Separate and combined effects of the GABA(B) agonist baclofen and Δ9-THC in humans discriminating Δ9-THC

Abstract

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 30 mg oral Δ9-THC from placebo and then received baclofen (25 and 50mg), Δ9-THC (5, 15 and 30 mg) 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 (50 mg) 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.

Figure 1

Separate and combined effects of Δ⁹-THC and baclofen on Δ⁹-THC-appropriate responding on the drug-discrimination task. Filled symbols indicate values that are significantly different from placebo. Asterisks indicate combinations of Δ⁹-THC and baclofen that are significantly different from that dose of Δ⁹-THC alone. The x-axis represents the Δ⁹-THC dose in mg; PL denotes placebo. Data points show means of 8 subjects. Uni-directional brackets indicate 1 SEM.

Figure 2

Peak (maximum value) Visual Analog Scale ratings for Δ⁹-THC and baclofen, alone and in combination, on the drug-effect questionnaire items Any Effect, High, Like Drug, and crossover point values (square root transformation) from a Multiple Choice Procedure. All other details are as in Figure 1.

Figure 3

Peak number of chains completed and total responses on the repeated acquisition task (minimum value) for Δ⁹-THC and baclofen, alone and in combination. All other details are as in Figure 1.

Figure 4

Peak heart rate (maximum value) for Δ⁹-THC and baclofen, alone and in combination. All other details are as in Figure 1.