Cannabinoids in Clinical Practice

Abstract

Cannabis has a potential for clinical use often obscured by unreliable and purely anecdotal reports. The most important natural cannabinoid is the psychoactive tetrahydrocannabinol (Δ9-THC); others include cannabidiol (CBD) and cannabigerol (CBG). Not all the observed effects can be ascribed to THC, and the other constituents may also modulate its action; for example CBD reduces anxiety induced by THC. A standardised extract of the herb may be therefore be more beneficial in practice and clinical trial protocols have been drawn up to assess this. The mechanism of action is still not fully understood, although cannabinoid receptors have been cloned and natural ligands identified.

Cannabis is frequently used by patients with multiple sclerosis (MS) for muscle spasm and pain, and in an experimental model of MS low doses of cannabinoids alleviated tremor. Most of the controlled studies have been carried out with THC rather than cannabis herb and so do not mimic the usual clincal situation. Small clinical studies have confirmed the usefulness of THC as an analgesic; CBD and CBG also have analgesic and antiinflammatory effects, indicating that there is scope for developing drugs which do not have the psychoactive properties ofTHC. Patients taking the synthetic derivative nabilone for neurogenic pain actually preferred cannabis herb and reported that it relieved not only pain but the associated depression and anxiety. Cannabinoids are effective in chemotherapy-induced emesis and nabilone has been licensed for this use for several years. Currently, the synthetic cannabinoid HU211 is undergoing trials as a protective agent after brain trauma. Anecdotal reports of cannabis use include case studies in migraine and Tourette’s syndrome, and as a treatment for asthma and glaucoma.

Apart from the smoking aspect, the safety profile of cannabis is fairly good. However, adverse reactions include panic or anxiety attacks, which are worse in the elderly and in women, and less likely in children. Although psychosis has been cited as a consequence of cannabis use, an examination of psychiatric hospital admissions found no evidence of this, however, it may exacerbate existing symptoms. The relatively slow elimination from the body of the cannabinoids has safety implications for cognitive tasks, especially driving and operating machinery; although driving impairment with cannabis is only moderate, there is a significant interaction with alcohol.

Natural materials are highly variable and multiple components need to be standardised to ensure reproducible effects. Pure natural and synthetic compounds do not have these disadvantages but may not have the overall therapeutic effect of the herb.

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References

  1. 1.

    Formukong EA, Evans AT, Evans FJ. The medicinal uses of cannabis and its constituents. Phytother Res 1989; 3(6): 219–31

    Article  CAS  Google Scholar 

  2. 2.

    Mechoulam R, Ben-Shabat S. From gan-zi-gun-nu to anandamide and 2 — arachidonoylglycerol: the ongoing story of cannabis. Nat Prod Rep 1999; 16: 131–43

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Evans FJ. The medicinal chemistry of cannabis: O’S-haughnessy’s legacy. Pharmaceutical Sci 1997; 3: 533–7

    CAS  Google Scholar 

  4. 4.

    Gurley RJ, Aranow R, Katz M. Medicinal marijuana: a review. J Psychoactive Drugs 1998; 30(2): 37–147

    Article  Google Scholar 

  5. 5.

    Hirst RA, Lambert DG, Notcutt WG. Pharmacology and potential therapeutic uses of cannabis. Br J Anaesth 1998; 81: 77–84

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Pertwee RG. Cannabis and cannabinoids: pharmacology and rationale for clinical use. Pharmaceutical Sci 1997; 3: 539–45

    CAS  Google Scholar 

  7. 7.

    Fairbairn JW, Hindmarch I, Simic S, et al. Cannabinoid content of some English reefers. Nature 1974; 249: 277–8

    Article  Google Scholar 

  8. 8.

    De Witt H, Wachtel S. Comparison of whole plant marijuana and Δ9THC in human volunteers. Symposium on the Cannabinoids; 1999 Jun 18–20: Acapulco. Burlington (VT): International Cannabinoid Research Society, 1999: 74

    Google Scholar 

  9. 9.

    Petitet F, Jeantaud B, Rebaude M, et al. Complex pharmacology of natural cannabinoids: Evidence for partial agonist activity of Δ9 tetrahydrocannabinol and antagonist activity of canna-bidiol on rat brain cannabinoid receptors. Life Sci 1998; 63; PL1–6

    PubMed  Article  CAS  Google Scholar 

  10. 10.

