Nine informed volunteers having previous experience with self-administered drugs were given small, frequent orally administered doses of dextroamphetamine sulfate. Within five days following supervised administration, eight subjects experienced a paranoid psychosis which rapidly abated with drug discontinuance. Factors such as sleep deprivation, predrug personality, or drug idiosyncrasy which have been thought crucial in the origin of amphetamine paranoia proved to be insufficient as explanations for the psychosis. Surprisingly, it was found that large long-term doses of dextroamphetamine caused the subjects to feel depressed rather than elated. This suggests that while the short-term effects of dextroamphetamine might be explained as a potentiation of catecholamines, the long-term effects of the drug, including paranoid symptoms, may result from depletion of the central nervous system's stores of catecholamine by dextroamphetamine or one of its metabolites, or both.