In this study we examined the effects of methylenedioxymethamphetamine (MDMA) administration on responsiveness to an in vivo immune challenge with lipopolysaccharide (LPS; 100 mu g/kg; i.p.). LPS produced an increase in circulating IL-1 beta and TNF-alpha in control animals. MDMA (20 mg/kg; i.p.) significantly impaired LPS-induced IL-1 beta and TNF-alpha secretion. The suppressive effect of MDMA on IL-1 beta secretion was transient and returned to control levels within 3 hours of administration. In contrast, the MDMA-induced suppression of TNF-alpha secretion was evident for up to 12 hours following administration. In a second study we examined the effect of cu-administration of MDMA (5, 10 and 20 mg/kg; i.p.) on LPS-induced IL-1 beta and TNF-alpha secretion, and demonstrated that all three doses potently suppressed LPS-induced TNF-alpha secretion, but only MDMA 10 and 20 mg/kg suppressed LPS-induced IL-1 beta secretion. In addition, serum MDMA concentrations displayed a dose-dependent increase, with the concentrations achieved following administration of 5 and 10 mg/kg being in the range reported in human MDMA abusers. In order to examine the possibility that the suppressive effect of MDMA on IL-1 beta and TNF-alpha could be due to a direct effect of the drug on immune cells, the effect of in vitro exposure to MDMA on IL-1 beta and TNF-alpha production in LPS-stimulated diluted whole blood was evaluated. However IL-1 beta or TNF-alpha production were not altered by in vitro exposure to MDMA. in conclusion, these data demonstrate that acute MDMA administration impairs IL-1 beta and TNF-alpha secretion following an in vivo LPS challenge, and that TNF-alpha is more sensitive to the suppressive effects of MDMA than is IL-1 beta. However the suppressive effect of MDMA on IL-1 beta and TNF-alpha could not be attributed to a direct effect on immune cells. The relevance of these findings to MDMA-induced immunomodulation is discussed. (C) 2000 Elsevier Science Inc. All rights reserved.