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

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Bornhein LM, Reid M. Influence of cannabinoids on brain levels of other drugs. Symposium on the Cannabinoids; 1999 Jun 18–20: Acapulco. Burlington (VT): International Cannabinoid Research Society, 1999: 84

    Google Scholar 

  12. 12.

    Working Party of the Pharmaceutical Society of Great Britain. Working Party on the therapeutic uses of cannabis: launch of the protocols for the clinical trials of cannabinoids. London: The Pharmaceutical Society of Great Britain, Jan 1999

    Google Scholar 

  13. 13.

    Llamas R, Hart R, Schneider N. Allergic bronchopulmonary aspergillosis associated with smoking moldy marijuana. Chest 1978; 6: 871–2

    Article  Google Scholar 

  14. 14.

    Matsuda LA, Lolait SJ, Brownstein MJ, et al. Structure of a cannabinoid receptor and functional expression of the cloned DNA. Nature 1990; 346: 561–4

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992; 258: 1946–9

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Monroe S, Thomas KL, Abu-Shaar M. Molecular characterisation of a peripheral receptor for cannabinoids. Nature 1993; 365: 61–5

    Article  Google Scholar 

  17. 17.

    Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that bonds to cannabinoid receptors. Biochem Pharmacol 1995; 50: 83–90

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Mechoulam R, Fride, E, Hanus L, et al. Anandamide may mediate sleep induction. Nature 1997; 389: 25–6

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Randall MD, McCulloch AI, Kendall DA. Comparative pharmacology of endothelium-derived hyperpolarizing factor and anandamide in rat isolated mesentery. Eur J Pharmacol 1997; 333(2–3): 191–7

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Fride E, Barg J, Levy D, et al. Low doses of anandamide inhibit pharmacological effects of Δ9 tetrahydrocannabinol. J Pharmacol Exp Ther 1995; 272: 699–707

    PubMed  CAS  Google Scholar 

  21. 21.

    Di Marzo V, Melck D, Bosogno T, et al. Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci 1998; 21(12): 521–8

    PubMed  Article  Google Scholar 

  22. 22.

    Consroe P. Brain cannabinoid systems as targets for the therapy of neurological disorders. Neurobiol Dis 1998; 5: 534–51

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Evans FJ. Cannabinoids: the separation of central from peripheral effects on a structural basis. Planta Med 1991; 57 Suppl.: 60–7

    Article  Google Scholar 

  24. 24.

    Formukong E, Garland LG, Evans AT, et al. Inhibition of A23187 induced release of CTB4 in mouse blood in vivo and human polymorphonuclear cells in vitro by analgesic cannabidiol. Phytother Res 1991; 5: 258–61

    Article  CAS  Google Scholar 

  25. 25.

    Morgan DR, editor. Therapeutic uses of cannabis: British Medical Association. Netherlands: Harwood Academic Publishers, 1997

    Google Scholar 

  26. 26.

    Select Committee on Science and Technology. Cannabis: the scientific and medical evidence. The House of Lords Session 1997–8. 9th report [HL paper 151]. London: The Stationary Office, 1998

    Google Scholar 

  27. 27.

    Clifford DB. Tetrahydrocannabinol for tremor in multiple sclerosis. Ann Neurol 1983; 13: 669–71

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Brenneisen R, Egli MA, Elsohly V, et al. The effect of orally and rectally administered delta-9-THC on spasticity: a pilot study with two patients. Int J Clin Pharmacol Ther 1996; 34: 446–52

    PubMed  CAS  Google Scholar 

  29. 29.

    Ungerleider JT, Andyrsiak T, Fairbanks L, et al. Δ9-THC in the treatment of spasticity associated with multiple sclerosis. Adv Alcohol Subst Abuse 1987; 7: 39–50

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Consroe P, Musty R, Rein R, et al. The perceived effects of smoked cannabis on patients with MS. Eur Neurol 1997; 38: 44–7

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Schon F, Hart P, Hodgson TR, et al. Suppression of Pendular Nystagmus by cannabis in a patient with multiple sclerosis. Neurology 1999; 53: 2209–10

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Willis S. The use of cannabis in multiple sclerosis. Pharm J 1995; 255: 237–8

    Google Scholar 

  33. 33.

