In a recreational use of 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”), some but not all users are stricken with a serious serotonin (5-hydroxytryptamine; 5-HT) syndrome. This raises a question as to whether there exist subpopulations that are more susceptible to MDMA intoxication. The hypothesis was tested with hyperthyroid versus euthyroid rats by measuring changes in body-core temperature (Tcor) and 5-HT in the hypothalamus. In the euthyroid rats, injection of MDMA at a recreationally relevant dose had no serious effect on Tcor. In contrast, the same dose was sufficient to evoke life-threatening hyperthermia in hyperthyroid rats. Neurochemical studies revealed that there was greater 5-HT efflux in the hyperthyroid than the euthyroid rats. These effects were blocked by pretreatment with M100907, a 5-HT2A receptor antagonist. In summary, our data support the hypothesis that individuals with hyperthyroidism are more susceptible to having a serious serotonin syndrome following MDMA administration.