Substitution profile of the cannabinoid agonist nabilone in human subjects discriminating Δ⁹-tetrahydrocannabinol

Objectives: The central effects of Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the primary active constituent of cannabis, are attributed to cannabinoid CB₁ receptor activity, although clinical evidence is limited. Drug discrimination has proven useful for examining the neuropharmacology of drugs, as data are concordant with the actions of a drug at the receptor level. The aim of this study was to determine the profile of behavioral and physiological effects of the cannabinoid agonist nabilone in humans trained to discriminate Δ⁹-THC. Methods: Six cannabis users learned to identify when they received oral Δ⁹-THC (25 mg) or placebo and then received a range of doses of the cannabinoid agonists nabilone (1, 2, 3, and 5 mg) and Δ⁹-THC (5, 10, 15, and 25 mg). The dopamine reuptake inhibitor methylphenidate (5, 10, 20, and 30 mg) was included as a negative control. Subjects completed the Multiple-Choice Procedure, and self-report, task performance, and physiological measures were collected. Results: Nabilone shared discriminative-stimulus effects with the training dose of Δ⁹-THC, produced subject-rated drug effects that were comparable to those of Δ⁹-THC, and increased heart rate. Methylphenidate did not engender Δ⁹-THC-like discriminative-stimulus effects. Conclusions: These data demonstrate that the interoceptive effects of nabilone are similar to Δ⁹-THC in cannabis users. The overlap in their behavioral effects is likely due to their shared mechanism as CB₁ receptor agonists. Given the relative success of agonist replacement therapy to manage opioid, tobacco, and stimulant dependence, these results also support the evaluation of nabilone as a potential medication for cannabis-use disorders.