Drugs of abuse, such as 3,4-methylenedioxymethamphetamine (MDMA), often have more powerful effects during states of increased activation and under specific environmental conditions. Because hyperthermia is a major complication of MDMA use and a factor potentiating neurotoxicity, we examined the effects of this drug (9 mg/kg, sc; approximately one-fifth of the known LD50 in rats) on brain [nucleus accumbens (Nacc) and hippocampus (Hippo)] and muscle (musculus temporalis) temperatures in male rats under conditions that either model human drug use (social interaction with female, warm temperature) or restrict heat dissipation from the brain (chronic occlusion of jugular veins). Under quiet resting conditions at 23 °C, MDMA induced a moderate but prolonged hyperthermia. Both NAcc and Hippo showed more rapid and stronger temperature increases than muscle, suggesting metabolic neural activation as a primary cause of brain hyperthermia. During social interaction with a female, brain hyperthermia induced by MDMA was significantly potentiated (+89%). Brain hyperthermia induced by MDMA was also strongly potentiated (+188%) in animals with chronically occluded jugular veins, suggesting impaired cerebral outflow enhances intrabrain heat accumulation. At 29 °C, MDMA pushed temperatures in the brain to its biological limits (>41 °C; +268%), resulting in fatalities in most (83%) tested animals. Therefore, by inducing metabolic brain activation and restricting heat dissipation, MDMA use under ‘party’ conditions may be much more dangerous than under standard laboratory conditions.