Neurochemical Research

, Volume 30, Issue 8, pp 1037–1043 | Cite as

Agonistic Properties of Cannabidiol at 5-HT1a Receptors

  • Ethan B. Russo
  • Andrea Burnett
  • Brian Hall
  • Keith K. ParkerEmail author

Cannabidiol (CBD) is a major, biologically active, but psycho-inactive component of cannabis. In this cell culture-based report, CBD is shown to displace the agonist, [3H]8-OH-DPAT from the cloned human 5-HT1a receptor in a concentration-dependent manner. In contrast, the major psychoactive component of cannabis, tetrahydrocannabinol (THC) does not displace agonist from the receptor in the same micromolar concentration range. In signal transduction studies, CBD acts as an agonist at the human 5-HT1a receptor as demonstrated in two related approaches. First, CBD increases [35S]GTPγS binding in this G protein coupled receptor system, as does the known agonist serotonin. Second, in this GPCR system, that is negatively coupled to cAMP production, both CBD and 5-HT decrease cAMP concentration at similar apparent levels of receptor occupancy, based upon displacement data. Preliminary comparative data is also presented from the cloned rat 5-HT2a receptor suggesting that CBD is active, but less so, relative to the human 5-HT1a receptor, in binding analyses. Overall, these studies demonstrate that CBD is a modest affinity agonist at the human 5-HT1a receptor. Additional work is required to compare CBD’s potential at other serotonin receptors and in other species. Finally, the results indicate that cannabidiol may have interesting and useful potential beyond the realm of cannabinoid receptors.


