Article Text

Original research
Long-term and serious harms of medical cannabis and cannabinoids for chronic pain: a systematic review of non-randomised studies
  1. Dena Zeraatkar1,2,
  2. Matthew Adam Cooper3,
  3. Arnav Agarwal4,
  4. Robin W M Vernooij5,
  5. Gareth Leung6,
  6. Kevin Loniewski7,
  7. Jared E Dookie8,
  8. Muhammad Muneeb Ahmed3,
  9. Brian Y Hong9,
  10. Chris Hong10,
  11. Patrick Hong11,
  12. Rachel Couban12,
  13. Thomas Agoritsas13,14,
  14. Jason W Busse15
  1. 1Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
  2. 2Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA
  3. 3Michael G. Degroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
  4. 4Department of Medicine, University of Toronto, Toronto, Ontario, Canada
  5. 5Department of Research and Development, Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands
  6. 6Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  7. 7Faculty of Health, York University, Toronto, Ontario, Canada
  8. 8Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
  9. 9Division of Plastic and Reconstructive Surgery, University of Toronto, Toronto, Ontario, Canada
  10. 10Health Research Methods, Evidence, and Impact, University of Toronto Faculty of Medicine, Toronto, Ontario, Canada
  11. 11Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, Ontario, Canada
  12. 12Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada
  13. 13Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
  14. 14Division of General Internal Medicine & Division of Epidemiology, University Hospitals Geneva, Geneve, Switzerland
  15. 15Anesthesia, McMaster University, Hamilton, Ontario, Canada
  1. Correspondence to Professor Jason W Busse; bussejw{at}


Objective To establish the prevalence of long-term and serious harms of medical cannabis for chronic pain.

Design Systematic review and meta-analysis.

Data sources MEDLINE, EMBASE, PsycINFO and CENTRAL from inception to 1 April 2020.

Study selection Non-randomised studies reporting on harms of medical cannabis or cannabinoids in adults or children living with chronic pain with ≥4 weeks of follow-up.

Data extraction and synthesis A parallel guideline panel provided input on the design and interpretation of the systematic review, including selection of adverse events for consideration. Two reviewers, working independently and in duplicate, screened the search results, extracted data and assessed risk of bias. We used random-effects models for all meta-analyses and the Grades of Recommendations, Assessment, Development and Evaluation approach to evaluate the certainty of evidence.

Results We identified 39 eligible studies that enrolled 12 143 adult patients with chronic pain. Very low certainty evidence suggests that adverse events are common (prevalence: 26.0%; 95% CI 13.2% to 41.2%) among users of medical cannabis for chronic pain, particularly any psychiatric adverse events (prevalence: 13.5%; 95% CI 2.6% to 30.6%). Very low certainty evidence, however, indicates serious adverse events, adverse events leading to discontinuation, cognitive adverse events, accidents and injuries, and dependence and withdrawal syndrome are less common and each typically occur in fewer than 1 in 20 patients. We compared studies with <24 weeks and ≥24 weeks of cannabis use and found more adverse events reported among studies with longer follow-up (test for interaction p<0.01). Palmitoylethanolamide was usually associated with few to no adverse events. We found insufficient evidence addressing the harms of medical cannabis compared with other pain management options, such as opioids.

Conclusions There is very low certainty evidence that adverse events are common among people living with chronic pain who use medical cannabis or cannabinoids, but that few patients experience serious adverse events.

  • Pain management

Data availability statement

Data are available in a public, open access repository. Data are available in a public, open access repository:

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:

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Data availability statement

Data are available in a public, open access repository. Data are available in a public, open access repository:

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  • Twitter @muneebahmed1a, @ThomasAgoritsas, @JasonWBusse

  • Contributors JWB and TA conceived the idea. RC designed and conducted the search. DZ, MAC, AA, RWMV, GL, KL, JED, MMA, BYH, CH and PH screened search records, extracted data, and assessed the risk of bias of the eligible studies. DZ conducted all analyses. DZ, JWB and TA interpreted the data. DZ wrote the first draft of the manuscript. JWB and TA critically revised the manuscript. All authors reviewed and approved the final version. DZ and JWB are the guarantors.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.