3,4-Methylenedioxymethamphetamine (MDMA) has been reported to cause hyponatraemia, which appears to result from inappropriate secretion of the antidiuretic hormone arginine vasopressin (AVP). After administration of a low dose of (R,S)-MDMA (40 mg) to eight healthy drug-free male volunteers, concentrations of AVP in plasma increased significantly at 1, 2, and 4 hours. Although no relation between plasma MDMA and AVP was found on an examination of the entire data set over the 24-hour study period, a statistically significant negative correlation was observed at 1 hour. As this occurred at a time when both AVP and MDMA concentrations were rising, it was postulated that a metabolite, or metabolites, could primarily be responsible for the increase in AVP. To test this hypothesis we examined the effect of MDMA and five of its metabolites, in the dose range 0.1-1,000 nM, on AVP release from the isolated rat hypothalamus. All compounds tested were found to increase AVP release (using 10 nM and 1,000 nM concentrations), with 4-hydroxy-3-methoxymethamphetamine (HMMA), the major metabolite of MDMA, being the most potent, and 3,4-dihydroxymethamphetamine (DHMA) the least potent. Each compound (1,000 nM), with the exception of DHMA, also enhanced the response to 40-mM potassium stimulation. Our findings confirm that metabolites of MDMA, in addition to the parent drug, contribute to AVP secretion in vitro. Further work will demonstrate whether this is also true in vivo.