Abstract: 3,4‐Methylenedioxymethamphetamine (MDMA) is a popular illicit drug that evokes transporter‐mediated release of serotonin (5‐HT) and dopamine (DA) from nerve cells. Recently, drug users have ingested combinations of the piperazine analogs, 1‐benzylpiperazine (BZP) and 1‐(m‐trifluoromethylphenyl)piperazine (TFMPP), in an attempt to mimic the subjective effects of MDMA. In the present study, we compared neurochemical effects of MDMA, BZP, and TFMPP in rat brain. The ability of MDMA, BZP, and TFMPP to stimulate efflux of [3H]5‐HT and [3H]MPP+ (a DA transporter substrate) was determined in vitro using release assays in synaptosomes. The ability of these drugs to increase extracellular 5‐HT and DA in vivo was assessed using intracranial microdialysis in nucleus accumbens. MDMA stimulated transporter‐mediated release of 5‐HT (EC50= 58 nM) and MPP+ (EC50= 119 nM). BZP was a selective releaser of MPP+ (EC50= 175 nM), whereas TFMPP was a selective releaser of 5‐HT (EC50= 121 nM). MDMA injections (1 and 3 mg/kg, i.v.) increased dialysate 5‐HT and DA in a dose‐related manner, but actions on 5‐HT were predominant. BZP (3 and 10 mg/kg, i.v.) elevated dialysate DA and 5‐HT, while TFMPP (3 and 10 mg/kg, i.v.) elevated only 5‐HT. The coadministration of BZP plus TFMPP (BZP/TFMPP) produced marked elevations in extracellular 5‐HT and DA that mirrored the effects of MDMA. At the high dose of BZP/TFMPP (10 mg/kg, i.v.), the rise in dialysate DA exceeded the summed effects of the drugs alone. Our results support the hypothesis that the BZP/TFMPP combination mimics the neurochemical mechanism of MDMA, providing a basis for recreational use of these agents. Additionally, the findings suggest possible drug‐drug synergism when piperazine drugs are coadministered at high doses.