Plant Profiler

Khat (Catha edulis)


Birch (Betula pendula) Image
Synonyms / Common Names / Related Terms
Abyssinian tea, African salad, Arabian-tea, bushman's tea, cat, cathine, cathinone, Catha edulis, Celastraceae (family), Celastrus edulis, chat, chaat, gat, herbal ecstasy, kat, kus es Salahin, miraa, oat, phenylpropanolamine, qat (Yemen), qat, qut, somali tea, tchaad, tohai, tohat, tshcut.





Mechanism of Action

Pharmacology:

  • Constituents: The active constituents of khat are cathine and cathinone. Cathine has 1/10 the stimulant effect of d-amphetamine. Cathinone, also called (-)-s-alpha-aminopropiophenone, is a more powerful stimulant than cathine and is structurally similar to ephedrine and amphetamine.4,13,14,15,16
  • Cathinone releases neurotransmitters from presynaptic storage sites that produce its central nervous system effects by acting through the same mechanism as amphetamine.1,14
  • Adrenergic effects: Khat chewing produced a fall in average and maximum urine flow rate. This effect was inhibited by indoramin. The urinary side effects of khat chewing are probably mediated through stimulation of alpha 1-adrenergic receptors.17
  • Cardiovascular effects: Khat has been reported to cause an increase in systolic and diastolic blood pressure and heart rate.4,5,6,7,8,9,10,11
  • Cathinone caused coronary vasoconstriction, negative inotropy and negative chronotropy in isolated hearts. The major metabolite of cathinone after its ingestion, 1R.2S-(-)-norephedrine (norephedrine), also caused coronary vasoconstriction comparable with that by cathinone. Norephedrine, however, had no effect on force or rate of cardiac contractions.18
  • Cellular effects: There is preliminary evidence that organic khat extracts induce selective-type human leukemia cell death in vitro .19
  • Gastrointestinal effects: There was no significant change in gallbladder volume after chewing khat compared with lettuce in the fasting state or in gallbladder emptying after a fatty meal and we conclude that khat chewing has no clinically significant effect on gallbladder motility.20
  • Oxidative effects: The effect of khat chewing and the combination of khat chewing and smoking on plasma lipid peroxidation as a biomarker of oxidative stress and free radical activity (measured as plasma malondialdehyde, MDA), as well as on the lipid profiles were investigated. The fasting plasma levels of MDA were non-significantly higher in both groups (4% in khat chewers and 9.2% in khat chewers and smokers), whereas these levels were observed to be significantly increased at post meal and 2 hours through the khat session. Post meal increase of plasma MDA could be attributed partially to the meal-induced oxidative stress and the possible decrease in the overall antioxidant capacity. This increase in plasma levels of MDA in both tested groups were found to be higher in the control group suggesting the presence of other contributing factors beside the meal-induced oxidative stress. Plasma levels of MDA were observed to fall slightly 2 hours through the khat session over the post meal levels, suggesting a lack of additive effect of khat consumption. Plasma triglycerides, total cholesterol, and LDL-cholesterol were shown to be non-significantly affected in this study by khat chewing or by the combination of khat chewing and smoking.21
  • Reproductive effects: Cathine may enhance natural fertility.22 Cathine significantly stimulated cAMP production in uncapacitated sperm suspensions, but significantly inhibited it in capacitated suspensions.
  • Stimulatory effects: The effect of khat, a plant used for its stimulant effects in eastern Africa and southern Arabia, has until recently been attributed to the pharmacological action of d-norpseudoephedrine, also known as cathine. The isolation in 1975 of cathinone revived an earlier suggestion that the fresh leaves contained a substance more potent than cathine. The pharmacological assays reported on in this paper appear to confirm the higher stimulant capacity of cathinone. This substance produces qualitatively similar locomotor stimulation in mice and comparable stereotypy in rats as amphetamine does, although it is approximately half as active. The results obtained after pre-treatment with reserpine or alpha-methyl-p-tyrosine, which interfere with the catecholamine system, strongly suggest that cathinone interacts with brain catecholamines by an indirect mechanism and, most probably, by affecting neurotransmitter release of the labile pool.23
  • The chewing of khat leaves as a stimulant is likely due to the phenylalkylamine alkaloid cathinone. Khat has been reported to cause euphorigenic and psychostimulant effects in humans.4
  • Two cases of khat addiction were successfully treated with bromocriptine.2 One man was detoxified with bromocriptine 1.25mg every six hours, which was titrated downward over four weeks.3
  • Sympathomimetic effects: Mydriasis, delayed gastric emptying, and increased heart rate and blood pressure reflect the sympathomimetic effects of khat.12,4,5,6,24,7,8,9,10,11
  • Tolerance and dependence effects: Researchers have noted that khat is habit-forming and has psychological dependency. Experiments found that animals could not distinguish between cathinone and amphetamine, with the two being almost equipotent.1,14 Cathinone releases neurotransmitters from presynaptic storage sites and produces CNS effects through a similar mechanism as amphetamine.1,14
  • In animal studies, rats were trained to discriminate the stimulant effect of cathine. When followed by cathinone, cathine, or maintenance treatment, the ability to discriminate was reduced. These results indicate a possible acute tolerance that is developed in cathine and cathinone use.25,26

