The long-term use of the serotonin-releaser and uptake-inhibitor 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") has been associated with memory impairments and increased liability to depressive mood and anxiety attacks. It is unclear, however, whether these psychologic deviations are reflected in alterations of the underlying neurophysiologic substrate. The authors compared mood and regional cerebral blood flow (rCBF) profiles between regular polytoxic Ecstasy users and Ecstasy-naive controls. Brain activity as indexed by rCBF was measured during cognitive activation by an attentional task using positron emission tomography and [H2(15)O]. Mood was assessed by means of the Hamilton Rating Scale for Depression (HAM-D) and the EWL Mood Rating Scale. Statistical parametric mapping revealed that brain activity did not differ between the two groups. Both groups also performed equally on the cognitive task requiring sustained attention. However, significantly higher levels of depressiveness as determined by the HAM-D and EWL scales were found in Ecstasy-using subjects. These data indicate that, despite differences in mood, polytoxic Ecstasy users do not differ from Ecstasy-naive controls in terms of local brain activity. Heightened depressiveness in the Ecstasy group was consistent with results from previous studies and could be related to serotonergic hypofunction resulting from repeated MDMA consumption. However, this study cannot exclude the possibility that the observed differences are preexisting rather than a result of Ecstasy use.