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Phytocannabinoids: Cannabidiol (CBD)

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Cannabinoids and Pain

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Abstract

Cannabinoids are chemicals either derived from cannabis (phytocannabinoids) like cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC); synthetic medications like nabilone, dronabinol, and rimonabant; or endogenous chemicals that stimulate cannabinoid receptors. Phytocannabinoids consist of natural products capable of either interacting directly with cannabinoid receptors or sharing chemical similarity with endocannabinoids or both. The two most studied phytocannabinoids are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD is a non-intoxicating phytocannabinoid and has low affinity to cannabinoid receptors. It acts as a partial antagonist of CB1R and as a weak inverse agonist of CB2R. CBD also interacts with other non-cannabinoid targets, including serotonin 1A receptor (or 5-TH1A), vanilloid receptor 1 (TRPV1), and adenosine A2A receptors, which regulates perception of pain. CBD has been associated with analgesic, anti-inflammatory, anticonvulsant, anxiolytic, and antipsychotic effects. CBD works synergistically with THC for its analgesic effect while decreasing its psychoactive and cognitive side effects such as sedation and memory impairment of THC. Further studies are required to validate the medicinal applications of CBD.

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References

  1. Zuardi AW. History of cannabis as a medicine: a review. Rev Bras Psiquiatr. 2006;28(2):153–7.

    Article  PubMed  Google Scholar 

  2. Fankhauser M. Chapter 4, History of cannabis in western medicine. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids. New York: The Haworth Integrative Healing Press; 2002. p. 37–51.

    Google Scholar 

  3. Gertsch J. Pertwee RG, Vincenzo DM, Phytocannabinoids beyond the Cannabis plant – do they exist? Br J Pharmacol. 2010;160(3):523–9.

    Google Scholar 

  4. Lewis MA, Russo EB, Smith KM. Pharmacological Foundations of Cannabis Chemovars. Planta Med. 2018;84(4):225–33. https://doi.org/10.1055/s-0043-122240.

    Article  CAS  PubMed  Google Scholar 

  5. Mechoulam R, Shvo Y. The structure of cannabidiol. Tetrahedron. 1963;19:2073–8.

    Article  CAS  PubMed  Google Scholar 

  6. Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond Ser B Biol Sci. 2012;367:3364–78.

    Article  CAS  Google Scholar 

  7. Vuckovic. Cannabinoids and pain: new insights from old molecules. Front Pharmacol. 2018;9:1259. Published online 2018 Nov 13.

    Article  CAS  Google Scholar 

  8. EPIDIOLEX (cannabidiol) oral solution. FDA product monograph https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf.

  9. Product monograph, including patient medication information, PrSATIVEX®, consulted on June 10th 2020. https://pdf.hres.ca/dpd_pm/00054388.PDF.

  10. Meng H, Johnston B, Englesakis M, Moulin DE, Bhatia A. Selective cannabinoids for chronic neuropathic pain: a systematic review and meta-analysis. Anesth Analg. 2017;125(5):1638–52.

    Article  CAS  PubMed  Google Scholar 

  11. Stockings E, Campbell G, Hall WD, Nielsen S, Zagic D, Rahman R, Murnion B, Farrell M, Weier M, Degenhardt L. Cannabis and cannabinoids for the treatment of people with chronic noncancer pain conditions: a systematic review and meta-analysis of controlled and observational studies. Pain. 2018;159(10):1932–54.

    Article  CAS  PubMed  Google Scholar 

  12. Johal H, Devji T, Chang Y, Simone J, Vannabouathong C, Bhandari M. Cannabinoids in chronic non-cancer pain: a systematic review and meta-analysis. Clin Med Insights Arthritis Musculoskelet Disord. 2020;13:1179544120906461.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Boland EG, Bennett MI, Allgar V, Boland JW. Cannabinoids for adult cancer-related pain: systematic review and meta-analysis. BMJ Support Palliat Care. 2020;10:14–24.

    Article  PubMed  Google Scholar 

  14. Häuser W, Welsch P, Klose P, et al. Efficacy, tolerability and safety of cannabis-based medicines for cancer pain: a systematic review with meta-analysis of randomised controlled trials. Schmerz. 2019;33:424–36.

