The Use of Cannabis and Cannabinoids in Treating Symptoms of Multiple Sclerosis: a Systematic Review of Reviews

Abstract

Purpose of Review

Pharmaceutical cannabinoids such as nabiximols, nabilone and dronabinol, and plant-based cannabinoids have been investigated for their therapeutic potential in treating multiple sclerosis (MS) symptoms. This review of reviews aimed to synthesise findings from high quality systematic reviews that examined the safety and effectiveness of cannabinoids in multiple sclerosis. We examined the outcomes of disability and disability progression, pain, spasticity, bladder function, tremor/ataxia, quality of life and adverse effects.

Recent Findings

We identified 11 eligible systematic reviews providing data from 32 studies, including 10 moderate to high quality RCTs. Five reviews concluded that there was sufficient evidence that cannabinoids may be effective for symptoms of pain and/or spasticity in MS. Few reviews reported conclusions for other symptoms.

Summary

Recent high quality reviews find cannabinoids may have modest effects in MS for pain or spasticity. Future research should include studies with non-cannabinoid comparators; this is an important gap in the evidence.

This is a preview of subscription content, log in to check access.

Fig. 1

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502–17. https://doi.org/10.1016/S0140-6736(08)61620-7.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):545–58. https://doi.org/10.1038/nri3871.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Gold R, Hartung H-P. Towards individualised multiple-sclerosis therapy. Lancet Neurol. 2005;4(11):693–4. https://doi.org/10.1016/S1474-4422(05)70205-2.

    Article  PubMed  Google Scholar 

  4. 4.

    Giovannoni G, Rhoades RW. Individualizing treatment goals and interventions for people with MS. Curr Opin Neurol. 2012;25(Suppl):S20–7. https://doi.org/10.1097/01.wco.0000413321.32834.aa.

    Article  PubMed  Google Scholar 

  5. 5.

    Broadley SA, Barnett MH, Boggild M, Brew BJ, Butzkueven H, Heard R, et al. Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 3 treatment practicalities and recommendations. MS Neurology Group of the Australian and New Zealand Association of Neurologists. J Clin Neurosci. 2014;21(11):1857–65. https://doi.org/10.1016/j.jocn.2014.01.017.

    Article  PubMed  Google Scholar 

  6. 6.

    Broadley SA, Barnett MH, Boggild M, Brew BJ, Butzkueven H, Heard R, et al. Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 1 historical and established therapies. MS Neurology Group of the Australian and New Zealand Association of Neurologists. J Clin Neurosci. 2014;21(11):1835–46. https://doi.org/10.1016/j.jocn.2014.01.016.

    Article  PubMed  Google Scholar 

  7. 7.

    Broadley SA, Barnett MH, Boggild M, Brew BJ, Butzkueven H, Heard R, et al. Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: an Australian and New Zealand perspective: part 2 new and emerging therapies and their efficacy. MS Neurology Group of the Australian and New Zealand Association of Neurologists. J Clin Neurosci. 2014;21(11):1847–56. https://doi.org/10.1016/j.jocn.2014.01.018.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Zajicek J, Fox P, Sanders H, Wright D, Vickery J, Nunn A, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet. 2003;362(9395):1517–26. https://doi.org/10.1016/S0140-6736(03)14738-1.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Clark AJ, Ware MA, Yazer E, Murray TJ, Lynch ME. Patterns of cannabis use among patients with multiple sclerosis. Neurology. 2004;62(11):2098–100. https://doi.org/10.1212/01.WNL.0000127707.07621.72.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Zajicek JP, Apostu VI. Role of cannabinoids in multiple sclerosis. CNS Drugs. 2011;25(3):187–201. https://doi.org/10.2165/11539000-000000000-00000.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Hadjimichael O, Kerns RD, Rizzo MA, Cutter G, Vollmer T. Persistent pain and uncomfortable sensations in persons with multiple sclerosis. Pain. 2007;127(1–2):35–41. https://doi.org/10.1016/j.pain.2006.07.015.

