The existing data indicate that MDMA produces long-term deficits in markers of 5-HT axon terminals in the rodent brain. Increased cleavage of the cytoskeletal protein tau, impairment of axonal transport, and functional consequences associated with a 5-HT depleting regimen of MDMA support the view that MDMA induces structural brain damage, that is, axonal degeneration. A confluence of oxidative stress and bioenergetic stress induced by MDMA is hypothesized to underlie the process of MDMA neurotoxicity (Fig. 3). The actions of MDMA on the 5-HT transporter to promote free radical formation and/or intracellular calcium may synergize with MDMA-induced disturbances in cellular energetics and hyperthermia to effect selective toxicity to 5-HT axon terminals.