    Article  PubMed  Google Scholar 

  15. Bruni N, Della Pepa C, Oliaro-Bosso S, Pessione E, Gastaldi D, Dosio F. Cannabinoid delivery systems for pain and inflammation treatment. Molecules. 2018;23(10):2478.

    Article  PubMed Central  CAS  Google Scholar 

  16. Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol. 2015;172(20):4790–805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Δ(9)-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172:737–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tham M, Yilmaz O, Alaverdashvili M, Kelly MEM, Denovan-Wright EM, Laprairie RB. Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. Br J Pharmacol. 2018;176:1455.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Campos AC, Guimarães FS. Evidence for a potential role for TRPV1 receptors in the dorsolateral periaqueductal gray in the attenuation of the anxiolytic effects of cannabinoids. Prog Neuro-Psychopharmacol Biol Psychiatry. 2009;33:1517–21.

    Article  CAS  Google Scholar 

  20. Linge R, Jiménez-Sánchez L, Campa L, Pilar-Cuéllar F, Vidal R, Pazos A, Adell A, Díaz Á. Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors. Neuropharmacology. 2016;103:16–26,ISSN 0028-3908. https://doi.org/10.1016/j.neuropharm.2015.12.017.

    Article  CAS  PubMed  Google Scholar 

  21. Pertwee RG, Ross RA, Craib SJ, Thomas A. (−)-Cannabidiol antagonizes cannabinoid receptor agonists and noradrenaline in the mouse vas deferens. Eur J Pharmacol. 2002;456:99–106.

    Article  CAS  PubMed  Google Scholar 

  22. Zhornitsky S, Potvin S. Cannabidiol in humans-the quest for therapeutic targets. Pharmaceuticals (Basel). 2012;5(5):529–52.

    Article  CAS  Google Scholar 

  23. Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E. Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn Schmiedeberg's Arch Pharmacol. 2006;372(5):354–61.

    Article  CAS  Google Scholar 

  24. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199–215.

    Article  CAS  PubMed  Google Scholar 

  25. Russo E, Guy GW. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses. 2006;66(2):234–46.

    Article  CAS  PubMed  Google Scholar 

  26. Laun AS, Shrader SH, Brown KJ, Song ZH. GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol. Acta Pharmacol Sin. 2019;40(3):300–8.

    Article  CAS  PubMed  Google Scholar 

  27. Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol. 2007;152(7):1092–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Schauer GL, King BA, Bunnell RE, Promoff G, McAfee TA. Toking, vaping, and eating for health or fun: Marijuana use patterns in adults, U.S., 2014. Am J Prev Med. 2016;50:1–8.

    Article  PubMed  Google Scholar 

  29. Subritzky T, Pettigrew S, Lenton S. Issues in the implementation and evolution of the commercial recreational cannabis market in Colorado. Int J Drug Policy. 2016;27:1–12.

    Article  Google Scholar 

  30. Russell C, Rueda S, Room R, Tyndall M, Fischer B. Routes of administration for cannabis use–basic prevalence and related health outcomes: a scoping review and synthesis. Int J Drug Policy. 2018;52:87–96.

    Article  PubMed  Google Scholar 

  31. Geshtakovska G, Stefkov G. Routes of cannabis administration: a brief review. Macedonian Pharm Bull. 2016;62:515–6.

    Google Scholar 

  32. Varlet V, Concha-Lozano N, Berthet A, Plateel G, Favrat B, De Cesare M, Lauer E, Augsburger M, Thomas A, Giroud C. Drug vaping applied to cannabis: is “cannavaping” a therapeutic alternative to marijuana? Sci Rep. 2016;6:25599.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. VanDolah HJ, Bauer B, Mauck K. Clinicians’ guide to Cannabidiol and Hemp oils. Mayo Clin Proc. 2019;94(9):1840–51. Epub 2019 Aug 22

    Article  CAS  PubMed  Google Scholar 

  34. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Callaway JC. Hempseed as a nutritional resource: an overview. Euphytica. 2004;140(1-2):65–72.

    Article  Google Scholar 

  36. Grof CPL. Cannabis, from plant to pill. Br J Clin Pharmacol. 2018;84(11):2463–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ohlsson A, Lindgren JE, Wahlen A, et al. Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Ther. 1980;28(3):409–16.

