TY - JOUR T1 - Antiemetic Effects of Cannabinoid Agonists in Nonhuman Primates JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.120.265710 SP - jpet.120.265710 AU - Lisa M Wooldridge AU - Lipin Ji AU - Yingpeng Liu AU - Spyros P Nikas AU - Alexandros Makriyannis AU - Jack Bergman AU - Brian D Kangas Y1 - 2020/01/01 UR - http://jpet.aspetjournals.org/content/early/2020/06/19/jpet.120.265710.abstract N2 - 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, FDA-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 3 of 4 subjects. Pretreatment with 10 mg/kg mAEA blocked nicotine-induced emesis in 3 of 4 subjects and LiCl-induced emesis in 1 of 4 subjects, and reduced both nicotine- and LiCl-induced hypersalivation. Antiemetic effects of Δ9-THC and mAEA were reversed by rimonabant pretreatment, providing verification of CB1 receptor-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 suggests 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 anti-emetic 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. ER -