Cannabinoid hyperemesis syndrome (CHS) is characterized by intense nausea and vomiting brought on by the use of high-dose Δ-tetrahydrocannabinol (THC), the main psychotropic compound in cannabis. Cannabidiol (CBD), a nonpsychotropic compound found in cannabis, has been shown to interfere with some acute aversive effects of THC. In this study, we evaluated if CBD would interfere with THC-induced nausea through a 5-HT receptor mechanism as it has been shown to interfere with nausea produced by lithium chloride (LiCl). Since CHS has been attributed to a dysregulated stress response, we also evaluated if CBD would interfere with THC-induced increase in corticosterone (CORT). The potential of CBD (5 mg/kg, ip) to suppress THC-induced conditioned gaping (a measure of nausea) was evaluated in rats, as well as the potential of the 5-HT receptor antagonist, WAY-100635 (WAY; 0.1 mg/kg, ip), to reverse the suppression of THC-induced conditioned gaping by CBD. Last, the effect of CBD (5 mg/kg, ip) on THC-induced increase in serum CORT concentration was evaluated. Pretreatment with CBD (5 mg/kg, ip) interfered with the establishment of THC-induced conditioned gaping (=0.007, relative to vehicle [VEH] pretreatment), and this was reversed by pretreatment with 0.1 mg/kg WAY. This dose of WAY had no effect on gaping on its own. THC (10 mg/kg, ip) significantly increased serum CORT compared with VEH-treated rats (=0.04). CBD (5 mg/kg, ip) pretreatment reversed the THC-induced increase in CORT. CBD attenuated THC-induced nausea as well as THC-induced elevation in CORT. The attenuation of THC-induced conditioned gaping by CBD was mediated by its action on 5-HT receptors, similar to that of LiCl-induced nausea.