Effect of Combined Doses of Δ 9-tetrahydrocannabinol and Cannabidiol or Tetrahydrocannabinolic Acid and Cannabidiolic Acid on Acute Nausea in Male Sprague-Dawley Rats

Psychopharmacology (Berl). 2020 Mar;237(3):901-914. doi: 10.1007/s00213-019-05428-4. Epub 2020 Jan 2.

Abstract

Rationale: This study evaluated the potential of combined cannabis constituents to reduce nausea.

Objectives: Using the lithium chloride (LiCl)-induced conditioned gaping model of nausea in male rats, we aimed to: 1) Determine effective anti-nausea doses of cannabidiol (CBD) 2) Determine effectiveness and the mechanism of action of combined subthreshold doses of CBD and Δ9-tetrahydrocannabinol (THC) 3) Determine effective doses of synthetic cannabidiolic acid (CBDA) 4) Determine effective doses of synthetic tetrahydrocannabinolic acid (THCA) 5) Determine the mechanism of action for THCA 6) Determine effectiveness and the mechanism of action of combined subthreshold doses of CBDA and THCA RESULTS: CBD (0.5-5 mg/kg, intraperitoneal [i.p.]) reduces LiCl-induced conditioned gaping (but 0.1, 20, 40 mg/kg are ineffective). Combined subthreshold doses of CBD (0.1 mg/kg, i.p.) and THC (0.1 mg/kg, i.p.) produce suppression of conditioned gaping, and this effect is blocked by administration of either WAY100635 (a serotonin 1A [5-HT1A]) receptor antagonist or SR141716 (SR; a CB1 receptor antagonist). THCA (0.01 mg/kg, i.p.) reduces conditioned gaping and administration of MK886 (a peroxisome proliferator-activated receptor alpha [PPARα] antagonist) blocked THCA's anti-nausea effect. Combined subthreshold doses of CBDA (0.00001 mg/kg, i.p.) and THCA (0.001 mg/kg, i.p.) produce suppression of conditioned gaping, and this effect is blocked by administration of WAY100635 or MK886.

Conclusion: Combinations of very low doses of CBD + THC or CBDA + THCA robustly reduce LiCl-induced conditioned gaping. Clinical trials are necessary to determine the efficacy of using single or combined cannabinoids as adjunct treatments with existing anti-emetic regimens to manage chemotherapy-induced nausea.

Keywords: 5-HT1A; CB1; Cannabidiol; Cannabidiolic acid; Conditioned gaping; PPARα; Tetrahydrocannabinolic acid; Δ9-tetrahydrocannabinol.