Ecstasy (MDMA) street tablets often contain several other compounds in addition to MDMA, particularly caffeine. Then, it becomes necessary to study the consequences of caffeine plus MDMA combination. MDMA (1 mg/kg) elicited an analgesic response both at the spinal and supraspinal levels. However, when associated, MDMA and caffeine did not show any synergistic interaction. When caffeine was administered prior to MDMA, a potentiation of locomotor activity was observed, which consisted in an increase in maximal values and in a prolonged time of activity. In the neurotoxicity studies, a hyperthermic effect of MDMA was observed. Although caffeine alone failed to alter body temperature, it potentiated MDMA-induced hyperthermia. This association also significantly increased MDMA lethality (from 22% to 34%). Following administration of MDMA to rats, there was a persistent decrease in the number of serotonin transporter sites in the cortex, striatum and hippocampus, which was potentiated by caffeine co-treatment. This MDMA toxicity in rats was accompanied by a transient dopaminergic impairment in the striatum, measured as decreased [(3)H]WIN35428 binding sites, by 31% 3 days after treatment, which was not modified by caffeine. A transient down-regulation of 5-HT(2) receptors occurred in the cortex of MDMA-treated rats, whose recovery was slowed by co-treatment with caffeine. In conclusion, the association of MDMA with caffeine does not generate any beneficial effects at the antinociceptive level. The acute effects stemming from this association, in tandem with the final potentiation of serotonergic terminals injury, provide evidence of the potentially greater long-term adverse effects of this particular recreational drug combination.