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Agonistic Properties of Cannabidiol at 5-HT1a Receptors

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.

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  1. 1.

    E. B. Russo (2003) ArticleTitleIntroduction: Cannabis: from pariah to prescription J. Cann. Therap. 3 IssueID3–4 1–29

    Google 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 Publishers

  3. 3.

    A. W. Zuardi F. S. Guimaraes (1997) Cannabidiol as an anxiolytic and antipsychotic M. L. Mathre (Eds) Cannabis in medical practice: a legal, historical and pharmacological overview of the therapeutic use of marijuana Jefferson NC: McFarland 133–141

    Google Scholar 

  4. 4.

    E. A. Carlini J. M. Cunha (1981) ArticleTitleHypnotic and antiepileptic effects of cannabidiol J. Clin. Pharmacol. 21 IssueID8–9 Suppl 417S–427S Occurrence Handle7028792

    PubMed  Google Scholar 

  5. 5.

    A. J. Hampson M. Grimaldi J. Axelrod D. Wink (1998) ArticleTitleCannabidiol, (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants Proc. Natl. Acad. Sci. USA. 95 IssueID14 8268–73 Occurrence Handle10.1073/pnas.95.14.8268 Occurrence Handle9653176

    Article  PubMed  Google Scholar 

  6. 6.

    T. Iuvone G. Esposito R. Esposito R. Santamaria M. Di Rosa A. A. Izzo (2004) ArticleTitleNeuroprotective effect of cannabidiol, a non-psychoactive component from cannabis sativa, on beta-amyloid-induced toxicity in PC 12 cells J. Neurochem. 89 134–141 Occurrence Handle15030397

    PubMed  Google Scholar 

  7. 7.

    A. N. Nicholson C. Turner B. M. Stone P. J. Robson (2004) ArticleTitleEffect of delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adults J. Clin. Psychopharmacol. 24 IssueID3 305–313 Occurrence Handle10.1097/ Occurrence Handle15118485

    Article  PubMed  Google Scholar 

  8. 8.

    J. McPartland V. Di Marzo L. Petrocellis ParticleDe A. Mercer M. Glass (2001) ArticleTitleCannabinoid receptors are absent in insects J. Comp. Neurol. 436 IssueID4 423–9 Occurrence Handle10.1002/cne.1078 Occurrence Handle11447587

    Article  PubMed  Google Scholar 

  9. 9.

    R.G. Pertwee (1997) ArticleTitle“Pharmacology of cannabinoid CB1 and CB2 Receptors” Pharmacol. Therap. 74 IssueID2 129–180 Occurrence Handle10.1016/S0163-7258(97)82001-3

    Article  Google Scholar 

  10. 10.

    B. F. Thomas A. F. Gilliam D. F. Burch M. J. Roche H. H. Seltzman (1998) ArticleTitle“Comparative receptor binding analysis of cannabinoid agonists and antagonists” J. Pharm. Exp. Therap 285 IssueID1 285–292

    Google Scholar 

  11. 11.

    F. Petitet B. Jeantaud M. Reibaud A. Imperato M. C. Dubroeueq (1998) ArticleTitle“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. 63 1 PL1–PL6 Occurrence Handle10.1016/S0024-3205(98)00238-0

    Article  Google Scholar 

  12. 12.

    J. M. McPartland E. B. Russo (2001) ArticleTitleCannabis and Cannabis Extracts: Greater Than the Sum of Their Parts? J. Cannabis Therap. 1 IssueID3–4 103–132 Occurrence Handle10.1300/J175v01n03_08

    Article  Google Scholar 

  13. 13.

    E. B. Russo (2001) ArticleTitleHemp for headaches: An in-depth historical and scientific review of cannabis in migraine treatment J. Cannabis Therap. 1 IssueID2 21–92 Occurrence Handle10.1300/J175v01n02_04

    Article  Google Scholar 

  14. 14.

    E. B. Russo (2004) ArticleTitleClinical endocannabinoid deficiency (CECD): Can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuroendocrinol. Lett. 25 IssueID1–2 31–39 Occurrence Handle10.1159/000077721 Occurrence Handle15159679

    Article  PubMed  Google Scholar 

  15. 15.

    M. D. Ferrari P. R. Saxena (1995) ArticleTitle5-HT1 receptors in migraine pathophysiology and treatment Eur. J. Neurol. 2 5–21

    Google Scholar 

  16. 16.

    M. Hershkowitz (1978) ArticleTitle“The effect of in vivo treatment with (-) /delta 1-tetrahydrocannabinol, and other psychoactive drugs on the in vitro uptake of biogenic amines” Adv. Biosci. 22–23 351–358 Occurrence Handle756835

    PubMed  Google Scholar 

  17. 17.

