Over the last 10 years there has been increasing animal evidence of MDMA's neurotoxicity upon serotonergic neurones with consequent worry over the possible functional implications in humans (for reviews see Steele et alM) and Green et al/1,9'). After administration of MDMA, animals have reduced levels of 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid, and tryptophan hydroxylase. Abnormal 5-HT regrowth has been reported after MDMA-induced damage (20) with a decrease in 5-HT terminal density, suggestive of what has been termed a 'chemical axotomy'. Pathological investigations suggest that 5-HT nerve terminals arising from the dorsal raphe nucleus are specifically involved. The duration and magnitude of these neurotoxic effects are dose dependent and are followed by differential rates of recovery, with 5-HT damage persisting for up to a year in the rat, and dopaminergic damage for up to 3 years in the rhesus monkey. (21) These changes appear to be species specific with primates being more sensitive to the neurotoxic damage than rodents.

Early findings suggesting dose-dependent damage led some to believe that human consumption was at such a level as to make such extrapolations to humans inconsequential. More recent research taking into account species scaling indicates that the average single dose size consumed by humans is indeed near to those levels found to be neurotoxic in animals. Early optimism regarding the risks of use were accompanied by initial expectations of low abuse potential. Subsequent reports suggest that although the majority use low levels of the drug, a significant minority use up to five tablets a night with a lifetime consumption of more than 1000 occasions/2) With such levels of self-administration and some users reporting a binge pattern, the cumulative doses are certainly reaching the levels found to be neurotoxic in animals and a dependence syndrome similar to that seen with other stimulant drugs remains a possibility. Since the dopaminergic system is influenced by MDMA, the ventral tegmental dopaminergic reward pathway may underlie any reinforcing potential.

Factors other than dose have been implicated in the pathogenesis of neurotoxicity associated with MDMA and some of these have practical relevance for the social context of human use. Core ambient temperature and hydration status have been implicated as key factors in the development of neurotoxicty and malignant hyperthermia respectively. The drug is usually taken during relentless hours of energetic dancing in crowded and poorly ventilated venues. The users sweat excessively and often make inadequate or inappropriate efforts at rehydration. (Studies on amphetamine aggregation toxicity may be relevant: mice grouped together had enhanced toxic and behavioural effects from amphetamine compared with mice housed alone.) These findings have influenced both public health messages (advising regular isotonic fluid replacement) and the dance club environment with access to 'chill out' rooms and to free water.

The neurochemical mechanism underlying neurotoxicity seems to be dependent upon intact dopaminergic and serotonergic systems since disruption of monoamine transmission in either system protects against MDMA-induced neurotoxicity. Recent studies implicating free radicals in the development of neuronal damage suggest that prior consumption of vitamin C could be protective.

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