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; 0.1 mg/kg i.v.); a second group (n = 6) discriminated the cannabinoid antagonist rimonabant (1 mg/kg i.v.) while receiving Δ9-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 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)
Pages (from-to)87-93
Number of pages7
JournalDrug and Alcohol Dependence
StatePublished - Aug 1 2016


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

ASJC Scopus subject areas

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


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