MDMA and its congeners MDA, MDEA (MDE) and MDBA (MBDB) were compared through in vivo and in vitro studies with rat synaptosomes. 2 ml/kg drug (saline, MDMA, MDE or MBDB) was administered i.p. twice daily for 4 days. MDMA and MDE produced locomotion, stereotypy, head weaving, Straub tail and rearing, with MDE less potent than MDMA, while MBDB did not produce any of these behaviors. Only MDMA induced significant weight loss. MDMA and MDE produced hyperthermia, (MDMA > MDE) with body temperature measured via ear temperature probe, but MBDB did not induce hyperthermia. MDMA significantly reduced [3H]-paroxetine binding in frontal cortex, striatum, hippocampus and amygdala, and MDE reduced paroxetine binding in frontal cortex and striatum. MBDB failed to reduce [3H]-paroxetine binding in any brain area studied. Measures of brain 5-HT and 5-HIAA content found similar patterns, with MDMA > MDE > MBDB. In vitro studies using 5 mg/kg - 20 mg/kg of each drug (MDA, MDMA, MDE and MBDB) found that MDA, MDMA and MDE all released an equal amount of 5-HT from synaptosomes, but that a greater amount of MBDB was needed to release 5-HT, and that MBDB did not release as much 5-HT. MDA and MDMA released more dopamine than MDE or MBDB, with MDA > MDMA > MDE = MBDB, and dopamine release was temperature-dependent. These findings lend support to the view that both 5-HT and DA release are required to produce at least some of the behavioral and neurotoxic effects of MDMA.