Living Systematic Review on Cannabis and Other Plant-Based Treatments for Chronic Pain

Objectives. To update the evidence on benefits and harms of cannabinoids and other plant-based compounds to treat subacute and chronic pain in adults and adolescents using a living systematic review approach. Data sources. Ovid® MEDLINE®, PsycINFO®, Embase®, the Cochrane Library, and SCOPUS® databases, and reference lists of included studies were searched to April 28th, 2025. Review methods. We grouped studies based on their tetrahydrocannabinol (THC) to cannabidiol (CBD) ratio and by product type: synthetic, purified (plant-derived product consisting of a single cannabinoid, e.g. dronabinol or CBD), or extracted (from whole plant, containing multiple cannabinoids). We conducted random effects meta-analyses and categorized magnitude of benefit (large, moderate, small, or no effect [less than small]). Results. Three new randomized controlled trials (RCTs) (n=90, 81, and 93) and three new observational studies (N=741, 148, and 96) were added for this annual update; no study addressed subacute pain or adolescents. One new RCT compared plant-derived topical hemp seed oil or diclofenac 1% gel versus placebo for knee osteoarthritis and one new RCT compared purified THC:CBD:cannabinol (CBN) versus placebo for diabetic neuropathy. Both of the cannabis product types evaluated in these trials were new for this review. The third new, head-to-head RCT compared purified inhaled comparable THC to CBD ratio (6.3% THC and 8% CBD) cannabis, 5 mg oxycodone tablets, or both for fibromyalgia. Since the inception of this living review, from 6,304 total abstracts identified, 29 RCTs (in 30 publications) (N=2,579) and 15 observational studies (N=49,453) of cannabinoids have been included; no study evaluated kratom. Studies were primarily short term, and 48 percent enrolled patients with neuropathic pain. Comparators were primarily placebo or usual care. Strength of evidence (SOE) for all comparisons and outcomes was low unless indicated otherwise. Compared with placebo, extracted, comparable ratio THC to CBD oral spray was associated with a small decrease in pain severity (7 RCTs, N=878, 0 to 10 scale, mean difference [MD] −0.54, 95% confidence interval [CI] −0.95 to −0.19, I2=39%; SOE: moderate); improvement in overall function favored the cannabis product but was slightly below the threshold for a small effect (6 RCTs, N=616, 0 to 10 scale [negative values indicate improved function], MD −0.42, 95% CI −0.73 to −0.16, I2=32%; SOE: moderate) versus placebo. There was no difference in likelihood of study withdrawals due to adverse events (WAEs). There was a large increased risk of dizziness and sedation, and a moderate increased risk of nausea (dizziness: 6 RCTs, N=866, relative risk [RR] 3.57, 95% CI 2.42 to 5.60, I2=0%; sedation: 6 RCTs, N=866, RR 5.04, 95% CI 2.10 to 11.89, I2=0%; and nausea: 6 RCTs, N=866, RR 1.79, 95% CI 1.19 to 2.77, I2=0%). Synthetic and purified high THC to CBD ratio __ products were associated with a small improvement in pain severity versus placebo (8 RCTs, N=507, 0 to 10 scale, MD −0.78, 95% CI −1.59 to −0.08, I2=64%), with no effect on overall function or disability. There was a moderate increase in risk of WAEs (6 RCTs, N=487, RR 1.92, 95% CI 1.10 to 4.80, I2=0%), a moderate increase in risk of sedation (5 RCTs, N=458, RR 1.57, 95% CI 1.11 to 2.29, I2=0%), and a large increase in risk of nausea (4 RCTs, N=425, RR 2.12, 95% CI 1.09 to 3.96; I2=0%). There was also moderate SOE for a large increase in risk of dizziness (4 RCTs, N=425, RR 2.30, 95% CI 1.53 to 3.52, I2=22%). Synthetic or purified oral CBD alone was not associated with decreased pain intensity (4 RCTs, N=334, 0 to 10 scale, MD 0.40, 95% CI −0.14 to 1.00, I2=20%; SOE: moderate), greater likelihood of pain response (4 RCTs, N=334, RR 0.84, 95% CI 0.62 to 1.10, I2=0%; SOE: moderate), or improved function (3 RCTs, N=272, standardized mean difference [SMD] 0.11, 95% CI −0.14 to 0.41, I2=0%; SOE: moderate) versus placebo, and combined oral THC plus CBD (~1:2 ratio) was not associated with decreased pain intensity (2 RCTs, N=123, 0 to 10 scale, MD 0.12, 95% CI −0.71 to 0.93, I2=0%), greater likelihood of experiencing ≥30 percent improvement in pain (2 RCTs, N=123, RR 1.07, 95% CI 0.73 to 1.57, I2=0%), or improved function (1 RCT, n=60, SMD 0.29, 95% CI −0.21 to 0.80) versus placebo. Evidence (including observational studies) on whole-plant cannabis, topical CBD, other cannabinoids (including one new RCT of a THC:CBD:CBN product and one new RCT of hemp seed oil), comparisons with active noncannabis treatments (including one new RCT of cannabis vs. opioids) or between cannabis-related products, and impact of cannabis on use of opioids remained insufficient. Evidence was not available on important harms such as psychosis, cannabis use disorder, and cognitive effects. Conclusions. Low- to moderate-strength evidence suggests small improvements in pain (mostly neuropathic) and moderate to large increases in common adverse events (dizziness, sedation, nausea) with extracted, comparable THC to CBD ratio and synthetic or purified high THC to CBD ratio products versus placebo during short-term treatment (1 to 6 months). Low- to moderate-strength evidence suggests that low THC to CBD ratio products may not be associated with improved outcomes versus placebo. Evidence for whole-plant cannabis and other comparisons, outcomes, and plant-based compounds was unavailable or insufficient to draw conclusions.