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 Administrationapproved 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, D 9 -tetrahydrocannabinol (D 9 -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 D 9 -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 D 9 -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 nicotineinduced 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 D 9 -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 D 9 -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 STATEMENTEmesis 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 D 9 -tetrahydrocannabinol and endocannabinoid analog methanandamide in nonhuman primates.

The Development of Cannabinoids as Therapeutic Agents in the United States

“…While preclinical and clinical evidence indicate Δ9-THC can increase food consumption and support its use for this condition (Morozov et al, 2017;Farokhnia et al, 2020), preclinical investigations into the capacity of Δ9-THC to reduce nausea and vomiting have been more challenging as the absence of a vomiting reflex in rodents has required a variety of animal models and emetic agents. For example, Δ9-THC has been shown to reduce cannabinoid antagonist-induced emesis in ferrets (Salamone et al, 2007) and nonhuman primates (Wooldridge et al, 2020), radiation-induced emesis in shrews (Darmani et al, 2007), and cisplatin-treated cats (McCarthy and Borison, 1981). Complicating our understanding of the cannabinoids' antiemetic effects even further, chronic cannabis use in humans can lead to a hyperemetic syndrome (Sorensen et al, 2017).…”