MDMA TOXICITY - NO EVIDENCE FOR A MAJOR INFLUENCE OF METABOLIC GENOTYPE AT CYP2D6

3,4 Methylenedioxymethamphetamine (MDMA or ecstasy) has become a major drug of abuse over the last decade. It produces a mixture of systemic and neuropsychological effects. Animal studies show a range of short- and long-term toxic effects, both systemically and neurochemically. I n humans, toxicity and death due to the drug have been attributed to a variety of causes, with 'idiosyncratic', or non-dose-related, reactio ns often cited. It has recently been established that MDMA is metaboli zed via the cytochrome P450 enzyme, debrisoquine hydroxylase. This enz yme is coded by the gene CYP2D6. This gene contains mutations which ef fect the function of the enzyme, and individuals homozygous for these mutations are known as poor metabolizers. Between 3 and 10% of the Cau casian population are thus affected, and therefore may be less able to metabolize MDMA. In this paper we examine the hypothesis that individ uals selected on the basis of having had an adverse reaction to MDMA w ill be more likely than the general population to have homozygous muta tions at CYP2D6. We obtained retrospectively seven cases of toxicity o r death thought to be due to MDMA. DNA was extracted from these patien ts, and their genotype ascertained. None of this small sample was show n to be homozygous for the mutation at CYP2D6. Three possible explanat ions are offered for these results. (1) The non-dose-related nature of MDMA toxicity may be due, either alone or in combination, to contamin ants in the drug, or ambient environmental/physiological factors. (2) Our genotyping methods may have missed one of the rare additional muta tions which effect gene function at CYP2D6. (3) Our study sample may b e too small to demonstrate a statistically significant result. A large r study is currently under way.