The most important goal of this meeting is to reach a conclusion about an old age problem; is the abuse of khat drug addiction or not? To solve this problem we have to deal with the medical and socio-economic consequences of khat consumption. In other words with the two basic aspects of any drug addiction. In the case of khat, these two aspects are linked. In fact, the high price of khat and the loss of working time reduce the income of the consumer' s family. This means that people may not have enough money to spend on food and therefore malnutrition may develop.

 

But besides this, addiction by itself is a medical problem, defined by the acute and pharmacological effects of drugs. And so, if we want to put khat into the class of drugs which induce addiction, we have to study, whether khat meets the criteria for such classification today.

In other words, we have to measure the acute and chronic pharmacological effects of khat, and especially to see if the chronic consumption of khat induces tolerance and if a withdrawal syndrome develops, when consumption is stopped.

 

To date, studies of clinical pharmacology designed to answer these questions are lacking and the clinical profile of the khat chewer is merely inferred from occasional case histories. We began to cover this field, by comparing the effects of the chewing of standard doses of khat, in habitual consumers and khat-naive subjects living in Mogadishu , ( Somalia) .

 

Regarding the choice of parameters, the presence of khat of phenylalkylamine compounds has directed our attention towards the pharmacology of amphetamines. In fact, there is no doubt that cathinone , the most active phenylalkylamine of khat is an amphetamine-like agent and the scantly clinical observations suggest that khat chewing has pharmacological effects reminiscent of amphetamine actions (1) . Accordingly, we would expect sympathetic tone to increase. Therefore we have studied physiological parameters controlled by the symphathetic system. They were : blood-pressure, pulse and respiratory rates, and body temperature. The sympathetic activity was further checked by determining the urinary levels of catecholamines and vanilmandelic acid.

 

Moreover, as one of the outstanding neuropharmacological effects of khat chewing is anorexia, we have also studied the changes in plasma levels of hormones involved in the regulation of feeding. Among these hormones, we have chosen beta-endorphin, corticotropin , growth hormone and prolactin.

 

Sympathetic activity: 

 

In basal conditions, physiological parameters examined were not statistically different in habitual consumers and naives. This probably means that a chronic, but moderate consumption of khat neither affects basal sympathetic tone permanently, nor induces the overshoots characteristics of the withdrawal syndrome.

 

However, khat chewing acutely affects several of the parameters studied; systolic, diastolic and mean blood pressure, as well as respiratory rate, significantly increased in both groups (Tab.1).The peak effect was reached 3 and 1/2 hours after the beginning of khat chewing and the morning following the test, effects, as a whole were over.

It is interesting to observe that, whereas habitual consumers received two bundles of khat (about 200 g),naives received only one bundle, because in a pilot test this dose was enough to induce a worrying increase of blood pressure in a naive volunteer. Nevertheless, the sympathetic activation was higher in naives and in the case of diastolic pressure and respiratory rate differences between the two groups were significant. Moreover, axillary temperature only increased in naives, whereas pulse rate slowed in this group, probably as a result of a reflex mechanism.

 

Laboratory findings confirm physiological results. In fact, urinary catecholamines increased during the test and again, values in naives were higher than in consumers. It is quite surprising that vanilmandelic acid levels did not rise, but actually decreased. A possible explanation of this finding is that something in khat induces an inhibition of monoamino-oxidase activity. It is worth noting that amphetamines too, are inhibitors of monoamino-oxidase enzymes.

 

In brief, physiological data and laboratory findings support the view that khat induces a sympathetic activation, but, in contrast with previous observations (2), tolerance to this effect seems to develop.

 

Neuroendocrine effects: 

 

As already recalled, another pharmacological effect of amphetamines shared by khat is anorexia. Mechanism of feeding control are very complex, involving monoaminergic and peptidergic pathways, which have their regulatory centres in the hypothalamus. Even though changes in blood concentrations of hormones or neuromediators do not necessarily reflect changes in their hypothalamic concentrations, it has been found that in obesity plasma levels of hormones, such as beta-endorphin, prolactin and growth hormone, rise (3). Likewise, anorectic drugs of the amphetamine-type affect the incretion of some of these hormones(4).

