Duration of neuroprotective effects produced by two SSRIs, fluoxetine and fluvoxamine, was examined by giving Dark Agouti rats injections of fluoxetine concurrently with MDMA or 2, 4 or 7 days pre-MDMA and by giving other rats fluvoxamine concurrently with MDMA or 24 h prior to MDMA. All rats were sacrificed 7 days post-MDMA, and concentrations of 5-HT, MDMA, fluoxetine and fluvoxamine in brain were measured. Binding to the serotonin transporter was also measured, and studies using a different group of rats examined the effects of fluoxetine on cortical MDMA concentration. Fluoxetine continued to attenuate MDMA-induced reductions in 5-HT and metabolites, even 7 days prior to MDMA, but fluvoxamine only attenuated MDMA-induced reductions in 5-HT when given immediately prior to MDMA. This is significant because fluoxetine and its primary metabolite norfluoxetine have long half-lives, while fluvoxamine does not. The authors conclude that fluoxetine produces its long-lasting neuroprotection through direct effects on the 5-HT transporter and not by reducing MDMA-induced hyperthermia or by interfering with MDMA metabolism.