Pharmacodynamics/Kinetics:

  • In one pharmacokinetic study, four volunteers chewed khat leaves in an amount equivalent to one-quarter of that used in a typical khat session. Blood samples were collected up to 80 hours and the alkaloids were assayed using gas chromatography-mass spectrometry. The plasma concentration-time data for the alkaloids could be described using a two-compartment model with two-segment absorption. The mucosa of the oral cavity is considered to be the first absorption segment, where the major proportion of the alkaloids is absorbed. Subjects absorbed a mean dose of 45mg of cathinone. Cathinone was eliminated from the central compartment with a mean half-life of 1.5 plus or minus 0.8 hours. The half-life of cathine was 5.2 plus or minus 3.4 hours. The metabolism of cathinone to norephedrine had a substantial influence on its plasma concentration profile.27
  • Another pharmacokinetic study reported the use of 0.8mg/kg body weight of khat in drug-naïve volunteers. The half-life was documented to be 260 plus or minus 102 minutes.11
  • Examination of urine collected from four healthy volunteers at predetermined intervals showed the presence of unchanged cathinone, d-norpseudoephedrine, and two unidentified basic substances. The observed biotransformation of cathinone to the less potent psychostimulant, d-norpseudoephedrine involves reduction of a ketone group to alcohol, a common metabolic pathway in humans.28