    P. J. Cowen (2000) ArticleTitlePsychopharmacology of 5-HT1a receptors Nuc. Med. Biol. 27 437–439 Occurrence Handle10.1016/S0969-8051(00)00108-6

    Article  Google Scholar 

  18. 18.

    N. M. Barnes T. Sharp (1999) ArticleTitleA review of central 5-HT receptors and their function Neuropharmacol. 38 IssueID8 1083–1152 Occurrence Handle10.1016/S0028-3908(99)00010-6

    Article  Google Scholar 

  19. 19.

    A. Fargin J. R. Raymond M. J. Lohse B. K. Kobilka M. G. Caron R. J. Lefkowitz (1988) ArticleTitleThe genomic clone G-21 which resembles a beta-adrenergic receptor sequence encodes the 5-HT1a receptor Nature 335 358–360 Occurrence Handle10.1038/335358a0 Occurrence Handle3138543

    Article  PubMed  Google Scholar 

  20. 20.

    D. L. Nelson P. J. Monroe G. Lambert H. I. Yamamura (1987) ArticleTitle[3H]Spiroxatrine labels a serotonin 1a-like site in rat hippocampus” Life Sci. 41 1567–1576 Occurrence Handle10.1016/0024-3205(87)90723-5 Occurrence Handle2957559

    Article  PubMed  Google Scholar 

  21. 21.

    J. T. Weber M.-F. O’Connor K. Hayataka N. Colson R. Medora E. B. Russo K. K. Parker (1997) ArticleTitleActivity of parthenolide at 5HT2a receptors J. Nat. Prods. 60 IssueID6 651–653 Occurrence Handle10.1021/np960644d

    Article  Google Scholar 

  22. 22.

    R. A. Glennon M. Teitler E. Sanders-Bush (1992) ArticleTitleHallucinogens and serotonergic mechanisms NIDA Res. Monographs 119 131–135

    Google Scholar 

  23. 23.

    P. B. Hedlund M. J. Carson J. G. Sutcliffe E. A. Thomas (1999) ArticleTitleAllosteric regulation by oleamide of the binding properties of 5-hydroxytryptamine 7 receptors Biochem. Pharmacol. 58 1807–1813 Occurrence Handle10.1016/S0006-2952(99)00274-9 Occurrence Handle10571256

    Article  PubMed  Google Scholar 

  24. 24.

    D. L. Boger J. E. Patterson Q. Jin (1998) ArticleTitleStructural requirements for 5-HT2A and 5-HT1A serotonin receptor potentiation by the biologically active lipid oleamide Proc. Natl. Acad, Sci, USA 95 IssueID8 4102–4107

    Google Scholar 

  25. 25.

    J. F. Cheer A. K. Cadogan C. A. Marsden K. C. Fone D. A. Kendall (1999) ArticleTitle“Modification of 5HT2a receptor mediated behaviour in the rat by oleamide and the role of cannabinoid receptors” Neuropharmacol. 38 IssueID4 533–545 Occurrence Handle10.1016/S0028-3908(98)00208-1

    Article  Google Scholar 

  26. 26.

    M. G. Devlin A. Christopoulos (2002) ArticleTitle“Modulation of cannabinoid agonist binding by 5-HT in the rat cerebellum” J. Neurochem. 80 IssueID6 1095–1102 Occurrence Handle10.1046/j.0022-3042.2002.00797.x Occurrence Handle11953460

    Article  PubMed  Google Scholar 

  27. 27.

    T. C. Ortiz M. C. Devereaux K. K. Parker (2000) ArticleTitleStructural variants of a human 5-HT1a receptor intracellular loop 3 peptide Pharmacol. 60 195–202 Occurrence Handle10.1159/000028369

    Article  Google Scholar 

  28. 28.

    D. Julius K. N. Huang T. J. Livelli R. Axel T. M. Jessel (1990) ArticleTitleThe 5HT2 receptor defines a family of structurally distinct but functionally conserved serotonin receptors” Proc. Natl. Acad. Sci.USA 87 928–932 Occurrence Handle2300586

    PubMed  Google Scholar 

  29. 29.

    B. Hall A. Burnett C. Halley L. Parker E. Russo K. K. Parker (2004) ArticleTitlePharmacology of cannabidiol at serotonin receptors Proc. West. Pharmacol. Soc. 47 43–(M24)

    Google Scholar 

  30. 30.

    P. A. Pierce S. J. Peroutka (1989) ArticleTitleHallucinogenic drug interactions with neurotransmitter receptor binding sites in human cortex” Psychopharmacol. 97 118–122 Occurrence Handle10.1007/BF00443425

    Article  Google Scholar 

  31. 31.

