Khat (Catha edulis) is a recreational, chewed herbal drug that has been used as a psychostimulant for centuries in East Africa and the Arabian Peninsula, namely in Somalia, Ethiopia, and Yemen. However, the growing worldwide availability of khat has produced widespread concern. The plant comprises a large number of active substances, among which cathinone, cathine, and norephedrine are the main constituents, which can be included in the group of sympathomimetics of natural origin. In fact, these compounds are amphetamine analogues, and, as such, they have amphetamine-like nervous system stimulant effects. Chewing the leaves gives people a sensation of well-being and increases energy, alertness, and self-confidence. The chronic use of khat is, however, associated with severe cardiac, neurological, psychological, and gastrointestinal complications. The psychological dependence and withdrawal symptoms of khat are the reasons for its prolonged use. The aim of this paper is to review current knowledge on the khat plant with toxicokinetic and toxicodynamic perspectives. Namely, this review paper addresses in vitro, in vivo, and human studies. The models used, as well as the concentrations and doses with the respective biological effects, are discussed. Additionally, the main drug interactions involved with khat are described.

Associate Laboratory i4HB Institute for Health and Bioeconomy Faculty of Pharmacy University of Porto 4050 313 Porto Portugal

Department of Pharmacology and Toxicology Faculty of Pharmacy Charles University 500 05 Hradec Králové Czech Republic

TOXRUN Toxicology Research Unit University Institute of Health Sciences CESPU CRL 4585 116 Gandra Portugal

UCIBIO Applied Molecular Biosciences Unit REQUINTE Toxicology Laboratory Biological Sciences Department Faculty of Pharmacy University of Porto 4050 313 Porto Portugal

Zobrazit více v PubMed

Abebe W. Khat: A Substance of Growing Abuse with Adverse Drug Interaction Risks. J. Natl. Med Assoc. 2018;110:624–634. doi: 10.1016/j.jnma.2018.04.001. PubMed DOI

Balint E.E., Falkay G., Balint G.A. Khat—A controversial plant. Wien Klin Wochenschr. 2009;121:604–614. doi: 10.1007/s00508-009-1259-7. PubMed DOI

Valente M.J., de Pinho P.G., Bastos M.D.L., Carvalho F., Carvalho M. Khat and synthetic cathinones: A review. Arch. Toxicol. 2014;88:15–45. doi: 10.1007/s00204-013-1163-9. PubMed DOI

Al-Hebshi N.N., Skaug N. Khat (Catha edulis)—An updated review. Addict. Biol. 2005;10:299–307. doi: 10.1080/13556210500353020. PubMed DOI

Al-Motarreb A., Baker K., Broadley K.J. Khat: Pharmacological and medical aspects and its social use in Yemen. Phytother. Res. 2002;16:403–413. doi: 10.1002/ptr.1106. PubMed DOI

Al-Habori M. The potential adverse effects of habitual use of Catha edulis(khat) Expert Opin. Drug Saf. 2005;4:1145–1154. doi: 10.1517/14740338.4.6.1145. PubMed DOI

Cochrane L., O’Regan D. Legal harvest and illegal trade: Trends, challenges, and options in khat production in Ethiopia. Int. J. Drug Policy. 2016;30:27–34. doi: 10.1016/j.drugpo.2016.02.009. PubMed DOI

Szendrei K. The chemistry of khat. Bull. Narc. 1980;32:5–35. PubMed

Kalix P. Cathinone, a natural amphetamine. Pharmacol. Toxicol. 1992;70:77–86. doi: 10.1111/j.1600-0773.1992.tb00434.x. PubMed DOI

Brenneisen R., Geisshüsler S. Psychotropic drugs.III. Analytical and chemical aspects of Catha edulis Forsk. Pharm. Acta Helv. 1985;60:290–301. PubMed

