Assessment of dependence potential and abuse liability of Δ8-tetrahydrocannabinol in mice

Abstract

Delta-8-tetrahydrocannabinol (Δ⁸-THC) is a psychotropic cannabinoid produced in low quantities in the cannabis plant. Refinements in production techniques, paired with the availability of inexpensive cannabidiol substrate, have resulted in Δ⁸-THC being widely marketed as a quasi-legal, purportedly milder alternative to Δ⁹-THC. Yet, little research has probed the behavioral and physiological effects of repeated Δ⁸-THC use. The present study aimed to evaluate the effects of acute and repeated exposure to Δ⁸-THC. We hypothesized that Δ⁸-THC produces effects similar to Δ⁹-THC, including signs of drug tolerance and dependence. Adult male and female C57BL/6J mice were treated acutely with Δ⁸-THC (6.25-100 mg/kg, i.p.) or vehicle and tested in the tetrad battery to quantify cannabimimetic effects (i.e., catalepsy, antinociception, hypothermia, immobility) as compared with a non-selective synthetic cannabinoid (WIN 55,212-2) and Δ⁹-THC. As previously reported, Δ⁸-THC (≥12.5 mg/kg) induced cannabimimetic effects. Pretreatment with the CB₁ receptor-selective antagonist rimonabant (3 mg/kg, i.p.) blocked each of these effects. In addition, repeated administration of Δ⁸-THC (50 mg/kg, s.c.) produced tolerance, as well as cross-tolerance to WIN 55,212-2 (10 mg/kg, s.c.) in tetrad, consistent with downregulated CB₁ receptor function. Behavioral signs of physical dependence in the somatic signs, tail suspension, and marble burying assays were also observed following rimonabant-precipitated withdrawal from Δ⁸-THC (≥10 mg/kg BID for 6 days). Lastly, Δ⁸-THC produced Δ⁹-THC-like discriminative stimulus effects in both male and female mice. Together, these findings demonstrate that Δ⁸-THC produces qualitatively similar effects to Δ⁹-THC, including risk of drug dependence and abuse liability.

Keywords: Cannabis use disorder; Drug dependence; Minor phytocannabinoid; Substance use disorder.