3,4-Methylenedioxymethamphetamine (MDMA) is an illegal drug that can induce life-threatening hyperthermia. No effective pharmacological treatment for MDMA-induced hyperthermia has yet been established. We investigated the effects of memantine, a non-competitive N-methyl-D-aspartate (NMDA)-type glutamate receptor antagonist and an α-7 nicotinic acetylcholine receptor (nAChR) antagonist, on MDMA-induced hyperthermia in rats. Treatment of animals with memantine (10 or 20 mg/kg) either before or after MDMA (10 mg/kg) administration significantly decreased the peak body temperature. Results from our microdialysis study indicated that pretreatment with memantine (20 mg/kg) before MDMA administration had no effect on the MDMA-induced increase in serotonin (5-HT) and dopamine (DA) levels in the anterior hypothalamus. MDMA-induced hyperthermia was significantly suppressed by pretreatment with the non-competitive NMDA receptor antagonist MK-801 (0.5 mg/kg) and the competitive NMDA antagonist CGS 19755 (5 mg/kg), but not by the selective α-7 nAChR antagonist methyllycaconitine (6 or 10 mg/kg). These results indicate that the inhibitory effect of memantine on MDMA-induced hyperthermia may be due to its activity as an NMDA receptor antagonist and not as a result of a direct effect on the 5-HT or DA systems. The present study suggests that moderate doses of memantine may be useful for the treatment of MDMA-induced hyperthermia in humans.