Separate and combined effects of the GABA_A positive allosteric modulator diazepam and δ⁹-THC in humans discriminating δ⁹-THC

Background: Our previous research suggested the involvement of γ-aminobutyric acid (GABA), in particular the GABA_B receptor subtype, in the interoceptive effects of δ⁹-tetrahydrocannabinol (δ⁹-THC). The aim of the present study was to determine the potential involvement of the GABA_A receptor subtype by assessing the separate and combined effects of the GABA_A positive allosteric modulator diazepam and δ⁹-THC using pharmacologically selective drug-discrimination procedures. Methods: Ten cannabis users learned to discriminate 30mg oral δ⁹-THC from placebo and then received diazepam (5 and 10mg), δ⁹-THC (5, 15 and 30mg) and placebo, alone and in combination. Self-report, task performance and physiological measures were also collected. Results: δ⁹-THC functioned as a discriminative stimulus, produced subjective effects typically associated with cannabinoids (e.g., High, Stoned, Like Drug) and elevated heart rate. Diazepam alone impaired performance on psychomotor performance tasks and increased ratings on a limited number of self-report questionnaire items (e.g., Any Effect, Sedated), but did not substitute for the δ⁹-THC discriminative stimulus or alter the δ⁹-THC discrimination dose-response function. Similarly, diazepam had limited impact on the other behavioral effects of δ⁹-THC. Conclusions: These results suggest that the GABA_A receptor subtype has minimal involvement in the interoceptive effects of δ⁹-THC, and by extension cannabis, in humans.