    M. M. Bradford (1976) ArticleTitleA rapid sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding Anal. Biochem. 72 248–254 Occurrence Handle942051

    PubMed  Google Scholar 

  32. 32.

    T. Wieland K. H. Jacobs (1994) ArticleTitleMeasurement of receptor-stimulated guanosine 5’-O-(gamma-thio)triphosphate)binding by G proteins Meth. Enzymol. 237 3–27 Occurrence Handle7935006

    PubMed  Google Scholar 

  33. 33.

    S. R. Wachtel M. A. ElSohly R. A. Ross J. Ambre H. Wit Particlede (2002) ArticleTitleComparison of the subjective effects of delta9-tetrahydrocannabinol and marijuana in humans Psychopharmacology 161 331–339 Occurrence Handle10.1007/s00213-002-1033-2 Occurrence Handle12073159

    Article  PubMed  Google Scholar 

  34. 34.

    J. M. McPartland E. B. Russo (2001) ArticleTitleCannabis and cannabis extracts: Greater than the sum of their parts? J. Cann. Therap. 1 IssueID3–4 103–132 Occurrence Handle10.1300/J175v01n03_08

    Article  Google Scholar 

  35. 35.

    E. B. Russo J. M. McPartland (2003) ArticleTitleCannabis is more than simply Delta(9)-tetrahydrocannabinol Psychopharmacology (Berl.) 165 IssueID4 431–2

    Google Scholar 

  36. 36.

    J. S. Berman C. Symonds R. Birch (2004) ArticleTitleEfficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomized controlled trial Pain 112 IssueID3 299–306 Occurrence Handle10.1016/j.pain.2004.09.013 Occurrence Handle15561385

    Article  PubMed  Google Scholar 

  37. 37.

    W. Notcutt M. Price R. Miller S. Newport C. Phillips S. Simmonds C. Sansome (2004) ArticleTitleInitial experiences with medicinal extracts of cannabis for chronic pain: results from 34 “N of 1” studies Anaesthesia 59 440–452 Occurrence Handle10.1111/j.1365-2044.2004.03674.x Occurrence Handle15096238

    Article  PubMed  Google Scholar 

  38. 38.

    D. T. Wade P. Makela P. Robson H. House C. Bateman (2004) ArticleTitleDo cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients Mult. Scler. 10 IssueID4 434–41 Occurrence Handle10.1191/1352458504ms1082oa Occurrence Handle15327042

    Article  PubMed  Google Scholar 

  39. 39.

    D. T. Wade P. Robson H. House P. Makela J. Aram (2003) ArticleTitleA preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms Clin. Rehabil. 17 18–26

    Google Scholar 

  40. 40.

    C. M. Brady R. DasGupta C. Dalton O. J. Wiseman K. J. Berkley C. J. Fowler (2004) ArticleTitleAn open-label pilot study of cannabis based extracts for bladder dysfunction in advanced multiple sclerosis Mult. Scler. 10 425–433 Occurrence Handle10.1191/1352458504ms1063oa Occurrence Handle15327041

    Article  PubMed  Google Scholar 

  41. 41.

    I. G. Karniol I. Shirakana N. Kasinski A. Pfeferman E. A. Carlini (1974) ArticleTitle“Cannabidiol Interferes With the Effects of Delta 9-Tetrahydrocannabinol in Man” Eur. J. Pharmacol. 28 IssueID1 172–177 Occurrence Handle10.1016/0014-2999(74)90129-0 Occurrence Handle4609777

    Article  PubMed  Google Scholar 

  42. 42.

    T. Bisogno L. Hanus L. Petrocellis ParticleDe S. Tchilibon D. E. Ponde I. Brandi A. S. Moriello J. B. Davis R. Mechloulam V. DiMarzo (2001) ArticleTitleMolecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide Br. J. Pharmacol. 134 IssueID4 845–852 Occurrence Handle10.1038/sj.bjp.0704327 Occurrence Handle11606325

    Article  PubMed  Google Scholar 

  43. 43.

    A.C. Howlett (2002) ArticleTitle“International union of pharmacology XXVII classification of cannabinoid receptors” Pharmacol. Rev. 54 IssueID2 161–202 Occurrence Handle10.1124/pr.54.2.161 Occurrence Handle12037135

    Article  PubMed  Google Scholar 

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Correspondence to Keith K. Parker.

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Russo, E.B., Burnett, A., Hall, B. et al. Agonistic Properties of Cannabidiol at 5-HT1a Receptors. Neurochem Res 30, 1037–1043 (2005).

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  • Cannabis
  • cannabidiol
  • cAMP
  • G Proteins
  • marijuana
  • serotonin
  • THC