    Formukong EA, Evans AT, Evans FJ. Inhibition of the cataleptic effects of Δ9-THC by other constituents of Cannabis sativa. J Pharm Pharmacol 1988; 40: 132–43

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Martyn CN, Illis LS, Thorn J. Nabilone in the treatment of multiple sclerosis. Lancet 1995; 345: 579

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Greenberg HS, Werness SAS, Pugh JE, et al. Short-term effects of smoking marihuana on balance in patients with multiple sclerosis and normal volunteers. Clin Pharmacol Ther 1994; 55: 324–8

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Meinck H, Schonle P, Conrad B. Effect of cannabinoids on spasticity and ataxia in multiple sclerosis. J Neurol 1989; 236: 120–2

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Consroe P, Sandyk R, Snider SR. Open label evaluation of cannabidiol in dystonic movement disorders. Int J Neurosci 1986; 30: 277–82

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Sandyk R, Snider SR, Consroe P, et al. Cannabidiol in dystonic movement disorders [letter]. Psychiatry Res 1986; 18(3): 291

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Snider SR, Consroe P. Treatment of Meige’s syndrome with cannabidiol. Neurology 1984; 34 Suppl.: 147

    Google Scholar 

  40. 40.

    Muller-Vahl K, Schneider U, Emrich HM. Nabilone increases choreatic movements in Huntingdon’s disease. Mov Disord 1999; 14(6): 1038–40

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Frankel JP, Hughes A, Lees AJ, et al. Marijuana for Parkinsonian tremor [letter]. J Neurol Neurosurg Psychiatry 1990; 53: 436

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Noyes R, Brunk ST, Avery DH, et al. The analgesic properties of Δ9-THC and codeine. Clin Pharmacol Ther 1975; 18: 84–9

    PubMed  Google Scholar 

  43. 43.

    Holdcroft A, Smith M, Jacklin A, et al. Pain relief with oral cannabinoids in familial Mediterranean fever. Anaesthesia 1997; 52: 483–8

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Notcutt WG, Price M, Chapman G. Clinical experience with nabilone for chronic pain. Pharm Sci 1997; 3: 551–5

    CAS  Google Scholar 

  45. 45.

    Formukong EA, Evans AT, Evans FJ. Analgesic and anti-inflammatory activity of the constituents of Cannabis sativa. Inflammation 1988; 12: 361–71

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    El-Mallakh R. Marijuana and migraine. Headache 1987; 27: 442–3

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Formukong EA, Evans AT, Evans FJ. The inhibitory effects of cannabinoids, the active constituents of Cannabis sativa on human and rabbit platelet aggregation. J Pharm Pharmacol 1989; 41: 705–9

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Martin BR, Lichtman AH. Cannabinoid transmission and pain perception. Neurobiol Dis 1998; 5: 447–61

    PubMed  Article  CAS  Google Scholar 

  49. 49.

    Hill SY, Schwin R, Goodwin DW, et al. Marijuana and pain. J Pharmacol Exp Ther 1974; 188: 415–18

    PubMed  CAS  Google Scholar 

  50. 50.

    Clark WC, Janal MN, Zeidenberg P, et al. Effects of moderate and high doses of marihuana on thermal pain: a sensory decision theory analysis. J Clin Pharmacol 1981; 21: 299S–310

    PubMed  CAS  Google Scholar 

  51. 51.

    Hampson AJ, Grimaldi M, Axelrod J, et al. Cannabidiol and ((−)-Δ9 tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A 1998; 95: 8268–73

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    French ED, Dillon K, Wu X. Cannabinoids excite dopamine neurons in the ventral tegmentum and substantia nigra. Neuroreport 1997; 8: 649–52

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Sandyk R, Awerbuch G. Marijuana and Tourette’s syndrome. J Clin Psychopharmacol 1988; 8: 444–5

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Hemming M, Yellowlees PM. Effective treatment of Tourett’s syndrome with marijuana. J Psychopharmacol 1993; 7: 389–91

    PubMed  Article  CAS  Google Scholar 

  55. 55.

    Muller-Vahl KR, Kolbe H, Schneider U, et al. Cannabinoids: possible role in pathophysiology and therapy of Gilles de la Tourette syndrome. Acta Psychiatrica Scand 1998; 98(6): 502–6

    Article  CAS  Google Scholar 

  56. 56.

    Muller-Vahl KR, Kolbe H, Dengler R. Gilles de la Tourette syndrome: influence of nicotine, alcohol and marijuana on the classical symptoms. Nervenartz 1997; 68(12): 985–9

    Article  CAS  Google Scholar 

  57. 57.

    Muller-Vahl K, Schneider U, Kolbe H, et al. Treatment of Tourette’s syndrome with delta-9-tetrahydrocannabinol. Am J Psychiatry 1999; 156(3): 495

    PubMed  CAS  Google Scholar 

  58. 58.

