Neurotoxicity of XTC: causality, course and clinical relevance
03 / 2001 - unknown
Database Zorg Onderzoek Nederland ZON
There is compelling evidence that the popular recreational drug 3, 4, methyelendioxymethamphetamine (MDMA or 'Ecstasy) is toxic toward brain 5 -HT neurons in animals and non human primates at doses that overlap those used by humans. The last couple of years, we and others have accumulated evidence indicating that human XTC users may incur MDMA related 5-HT neurotoxic injury/ brain pathology, 4,5 and possibly, functional seqeulae. 5,8 However, despite the vastly growing scientific lieterature on XTC's effects in the human brain, some crucial questions regarding the causality, course and clinical relevance of XTC's neurotoxicity have not been answered. .6,8 Objectives To come to scientific sound conclusions regarding the neurotoxicity of XTC that can be validly used in prevention messages, clinical decision making and the development of a national XTC policy. Primary objectives 1. to study the causality of XTC use and observed brain pathology in humans 2.to study the course of XTC use and observed brain pathology in humans 3.to study the clinical relevance of observed brain pathology in people who use XTC Secondary objectives 1. To study the dose response characteristics of XTC in the production of brain pathology 2.To study the vulnerability and protective factors in the causation of brain pathology among XTC users 3.To study the risk of neurotoxicity when XTC is used in combination with other drugs of abuse 4.To study the presence of functional or structural damage to neurotransmitter systems other than 5HT following XTC exposure The present proposal aims to investigate the causality, course and clinical relevance of the observed neurotoxicity in the human brain among users of the popular recreational drug, 3,4 -methylenedioxymethamphetamine (MDMA). Studies in animals and non-human primates suggests 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 havebeen 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 as 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 naïve coffee shop visitors with a two year follow up of 50 incident-, and 50 continuously XTC naïve subjects, and a retrospective study of 50 subjects with and 50 without prior exposure to XTC selected from a large representative cohort of adolescents (n=1600) that was prospectively followed from the age of 12. Among the 50 incident cases and the sample of 50 continuously XTC naïve 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 use has taken place in the incident cases. In the retrospective cohort, subjects with life-time XTC exposure will be compared with XTC naïve subjects on the same neurotoxicity, neural injury and psychopathology parameters, controlling for potential confounders that were assessed prior to the first use of XTC. The combined results will result in conclusions that can be validly used in prevention messages, clinical decision making and the development of a national XTC policy.