While the pre-synaptic effects of 3,4-methylenedioxymethamphetamine (MDMA) on serotonin (5-HT) neurons have been studied extensively, little is known about its effects on post-synaptic 5-HT(2) receptors. Therefore, cortical 5-HT(2A) receptor densities and 5-HT concentration were studied in MDMA treated rats (10 mg/kg s.c.). Furthermore, 5-HT(2A) post-synaptic receptor densities in the cerebral cortex of recent as well as ex-MDMA users were studied using [123I]R91150 SPECT. In rats we observed a decrease followed by a time-dependent recovery of cortical 5-HT(2A) receptor densities, which was strongly and positively associated with the degree of 5-HT depletion. In recent MDMA users, post-synaptic 5-HT(2A) receptor densities were significantly lower in all cortical areas studied, while 5-HT(2A) receptor densities were significantly higher in the occipital cortex of ex-MDMA users. The combined results of this study suggest a compensatory upregulation of post-synaptic 5-HT(2A) receptors in the occipital cortex of ex-MDMA users due to low synaptic 5-HT levels.