Cannabis cannabidiol cAMP G Proteins marijuana serotonin THC 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Russo, E. B. 2003Introduction: Cannabis: from pariah to prescriptionJ. Cann. Therap.3129Google Scholar
  2. 2.
    Pertwee, R. G. 2004. The pharmacology and therapeutic potential of Cannibidiol. Pages 1–52, in DiMarzo, V. (ed.), Cannabinoids. Kluwer Academic/Plenum PublishersGoogle Scholar
  3. 3.
    Zuardi, A. W., Guimaraes, F. S. 1997Cannabidiol as an anxiolytic and antipsychoticMathre, M. L. eds. Cannabis in medical practice: a legal, historical and pharmacological overview of the therapeutic use of marijuanaJeffersonNC: McFarland133141Google Scholar
  4. 4.
    Carlini, E. A., Cunha, J. M. 1981Hypnotic and antiepileptic effects of cannabidiolJ. Clin. Pharmacol.21417S427SPubMedGoogle Scholar
  5. 5.
    Hampson, A. J., Grimaldi, M., Axelrod, J., Wink, D. 1998Cannabidiol, (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidantsProc. Natl. Acad. Sci. USA.95826873CrossRefPubMedGoogle Scholar
  6. 6.
    Iuvone, T., Esposito, G., Esposito, R., Santamaria, R., Di Rosa, M., Izzo, A. A. 2004Neuroprotective effect of cannabidiol, a non-psychoactive component from cannabis sativa, on beta-amyloid-induced toxicity in PC 12 cellsJ. Neurochem.89134141PubMedGoogle Scholar
  7. 7.
    Nicholson, A. N., Turner, C., Stone, B. M., Robson, P. J. 2004Effect of delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adultsJ. Clin. Psychopharmacol.24305313CrossRefPubMedGoogle Scholar
  8. 8.
    McPartland, J., Di Marzo, V., Petrocellis, L., Mercer, A., Glass, M. 2001Cannabinoid receptors are absent in insectsJ. Comp. Neurol.4364239CrossRefPubMedGoogle Scholar
  9. 9.
    Pertwee, R.G. 1997“Pharmacology of cannabinoid CB1 and CB2 Receptors”Pharmacol. Therap.74129180CrossRefGoogle Scholar
  10. 10.
    Thomas, B. F., Gilliam, A. F., Burch, D. F., Roche, M. J., Seltzman, H. H. 1998“Comparative receptor binding analysis of cannabinoid agonists and antagonists”J. Pharm. Exp. Therap285285292Google Scholar
  11. 11.
    Petitet, F., Jeantaud, B., Reibaud, M., Imperato, A., Dubroeueq, M. C. 1998“Complex pharmacology of natural cannabinoids: Evidence for partial agonist activity at delta 9-tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors”Life Sci. 631PL1PL6CrossRefGoogle Scholar
  12. 12.
    McPartland, J. M., Russo, E. B. 2001Cannabis and Cannabis Extracts: Greater Than the Sum of Their Parts?J. Cannabis Therap.1103132CrossRefGoogle Scholar
  13. 13.
    Russo, E. B. 2001Hemp for headaches: An in-depth historical and scientific review of cannabis in migraine treatmentJ. Cannabis Therap.12192CrossRefGoogle Scholar
  14. 14.
    Russo, E. B. 2004Clinical endocannabinoid deficiency (CECD): Can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?Neuroendocrinol. Lett.253139CrossRefPubMedGoogle Scholar
  15. 15.
    Ferrari, M. D., Saxena, P. R. 19955-HT1 receptors in migraine pathophysiology and treatmentEur. J. Neurol.2521Google Scholar
  16. 16.
    Hershkowitz, M. 1978“The effect of in vivo treatment with (-) /delta 1-tetrahydrocannabinol, and other psychoactive drugs on the in vitro uptake of biogenic amines”Adv. Biosci.22–23351358PubMedGoogle Scholar
  17. 17.
    Cowen, P. J. 2000Psychopharmacology of 5-HT1a receptorsNuc. Med. Biol.27437439CrossRefGoogle Scholar
  18. 18.
    Barnes, N. M., Sharp, T. 1999A review of central 5-HT receptors and their functionNeuropharmacol.3810831152CrossRefGoogle Scholar
  19. 19.
    Fargin, A., Raymond, J. R., Lohse, M. J., Kobilka, B. K., Caron, M. G., Lefkowitz, R. J. 1988The genomic clone G-21 which resembles a beta-adrenergic receptor sequence encodes the 5-HT1a receptorNature335358360CrossRefPubMedGoogle Scholar
  20. 20.
    Nelson, D. L., Monroe, P. J., Lambert, G., Yamamura, H. I. 1987[3H]Spiroxatrine labels a serotonin 1a-like site in rat hippocampus”Life Sci.4115671576CrossRefPubMedGoogle Scholar
  21. 21.
    Weber, J. T., O’Connor, M.-F., Hayataka, K., Colson, N., Medora, R., Russo, E. B., Parker, K. K. 1997Activity of parthenolide at 5HT2a receptorsJ. Nat. Prods.60651653CrossRefGoogle Scholar
  22. 22.
    Glennon, R. A., Teitler, M., Sanders-Bush, E. 1992Hallucinogens and serotonergic mechanismsNIDA Res. Monographs119131135Google Scholar
  23. 23.
