3,4-Methylenedioxymethamphetamine (MDMA), known on the street as """"""""Ecstasy"""""""", is reported to be increasingly popular among student and young professionals. Abuse of this Schedule 1 drug is a serious health concern because MDMA is known to be neurotoxic in laboratory animals. The mechanism of MDMA's neurotoxicity has not been determined, although it has been suggested that metabolites of the drug may be responsible. For these reasons, we undertook a study of the metabolism of MDMA and have succeeded in identifying seven previously unreported metabolites in the rat. We propose to continue our investigation of the metabolism of MDMA with particular emphasis on metabolites generated in the rat brain and in the 10,000 x g supernatant from human liver tissue obtained during autopsy. We will also investigate whether the neurotoxicity of MDMA is due to reactive metabolites of MDMA, or to further aromatic oxidation of neurotransmitters to neurotoxins. Successful completion of these studies will require ultra-sensitive mass spectrometric techniques. Recent research in our laboratory and in others has shown that the ion trap mass spectrometer has exceptional sensitivity in both the electron ionization (El) and chemical ionization (Cl) modes of operation. Furthermore, sequential mass analyses (MS/MS) can be performed with higher efficiencies than are normally achieved with other types of mass spectrometers. However, in order to fully exploit the potential of this instrumentation for biochemical research, it will be necessary to better define optimum operational parameters, and to develop procedures for optimal sample preparation and sample introduction. Therefore, we propose to develop and apply specific ion trap mall spectrometric techniques for ultra-sensitive detection and measurement of MDMA and its metabolites in brain and liver tissues. The analytical methods to be developed will be applicable to many related areas of pharmacological and toxicological research.