Kelly J.P. Cathinone derivatives: A review of their chemistry, pharmacology and toxicology. Drug Test. Anal. 2011;3:439–453. doi: 10.1002/dta.313. PubMed DOI

Kalix P., Braenden O. Pharmacological aspects of the chewing of khat leaves. Pharmacol. Rev. 1985;37:149–164. PubMed

Geisshüsler S., Brenneisen R. The content of psychoactive phenylpropyl and phenylpentenyl khatamines in Catha edulis Forsk. of different origin. J. Ethnopharmacol. 1987;19:269–277. doi: 10.1016/0378-8741(87)90004-3. PubMed DOI

Kalix P. Pharmacological properties of the stimulant khat. Pharmacol. Ther. 1990;48:397–416. doi: 10.1016/0163-7258(90)90057-9. PubMed DOI

Feyissa A.M., Kelly J.P. A review of the neuropharmacological properties of khat. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2008;32:1147–1166. doi: 10.1016/j.pnpbp.2007.12.033. PubMed DOI

Feng L.-Y., Battulga A., Han E., Chung H., Li J.-H. New psychoactive substances of natural origin: A brief review. J. Food Drug Anal. 2017;25:461–471. doi: 10.1016/j.jfda.2017.04.001. PubMed DOI PMC

Patel N.B. Khat (Catha edulis Forsk)—And now there are three. Brain Res. Bull. 2019;145:92–96. doi: 10.1016/j.brainresbull.2018.07.014. PubMed DOI

Sawair F.A., Al-Mutwakel A., Al-Eryani K., Al-Surhy A., Maruyama S., Cheng J., Al-Sharabi A., Saku T. High relative frequency of oral squamous cell carcinoma in Yemen: Qat and tobacco chewing as its aetiological background. Int. J. Environ. Health Res. 2007;17:185–195. doi: 10.1080/09603120701254813. PubMed DOI

Toennes S.W., Harder S., Schramm M., Niess C., Kauert G.F. Pharmacokinetics of cathinone, cathine and norephedrine after the chewing of khat leaves. Br. J. Clin. Pharmacol. 2003;56:125–130. doi: 10.1046/j.1365-2125.2003.01834.x. PubMed DOI PMC

Toennes S.W., Kauert G.F. Excretion and detection of cathinone, cathine, and phenylpropanolamine in urine after kath chewing. Clin. Chem. 2002;48:1715–1719. doi: 10.1093/clinchem/48.10.1715. PubMed DOI

Widler P., Mathys K., Brenneisen R., Kalix P., Fisch H.-U. Pharmacodynamics and pharmacokinetics of khat: A controlled study. Clin. Pharmacol. Ther. 1994;55:556–562. doi: 10.1038/clpt.1994.69. PubMed DOI

Halket J.M., Karasu Z., Murray-Lyon I.M. Plasma cathinone levels following chewing khat leaves (Catha edulis Forsk) J. Ethnopharmacol. 1995;49:111–113. doi: 10.1016/0378-8741(95)90038-1. PubMed DOI

Brenneisen R., Fisch H.U., Koelbing U., Geisshusler S., Kalix P. Amphetamine-like effects in humans of the khat alkaloid cathinone. Br. J. Clin. Pharmacol. 1990;30:825–828. doi: 10.1111/j.1365-2125.1990.tb05447.x. PubMed DOI PMC

Brenneisen R., Geisshüsler S., Schorno X. Metabolism of cathinone to (−)-norephedrine and (−)-norpseudoephedrine. J. Pharm. Pharmacol. 1986;38:298–300. doi: 10.1111/j.2042-7158.1986.tb04571.x. PubMed DOI

Mathys K., Brenneisen R. Determination of (S)-(−)-cathinone and its metabolites (R,S)-(−)-norephedrine and (R,R)-(−)-norpseudoephedrine in urine by high-performance liquid chromatography with photodiode-array detection. J. Chromatogr. 1992;593:79–85. doi: 10.1016/0021-9673(92)80270-5. PubMed DOI

