The role of anti-oxidants in MDMA-induced dopaminergic neurotoxicity in mice was investigated in male BALB mice by comparing mice given sufficient vitamin E (dietary antioxidant) with nice given a vitamin-E deficient diet. Mice were either given 4 s.c. injections saline, 5 mg/kg or 10 mg/kg S(+)-MDMA every 2 h, and neurotransmitters, alpha-tocopherol, glial fibrillary acidic protein (GFAP), protein thiols and total anti-oxidant reserve were measured in brains taken 72 h after S(+)-MDMA. Liver cells and presence of glutothione (GSH), protein thiols, alpha-tocopherol and total antioxidant reserves were also measured in livers taken 72 h after S(+)-MDMA. Neurotransmitters and alpha-tocopherol were assayed via HPLC, GFAP was assayed through immunoassay, liver cells were examined visually, glutothione and protein thiols were assayed via fluorescence assay and total anti-oxidant reserve was assayed via chemiluminescence assay. A vitamin-E deficient diet reduced glutothione and total anti-oxidant reserve in both brain and liver, but this diet did not reduce striatal DA. D-MDMA reduced striatal DA and elevated GFAP in all mice, with the reduction dose-dependent (greater with a higher dose). Reduction in striatal DA and elevation in GFAP after S(+)-MDMA was greater in vitamin-E deficient mice than in vitamin-E sufficient mice. Given alone, S(+)-MDMA reduced vitamin E, total anti-oxidant reserve and protein thiols in brain of vitamin-E sufficient mice, and S(+)-MDMA non-significantly decreased glutothione levels. In liver from vitamin-E sufficient controls, S(+)-MDMA dose-dependently reduced total anti-oxidant reserve and glutothione, but not liver vitamin E or protein thiols. While S(+)-MDMA decreased total anti-oxidant reserve in brain and liver of vitamin-E deficient mice, S(+)-MDMA did not lower brain vitamin E, glutothione or protein thiol levels any farther than the reduction produced by vitamin E deficiency alone. Since dietary deficiency severely lowered liver vitamin E, any further reduction produced by S(+)-MDMA was undetectable. 10 mg/kg, but not 5 mg/kg S(+)-MDMA produced greater hyperthermia in vitamin-E deficient mice compared with vitamin-E sufficient controls. Vitamin E deficiency altered liver cytoarchitecture in only one case, and produced a dose-dependent increase in micro-vesicles replacing cytoplasm of hepatocytes. However, when 10 mg/kg S(+)-MDMA was given to vitamin E-deficient mice, signs of frank necrosis and greater areas of micro-vesicles. These findings suggest that, perhaps through impairing the ability to combat oxidative stress, vitamin E deficiency may exacerbate the effects of MDMA in brain and liver, perhaps with a greater additive effect on liver than brain. Liver damage has been reported to occur in ecstasy users. If generalized to humans, study findings suggest that nutritional deficiencies in humans, and specifically vitamin E deficiency, may play some role in the induction of liver problems appearing after ecstasy use. It should be noted that humans administer racemic MDMA, and not one enantiomer only. It is possible that the R-(-)MDMA might attenuate the effects of the more active enantiomer (S-(+)-MDMA) on oxidative stress in liver and other tissues.