single dose of 0.8 mg/kg of cathinone, corresponding to 54 to 71 g fresh khat leaves, was administered in a pharmacokinetic study examining the amphetamine-like stimulatory effects of khat.Widler 1994

Pregnancy / Lactation

Chronic khat use is associated with harmful effects on fetal development, delivery outcomes, and postnatal maternal and infant health.Nakajima 2017 Despite various negative effects of khat use in pregnancy and breastfeeding, there is a substantial prevalence of use among pregnant women in East African countries. In one study in Ethiopia, a survey showed that 25% of pregnant women had chewed khat at least once in their lifetime, most identifying as current khat users. This study also showed environmental and social influences on khat use in pregnant women.Nakajima 2017 In another study in Ethiopia to explore the acceptable and problematic uses of khat, female khat users reported the practice of drinking aweza (a hot beverage made from boiling fresh khat leaves in water) to induce abortions.Mihretu 2017

A study in Ethiopia determined that khat use may be associated with an increased risk of anemia in pregnant women. A significantly higher prevalence of anemia in pregnant women who had restrictive dietary habits due to pregnancy (ie, reduced meal size or frequency, which may lead to poor iron intake) and in those who chewed khat was observed. The association of frequent khat chewing with the higher risk of anemia could be explained by its appetite suppressant effects as well as its tannin content, which reduces the bioavailability of nonheme iron from the maternal diet. Risks to fetal development should be considered.Kedir 2013

Studies have also shown that khat use is associated with a higher number of low-birth-weight infants.Nakajima 2017, Patel 2015 Khat use during pregnancy may reduce placental blood flow and impair fetal growth; reduced placental blood flow can be determined by evaluating the mother's urinary concentrations of (+)-norpseudoephedrine.Patel 2015 Low birth weight is a risk factor for perinatal and young infant death; therefore, khat chewing during pregnancy may contribute adversely to normal child development and may increase the risk of infant mortality.Patel 2015

One study in Ethiopia found a high prevalence of habitual khat use among women during pregnancy. Current and former khat chewers had higher levels of depressive symptoms and psychological distress, and social and familial factors also appeared to influence khat use habits. It is not clear whether chronic khat use causes increased distress and negative effects during pregnancy, or if individuals predisposed to vulnerability to stress are more likely to use khat during pregnancy. Maternal khat use and psychological distress may share common pathways in terms of potential negative impacts on pregnancy outcomes; both are associated with effects on the hypothalamic-pituitary-adrenocortical (HPA) and cardiovascular systems, which play important roles in pregnancy outcomes, including preterm labor leading to infant morbidity and mortality.Nakajima 2017

Psychoactive drugs cross the blood-brain barrier, and even more easily, the placental barrier.Patel 2015 Neonatal exposure to psychostimulants is associated with morphological and functional changes in the CNS, which results in motor dysfunction, cognitive impairment, altered stress response, and effects on learning and memory.Patel 2015 In one study, cathine was found in the breast milk of a khat-chewing mother and in her infant's urine.Nakajima 2017 Women have reported behavioral changes in their babies when breastfeeding after chewing khat. These changes included poor sleeping habits, excessive crying and screaming, and apparent abdominal pain.Mihretu 2017

Low weights in breastfeeding infants have also been reported, likely due to khat-associated decreases in the mother's appetite, which results in decreased milk production and thus potential malnourishment of the breastfeeding infant.Mihretu 2017

Interactions

GI 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.Attef 1997 The percentage of unchanged amoxicillin and ampicillin doses excreted in the urine and peak excretion levels were reduced 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 bioavailability of the antibiotics.