    Hedlund, P. B., Carson, M. J., Sutcliffe, J. G., Thomas, E. A. 1999Allosteric regulation by oleamide of the binding properties of 5-hydroxytryptamine 7 receptorsBiochem. Pharmacol.5818071813CrossRefPubMedGoogle Scholar
  24. 24.
    Boger, D. L., Patterson, J. E., Jin, Q. 1998Structural requirements for 5-HT2A and 5-HT1A serotonin receptor potentiation by the biologically active lipid oleamideProc. Natl. Acad, Sci, USA9541024107Google Scholar
  25. 25.
    Cheer, J. F., Cadogan, A. K., Marsden, C. A., Fone, K. C., Kendall, D. A. 1999“Modification of 5HT2a receptor mediated behaviour in the rat by oleamide and the role of cannabinoid receptors”Neuropharmacol.38533545CrossRefGoogle Scholar
  26. 26.
    Devlin, M. G., Christopoulos, A. 2002“Modulation of cannabinoid agonist binding by 5-HT in the rat cerebellum”J. Neurochem.8010951102CrossRefPubMedGoogle Scholar
  27. 27.
    Ortiz, T. C., Devereaux, M. C., Parker, K. K. 2000Structural variants of a human 5-HT1a receptor intracellular loop 3 peptidePharmacol.60195202CrossRefGoogle Scholar
  28. 28.
    Julius, D., Huang, K. N., Livelli, T. J., Axel, R., Jessel, T. M. 1990The 5HT2 receptor defines a family of structurally distinct but functionally conserved serotonin receptors”Proc. Natl. Acad. Sci.USA87928932PubMedGoogle Scholar
  29. 29.
    Hall, B., Burnett, A., Halley, C., Parker, L., Russo, E., Parker, K. K. 2004Pharmacology of cannabidiol at serotonin receptorsProc. West. Pharmacol. Soc.4743(M24)Google Scholar
  30. 30.
    Pierce, P. A., Peroutka, S. J. 1989Hallucinogenic drug interactions with neurotransmitter receptor binding sites in human cortex”Psychopharmacol.97118122CrossRefGoogle Scholar
  31. 31.
    Bradford, M. M. 1976A rapid sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnal. Biochem.72248254PubMedGoogle Scholar
  32. 32.
    Wieland, T., Jacobs, K. H. 1994Measurement of receptor-stimulated guanosine 5’-O-(gamma-thio)triphosphate)binding by G proteinsMeth. Enzymol.237327PubMedGoogle Scholar
  33. 33.
    Wachtel, S. R., ElSohly, M. A., Ross, R. A., Ambre, J., Wit, H. 2002Comparison of the subjective effects of delta9-tetrahydrocannabinol and marijuana in humansPsychopharmacology161331339CrossRefPubMedGoogle Scholar
  34. 34.
    McPartland, J. M., Russo, E. B. 2001Cannabis and cannabis extracts: Greater than the sum of their parts?J. Cann. Therap.1103132CrossRefGoogle Scholar
  35. 35.
    Russo, E. B., McPartland, J. M. 2003Cannabis is more than simply Delta(9)-tetrahydrocannabinolPsychopharmacology (Berl.)1654312Google Scholar
  36. 36.
    Berman, J. S., Symonds, C., Birch, R. 2004Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomized controlled trialPain112299306CrossRefPubMedGoogle Scholar
  37. 37.
    Notcutt, W., Price, M., Miller, R., Newport, S., Phillips, C., Simmonds, S., Sansome, C. 2004Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 “N of 1” studiesAnaesthesia59440452CrossRefPubMedGoogle Scholar
  38. 38.
    Wade, D. T., Makela, P., Robson, P., House, H., Bateman, C. 2004Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patientsMult. Scler.1043441CrossRefPubMedGoogle Scholar
  39. 39.
    Wade, D. T., Robson, P., House, H., Makela, P., Aram, J. 2003A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptomsClin. Rehabil.171826Google Scholar
  40. 40.
    Brady, C. M., DasGupta, R., Dalton, C., Wiseman, O. J., Berkley, K. J., Fowler, C. J. 2004An open-label pilot study of cannabis based extracts for bladder dysfunction in advanced multiple sclerosisMult. Scler.10425433CrossRefPubMedGoogle Scholar
  41. 41.
    Karniol, I. G., Shirakana, I., Kasinski, N., Pfeferman, A., Carlini, E. A. 1974“Cannabidiol Interferes With the Effects of Delta 9-Tetrahydrocannabinol in Man”Eur. J. Pharmacol.28172177CrossRefPubMedGoogle Scholar
  42. 42.
    Bisogno, T., Hanus, L., Petrocellis, L., Tchilibon, S., Ponde, D. E., Brandi, I., Moriello, A. S., Davis, J. B., Mechloulam, R., DiMarzo, V. 2001Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamideBr. J. Pharmacol.134845852CrossRefPubMedGoogle Scholar
  43. 43.
    Howlett, A.C. 2002“International union of pharmacology XXVII classification of cannabinoid receptors”Pharmacol. Rev.54161202CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Ethan B. Russo
    • 1
  • Andrea Burnett
    • 1
  • Brian Hall
    • 1
  • Keith K. Parker
    • 1
    Email author
  1. 1.Skaggs School of PharmacyThe University of MontanaMissoulaUSA

Personalised recommendations