Sympathomimetics, such as Ephedra alkaloids, are associated with an increased incidence of intracerebral hemorrhage believed to be secondary to concomitant elevations in blood pressure. We hypothesized that sympathomimetics decrease platelet aggregation. Reductions in epinephrine-mediated platelet aggregation by ephedrine, phenylpropanolamine, and racemic amphetamine were determined by measuring the changes that these sympathomimetics induced in the optical density of platelet-rich plasma from healthy individuals. Intracellular signal transduction was followed ex vivo by assaying the release of intracellular cyclic AMP and the ligand for the cytokine chemoreceptor 5 (RANTES) into platelet rich plasma. The effect of ephedrine on epinephrine-mediated increases in platelet selectin (CD62p) activation was assessed with flow cytometry. Data were analyzed with repeated-measures analyses of variance. Aggregation responses to epinephrine were greatly reduced in the presence of commonly used sympathomimetics such as ephedrine, phenylpropanolamine, and racemic amphetamine that have been found in cold remedies, appetite suppressants, or used in the treatment of attention-deficit hyperactivity disorder, respectively. Ephedrine diminished aggregation responses to ADP and gamma-thrombin, and this sympathomimetic reduced RANTES exocytosis, basal CD62p expression, and aggregation in platelets exposed to caffeine. Caffeine enhanced the effect of ephedrine on platelet function, and phenylpropanolamine amplified the inhibitory effect of aspirin on platelet aggregation. Sympathomimetics significantly alter platelet function, and they may increase the potential for bleeding independently of their effects on blood pressure. Despite restrictions imposed on their use, the consumption of sympathomimetics should be considered when any patient presents with findings of cerebral hemorrhage.