Tetrahydrocannabivarin (THCV) Dose Dependently Blocks or Substitutes for Tetrahydrocannabinol (THC) in a Drug Discrimination Task in Rats

Delta-9-Tetrahydrocannabivarin (THCV), a naturally occurring cannabinoid and structural analog of THC, exhibits a dual pharmacological profile as a CB1 receptor agonist/antagonist and a partial CB2 agonist. This study evaluated the effects of THCV in a THC discrimination model in rats. Male Sprague-Dawley rats (<i>n</i> = 16, 300-340 g, PND60) were trained under a fixed ratio 20 (FR20) schedule to discriminate THC (3 mg/kg) from vehicle. Substitution tests were conducted with THC (0.325-3 mg/kg), THCV (0.75-6 mg/kg), and THC-THCV combinations. THCV produced an inverted U-shaped substitution curve, significantly differing from vehicle (<i>p</i> = 0.008). At 3 mg/kg, THCV partially substituted for THC (54.6% ± 17.82, <i>p</i> = 0.003). Response rate significantly increased during the substitution test with 3 mg/kg of THCV (<i>p</i> = 0.042). THCV (6 mg/kg) reversed THC (0.75 mg/kg)-induced responding (<i>p</i> = 0.040), with no significant change in response rate (<i>p</i> = 0.247). However, THCV combined with THC (1.5 mg/kg) affected response rates (<i>p</i> = 0.012), with 6 mg/kg significantly reducing rates vs. 3 mg/kg (<i>p</i> = 0.013). Blood THC and 11-OH-THC levels remained unchanged when THC was combined with THCV. The findings suggest THCV can partially mimic or block THC's discriminative effects in a dose-dependent manner, possibly acting as a partial CB1 agonist.