References

  1. Kalix, P. Catha edulis, a plant that has amphetamine effects. Pharm World Sci 1996;18(2):69-73. 8739260
  2. Giannini, A. J., Miller, N. S., and Turner, C. E. Treatment of khat addiction. J Subst Abuse Treat 1992;9(4):379-382. 1362228
  3. Giannini, A. J. and Nakoneczie, A. M. Treatment of Khat Addiction with Bromocriptine Mesylate: A Case Report and Review of Cocaine- and Amphetamine-Like Effects. Am J Ther 1995;2(7):487-489. 11850696
  4. Brenneisen, R., Fisch, H. U., Koelbing, U., Geisshusler, S., and Kalix, P. Amphetamine-like effects in humans of the khat alkaloid cathinone. Br J Clin Pharmacol 1990;30(6):825-828. 2288828
  5. Hassan, N. A., Gunaid, A. A., El Khally, F. M., Al Noami, M. Y., and Murray-Lyon, I. M. Khat chewing and arterial blood pressure. A randomized controlled clinical trial of alpha-1 and selective beta-1 adrenoceptor blockade. Saudi Med J 2005;26(4):537-541. 15900355
  6. Hassan, N. A., Gunaid, A. A., Abdo-Rabbo, A. A., Abdel-Kader, Z. Y., al Mansoob, M. A., Awad, A. Y., and Murray-Lyon, I. M. The effect of Qat chewing on blood pressure and heart rate in healthy volunteers. Trop Doct 2000;30(2):107-108. 10842563
  7. Kalix, P., Geisshusler, S., Brenneisen, R., Koelbing, U., and Fisch, H. U. Cathinone, a phenylpropylamine alkaolid from khat leaves that has amphetamine effects in humans. NIDA Res Monogr 1990;105:289-290. 1876014
  8. Kuczkowski, K. M. Herbal ecstasy: cardiovascular complications of khat chewing in pregnancy. Acta Anaesthesiol Belg 2005;56(1):19-21. 15822415
  9. Mion, G., Ruttimann, M., Oberti, M., and Aversenq, C. [Acute Khat-induced psychotic crisis]. Ann Fr Anesth Reanim 1997;16(2):201-202. 9686083
  10. Nencini, P., Ahmed, A. M., Amiconi, G., and Elmi, A. S. Tolerance develops to sympathetic effects of khat in humans. Pharmacology 1984;28(3):150-154. 6718481
  11. Widler, P., Mathys, K., Brenneisen, R., Kalix, P., and Fisch, H. U. Pharmacodynamics and pharmacokinetics of khat: a controlled study. Clin Pharmacol Ther 1994;55(5):556-562. 7910126
  12. Belhadj-Tahar, H. and Sadeg, N. Methcathinone: a new postindustrial drug. Forensic Sci Int 10-4-2005;153(1):99-101. 15919169
  13. Kalix, P. Khat, an amphetamine-like stimulant. J Psychoactive Drugs 1994;26(1):69-74. 7913130
  14. Kalix, P. Cathinone, a natural amphetamine. Pharmacol Toxicol 1992;70(2):77-86. 1508843
  15. Patel, N. B. Mechanism of action of cathinone: the active ingredient of khat (Catha edulis). East Afr Med J 2000;77(6):329-332. 12858935
  16. Randall, T. Khat abuse fuels Somali conflict, drains economy. JAMA 1-6-1993;269(1):12, 15. 8416391
  17. Nasher, A. A., Qirbi, A. A., Ghafoor, M. A., Catterall, A., Thompson, A., Ramsay, J. W., and Murray-Lyon, I. M. Khat chewing and bladder neck dysfunction. A randomized controlled trial of alpha 1-adrenergic blockade. Br J Urol 1995;75(5):597-598. 7613796
  18. Al Motarreb, A. L. and Broadley, K. J. Coronary and aortic vasoconstriction by cathinone, the active constituent of khat. Auton Autacoid Pharmacol 2003;23(5-6):319-326. 15255816
  19. Dimba, E. A., Gjertsen, B. T., Bredholt, T., Fossan, K. O., Costea, D. E., Francis, G. W., Johannessen, A. C., and Vintermyr, O. K. Khat (Catha edulis)-induced apoptosis is inhibited by antagonists of caspase-1 and -8 in human leukaemia cells. Br J Cancer 11-1-2004;91(9):1726-1734. 15477863
  20. Murugan, N., Burkhill, G., Williams, S. G., Padley, S. P., and Murray-Lyon, I. M. The effect of khat chewing on gallbladder motility in a group of volunteers. J Ethnopharmacol 2003;86(2-3):225-227. 12738091
  21. Al Zubairi, A., Al Habori, M., and Al Geiry, A. Effect of Catha edulis (khat) chewing on plasma lipid peroxidation. J Ethnopharmacol 2003;87(1):3-9. 12787947
  22. Adeoya-Osiguwa, S. A. and Fraser, L. R. Cathine and norephedrine, both phenylpropanolamines, accelerate capacitation and then inhibit spontaneous acrosome loss. Hum Reprod 2005;20(1):198-207. 15513978
  23. Zelger, J. L., Schorno, H. X., and Carlini, E. A. Behavioural effects of cathinone, an amine obtained from Catha edulis Forsk.: comparisons with amphetamine, norpseudoephedrine, apomorphine and nomifensine. Bull Narc 1980;32(3):67-81. 6911034
  24. Heymann, T. D., Bhupulan, A., Zureikat, N. E., Bomanji, J., Drinkwater, C., Giles, P., and Murray-Lyon, I. M. Khat chewing delays gastric emptying of a semi-solid meal. Aliment Pharmacol Ther 1995;9(1):81-83. 7766749
  25. Pehek, E. A. and Schechter, M. D. Discriminative stimulus properties of (+)cathine, an alkaloid of the khat plant. Pharmacol Biochem Behav 1990;36(2):267-271. 2356199
  26. Schechter, M. D. Dopaminergic nature of acute cathine tolerance. Pharmacol Biochem Behav 1990;36(4):817-820. 1977178
  27. Toennes, S. W., Harder, S., Schramm, M., Niess, C., and Kauert, G. F. Pharmacokinetics of cathinone, cathine and norephedrine after the chewing of khat leaves. Br J Clin Pharmacol 2003;56(1):125-130. 12848785
  28. Guantai, A. N. and Maitai, C. K. Metabolism of cathinone to d-norpseudoephedrine in humans. J Pharm Sci 1983;72(10):1217-1218. 6644577




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