Assessment of the role of α-methylapinine in the neurotoxicity of MDMA

Abstract To assess the potential involvement of metabolism of 3,4-methylenedioxymethamphetamine (MDMA) to the catechol α-methylepinine in producing serotonergic neurotoxicity, we attempted to correlate aspects of this reaction with the neurotoxicity profile of MDMA. In contrast to the stereoselectivity of S -(+)-MDMA in causing persistent declines in rat brain 5-hydroxynidole levels, no stereochemical component to the metabolic reaction was apparent. Rat liver microsomes generated a significantly greater amount of α-methylepinine than did mouse microsomes, but similar amounts of metabolite were produced by brain microsomes from the two species. Formation of α-methylepinine by hepatic, but not brain, microsomes was inhibited by SKF 525A and induced by phenobarbital, possibly indicating a tissue specificity in cytochrome P-450-dependent metabolism of MDMA. To directly assess whether α-methylepinine is a likely mediator of MDMA neurotoxicity, the compound was administered intracerebroventricularly. No persistent declines in biogenic amines or their metabolites were observed one week following treatment. These data suggest that α-methylepinine alone is not responsible for the neurotoxic effects of MDMA.