Enhanced discriminative stimulus effects of 9-THC in the presence of cannabidiol and 8-OH-DPAT in rhesus monkeys

Background: Cannabidiol, a therapeutic with potential serotonin (5-hydroxytryptamine; 5-HT) 5- HT1A receptor agonist activity, is the second most prevalent cannabinoid in Cannabis after  9 – THC. The extent to which cannabidiol modifies the effects of  9 -THC has not been firmly established, especially with respect to abuse-related effects in rhesus monkeys where previously antagonistic interactions have been reported for some behavioral outcomes.

Methods: Cannabidiol and the 5-HT1A receptor agonist (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OHDPAT) were tested in two separate discrimination assays in rhesus monkeys. One group (n=6) discriminated  9 -tetrahydrocannabinol ( 9 -THC; 0.1 mg/kg i.v.); a second group (n=6) discriminated the cannabinoid antagonist rimonabant (1 mg/kg i.v.) while receiving  9 -THC daily (1 mg/kg/12 h s.c.). Responding was maintained under a fixed ratio 5 schedule of stimulus-shock termination.

Results: Both training drugs dose-dependently increased the percentage of responses on the respective drug-associated levers. Cannabidiol (up to 17.8 mg/kg) and 8-OH-DPAT (up to 0.178 mg/kg) did not substitute for either training drug; however, both significantly increased the potency of  9 -THC to produce discriminative stimulus effects. Moreover, 8-OH-DPAT significantly attenuated the discriminative stimulus effects of rimonabant, whereas cannabidiol did not modify the rimonabant discriminative stimulus.

Conclusions: These results, which are 3 consistent with cannabidiol lacking CB1 receptor agonist or antagonist activity in vivo, demonstrate enhancement of the effects of  9 -THC by cannabidiol, albeit at cannabidiol amounts larger than those in Cannabis or cannabidiol-based therapeutics (nabiximols). In addition to showing that cannabidiol and a 5-HT1A receptor agonist have overlapping behavioral effects, the current results suggest that 5-HT1A agonism enhances the CB1 receptor-mediated effects of  9 – THC.