Authors of a systematic review and meta-analysis published in JAMA Network Open found that placebo contributed significantly to pain reduction in cannabinoid clinical trials.
Investigators from Karolinska Institutet and the University of Gothenburg in Sweden searched publication databases through September 2021 for placebo-controlled trials evaluating the efficacy of cannabinoids on self-reported pain intensity. A total of 20 trials were included in this analysis.
The study population consisted of 1459 patients, the mean age of whom was 51 (range, 39-62) years. Study participants had neuropathic pain, multiple sclerosis, or other pain conditions.
The interventions included cannabidiol (CBD), dronabinol, nabilone, nabiximols, and tetrahydrocannabinol. Among interventions, CBD was the only nonpsychotropic cannabinoid formulation studied.
Placebo was found to have a significant effect on pain intensity with a moderate to large effect size (g, 0.64; I2, 87.08%; P <.001) compared with a large effect for the active intervention (g, 0.95; I2, 84.07%; P <.001). The between-group effect did not differ significantly between placebo and active interventions (g mean difference [MD], 0.32; P =.09).
Significant moderation effects were observed between placebo response and risk of bias (q1, 5.47; I2, 87.08%; P =.02) as well as blinding (q1, 4.26; I2, 87.08%; P =.04). No moderator effects were observed for magnitude of placebo response and study duration (q1, 0.54; I2, 87.08%; P =.54). The investigators report that poor blinding was associated with a lower placebo response.
No significant effects of route of intervention delivery (eg, pills, sprays, oils, smoke, vaporized cannabis) were observed.
The major limitation of this analysis was the high heterogeneity observed in the comparisons, however, that was expected due to the large difference in study settings.
Study authors conclude, “The findings of this systematic review and meta-analysis suggest that placebo responses contribute significantly to pain reduction in cannabinoid clinical trials. The unusually high media attention surrounding cannabinoid trials, with positive reports irrespective of scientific results, may uphold high expectations and shape placebo responses in future trials. This influence may impact the outcome of clinical trials, regulatory decisions, clinical practice, and ultimately patient access to cannabinoids for pain relief.”
Gedin P, Blomé S, Pontén M, et al. Placebo response and media attention in randomized clinical trials assessing cannabis-based therapies for pain: a systematic review and meta-analysis. JAMA Netw Open. Published online November 28, 2022. doi:10.1001/jamanetworkopen.2022.43848