    Article  CAS  PubMed  Google Scholar 

  38. Ridgeway G, Kilmer B. Bayesian interference for the distribution of grams of marijuana in a joint. Drug Alcohol Depend. 2016;165:175–80.

    Article  PubMed  Google Scholar 

  39. Abrams DI, Vizoso HP, Shade SB, Jay C, Kelly ME, Benowitz NL. Vaporization as a smokeless cannabis delivery system: a pilot study. Clin Pharmacol Ther. 2007;82(0009-9236; 5):572–8.

    Article  CAS  PubMed  Google Scholar 

  40. Ohlsson A, Lindgren JE, Andersson S, Agurell S, Gillespie H, Hollister LE. Single-dose kinetics of deuterium-labelled cannabidiol in man after smoking and intravenous administration. Biomed Environ Mass Spectrom. 1986;13(2):77–83.

    Article  CAS  PubMed  Google Scholar 

  41. Harvey DJ. Chapter 2, Absorption, distribution and biotransformation of the cannabinoids. In: Nahas CG, Sutin KM, Harvey DJ, Agurell S, editors. Marihuana and medicine. Totowa, New Jersey: Humana Press; 1999. page 94.

    Google Scholar 

  42. Agurell S, Carlsson S, Lindgren JE, Ohlsson A, Gillespie H, Hollister L. Interactions of delta 1-tetrahydrocannabinol with cannabinol and cannabidiol following oral administration in man. assay of cannabinol and cannabidiol by mass fragmentography. Experientia. 1981;37(10):1090–2.

    Article  CAS  PubMed  Google Scholar 

  43. Consroe P, Kennedy K, Schram K. Assay of plasma cannabidiol by capillary gas chromatography/ion trap mass spectroscopy following high-dose repeated daily oral administration in humans. Pharmacol Biochem Behav. 1991;40(3):517–22.

    Article  CAS  PubMed  Google Scholar 

  44. Zgair A, Lee JB, Wong JCM, et al. Oral administration of cannabis with lipids leads to high levels of cannabinoids in the intestinal lymphatic system and prominent immunomodulation. Sci Rep. 2017;7(1):14542. Published 2017 Nov 6. https://doi.org/10.1038/s41598-017-15026-z.

    Article  CAS  Google Scholar 

  45. Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007;4(1612-1880; 1612-1872; 8):1770–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Stinchcomb AL, Valiveti S, Hammell DC, Ramsey DR. Human skin permeation of Delta8-tetrahydrocannabinol, cannabidiol and cannabinol. J Pharm Pharmacol. 2004;56(0022-3573; 0022-3573; 3):291–7.

    CAS  PubMed  Google Scholar 

  47. Giacoppo S, Galuppo M, Pollastro F, Grassi G, Bramanti P, Mazzon E. A new formulation of cannabidiol in cream shows therapeutic effects in a mouse model of experimental autoimmune encephalomyelitis. Daru. 2015;23:48,015-0131-8.

    Article  CAS  Google Scholar 

  48. Paudel KS, Hammell DC, Agu RU, Valiveti S, Stinchcomb AL. Cannabidiol bioavailability after nasal and transdermal application: effect of permeation enhancers. Drug Dev Ind Pharm. 2010;36(9):1088–97.

    Article  CAS  PubMed  Google Scholar 

  49. Hindocha C, Freeman TP, Ferris JA, Lynskey MT, Winstock AR. No smoke without tobacco: a global overview of cannabis and tobacco routes of administration and their association with intention to quit. Front Psych. 2016;7:104.

    Google Scholar 

  50. Agurell S, Halldin M, Lindgren JE, Ohlsson A, Widman M, Gillespie H, Hollister L. Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev. 1986;38:21–43.

    CAS  PubMed  Google Scholar 

  51. Harvey DJ, Martin BR, WDM P. In: Nahas GG, Paton WDM, editors. Marijuana: Biological Effects. Oxford: Pergamon Press; 1979. p. 45.

    Chapter  Google Scholar 

  52. Wall ME, Brine DR, Perez-Reyes M. In: Braude MC, Szara S, editors. The pharmacology of marihuana. New York: Raven Press; 1976. p. 93.

