Mescaline sulfate infused iv in anesthetized dogs and cats produced dose-related systemic hypotension and bradycardia, whereas pressor responses were obtained in rats. Mescaline-induced hypotension and bradycardia were not significantly altered by prior atropinization and bilateral vagotomy in dogs and cats, thus obviating a cholinergic mechanism. Similarly, cardiovascular responses to isoproterenol injections were not antagonized by mescaline; therefore, bradycardia and hypotension are probably not mediated via beta-adrenergic receptor blockade by mescaline. Although antihistamine pretreatment in dogs did not significantly reduce mescaline-induced hypotension, evidence that histamine release is implicated in this vascular response to mescaline was provided by several observations: tachyphylaxis to the hypotension in dogs and cats, narrow separation between ineffective and markedly hypotensive doses, a rise in pulmonary arterial pressure and an elevation of plasma histamine concentrations following the iv administration of mescaline in dogs. No evidence of increased plasma histamine concentrations was found in rats, a species in which mescaline produced only hypertensive responses. © 1973.