Separate and combined effects of the GABA_B agonist baclofen and Δ⁹-THC in humans discriminating Δ⁹-THC

Background: Our previous research with the GABA reuptake inhibitor tiagabine suggested the involvement GABA in the interoceptive effects of Δ⁹-THC. The aim of the present study was to determine the potential involvement of the GABA_B receptor subtype by assessing the separate and combined effects of the GABA_B-selective agonist baclofen and Δ⁹-THC using pharmacologically specific drug-discrimination procedures. Methods: Eight cannabis users learned to discriminate 30mg oral Δ⁹-THC from placebo and then received baclofen (25 and 50mg), 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), elevated heart rate and impaired rate and accuracy on a psychomotor performance task. Baclofen alone (50mg) substituted for the Δ⁹-THC discriminative stimulus, and both baclofen doses shifted the discriminative-stimulus effects of Δ⁹-THC leftward/upward. Similar results were observed on other cannabinoid-sensitive outcomes, although baclofen generally did not engender Δ⁹-THC-like subjective responses when administered alone. Conclusions: These results suggest that the GABA_B receptor subtype is involved in the abuse-related effects of Δ⁹-THC, and that GABA_B receptors were responsible, at least in part, for the effects of tiagabine-induced elevated GABA on cannabinoid-related behaviors in our previous study. Future research should test GABAergic compounds selective for other GABA receptor subtypes (i.e., GABA_A) to determine the contribution of the different GABA receptors in the effects of Δ⁹-THC, and by extension cannabis, in humans.