Engidawork E. Pharmacological and Toxicological Effects of Catha edulisF. (Khat) Phytotherapy Res. 2017;31:1019–1028. doi: 10.1002/ptr.5832. PubMed DOI

Odenwald M., al’Absi M. Khat use and related addiction, mental health and physical disorders: The need to address a growing risk. East Mediterr. Health J. 2017;23:236–244. doi: 10.26719/2017.23.3.236. PubMed DOI

Cox G., Rampes H. Adverse effects of khat: A review. Adv. Psychiatr. Treat. 2003;9:456–463. doi: 10.1192/apt.9.6.456. DOI

Heal D.J., Smith S.L., Gosden J., Nutt D.J. Amphetamine, Past and present—A pharmacological and clinical perspective. J. Psychopharmacol. 2013;27:479–496. doi: 10.1177/0269881113482532. PubMed DOI PMC

Mladěnka P., Applová L., Patočka J., Costa V.M., Remiao F., Pourová J., Mladěnka A., Karlíčková J., Jahodář L., Vopršalová M., et al. Comprehensive review of cardiovascular toxicity of drugs and related agents. Med Res Rev. 2018;38:1332–1403. doi: 10.1002/med.21476. PubMed DOI PMC

Nencinp P., Amiconi G., Befani O., Abdullahi M., Anania M. Possible involvement of amine oxidase inhibition in the sympathetic activation induced by khat (catha edulis) chewing in humans. J. Ethnopharmacol. 1984;11:79–86. doi: 10.1016/0378-8741(84)90097-7. PubMed DOI

Osorio-Olivares M., Rezende M.C., Sepúlveda-Boza S., Cassels B.K., Fierro A. MAO inhibition by arylisopropylamines: The effect of oxygen substituents at the beta-position. Bioorg. Med. Chem. 2004;12:4055–4066. doi: 10.1016/j.bmc.2004.05.033. PubMed DOI

Basker G. A review on hazards of khat chewing. Int. J. Pharm. Pharm. Sci. 2013;5:74–77.

Nielen R.J., A Van Der Heijden F.M.M., Tuinier S., A Verhoeven W.M. Khat and mushrooms associated with psychosis. World J. Biol. Psychiatry. 2004;5:49–53. doi: 10.1080/15622970410029908. PubMed DOI

Patel N.B. Mechanism of action of cathinone: The active ingredient of khat (Catha edulis) East Afr. Med J. 2009;77:329–332. doi: 10.4314/eamj.v77i6.46651. PubMed DOI

Al-Meshal I.A., Qureshi S., Ageel A.M., Tariq M. The toxicity of Catha edulis (khat) in mice. J. Subst. Abus. 1991;3:107–115. doi: 10.1016/S0899-3289(05)80011-2. PubMed DOI

Ahmed M.B., el-Qirbi A.B. Biochemical effects of Catha edulis, cathine and cathinone on adrenocortical functions. J. Ethnopharmacol. 1993;39:213–216. doi: 10.1016/0378-8741(93)90039-8. PubMed DOI

Islam M.W., Al-Shabanah O.A., Al-Harbi M.M., Al-Gharably N.A. Evaluation of teratogenic potential of khat (Catha edulis forsk.) In rats. Drug Chem. Toxicol. 1994;17:51–68. doi: 10.3109/01480549409064046. PubMed DOI

Al-Motarreb A.L., Broadley K.J. Coronary and aortic vasoconstriction by cathinone, the active constituent of khat. Auton. Autacoid Pharmacol. 2003;23:319–326. doi: 10.1111/j.1474-8673.2004.00303.x. PubMed DOI

Banjaw M.Y., Miczek K., Schmidt W.J. Repeated Catha edulis oral administration enhances the baseline aggressive behavior in isolated rats. J. Neural. Transm. 2006;113:543–556. doi: 10.1007/s00702-005-0356-7. PubMed DOI