    Article  PubMed  Google Scholar 

  12. 12.

    Walker JM, Hohmann AG, Martin WJ, Strangman NM, Huang SM, Tsou K. The neurobiology of cannabinoid analgesia. Life Sci. 1999;65(6–7):665–73. https://doi.org/10.1016/S0024-3205(99)00289-1.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199–215. https://doi.org/10.1038/sj.bjp.0707442.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Walker JM, Huang SM. Cannabinoid analgesia. Pharmacol Ther. 2002;95(2):127–35. https://doi.org/10.1016/S0163-7258(02)00252-8.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Quartilho A, Mata HP, Ibrahim MM, Vanderah TW, Porreca F, Makriyannis A, et al. Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors. Anesthesiology. 2003;99(4):955–60. https://doi.org/10.1097/00000542-200310000-00031.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Ibrahim M, Rude ML, Stagg NJ, Mata HP, Lai J, Vanderah TW, et al. CB2 cannabinoid receptor mediation of antinociception. Pain. 2006;122(1):36–42. https://doi.org/10.1016/j.pain.2005.12.018.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Gui H, Tong Q, Qu W, Mao CM, Dai SM. The endocannabinoid system and its therapeutic implications in rheumatoid arthritis. Int Immunopharmacol. 2015;26(1):86–91. https://doi.org/10.1016/j.intimp.2015.03.006.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Makriyannis A, et al. Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J. 2001;15(2):300–2. https://doi.org/10.1096/fj.00-0399fje.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    • Karabudak R, Dahdaleh M, Aljumah M, Alroughani R, Alsharoqi IA, AlTahan AM, et al. Functional clinical outcomes in multiple sclerosis: current status and future prospects. Mult Scler Relat Disord. 2015;4(3):192–201. This paper highlights key clinical outcomes in multiple sclerosis, infoming which measures should be examined in future studies. https://doi.org/10.1016/j.msard.2015.03.004.

    Article  PubMed  Google Scholar 

  20. 20.

    Shea BJ, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol. 2007;7(1):1–7.

    Article  Google Scholar 

  21. 21.

    Scottish Intercollegiate Guidelines Network (SIGN), SIGN 50: a guideline developer’s handbook. Edinburgh (SIGN publication no. 50). 2014.

  22. 22.

    Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. Br Med J. 2008;336(7650):924–6. https://doi.org/10.1136/bmj.39489.470347.AD.

    Article  Google Scholar 

  23. 23.

    Mills, R.J., L. Yap, and Young C.A. Treatment for ataxia in multiple sclerosis. Cochrane Database of Systematic Reviews 2007(1): CD005029.

  24. 24.

    Shakespeare, D.T., M. Boggild, and Young C. Anti-spasticity agents for multiple sclerosis. Cochrane Database of Systematic Reviews 2003(4): CD001332.

  25. 25.

    Lakhan SE, Rowland M. Whole plant cannabis extracts in the treatment of spasticity in multiple sclerosis: a systematic review. BMC Neurol. 2009;9:ArtID 59.

    Article  PubMed  Google Scholar 

  26. 26.

    Jawahar R, Oh U, Yang S, Lapane KL. A systematic review of pharmacological pain management in multiple sclerosis. Drugs. 2013;73(15):1711–22. https://doi.org/10.1007/s40265-013-0125-0.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Andrzejewski K, Barbano R, Mink J. Cannabinoids in the treatment of movement disorders: a systematic review of case series and clinical trials. Basal Ganglia. 2016;6(3):173–81. https://doi.org/10.1016/j.baga.2016.06.001.

    Article  Google Scholar 

  28. 28.

    • Koppel BS, Brust JCM, Fife T, Bronstein J, Youssof S, Gronseth G, et al. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014;82(17):1556–63. This recent review conluded that concluded that some cannabinoids are probably or possibly effective in treating painful spasticity, however cautioned that adverse effects such as cognitive impairment are of concern in this population. https://doi.org/10.1212/WNL.0000000000000363.

