In the isolated heart of the bullfrog, both the spontaneous contractile force of the atrium and the electrically-induced contractile force of the ventricle were enhanced by the initial administration of methamphetamine. However, a second administration of the drug caused a dose-dependent negative inotropic effect. The methamphetamine-induced positive inotropic effect was reduced or abolished by either practolol or cocaine pre-treatment. The negative inotropic effect of methamphetamine was markedly attenuated after theophylline or practolol pre-treatment, but was not affected by cocaine, atropine and phentolamine pre-treatment. Methamphetamine caused a slight decrease of the adenylatecyclase activity of the intact myocardium. It also inhibited not only the cardiac excitation (contractile force and rate) but also the facilitation of adenylatecyclase activity induced by isoproterenol. A slight reduction of the methamphetamine-induced ventricular inhibition was observed by increasing the external calcium concentration; however, the inhibition was not affected by MnCl2 or verapamil pre-treatment. From these results, it is suggested that the inhibitory effect of methamphetamine on the heart may be produced through the blocking of post-synaptic beta-adrenoceptors.