Enhanced discriminative stimulus effects of δ9-THC in the presence of cannabidiol and 8-OH-DPAT in rhesus monkeys

Lance R. McMahon

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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 δ9-THC. The extent to which cannabidiol modifies the effects of δ9-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-OH-DPAT) were tested in two separate discrimination assays in rhesus monkeys. One group (n=6) discriminated δ9-tetrahydrocannabinol (δ9-THC; 0.1mg/kg i.v.); a second group (n=6) discriminated the cannabinoid antagonist rimonabant (1mg/kg i.v.) while receiving δ9-THC daily (1mg/kg/12hs.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 17.8mg/kg) and 8-OH-DPAT (up to 0.178mg/kg) did not substitute for either training drug; however, both significantly increased the potency of δ9-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 consistent with cannabidiol lacking CB1 receptor agonist or antagonist activity in vivo, demonstrate enhancement of the effects of δ9-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 δ9-THC.

Original languageEnglish (US)
JournalDrug and Alcohol Dependence
StateAccepted/In press - Apr 8 2016


  • 5-HT1A
  • 8-OH-DPAT
  • Cannabidiol
  • Cannabinoid
  • Dependence
  • Drug discrimination
  • Rhesus monkey
  • Rimonabant
  • Serotonin

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Toxicology
  • Pharmacology
  • Pharmacology (medical)

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