Long-lasting depletion of dopamine and concomitant loss of dopamine uptake sites follow repeated administration of methylamphetamine to rats. We found similar effects after similar treatment with d-amphetamine, but not after treatment with methylphenidate. Methylphenidate also failed to produce long-term depletion of regional catecholamine levels in rhesus monkeys. These long-lasting alterations of the dopaminergic system suggest that amphetamines or their metabolites have toxic interactions with dopaminergic neurons, which do not occur with methylphenidate.