The effect of the plant-derived nonpsychotropic cannabinoid, cannabidiol (CBD), on the function of hydroxytryptamine (5-HT)3A receptors expressed in Xenopus laevis oocytes was investigated using two-electrode voltage-clamp techniques. CBD reversibly inhibited 5-HT (1 M)-evoked currents in a concentration-dependent manner (IC50 0.6 M). CBD (1 M) did not alter specific binding of the 5-HT3A antagonist [3 H]3-(5-methyl-1H-imidazol-4-yl)-1-(1-methylindol-3-yl)propan-1-one (GR65630), in oocytes expressing 5-HT3A receptors. In the presence of 1 M CBD, the maximal 5-HT-induced currents were also inhibited. The EC50 values were 1.2 and 1.4 M, in the absence and presence of CBD, indicating that CBD acts as a noncompetitive antagonist of 5-HT3 receptors. Neither intracellular BAPTA...