REVIEW ARTICLE

Effect of Khat on the Heart and Blood Vessels

Al-Motarreb Ahmed, MD, FGHA*
Cardiac Centre, Al-Thawra Hospital, Faculty of Medicine and Health Sciences
Sana'a University, Sana'a -Yemen

Keywords: khat, amphetamine, cathinone, and acute myocardial infarction

Introduction

Khat-chewing is a common habit in Yemen and East African Countries. Millions of people chew Khat leaves every day. We do not have the exact figure of the prevalence of the khat-chewing habit in the society. Al-Motarreb et al1 studied the effect of khat on acute myocardial infarction (AMI) presentation, and found that among male patients, 83% were khat chewers and 43.7% of female patients were khat chewers also. This suggests that the majority of the society is chewing khat. Female and school age children are increasingly participating in this habit in larger scale than before.

The main effect of khat is an increase in energy, alertness and a feeling of relaxation. The main active substance in Khat is cathinone (alpha-amino-proprophenone). This substance is a potent amphetamine-like compound with a sympathomimetic effect2. 

Khat represents a real medical problem. There are few clinical studies linking khat-chewing and diseases in different organ systems. Khat-chewing has been suggested in modifying the circadian rhythm in acute myocardial infarction3,1. 

This is may be due to its effect on increasing blood pressure and heart rate4,5,6. These effects may precipitate AMI, just like amphetamine. 

Since khat chewers like closed and warm rooms, the habit promotes active and passive smoking, and lack of physical activity. It also causes nervous tension, lack of concentration, irritability and Insomnia3. 


Khat as a social problem

Everyone in Yemen knows that khat is a social, financial and medical problem. Like any habit, chewers try to find excuses for their habit but they know for sure that khat-chewing is not a good habit. Unfortunately, khat chewing has a strong influence in the life of the society7. Too much time is spent buying khat leaves and chewing sessions last up to 6 hours or more. This comes at the expense of work time and family time. The price of khat varies according to the type; good quality is expensive. Sometimes, the daily cost of khat exceeds the expenditure on food for the family. 

Women have their own khat sessions; they have started to chew khat more than before8. This takes too much time away from the children as women do not take their kids to the khat session. They leave their children with someone else to look after them. This affects the relationship between the mothers and their children9. Khat chewing has a negative impact on work, children, health and the whole family.

Constituent of Khat leaves

There are three main alkaloids present in khat leaves: Cathinone, cathine and ephedrine10,2. Cathinone is the main active substance in khat leaves6. Cathinone is amphetamine-like substance that release endogenous catecholamines from peripheral and central neurones. Cathinone major metabolites are norpseudoephedrine and ephedrine. These two substances have weaker sympathomimetic activities and central stimulant properties. Cathinone is responsible for the CNS effect of khat while norpseudoephedrine is responsible for its peripheral effects10.


Cathinone dependence and tolerance

Cathinone is the dependence-producing constituent of khat leaves which re-inforces the khat chewer to repeat the habit again11. The idea of dependence and tolerance development is reinforced by the need of the user to secure his daily supply at the expense of his food and family need. Since chewers do not have symptoms of withdrawal when they stop the habit, khat-chewing is not associated with addiction such as in narcotics and alcohol12. But there is psychological dependence since chronic khat chewers have the desire to chew khat leaves when they stop chewing. This can be noticed easily when people go outside Yemen or stop for any other reasons. They do not experience any major symptoms apart from Razem (nightmares), lethargy, and hotness of the lower limbs and a desire to chew khat again12. Tolerance to the central effects of amphetamine and cathinone have been frequently described2.


Action of cathinone

Central effect

The CNS stimulating effect of Khat is mainly due to its cathinone content in the fresh leaves10. Cathinone, like amphetamine, exerts pronounced behavioral effects including euphoria, excitability, hyperactivity and restlessness13,11. Cathinone acts by releasing catecholamines from presynaptic storage sites. It appears to have a similar mechanism of action to that of amphetamine2. Norpseudoephedrine has effects similar to those of cathinone, but it is less potent11.

Cathinone and norpseudoephedrine have the same sympathomimetic effect of Khat if present at the same concentration. However, since Khat leaves contain more norpseudoephedrine than cathinone, the peripheral effect of the leaf is considered to be due to norpseudoephedrine11. Thus, the CNS stimulating effect of Khat is mainly due to its cathinone content in the fresh leaves, while the peripheral sympathomimetic effect is mainly due to norpseudoephedrine and norephedrine10.

