Substitution profile of Delta9-tetrahydrocannabinol, triazolam, hydromorphone, and methylphenidate in humans discriminating Delta9-tetrahydrocannabinol.

Abstract

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. The aims of this study were to assess whether oral Delta(9)-tetrahydrocannabinol (Delta(9)-THC) would function as a discriminative stimulus in humans and to examine the substitution profile of drugs acting at opioid, GABA, and dopamine systems. Healthy subjects who reported moderate cannabis use were enrolled. Subjects learned to identify when they received oral 25 mg Delta(9)-THC or placebo under double-blind conditions. Once subjects acquired the discrimination (i.e., > or =80% drug-appropriate responding for four consecutive sessions), multiple doses of Delta(9)-THC, the GABA(A) positive modulator triazolam, the micro-opioid agonist hydromorphone and the dopamine reuptake inhibitor methylphenidate were tested to determine if they shared discriminative-stimulus effects with the training dose of Delta(9)-THC. Eight subjects (N = 8) accurately discriminated Delta(9)-THC and completed the study. The training dose of Delta(9)-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 Delta(9)-THC substituted for the training dose. These results suggest that the discriminative-stimulus effects of Delta(9)-THC in humans are not directly mediated through central neurotransmitter systems acted upon by the drugs tested in this study.