Antiemetic Effects of Cannabinoid Agonists in Nonhuman Primates

J Pharmacol Exp Ther. 2020 Sep;374(3):462-468. doi: 10.1124/jpet.120.265710. Epub 2020 Jun 19.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antiemetics / pharmacology*
  • Antiemetics / therapeutic use
  • Arachidonic Acids / pharmacology
  • Arachidonic Acids / therapeutic use
  • Cannabinoid Receptor Agonists / pharmacology*
  • Cannabinoid Receptor Agonists / therapeutic use
  • Dronabinol / pharmacology
  • Dronabinol / therapeutic use
  • Drug Interactions
  • Male
  • Receptor, Cannabinoid, CB1 / agonists
  • Saimiri
  • Salivation / drug effects
  • Vomiting / drug therapy


  • Antiemetics
  • Arachidonic Acids
  • Cannabinoid Receptor Agonists
  • Receptor, Cannabinoid, CB1
  • methanandamide
  • Dronabinol