The effect of caffeine when combined with cocaine or amphetamine was studied in rats. Animals were pretreated with intraperitoneal vehicle (normal saline [NS]) or caffeine 100 mg/kg, then challenged with intraperitoneal cocaine (0, 35, 50, 70, or 90 mg/kg) or intraperitoneal d-amphetamine (0, 15, 25, 35, or 42 mg/kg). Animal behavior, time to, and incidences of seizures and death were recorded. This dose of caffeine alone did not cause seizures or death. Caffeine pretreatment significantly incresed the incidence of overt seizures induced by either cocaine or amphetamine. Caffeine increased the incidence of cocaine-induced death from 10% to 90% at the 70 mg/kg cocaine dose (P < .01). Caffeine increased amphetamine-induced death from 0% to 80% at 15 mg/kg (P ≤ .01), 10% to 70% at 25 mg/kg (P ≤ .01), and 30% to 80% at 35 mg/kg (P ≤ .01). To investigate mechanisms, additional animals were pretreated withtthe adenosine agonist, 2-chloroadenosine (2.5 and 10 mg/kg), before being challenged with NS, 90 mg/kg cocaine, or 42 mg/kg amphetamine. Pretreatment with 2-chloroadenosine had no affect in reducing cocaine or amphetamine toxicity. Combination pretreatment with caffeine and 2-chloroadenosine potentiated cocaine toxicity. The phosphodiesterase inhibitor, pentoxifylline, did not potentiate cocaine toxicity. The authors conclude that caffeine potentiates the acute toxicity of both cocaine and amphetamine, and that the failure of 2-chloroadenosine to alter this suggests that the toxicity of the stimulants cocaine and amphetamine may be modulated by nonspecific rather than specific adenosine- or phosphodiesterase-induced mechanisms.