Cigarette smoking and caffeine enhance the stimulant activity of khat during chewing.Kassim 2011, Mihretu 2017 Concurrent khat and tobacco use is more common in men and presents an increased health risk compared to khat use alone (ie, altered psychophysiological stress response, impaired cognitive performance). Data suggest khat use may be a gateway to tobacco use in those who are not current tobacco users.Nakajima 2016

A case of suspected reversible cerebral vasoconstriction syndrome, manifesting as episodes of severe sudden onset of throbbing headache and photophobia, was reported in a 26-year-old man who was taking a monoamine oxidase inhibitor (MAOI) (tranylcypromine 10 mg/day) for severe depression and also chewing khat recreationally. Frontal and occipital subarachnoidal hemorrhage, segmental narrowing of multiple cerebral arteries, and increased signal intensity in the cervicothoracal myelum were documented, likely a result of the sympathomimetic and vasoconstrictor activity of khat's main active psychostimulant constituents (cathinone and cathine) and combined use with an MAOI.Tuladhar 2013

Adverse Reactions

Some adverse effects of khat include depression, insomnia, suicidal ideation, feeling of anxiousness and irritability, loss of appetite, nausea and vomiting, difficulty concentrating, numbness, and CNS deficits.Mihretu 2017

The acute, desired effects of khat are often quickly followed by a vast array of adverse effects, including excessive tension, emotional instability, and restlessness within 2 hours, followed by feelings of numbness, lack of concentration, sluggishness, and insomnia.Berihu 2017 Other common adverse effects include dysphoria, lethargy, fatigue, depressed mood, anxiety, disruptions in sleep, irritability, irascibility, anorexia, hyperthermia, mydriasis, endocrinological disturbances, and acute autonomic responses, such as elevated blood pressure and tachycardia.Al'absi 2013, El-Sayed 2012, Nakajima 2016, Nakajima 2017, Patel 2015

In one study, increased subjective temperature, sleep disturbance, gastric problems, emotional distress, and increased heartbeat were the most frequent complaints.Mihretu 2017 In another study, khat users reported a higher incidence of undefined physical symptoms.Al'absi 2013

Similar to other psychostimulants, chronic khat use may impact functions related to dopaminergic, adrenergic, opioid, and HPA axis activity. In one study, khat users exhibited enhanced evening and attenuated morning cortisol levels, reflecting a more flattened diurnal pattern than nonusers and suggesting disruption in circadian function in khat users. In khat users, cortisol levels also decreased following stressors. It is possible that long-term use of khat leads to allostatic changes manifested by hyporesponsiveness to stress and flattened diurnal pattern. Khat use has been associated with alterations in central hormonal regulatory functions.Al'absi 2013

Khat use has been associated with cardiovascular complications, including tachycardia, palpitations, hypertension, arrhythmias, vasoconstriction, MI, cerebral hemorrhage, and pulmonary edema.Mihretu 2017 In one study, khat users showed blunted blood pressure responses to stress compared with nonusers.Al'absi 2013 Another study compared khat-chewing acute coronary syndrome (ACS) patients to nonkhat-chewing ACS patients in regard to clinical characteristics, therapy, in-hospital outcomes, and 1-year outcomes; khat users were more likely to present with ST-segment elevation myocardial infarction (STEMI), followed by unstable angina and non-STEMI.Ali 2011 The study found the majority of khat users presented late following the onset of symptoms and were therefore less likely to have received thrombolytic therapy or percutaneous coronary intervention. In-hospital, 1-month, and 1-year mortality rates were higher and more adverse events (eg, heart failure, recurrent MI, ventricular arrhythmia, cardiogenic shock, stroke) occurred in the khat-chewing group. The cardiac effects in khat users may be due to increased myocardial oxygen demand resulting from elevated blood pressure and heart rate, which can precipitate ACS.Ali 2011

The psychotropic effects of khat are caused by amphetamine-like compounds, with cathinone being found in highest concentration. The stimulating effects of khat can be described as somewhere between those of 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.Pehek 1990