    Gruber AJ, Pope HG, Brown ME. Do patients use marijuana as an antidepressant? Depression 1996; 4(2): 77–80

    PubMed  Article  CAS  Google Scholar 

  59. 59.

    Fishman SM, Rosenbaum JF, Yabusaki DI, et al. Marijuana-related anxiety: a questionnaire based pilot study of normal and psychiatric populations. Res Comm Subst Abuse 1988; 9(3–4): 219–26

    Google Scholar 

  60. 60.

    Musty RE, Kaback L. Relationship between motivation and depression in chronic marijuana users. Life Sci 1995; 56(23–24): 2151–8

    PubMed  Article  CAS  Google Scholar 

  61. 61.

    Grinspoon L, Bahalar JB. The use of cannabis as a mood stabilizer in bipolar disorder: anecdotal evidence and the need for clinical research. J Psychoactive Drugs 1998; 30(2): 171–7

    PubMed  Article  CAS  Google Scholar 

  62. 62.

    Gruber A, Pope H. Cannabis psychotic disorder: does it exist? Am J Addict 1994; 3: 72–83

    Google Scholar 

  63. 63.

    Pope H, Gruber A, Yurgelan-Todd D. The residual neuropsychological effects of cannabis: the current status of research. Drug Alcohol Depend 1995; 38: 25–34

    PubMed  Article  Google Scholar 

  64. 64.

    Ries R K. The dually diagnosed patient with psychotic symptoms. J Addict Dis 1993; 12(3): 103–122

    PubMed  Article  CAS  Google Scholar 

  65. 65.

    Leweke FM, Guiffrida A, Wurster U, et al. Elevated endogenous cannabinoids in schizophrenia. Neuroreport. 1999; 10(8): 1665–9

    PubMed  Article  CAS  Google Scholar 

  66. 66.

    Emrich HM, Leweke FM, Scheiner U. Pharmacol Biochem Behav 1997; 56(4): 803–7

    PubMed  Article  CAS  Google Scholar 

  67. 67.

    Zuardi AW, Rodrigues J, Cunha JM. Effects of cannabidiol in animal models predictive of antipsychotic activity. Psycho-pharmacology 1991; 104(2): 260–4

    CAS  Google Scholar 

  68. 68.

    Zuardi AW, Morais SL, Guimares FS, et al. Antipsychotic effect of cannabidiol. J Clin Psychiatry 1995; 56(10): 485–6

    PubMed  CAS  Google Scholar 

  69. 69.

    Wagner J, Varga K, Kunos G. Cardiovascular actions of the cannabinoids and their generation during shock. J Mol Med 1998; 76: 824–36

    PubMed  Article  CAS  Google Scholar 

  70. 70.

    Adams MD, Earnhard JT, Martin BR, et al. Acannabinoid with cardiovascular activity but no overt behavioural effects. Experientia 1977; 33: 1204–5

    PubMed  Article  CAS  Google Scholar 

  71. 71.

    Hepler RS, Frank IM. Marijuana smoking and intraocular pressure. JAMA 1971; 217: 1392–4

    PubMed  Article  CAS  Google Scholar 

  72. 72.

    Green K, Wynn H, Bowman KA. A comparison of topical cannabinoids on the intraocular pressure. Exp Eye Res 1978; 27: 239–46

    PubMed  Article  CAS  Google Scholar 

  73. 73.

    Maor D, Trevess T, Korczyn AD. Lack of effect of cannabinoids on carbonic anhydrase. J Neural Transm 1980; 49: 205–6

    PubMed  Article  CAS  Google Scholar 

  74. 74.

    Merritt JC, Perry DD, Russell DN, et al. Topical Δ9 tetrahydrocannabinol and aqueous humor dynamics in glaucoma. J Clin Pharmacol 1981; 21 (8–9 Suppl.): 467S–71

    PubMed  CAS  Google Scholar 

  75. 75.

    Green K. Marijuana smoking vs cannabinoids for glaucoma therapy. Arch Ophthalmol 1998; 116(11): 433–1437

    Google Scholar 

  76. 76.

    Chang A, Shiling D, Stillman R, et al. Δ9 tetrahydrocannabinol as an antiemetic in cancer patients receiving high dose methotrexate. Ann Intern Med 1979; 91: 819–24

    PubMed  CAS  Google Scholar 

  77. 77.

