Evidence that the plant cannabinoid Delta9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist

Br J Pharmacol. 2005 Dec;146(7):917-26. doi: 10.1038/sj.bjp.0706414.


Delta9-tetrahydrocannabivarin (THCV) displaced [(3)H]CP55940 from specific binding sites on mouse brain and CHO-hCB(2) cell membranes (K(i)=75.4 and 62.8 nM, respectively).THCV (1 microM) also antagonized CP55940-induced stimulation of [(35)S]GTPgammaS binding to these membranes (apparent K(B)=93.1 and 10.1 nM, respectively). In the mouse vas deferens, the ability of Delta9-tetrahydrocannabinol (THC) to inhibit electrically evoked contractions was antagonized by THCV, its apparent K(B)-value (96.7 nM) approximating the apparent K(B)-values for its antagonism of CP55940- and R-(+)-WIN55212-induced stimulation of [(35)S]GTPgammaS binding to mouse brain membranes. THCV also antagonized R-(+)-WIN55212, anandamide, methanandamide and CP55940 in the vas deferens, but with lower apparent K(B)-values (1.5, 1.2, 4.6 and 10.3 nM, respectively).THCV (100 nM) did not oppose clonidine, capsaicin or (-)-7-hydroxy-cannabidiol-dimethylheptyl-induced inhibition of electrically evoked contractions of the vas deferens. Contractile responses of the vas deferens to phenylephrine hydrochloride or beta,gamma-methylene-ATP were not reduced by 1microM THCV or R-(+)-WIN55212, suggesting that THCV interacts with R-(+)-WIN55212 at prejunctional sites. At 32 microM, THCV did reduce contractile responses to phenylephrine hydrochloride and beta,gamma-methylene-ATP, and above 3 microM it inhibited electrically evoked contractions of the vas deferens in an SR141716A-independent manner. In conclusion, THCV behaves as a competitive CB(1) and CB(2) receptor antagonist. In the vas deferens, it antagonized several cannabinoids more potently than THC and was also more potent against CP55940 and R-(+)-WIN55212 in this tissue than in brain membranes. The bases of these agonist- and tissue-dependent effects remain to be established.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonic Acids / antagonists & inhibitors
  • Benzoxazines
  • CHO Cells
  • Cannabinoids / pharmacology*
  • Cannabis / chemistry*
  • Clonidine / pharmacology
  • Cricetinae
  • Dose-Response Relationship, Drug
  • Dronabinol / analogs & derivatives*
  • Dronabinol / pharmacology
  • Endocannabinoids
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • In Vitro Techniques
  • Male
  • Mice
  • Morpholines / antagonists & inhibitors
  • Muscle Contraction / drug effects
  • Naphthalenes / antagonists & inhibitors
  • Polyunsaturated Alkamides
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
  • Receptor, Cannabinoid, CB2 / antagonists & inhibitors*
  • Vas Deferens / drug effects
  • Vas Deferens / physiology


  • Arachidonic Acids
  • Benzoxazines
  • Cannabinoids
  • Endocannabinoids
  • Morpholines
  • Naphthalenes
  • Polyunsaturated Alkamides
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • tetrahydrocannabivarin 9
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • Dronabinol
  • Clonidine
  • anandamide