Substitution profile of Δ9-tetrahydrocannabinol, triazolam, hydromorphone, and methylphenidate in humans discriminating Δ9-tetrahydrocannabinol

Abstract

Rationale: Preclinical evidence suggests that non-cannabinoid neurotransmitter systems are involved in the behavioral and physiological effects of cannabinoids, but relatively little research has been conducted in humans. Objectives: The aims of this study were to assess whether oral Δ9-tetrahydrocannabinol (Δ9-THC) would function as a discriminative stimulus in humans and to examine the substitution profile of drugs acting at opioid, GABA, and dopamine systems. Methods: Healthy subjects who reported moderate cannabis use were enrolled. Subjects learned to identify when they received oral 25 mg Δ9-THC or placebo under double-blind conditions. Once subjects acquired the discrimination (i.e., ≥80% drug-appropriate responding for four consecutive sessions), multiple doses of Δ9-THC, the GABAA positive modulator triazolam, the μ-opioid agonist hydromorphone and the dopamine reuptake inhibitor methylphenidate were tested to determine if they shared discriminative-stimulus effects with the training dose of Δ9- THC. Results: Eight subjects (N∈=∈8) accurately discriminated Δ9-THC and completed the study. The training dose of Δ9-THC functioned as a discriminative stimulus and produced prototypical subject-rated drug effects. All of the drugs tested produced significant effects on the self-report questionnaires, but only Δ9-THC substituted for the training dose. Conclusion: These results suggest that the discriminative-stimulus effects of Δ9- THC in humans are not directly mediated through central neurotransmitter systems acted upon by the drugs tested in this study. © 2008 Springer-Verlag.