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

Drug Alcohol Depend. 2022 Nov 1;240:109640. doi: 10.1016/j.drugalcdep.2022.109640. Epub 2022 Sep 20.

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.

MeSH terms

  • Animals
  • Calcium Carbonate
  • Cannabidiol*
  • Cannabinoids*
  • Dronabinol / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Receptor, Cannabinoid, CB1
  • Rimonabant

Substances

  • Dronabinol
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • Rimonabant
  • Cannabidiol
  • Piperidines
  • Pyrazoles
  • Cannabinoids
  • Calcium Carbonate
  • Receptor, Cannabinoid, CB1