Abdulwaheb M., Makonnen E., Debella A., Abebe D. Effect of Catha edulis foresk (khat) extracts on male rat sexual behavior. J. Ethnopharmacol. 2007;110:250–256. doi: 10.1016/j.jep.2006.09.019. PubMed DOI

Al-Ahdal M.N., McGarry T.J., Hannan M.A. Cytotoxicity of Khat (Catha edulis) extract on cultured mammalian cells: Effects on macromolecule biosynthesis. Mutat. Res. 1988;204:317–322. doi: 10.1016/0165-1218(88)90105-X. PubMed DOI

Nyongesa A.W., Patel N.B., Onyango D.W., Wango E.O., Odongo H.O. In vitro study of the effects of khat (Catha edulis Forsk) extract on isolated mouse interstitial cells. J. Ethnopharmacol. 2007;110:401–405. doi: 10.1016/j.jep.2006.09.040. PubMed DOI

Dimba E.A., Gjertsen B.T., Bredholt T., Fossan K.O., Costea D.E., Francis G.W., Johannessen A.C., Vintermyr O.K. Khat (Catha edulis)-induced apoptosis is inhibited by antagonists of caspase-1 and -8 in human leukaemia cells. Br. J. Cancer. 2004;91:1726–1734. doi: 10.1038/sj.bjc.6602197. PubMed DOI PMC

Bredholt T., Dimba E.A., Hagland H.R., Wergeland L., Skavland J., O Fossan K., Tronstad K.J., Johannessen A.C., Vintermyr O.K., Gjertsen B.T. Camptothecin and khat (Catha edulis Forsk.) induced distinct cell death phenotypes involving modulation of c-FLIPL, Mcl-1, procaspase-8 and mitochondrial function in acute myeloid leukemia cell lines. Mol. Cancer. 2009;8:101. doi: 10.1186/1476-4598-8-101. PubMed DOI PMC

Abou-Elhamd A.S., Kalamegam G., Ahmed F., Assidi M., Alrefaei A.F., Pushparaj P.N., Abu-Elmagd M. Unraveling the Catha edulis Extract Effects on the Cellular and Molecular Signaling in SKOV3 Cells. Front. Pharmacol. 2021;12:666885. doi: 10.3389/fphar.2021.666885. PubMed DOI PMC

Abebe M., Kindie S., Adane K. Adverse Health Effects of Khat: A Review. Fam. Med. Med. Sci. Res. 2015;4:154.

Tesfaye F., Byass P., Wall S., Berhane Y., Bonita R. Association of Smoking and Khat (Catha edulis Forsk) Use With High Blood Pressure Among Adults in Addis Ababa, Ethiopia, 2006. Prev. Chronic Dis. 2008;5:A89. PubMed PMC

Al-Motarreb A., Briancon S., Al-Jaber N., Al-Adhi B., Al-Jailani F., Salek M.S., Broadley K. Khat chewing is a risk factor for acute myocardial infarction: A case-control study. Br. J. Clin. Pharmacol. 2005;59:574–581. doi: 10.1111/j.1365-2125.2005.02358.x. PubMed DOI PMC

Alkadi H., A Noman M., Al-Thobhani A.K., Al-Mekhlafi F.S., Raja’A Y. Clinical and experimental evaluation of the effect of Khat-induced myocardial infarction. Saudi Med. J. 2002;23:1195–1198. PubMed

Ahmed A.M. Effect of Khat on the Heart and Blood Vessels. Heart Views. 2004;5:54–57.

