The effect of varying the dose and frequency of administration of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') on both the acute hyperthermic response and the long term neurodegeneration of 5-hydroxytryptamine (5-HT) nerve terminals in the brain has been studied in Dark Agouti rats. A single injection (4-15 mg/kg i.p.) of MDMA produced immediate dose-related hyperthermia and a dose-related decrease in 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and [3H]paroxetine binding in regions of the brain 7 days later, with a dose of 4 mg/kg having no degenerative effect. This dose was also without effect when given once daily for 4 days, but produced a marked loss of [3H]paroxetine binding and indole concentration ( approximately 55%) when given twice daily for 4 days. When a dose of 4 mg/kg was given twice weekly for 8 weeks it had no effect on these serotoninergic markers, despite a clear anorectic effect of the drug being seen. These data demonstrate that MDMA-induced neurodegeneration is related to both the dose and frequency of administration and indicate that damage to 5-HT neurones can occur in the absence of a hyperthermic response to the drug. We suggest that damage occurs when endogenous free radical scavenging mechanisms become overwhelmed or exhausted.