One study showed lower serum insulin levels in diabetic khat chewers than in diabetic non-khat chewers.El-Sayed 2012 The study also showed an increase in fasting blood glucose associated with khat chewing in both healthy khat chewers and diabetic khat chewers. The study concluded that khat chewing results in increased insulin resistance as well as increased fasting blood glucose in patients with type 2 diabetes due to increased resistin levels and cathinone-induced catecholamine secretion of khat. Another study showed higher mean glycosylated hemoglobin levels in khat chewers (83.5% of whom had chewed for more than 10 years) than in non-khat chewers. Most patients (97.5%) reported no hypoglycemia during or after khat chewing.Al-Sharafi 2015

Khat use has been associated with GI adverse effects, including chronic gastritis, constipation, hemorrhoids, dental complications, duodenal ulcer, and upper GI malignancy.Mihretu 2017, Nigussie 2013 The astringent characteristics of tannins in khat account for GI tract disorders such as periodontal disease, stomatitis, esophagitis, and gastritis. Tannins and cathinone contribute to constipation, which is the most common complaint of khat users.Nigussie 2013, Patel 2015 Constipation may be due to cathinone's sympathomimetic effects, in which sympathetic stimulation inhibits colon motility and increases sphincter tone.Nigussie 2013 Furthermore, the straining during constipation and long hours of sitting during khat sessions may contribute to hemorrhoids.Nigussie 2013 Two separate studies in healthy volunteers showed that chewing khat slows whole gut transit time, possibly due to the sympathomimetic action of cathinone.Gunaid 1999, Heymann 1995 Prevalence of GI disorders increases with frequency of khat chewing and duration of the habit; overall, GI disorders were higher among khat users compared to nonusers and the magnitude of these disorders increased with frequency of khat chewing.Nigussie 2013

Khat has been reported to have detrimental effects on dental and oral tissues, including keratotic white lesions, mucosal pigmentations, plasma cell stomatitis, teeth attrition and discoloration, gingival recession, and xerostomia.Al-Maweri 2017, Heymann 1995 Although poor oral hygiene is common among khat users, prolonged khat use may result in increased attachment loss and gingival recession.Al-Maweri 2017 One study showed an association between khat use and dental problems such as caries, decay, fillings, and extractions. In this study, the severity of GI disorders (including dental disorders) increased with frequency of khat chewing.Nigussie 2013

Although khat is perceived to improve concentration and memory, studies show that chronic khat use is associated with impaired working memory and mental impairments. Although khat does not demonstrate effects on long-term memory, there is evidence of short-term memory discrepancy depending on the duration of exposure.Berihu 2017 In one study examining effects of khat on cognitive control functions, working memory performance and cognitive flexibility were impaired in khat users compared with nonusers.Colzato 2011 Chronic khat use is likely associated with dysfunction in the prefrontal cortex as well as reduced dopamine levels in the striatum; dopamine plays an important role in cognitive flexibility and updating working memory.Colzato 2011

There is also a link between khat use and psychotic symptoms, with a higher tendency toward aggressive and hyperactive behavior.Odenwald 2005 In a study evaluating the relationship between khat and psychosis, a positive relationship between khat use and posttraumatic stress disorder and paranoia was found.Patel 2015 Psychosis and delusions are also known to be triggered by long-term use.Kassim 2013, Robinson 2013 In one study, users reported increased negative affect in response to stressors, as well as decreased positive affect compared with nonusers; these findings confirm the possibility that dysphoric mood may be linked to dysregulation of cortisol, although the association between cortisol concentrations and negative affect was only significant in nonusers.Al'absi 2013 According to another study, current and former khat chewers had higher levels of depressive symptoms and psychological distress compared with nonchewers.Nakajima 2017

One study reported tachypnea and bronchitis associated with khat use.Mihretu 2017

Withdrawal symptoms include increased appetite, fatigue, decreased energy, irritability, loss of motivation and concentration, restlessness, cravings, depressed mood, and unpleasant dreams. The most frequently reported withdrawal symptoms in an exploratory study were yawning, irritability, cravings, and depression; users often manage morning withdrawal symptoms by consuming excess amounts of caffeine or smoking cigarettes.Mihretu 2017