    McCabe M, Smith F, Macdonald J, et al. Efficacy of tetrahydrocannabinol in patients refractory to standard antiemetic therapy. Invest New Drugs 1988; 6: 243–6

    PubMed  Article  CAS  Google Scholar 

  78. 78.

    Tortorice P, O’Connell M. Management of chemotherapy-induced nausea and vomiting. Pharmacotherapy 1990; 10(2): 129–45

    PubMed  CAS  Google Scholar 

  79. 79.

    Cunningham D, Bradley C, Forrest G, et al. A randomized trial of oral nabilone and prochlorperazine compared to intravenous metoclopramide and dexamethasone in the treatment of nausea and vomiting induced by chemotherapy regimens containing cisplatin or cisplatin analogs. Eur J Cancer Clin Oncol 1988; 24: 685–9

    PubMed  Article  CAS  Google Scholar 

  80. 80.

    Abrahamov A, Abrahamov A, Mechoulam R. An efficient new cannabinoid antiemetic in pediatric oncology. Life Sci 1995; 56(23–24): 2097–102

    PubMed  Article  CAS  Google Scholar 

  81. 81.

    Cat L, Coleman D. DIAS rounds: treatment for HIV wasting syndrome. Ann Pharmacother 1994; 28: 505–7

    Google Scholar 

  82. 82.

    Plasse TF, Gorter RW, Krasnow SH, et al. Recent clinical experience with dronabinol. Pharmacol Biochem Behav 1991; 40: 695–700

    PubMed  Article  CAS  Google Scholar 

  83. 83.

    Beale JE, Olson R, Laubenstein L, et al. J Pain Symptom Manage 1995; 10(2): 89–97

    Article  Google Scholar 

  84. 84.

    Abboud R, Sanders H. Effect of oral administration of delta-9-tetrahydrocannabinol on airway mechanics in normal and asthmatic subjects. Chest 1976; 70: 480–5

    PubMed  Article  CAS  Google Scholar 

  85. 85.

    Williams S, Hartley J, Graham J. Bronchodilator effect of delta-9-tetrahydrocannabinol administered by aerosol to asthmatic patients. Thorax 1976; 31: 720–3

    PubMed  Article  CAS  Google Scholar 

  86. 86.

    Kirk JM, Doty P, De Wit H. Effects of expectancies on subjective responses to oral Δ9 tetrahydrocannabinol. Pharmacol Biochem Behav 1998; 59(2): 287–93

    PubMed  Article  CAS  Google Scholar 

  87. 87.

    Huestis MA, Cone EJ. Urinary excretion half-life of 11-nor-9-carboxy-Δ9-tetrahydrocannabinol in humans. Ther Drug Monit 1998; 20: 570–6

    PubMed  Article  CAS  Google Scholar 

  88. 88.

    Johansson E, Noren K, Sjovall J, et al. Determination of delta-1-tetrahydrocannabinol in human fat biopsies from marihuana users by gas chromatography-mass spectrometry. Biomed Chromatogr 1989; 3: 35–8

    PubMed  Article  CAS  Google Scholar 

  89. 89.

    Hunt CA, Jones RT. Tolerance and disposition of tetrahydrocannabinol in man. J Pharmacol Exp Ther 1980; 213: 35–44

    Google Scholar 

  90. 90.

    Robbe H. Marijuana’s impairing effects on driving are moderate when taken alone but severe when combined with alcohol. Hum Psychopharmacol Clin Ther 1998; 13: S70–8

    Article  Google Scholar 

  91. 91.

    Fant R, Heishman SJ, Bunker EB, et al. Acute and residual effects of marijuana in humans. Pharmacol Biochem Behav 1998; 60(4): 777–84

    PubMed  Article  CAS  Google Scholar 

  92. 92.

    Anon. Cannabis complication. Pharm J 1999; 263: 146–92

  93. 93.

    Manzanares J, Corchero J, Romero J, et al. Pharmacological and biochemical interactions between opioids and cannabinoids. Trends Pharm Sci 1999: 20: 287–94

    PubMed  Article  CAS  Google Scholar 

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Correspondence to Dr Elizabeth M. Williamson.

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Williamson, E.M., Evans, F.J. Cannabinoids in Clinical Practice. Drugs 60, 1303–1314 (2000). https://doi.org/10.2165/00003495-200060060-00005

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Keywords

  • Multiple Sclerosis
  • Familial Mediterranean Fever
  • Anandamide
  • Cannabis User
  • Cannabidiol