Cannabinoids versus placebo for pain: A systematic review with meta-analysis and Trial Sequential Analysis

Jehad Barakji*, Steven Kwasi Korang, Joshua Feinberg, Mathias Maagaard, Ole Mathiesen, Christian Gluud, Janus Christian Jakobsen

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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OBJECTIVES: To assess the benefits and harms of cannabinoids in participants with pain.

DESIGN: Systematic review of randomised clinical trials with meta-analysis, Trial Sequential Analysis, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

DATA SOURCES: The Cochrane Library, MEDLINE, Embase, Science Citation Index, and BIOSIS.

ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Published and unpublished randomised clinical trials comparing cannabinoids versus placebo in participants with any type of pain.

MAIN OUTCOME MEASURES: All-cause mortality, pain, adverse events, quality of life, cannabinoid dependence, psychosis, and quality of sleep.

RESULTS: We included 65 randomised placebo-controlled clinical trials enrolling 7017 participants. Fifty-nine of the trials and all outcome results were at high risk of bias. Meta-analysis and Trial Sequential Analysis showed no evidence of a difference between cannabinoids versus placebo on all-cause mortality (RR 1.20; 98% CI 0.85 to 1.67; P = 0.22). Meta-analyses and Trial Sequential Analysis showed that cannabinoids neither reduced acute pain (mean difference numerical rating scale (NRS) 0.52; 98% CI -0.40 to 1.43; P = 0.19) or cancer pain (mean difference NRS -0.13; 98% CI -0.33 to 0.06; P = 0.1) nor improved quality of life (mean difference -1.38; 98% CI -11.81 to 9.04; P = 0.33). Meta-analyses and Trial Sequential Analysis showed that cannabinoids reduced chronic pain (mean difference NRS -0.43; 98% CI -0.72 to -0.15; P = 0.0004) and improved quality of sleep (mean difference -0.42; 95% CI -0.65 to -0.20; P = 0.0003). However, both effect sizes were below our predefined minimal important differences. Meta-analysis and Trial Sequential Analysis indicated that cannabinoids increased the risk of non-serious adverse events (RR 1.20; 95% CI 1.15 to 1.25; P < 0.001) but not serious adverse events (RR 1.18; 98% CI 0.95 to 1.45; P = 0.07). None of the included trials reported on cannabinoid dependence or psychosis.

CONCLUSIONS: Cannabinoids reduced chronic pain and improved quality of sleep, but the effect sizes are of questionable importance. Cannabinoids had no effects on acute pain or cancer pain and increased the risks of non-serious adverse events. The harmful effects of cannabinoids for pain seem to outweigh the potential benefits.

Original languageEnglish
Article numbere0267420
Issue number1
Number of pages26
Publication statusPublished - Jan 2023

Bibliographical note

Publisher Copyright:
© 2023 Barakji et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


  • Acute Pain
  • Cancer Pain
  • Cause of Death
  • Chronic Pain/drug therapy
  • Humans
  • Quality of Life


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