The study aims to investigate the causality, course and clinical relevance of the observed neurotoxicity in het human brain among users of the popular recreational drug 3,4-methylenedioxymethamphetamine (MDMA). Studies in animals and non-human primates suggest that MDMA is toxic toward brain serotonin neurons at doses that overlap those used by humans. Much less is known about the effects of this drug on the human brain. Recent studies, however, suggest that MDMA might also be neurotoxic to 5-HT neurons in humans, and that it is associated with functional consequences, such as memory impairment and depression. However, these studies have been retrospective and potentially vulnerable to selection bias and confounding. Clearly, only a prospective study can ascertain that recreational XTC is neurotoxic in humans. However, given the existing data such a study is ethically not acceptable. In the present project, therefore, we have chosen a naturalistic study using a combination of prospective and retrospective approaches: a prospective study among 200 XTC naive subjects with a high-risk profile for first XTC use with a two-year follow up of 50 incident-, and 50 continuously XTC naive subjects, and a retrospective design of 25 subjects with and 25 subjects without prior exposure to XTC selected from a large representative cohort (N=1600) that was prospectively followed from the age of 12. In addition, a cross sectional design is used of 70 subjects with variation in type and amount of drugs used, besides a history of frequent XTC use. Among the 50 incident cases and the sample of 50 continuously XTC-naive subjects in the prospective cohort, indicators of neurotoxicity (SPECT,1H-MRS), markers of neuronal injury (fMRI, Perfusion MRI), and clinical assessments of memory, mood and personality prior to any XTC use will be compared with the same parameters two years later, i.e. after XTC user has taken place in the incident cases. In the retrospective cohort, subjects with lifetime XTC exposure will be compared with XTC naive subjects on the same neurotoxicity, neural injury and psychopathology parameters, controlling for potential confounders that were assessed prior to the first use of XTC. In the cross sectional cohort, all subjects will be assessed on the same neurotoxicity, neural injury and psychopathology parameters, controlling for the confounding effects of the use of other psychoactive drugs besides XTC. The combined results will result in conclusions that can be validly used in prevention messages, clinical decision making and the development op a national XTC policy.