Involvement of the glutathione antioxidant system is a characteristic feature of oxidative stress. We examined the influence of binge (4 x 20 mg/kg every 5 h) and chronic daily (20 mg/kg per day for 10 days) administration of methamphetamine (MA) on brain levels of total glutathione and major glutathione-related enzymes (glutathione peroxidase and reductase; gamma-glutamyltranspeptidase; glucose-6-phosphate dehydrogenase) in the rat. Binge, but not chronic MA administration was associated with a regionally specific reduction (-17%, P < 0.05) in striatal levels of glutathione 3 h after the last dose of MA, whereas striatal levels of the glutathione-related enzymes were normal. Although the magnitude of the reduction was only modest, these data are compatible with a more severe glutathione decrease localized to dopamine/serotonin nerve terminal areas. Our observations provide further evidence in support of the oxidative stress hypothesis of MA neurotoxicity and indirectly suggest that drugs designed to increase glutathione might protect against such damage.