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Karst M, Wippermann S, Ahrens J. Role of cannabinoids in the treatment of pain and (painful) spasticity. Drugs. 2010;70(18):2409–38. https://doi.org/10.2165/11585260-000000000-00000.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    •• Whiting PF, Wolff RF, Deshpande S, di Nisio M, Duffy S, Hernandez AV, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015;313(24):2456–73. This review represents one of the most comprehensive and high quality reviews to date on the therapeutic use of cannabinoids, and includes meta-analyses that found modest statistically signifcant effects of cannabinoids for spasticity in multiple sclerosis when measured with a numerical rating scale, but not when measured with the Ashworth scale. https://doi.org/10.1001/jama.2015.6358.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Zhornitsky S, Potvin S. Cannabidiol in humans-the quest for therapeutic targets. Pharmaceuticals. 2012;5(5):529–52. https://doi.org/10.3390/ph5050529.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Wang T, Collet JP, Shapiro S, Ware MA. Adverse effects of medical cannabinoids: a systematic review. CMAJ Can Med Assoc J. 2008;178(13):1669–78. https://doi.org/10.1503/cmaj.071178.

    Article  Google Scholar 

  33. 33.

    Ben Amar M. Cannabinoids in medicine: a review of their therapeutic potential. J Ethnopharmacol. 2006;105(1–2):1–25. https://doi.org/10.1016/j.jep.2006.02.001.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Lee K-C, et al. The Ashworth scale: a reliable and reproducible method of measuring spasticity. J Neurol Rehabil. 1989;3(4):205–9.

    Google Scholar 

  35. 35.

    Collin C, Ehler E, Waberzinek G, Alsindi Z, Davies P, Powell K, et al. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurol Res. 2010;32(5):451–9. https://doi.org/10.1179/016164109X12590518685660.

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

The editors would like to thank Dr. John Brust and Dr. José Biller for taking the time to review this manuscript.

Funding

Funding was received from the Commonwealth Department of Health and the NSW Government Centre for Medicinal Cannabis Research and Innovation, who determined the topics and scope of the reviews to be conducted and funded the salary of MW. SN and LD are supported by NHMRC research fellowships (no. 1132423 and no. 1041472). The National Drug and Alcohol Research Centre at the University of New South Wales is supported by a funding from the Australian Government under the Substance Misuse Prevention and Service Improvements Grant Fund.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Suzanne Nielsen.

Ethics declarations

Conflict of Interest

SN, MF and LD have all been investigators on untied investigator-driven educational grants funded by Reckitt Benckiser. MF and LD have received untied educational grant from Mundipharma for post-marketing surveillance studies of new opioid medications. SN, MF and LD have been investigators on untied investigator-driven educational grants funded by Indivior and Reckitt-Benckiser. NB is a member of the medical cannabis expert panel for New South Wales Health. WH provided evidence to parliamentary committees on medical uses of cannabis in Australia and the United Kingdom and is a member of the Australian Advisory Council on Medical Uses of Cannabis. SN, WH, MF, MW and LD have previously published manuscripts on the topic of therapeutic use of cannabis. Other authors declare no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Neurology of Systemic Diseases

PROSPERO registration number CRD42016051264

Electronic supplementary material

ESM 1

(DOCX 189 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nielsen, S., Germanos, R., Weier, M. et al. The Use of Cannabis and Cannabinoids in Treating Symptoms of Multiple Sclerosis: a Systematic Review of Reviews. Curr Neurol Neurosci Rep 18, 8 (2018). https://doi.org/10.1007/s11910-018-0814-x

Download citation

Keywords

  • Multiple sclerosis
  • Cannabinoid
  • Pain
  • Spasticity
  • Nabiximols
  • Dronabinol
  • Cannabis