Antiemetic Effects of Cannabinoid Agonists in Nonhuman Primates

Abstract

Attenuating emesis elicited by both disease and medical treatments of disease remains a critical public health challenge. Although cannabinergic medications have been used in certain treatment-resistant populations, Food and Drug Administration-approved cannabinoid antiemetics are associated with undesirable side effects, including cognitive disruption, that limit their prescription. Previous studies have shown that a metabolically stable analog of the endocannabinoid anandamide, methanandamide (mAEA), may produce lesser cognitive disruption than that associated with the primary psychoactive constituent in cannabis, Δ⁹-tetrahydrocannabinol (Δ⁹-THC), raising the possibility that endocannabinoids may offer a therapeutic advantage over currently used medications. The present studies were conducted to evaluate this possibility by comparing the antiemetic effects of Δ⁹-THC (0.032-0.1 mg/kg) and mAEA (3.2-10.0 mg/kg) against nicotine- and lithium chloride (LiCl)-induced emesis and prodromal hypersalivation in squirrel monkeys. Pretreatment with 0.1 mg/kg Δ⁹-THC blocked nicotine-induced emesis and reduced hypersalivation in all subjects and blocked LiCl-induced emesis and reduced hypersalivation in three of four subjects. Pretreatment with 10 mg/kg mAEA blocked nicotine-induced emesis in three of four subjects and LiCl-induced emesis in one of four subjects and reduced both nicotine- and LiCl-induced hypersalivation. Antiemetic effects of Δ⁹-THC and mAEA were reversed by rimonabant pretreatment, providing verification of cannabinoid receptor type 1 mediation. These studies systematically demonstrate for the first time the antiemetic effects of cannabinoid agonists in nonhuman primates. Importantly, although Δ⁹-THC produced superior antiemetic effects, the milder cognitive effects of mAEA demonstrated in previous studies suggest that it may provide a favorable treatment option under clinical circumstances in which antiemetic efficacy must be balanced against side effect liability. SIGNIFICANCE STATEMENT: Emesis has significant evolutionary value as a defense mechanism against ingested toxins; however, it is also one of the most common adverse symptoms associated with both disease and medical treatments of disease. The development of improved antiemetic pharmacotherapies has been impeded by a paucity of animal models. The present studies systematically demonstrate for the first time the antiemetic effects of the phytocannabinoid Δ⁹-tetrahydrocannabinol and endocannabinoid analog methanandamide in nonhuman primates.