Long-term and serious harms of medical cannabis and cannabinoids for chronic pain: A systematic review of non-randomized studies
Authors: Zeraatkar Dena , Cooper Matthew Adam , Agarwal Arnav , Vernooij Robin W. M. , Leung Gareth , Loniewski Kevin , Dookie Jared E. , Ahmed Muhammad Muneeb , Hong Brian Younho , Hong Chris J. , Hong Patrick Jiho , Couban Rachel , Agoritsas Thomas , Busse Jason W. 
Published: May 2021

AbstractObjectiveTo establish the risk and prevalence of long-term and serious harms of medical cannabis and cannabinoids for chronic pain.DesignSystematic review and meta-analysis.Data sourcesMEDLINE, EMBASE, PsycInfo, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to April 1, 2020.Study selectionNon-randomized studies reporting on harms of medical cannabis or cannabinoids in people living with chronic pain with ≥4 weeks of follow-up.Data extraction and synthesisA 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 GRADE approach to evaluate the certainty of evidence.ResultsWe identified 39 eligible studies that enrolled 12,143 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 or cannabinoids for chronic pain, particularly any psychiatric adverse events (prevalence: 13.5%; 95% CI 2.6 to 30.6). However, very low certainty evidence indicates serious adverse events, adverse events leading to discontinuation, cognitive adverse events, accidents and injuries, and dependence and withdrawal syndrome are uncommon and typically occur in fewer than one in 20 patients. We compared studies with <24 weeks and ≥ 24 weeks cannabis use and found more adverse events reported among studies with longer follow-up (test of 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 to other pain management options, such as opioids.ConclusionsThere 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. Future research should compare long-term and serious harms of medical cannabis with other management options for chronic pain, including opioids.Systematic review registrationhttps://osf.io/25bxfWhat is already known on this topicMedical cannabis and cannabinoids are increasingly used for the management of chronic pain.Clinicians and patients considering medical cannabis or cannabinoids as a treatment option for chronic pain require evidence on benefits and harms, including long-term and serious adverse events to make informed decisions.What this study addsVery low certainty evidence suggests that adverse events are common among people living with chronic pain who use medical cannabis or cannabinoids, including psychiatric adverse events, though serious adverse events, adverse events leading to discontinuation, cognitive adverse events, accidents and injuries, and dependence and withdrawal syndrome are uncommon.There is insufficient evidence comparing the harms of medical cannabis or cannabinoids to other pain management options, such as opioids.