    Google Scholar 

  53. Ujvary I, Hanus L. Human metabolites of cannabidiol: a review on their formation, biological activity, and relevance in therapy. Cannabis Cannabinoid Res. 2016;1(1):90–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf. 2011;6(4):237–49.

    Article  CAS  PubMed  Google Scholar 

  55. Rosenkrantz H, Fleischman RW, Grant RJ. Toxicity of short-term administration of cannabinoids to rhesus monkeys. Toxicol Appl Pharmacol. 1981;30:118–31.

    Article  Google Scholar 

  56. Szaflarski JP, Bebin EM, Comi AM, Patel AD, Joshi C, Checketts D, Beal JC, Laux LC, De Boer LM, Wong MH, Lopez M, Devinsky O, Lyons PD, Zentil PP, Wechsler R. CBD EAP study group. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: expanded access program results. Epilepsia. 2018;59:1540–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Klein C, Karanges E, Spiro A, Wong A, Spencer J, Huynh T, Gunasekaran N, Karl T, Long LE, Huang XF, et al. Cannabidiol potentiates delta(9)-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats. Psychopharmacology. 2011;218(2):443–57.

    Article  CAS  PubMed  Google Scholar 

  58. Nadulski T, Pragst F, Weinberg G, Roser P, Schnelle M, Fronk EM, Stadelmann AM. Randomized, double-blind, placebo-controlled study about the effects of cannabidiol (CBD) on the pharmacokinetics of Delta9-tetrahydrocannabinol (THC) after oral application of THC versus standardized cannabis extract. Ther Drug Monit. 2005;27(0163-4356; 0163-4356; 6):799–810.

    Article  CAS  PubMed  Google Scholar 

  59. Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology. 1982;76(3):245–50.

    Article  CAS  PubMed  Google Scholar 

  60. Karniol IG, Shirakawa I, Kasinski N, Pfeferman A, Carlini EA. Cannabidiol interferes with the effects of delta 9 - tetrahydrocannabinol in man. Eur J Pharmacol. 1974;28(0014-2999; 0014-2999; 1):172–7.

    Article  CAS  PubMed  Google Scholar 

  61. Paton WD, Pertwee RG. Effect of cannabis and certain of its constituents on pentobarbitone sleeping time and phenazone metabolism. Br J Pharmacol. 1972;44:250–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Jones G, Pertwee RG. A metabolic interaction in vivo between cannabidiol and 1-tetrahydrocannabinol. Br J Pharmacol. 1972;45:375–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zuardi AW, Hallak JE, Crippa JA. Interaction between cannabidiol (CBD) and (9)-tetrahydrocannabinol (THC): influence of administration interval and dose ratio between the cannabinoids. Psychopharmacology. 2012;219(1432-2072; 0033-3158; 1):247–9.

    Article  CAS  PubMed  Google Scholar 

  64. Zuardi AW, Karniol IG. Pharmacological interaction between 9-tetrahydrocannabinol and cannabidiol, two active constituents of Cannabis sativa. Ciência e Cultura. 1984;36(6):386–94.

    CAS  Google Scholar 

  65. Bhattacharyya S, Morrison PD, Fusar-Poli P, Martin-Santos R, Borgwardt S, Winton-Brown T, Nosarti C, O' Carroll CM, Seal M, Allen P, Mehta MA, Stone JM, Tunstall N, Giampietro V, Kapur S, Murray RM, Zuardi AW, Crippa JA, Atakan Z, McGuire PK. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology. 2010;35:764–74.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Anesthesia and Pain Management, Toronto General Hospital, University of Toronto, Toronto, ON, Canada

    Priodarshi Roychoudhury

  2. Department of Anesthesia and Pain Management, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada

    Ning Nan Wang

  3. Western Reserve Hospital, Center For Pain Medicine, Cuyahoga Falls, OH, USA

    Samer N. Narouze

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  1. Priodarshi Roychoudhury
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  1. Western Reserve Hospital, Center For Pain Medicine, Cuyahoga Falls, OH, USA

    Samer N. Narouze

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Roychoudhury, P., Wang, N.N., Narouze, S.N. (2021). Phytocannabinoids: Cannabidiol (CBD). In: Narouze, S.N. (eds) Cannabinoids and Pain. Springer, Cham. https://doi.org/10.1007/978-3-030-69186-8_11

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