On the mechanisms underlying 3,4-methylenedioxymethamphetamine toxicity: the dilemma of the chicken and the egg

Administration of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) to various experimental animals has been shown to induce a selective damage to serotonergic axon terminals. While a great consensus appears to exist regarding the causative role of reactive oxygen species (ROS) in the mechanisms underlying MDMA toxicity, the source of free radicals is still a matter of debate. While some authors support dopamine metabolism/oxidation inside 5-hydroxytryptamine (5-HT) terminals as the key factor responsible for ROS formation and final 5-HT terminal degeneration, others believe it is MDMA metabolism into pro-oxidant compounds. Although at first sight both hypotheses appear to contend with each other, it may not be the case. This mini-review was therefore undertaken to try to reconcile both hypotheses and to address the dilemma of the causality of MDMA neurotoxicity.