 

Khat also seems to have neuroendocrine effects (Tab.2). In fact, plasma concentration of ACTH significantly increased during the test in both groups. This effect agrees with the proposed amphetamine-like activity of khat, because the enhancement of ACTH and cortisol incretion is one of the most evident feature of amphetamines.

Also immunoreactive beta-endorphin, the other hormone derived from pro-opimelacortin, significantly increased but only in the group of habitual consumers. On the contrary, it fell to indetectable levels in all the naive subjects, when the peak of physiological effects of khat was reached, namely 3 and 1/2 hours from the beginning of chewing.

 

If we assume that khat is an amphetamine-like drug, the finding that it inhibits beta-endorphin incretion in naive subjects is in conflict with the observation that d-amphetamine infusion in normal humans induces an increase of plasma beta-endorphin. A possible explanation may take into account the fact that adenohypophysial incretion of beta-endorphin is controlled in the opposite way by mono-aminergic neuromediators. In fact there is evidence that dopaminergic agents inhibit (5), whereas alpha-adrenergic (6) and serotoninergic (7) drugs increase beta - endorphin incretion. Perhaps khat in naives inhibits beta-endorphin incretion by an increase of dopaminergic tone, because cathinone induces dopamine release (8). In chronic consumers, tolerance develops to the dopaminergic effect and an increase of beta-endorphin incretion appears, as a result of khat mechanisms refractory to tolerance (i.e.: alpha-adrenergic or serotoninergic actions). Of course, more data are needed to support this suggestion.

 

Another endocrine effect of amphetamine shared by khat is the increase in plasma concentration of growth hormone. This increase was again significant only in the group of khat-naives. Khat chewing does not, however, seem to affect prolactin plasma levels significantly. Amphetamines too are devoid of effects on prolactin incretion in humans.

 

Conclusions:

 

There is no doubt that khat consumption is followed by physiological and neuroendocrine changes. In other words, khat has specific pharmacological effects in humans and, on the whole, these effects appear to be of amphetamine-like type as shown in Tab.3.

Moreover, from this study we can infer that tolerance develops to pharmacological effects of khat, even if some caution is needed. In fact, as we realize that the parameters examined in this study are also markers of stress, we may argue that they changed more in naives because these subjects found the test stressful. On the other hand in both groups the peak effect was reached 3 and 1/2 hours after the beginning of chewing and this delay is more likely to reflect pharma-

cological latency than stress evolution. We hope that more insight into this Koblem will come from the pharmacokinetic studies now in progress in our laboratory.

However, tolerance to amphetamine actions does develop and so it is not surprising if tolerance to khat actions develop too.

 

This study did not give evidence of a withdrawal syndrome, because there were no differences between consumers and naives with regard to their basal conditions, and because consumers did not show a rebound of the parameters studied on the morning following the test.

However , we consider our data inconclusive from this point of view , because subjects in the study were not very heavy consumers and because a careful follow-up of hospitalized consumers is needed to give evidence of an abstinence syndrome, which is probably not easily recognizable.

 

As a whole, our clinical data show that khat abuse is not far from amphetamine addiction from a qualitative point of view .

There is one aspect of khat abuse that our work did not deal with. I am referring to neuropsychopharmacological effects of khat. It is well known that chronic abuse of amphetamines induces dyskinesias and toxic psychosis. Does the same thin happen in heavy consumers of khat? I think that an answer to this question is mandatory to decide if khat is a recreational item or a drug dangerous for health and society.

Finally, there is another aspect of khat which is worth mentioning. To date, research on khat has followed the methodology used to study amphetamines and actually we have found that khat is an amphetamine. But there are several other substances in khat, which may have different, and possibly therapeutically useful, pharmacological activities. I think that pharmacologists would be glad if research chemists provided them with these substances.

 

Acknowledgements. 

 

These studies have been carried out at the Institute of Medical Pharmacology of the University of Rome and at the Department of Pharmacology of the University of Mogadishu. They were financed by a grant from the Italian Ministry of Foreign Affairs.

 

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