Cathinone and amphetamine induce dopamine release from central dopaminergic nerve terminals and this increases the activity of dopaminergic pathways. Cathinone has little effect on brain noradrenaline turnover but increases that of dopamine significantly, although to a lesser extent than amphetamine. Therefore induction of transmitter release at central dopaminergic nerve terminals can be considered the mechanism of action of cathinone13. Cathinone has to penetrate to interneuronal sites in order to develop its release effect. Therefore cathinone acts by inducing release rather than by inhibiting the re-uptake of spontaneously released neurotransmitter2. In slices of rabbit caudate nucleus, cocaine blocked the releasing effect of cathinone almost completely14.

Peripheral effects

On the cardiovascular system, cathinone increases blood pressure, has positive inotropic and chronotropic actions in isolated atria15 and increases heart rate in anaesthetized rats11 and dogs16. Direct vasoconstriction of isolated blood vessels does not appear to have been demonstrated, but there is potentiation of the vasoconstriction due to electrical field stimulation. These studies indicate that the peripheral responses are due to enhanced release of noradrenaline with an action and potency similar to those of amphetamine2.

Cathinone and norpseudoephedrine increase the heart rate and blood pressure with similar potency11. At the peripheral noradrenaline storage site, where cathinone acts like amphetamine, the noradrenaline releasing effect of cathinone was abolished by the noradrenaline reuptake inhibitors, cocaine or desipramine17. Therefore cathinone, like amphetamine, is an indirect acting sympathomimetic2.

Effect of Khat on the heart and blood vessels 

Many reports have linked khat-chewing and its main constituent, cathinone, to systemic hypertension and increased heart rate4-6,16,18,19. These clinical findings were concomitant to the level of cathinone in blood6,19.

Tension, insomnia and lack of physical activity are associated with khat chewing. In addition to the increased desire to smoke cigarettes during the khat session, khat also led to passive smoking as chewers like to be in close and warm rooms3. 

Palpitation, sweating and cold peripheral extremities are also associated with khat-chewing. The mechanism of elevated blood pressure is assumed to be vasoconstriction. Laboratory work in animal blood vessels demonstrated that cathinone and its major metabolite norpseudoephedrine cause dose-related vasoconstriction of the blood vessels. Noradrenaline, the neurotransmitter of cathinone is an indirect sympathomimetic agent and showed a dose-related vasoconstriction of the blood vessels20. All of these effects of cathinone, norpseudoephedrine and noradrenaline contributes to the mechanism of elevated blood pressure observed during and after the khat-chewing sessions in subjects. It also explains the clinical observation of cold extremities of chewers at the end of the khat session21. 

Khat chewing changes the circadian rhythm of acute MI presentation1 where most of the chewers had their heart attack during the khat effective period [1200-2400 hours.] (figure 1) and was an independent dose-related risk factor for acute myocardial infarction22. 

The underlying pathophysiologal mechanisms of the effect of khat on the cardiovascular system were studied. Laboratory evidence was necessary to confirm these effects of khat chewing in the cardiovascular system. Therefore, the effect of khat and its active substance, cathinone, on the cardiovascular system and in particular the coronary vasculature were carried out using a pharmacological technique. The effects of fresh cathinone on the heart muscle and coronary arteries were investigated on guinea pig isolated hearts. Cathinone produced vasoconstriction of the coronary arteries20 (figure 2). These findings are strong evidence to support the clinical observation that khat can produce acute myocardial infarction through coronary spasm. Cathinone has minimal positive chronotropic activity. However, there was pronounced negative inotropy (figure 2) presumably due to impaired coronary perfusion. 

The vasoconstrictor effects of cathinone on coronary arteries were not inhibited by the -adrenoceptor antagonist, prazosin, suggesting that it was not due to a sympathomimetic effect. The mechanism for this vasoconstrictor action remains to be determined.

References
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20. Al-Motarreb A, and Kenneth J Broadley KJ. Coronary and Aortic vasoconstriction by cathinone, the active constituent of khat. Auton Autacoid Pharmacol. 2003;23(5-6):319-26.

21. Al-Motarreb A. Effect of Cathinone on blood vessels; Proceeding in the 4th Yemeni-Italian conference 2004;18-20 January, Sana'a, Yemen.

22. Al-Motarreb A, George SJB.(2004): Khat Chewing is a risk factor for acute Myocardial Infarction; Proceedings Second GCC Cardiovascular Conference, 2004;12-15 January; Muscat Oman.

Correspondence to: Ahmed Al-Motarreb, MD, Cardiac Centre, Al-Thawra Hospital 
Sanaa -Yemen. Tel: 00967-1-246983 / 00967-1-246980. Fax: 00967-1-246971.
E-mail: A.MOTARREB@y.net.ye 

*Fellow Gulf Heart Association (Arabian Gulf)