Hill C.M., Gibson A. The oral and dental effects of q’at chewing. Oral. Surg. Oral. Med. Oral. Pathol. 1987;63:433–436. doi: 10.1016/0030-4220(87)90255-6. PubMed DOI

Goldenberg D., Lee J., Koch W.M., Kim M.M., Trink B., Sidransky D., Moon C.-S. Habitual Risk Factors for Head and Neck Cancer. Otolaryngol. Neck Surg. 2004;131:986–993. doi: 10.1016/j.otohns.2004.02.035. PubMed DOI

Heymann T.D., Bhupulan A., Zureikat N.E.K., Bomanji J., Drinkwater C., Giles P., Murray-Lyon I.M. Khat chewing delays gastric emptying of a semi-solid meal. Aliment. Pharmacol. Ther. 2007;9:81–83. doi: 10.1111/j.1365-2036.1995.tb00356.x. PubMed DOI

Tucci S.A. Phytochemicals in the Control of Human Appetite and Body Weight. Pharmaceuticals. 2010;3:748–763. doi: 10.3390/ph3030748. PubMed DOI PMC

Chapman M.H., Kajihara M., Borges G., O’Beirne J., Patch D., Dhillon A.P., Crozier A., Morgan M.Y. Severe, Acute Liver Injury and Khat Leaves. N. Engl. J. Med. 2010;362:1642–1644. doi: 10.1056/NEJMc0908038. PubMed DOI

Stuyt R.J.L., Willems S.M., Wagtmans M.J., Van Hoek B. Chewing khat and chronic liver disease. Liver Int. 2011;31:434–436. doi: 10.1111/j.1478-3231.2010.02440.x. PubMed DOI

Mwenda J., M’Arimi M.M., Kyama M., Langat D. Effects of khat (Catha edulis) consumption on reproductive functions: A review. East Afr. Med J. 2005;80:318–323. doi: 10.4314/eamj.v80i6.8709. PubMed DOI

Dhadphale M., Mengech A., Chege S.W. Miraa (Catha edulis) as a cause of psychosis. East Afr. Med. J. 1981;58:130–135. PubMed

Critchlow S., Seifert R. Khat-induced Paranoid Psychosis. Br. J. Psychiatry. 2018;150:247–249. doi: 10.1192/bjp.150.2.247. PubMed DOI

Jager A.D., Sireling L. Natural history of Khat psychosis. Aust. N. Z. J. Psychiatry. 1994;28:331–332. doi: 10.3109/00048679409075648. PubMed DOI

Alem A., Shibre T. Khat induced psychosis and its medico-legal implication: A case report. Ethiop. Med. J. 1997;35:137–139. PubMed

Abdulkarim K. Ph.D. Thesis. University of Khartoum; Khartoum, Sudan: 2004. Cephradine Bioequivalence and Its Interaction with Khat and Food (Al-Sayadeyah) in Yemen.

Attef O.A., Ali A.A., Ali H.M. Effect of Khat chewing on the bioavailability of ampicillin and amoxycillin. J. Antimicrob. Chemother. 1997;39:523–525. doi: 10.1093/jac/39.4.523. PubMed DOI

Bamashmus M., Othrob N.Y., Mousa A., Al-Tay W. Effect of Khat (Qat) consumption on pain during and after local anesthesia for patients undergoing cataract surgery. Med Sci. Monit. 2010;16:SR29–SR33. PubMed

Bamgbade O.A. The perioperative implications of khat use. Eur. J. Anaesthesiol. 2008;25:170–172. doi: 10.1017/S026502150700258X. PubMed DOI

Farah F., Attef O., Ali A.-A. The Influence of Khat on the In-vitro and In-vivo availability of Tetracycline-HCl. Res. J. Pharm. Dos. Technol. 2015;7:1–6.

Bedada W., de Andrés F., Engidawork E., Pohanka A., Beck O., Bertilsson L., Llerena A., Aklillu E. The Psychostimulant Khat (Catha edulis) Inhibits CYP2D6 Enzyme Activity in Humans. J. Clin. Psychopharmacol. 2015;35:694–699. doi: 10.1097/JCP.0000000000000413. PubMed DOI

Natural Sympathomimetic Drugs: From Pharmacology to Toxicology