The phytocannabinoid, Δ⁹-tetrahydrocannabivarin, can act through 5-HT₁A receptors to produce antipsychotic effects

Br J Pharmacol. 2015 Mar;172(5):1305-18. doi: 10.1111/bph.13000.


Background and purpose: This study aimed to address the questions of whether Δ(9)-tetrahydrocannabivarin (THCV) can (i) enhance activation of 5-HT1 A receptors in vitro and (ii) induce any apparent 5-HT₁A receptor-mediated antipsychotic effects in vivo.

Experimental approach: In vitro studies investigated the effect of THCV on targeting by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) of 5-HT₁A receptors in membranes obtained from rat brainstem or human 5-HT₁A CHO cells, using [(35)S]-GTPγS and 8-[(3)H]-OH-DPAT binding assays. In vivo studies investigated whether THCV induces signs of 5-HT₁A receptor-mediated antipsychotic effects in rats.

Key results: THCV (i) potently, albeit partially, displaced 8-[(3) H]-OH-DPAT from specific binding sites in rat brainstem membranes; (ii) at 100 nM, significantly enhanced 8-OH-DPAT-induced activation of receptors in these membranes; (iii) produced concentration-related increases in 8-[(3)H]-OH-DPAT binding to specific sites in membranes of human 5-HT₁A receptor-transfected CHO cells; and (iv) at 100 nM, significantly enhanced 8-OH-DPAT-induced activation of these human 5-HT₁A receptors. In phencyclidine-treated rats, THCV, like clozapine (i) reduced stereotyped behaviour; (ii) decreased time spent immobile in the forced swim test; and (iii) normalized hyperlocomotor activity, social behaviour and cognitive performance. Some of these effects were counteracted by the 5-HT₁A receptor antagonist, WAY100635, or could be reproduced by the CB₁ antagonist, AM251.

Conclusions and implications: Our findings suggest that THCV can enhance 5-HT₁A receptor activation, and that some of its apparent antipsychotic effects may depend on this enhancement. We conclude that THCV has therapeutic potential for ameliorating some of the negative, cognitive and positive symptoms of schizophrenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / pharmacology*
  • CHO Cells
  • Cannabinoids / chemistry
  • Cannabinoids / pharmacology*
  • Cricetulus
  • Dronabinol / analogs & derivatives*
  • Dronabinol / chemistry
  • Dronabinol / pharmacology
  • Male
  • Molecular Sequence Data
  • Molecular Structure
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Schizophrenia / drug therapy*
  • Schizophrenic Psychology


  • Antipsychotic Agents
  • Cannabinoids
  • Receptor, Serotonin, 5-HT1A
  • tetrahydrocannabivarin 9
  • Dronabinol

Associated data

  • GENBANK/F15063