The Role of γ-Aminobutyric Acid in the Interoceptive Effects of Oral Δ⁹-Tetrahydrocannabinol in Humans

This chapter focuses on the involvement of δ-aminobutyric acid (ie, GABA) in the interoceptive effects of Δ⁹-tetrahydrocannabinol (ie, Δ⁹-THC) in humans. The interoceptive effects of drugs can be assessed using drug discrimination methodology, which is a selective means to examine neuropharmacological interactions between neurotransmitter systems. In humans trained to discriminate oral Δ⁹-THC, the GABA reuptake inhibitor tiagabine substituted for Δ⁹-THC, and enhanced the discriminative stimulus effects of Δ⁹-THC. The GABA_B agonist baclofen, but not the GABA_A positive allosteric modulator diazepam, also substituted for Δ⁹-THC, and enhanced the discriminative stimulus effects of Δ⁹-THC. The results from these clinical drug-discrimination studies disagree with preclinical data, suggesting that the neuropharmacological interactions between GABA and CB systems differ between human and nonhuman species. The studies reviewed here indicate that GABA, particularly the GABA_B receptor subtype, plays a significant part in the interoceptive effects produced by Δ⁹-THC, and by extension cannabis, in humans.