Caffeine-amphetamine interactions were studied to determine whether attenuation of amphetamine-induced activity by caffeine pretreatment (30 mg/kg) is the result of increased or decreased sensitivity to amphetamine. Caffeine pretreatment attenuated amphetamine activity in the rats without producing a horizontal shift in the dose-response curve. Results support a reduction in sensitivity to amphetamine. A cross-tolerance design revealed an asymmetrical interaction between caffeine and amphetamine. Multiple caffeine treatments (30 mg/kg) produced tolerance and attenuation of subsequent amphetamine activity (1.5 mg/kg). Amphetamine did not produce tolerance or affect subsequent caffeine-induced activity.