Toxicology

The following severe adverse effects have been associated with khat use: migraines, hepatotoxicity, cardiotoxicity, carcinoma, GI tract disorders, and mental impairment. Long-term khat use and exposure to its constituents (cathinone and cathine) may lead to receptor- and synaptic-related changes in multiple regions of the brain,Al'absi 2013 as well as liver and renal toxicity.Al-Maweri 2017 Long-term use has been reported to cause cardiovascular, GI tract, psychological, and mental disorders.Al-Maweri 2017 One study found that habitual khat chewing in males was an independent risk factor for type 2 diabetes mellitus diagnosis at an earlier age and that khat chewing in any population is likely associated with poor glycemic control.Al-Sharafi 2015

The tannins in khat leaves thicken the mucosa of the oropharynx and esophagus and may be carcinogenic.Gunaid 1995 In a study of khat-chewing men living in the horn of Africa, an increased risk of oral carcinoma was reported, especially when khat chewing was accompanied by alcohol and tobacco consumption.Kassie 2001 However, a more recent study showed no association with oral cancers.Nasher 2014 Another pilot study showed no link between khat chewing and esophageal or gastroesophageal junction cancers.Leon 2017 Although more recent studies suggest no association between khat use and oral cancers, additional studies are needed.

One study suggested that khat use is an independent risk factor for development of acute MI.Al-Motarreb 2010 Other studies showed an increased risk for acute MI and stroke, possibly due to the vasoconstrictor effects of cathinone.Ali 2010, Al-Motarreb 2010 Furthermore, through cerebral circulation vasospasm, khat may predispose users to stroke.Ali 2010 Khat chewers are more likely to experience cardiogenic shock, stroke, recurrent myocardial ischemia, ventricular arrhythmia, and heart failure when not taking a beta-blocker.Ali 2011

In one study, 8 individuals who presented to a Somaliland hospital with decompensated liver cirrhosis over a period of 14 months were extensively interviewed to determine possible causes of cirrhosis. All 8 subjects admitted to chronic khat use, and the most common causes of cirrhosis were either denied by patients or excluded based on patient history, physical exam, or lab tests. Four of the subjects showed clinical improvement after ceasing khat use.Mahamoud 2016 More studies are needed to show a definitive correlation between khat use and hepatotoxicity. Khat consumption leading to hepatotoxicity could be due to several factors. In one in vitro study, khat inhibited the growth of human hepatic L02 cells and demonstrated that caspase-8 and -9 may be involved in the cellular event cascade leading to khat-induced cell death. More specifically, the study showed that khat-induced apoptosis of hepatocytes is mainly mediated by the sustained activation of the Jun amino-terminal kinases (JNK) pathway. The effect of khat on L02 cells triggers generation of intracellular reactive oxygen species, which leads to the activation of JNK. This cascade results in cell apoptosis.Abid 2013

Physical dependence does not occur with chronic use of khat, and the mental depression, sedation, and social separation that may follow withdrawal are a rebound phenomenon rather than an abstinence syndrome. Though cathinone possesses a pharmacological profile closely resembling that of amphetamine, the mental dependence potential is less with cathinone than with amphetamine. Also, development of tolerance to effects of cathinone is more rapid than with amphetamine, and there is a cross-tolerance between the effects of cathinone and amphetamine.Kalix 1992 In one study of khat users, mirqanna, or "feeling high," was defined by users as distressing overstimulation beyond their control. Symptoms of mirqanna include dilated pupils; feeling uneasy; internal fear; involuntary and uncontrollable movements of lips, hands, tongue or mouth; feeling restless; and taking long walks without apparent purpose. Users experiencing mirqanna become easily annoyed, fearful, or cheerful. Some reported experiencing exaggerated attention and recall of information that may lead to confusion. Increases in body temperature and pulse rate, perceptual disturbances, hypervigilance, confusion, poor recognition of familiar environments, and misinterpretation of external stimuli in others have also been reported.Mihretu 2017

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