Introduction

In an effort to address the opioid epidemic, a prominent goal of current research is to identify alternative treatments with equal or better benefits for pain while avoiding potential unintended consequences that could result in harms.  This 'living' systematic review assesses the effectiveness and harms of cannabis and other plant-based treatments for chronic pain conditions.  For the purposes of this review, plant-based compounds (PBCs) included are those that are similar to opioids in effect and that have the potential for addiction, misuse, and serious adverse effects; other PBCs such as herbal treatments are not included.  The intended audience includes policy and decision makers, funders and researchers of treatments for chronic pain, and clinicians who treat chronic pain.  The literature is undergoing continuous surveillance, and the systematic review will be updated annually.  Findings from the quarterly surveillance reports are available here:

•  SURVEILLANCE REPORT: 2024 Update (PDF, 9 MB)
•  Appendix E (XLSX, 27 KB)
•  Appendix F (XLSX, 68 KB)

Key Messages

Since the second annual update of the systematic review published in August 2023, three new placebo-controlled randomized controlled trials (RCTs) in four publications and two new observational studies were added, for a total of 26 RCTs (in 27 publications) and 12 observational studies. One of the new RCTs evaluated oral purified THC (dronabinol), synthetic CBD, or both; one new RCT evaluated purified CBD; and one new RCT evaluated topical (intraoral) CBD (unclear if synthetic or plant-derived). The new observational studies evaluated various (low, comparable, or high THC to CBD ratio) products. In patients with chronic (mainly neuropathic) pain with short-term treatment (4 weeks to <6 months):

• Extracted, comparable THC to CBD ratio oral spray is probably associated with small improvements in pain severity (strength of evidence [SOE]: moderate) and overall function versus placebo (SOE: moderate). There may be no increase in risk of serious adverse events (SAEs) (SOE: low) or withdrawal due to adverse events (WAEs) (SOE: low). There may be a large increased risk of dizziness and sedation (SOE: low) and a moderate increased risk of nausea (SOE: low).
• Synthetic and purified THC (high THC to CBD) may be associated with small improvement in pain severity (SOE: low), but with increased risk of WAEs (SOE: low), sedation (SOE: low), and nausea (SOE: low) versus placebo. Synthetic and purified THC is probably associated with a large increased risk of dizziness (SOE: moderate).
• Low THC to CBD ratio oral products (synthetic or purified CBD alone or combined purified THC plus synthetic CBD in ratio ~1:2) may not be associated with improved pain and function versus placebo (SOE: moderate for CBD alone and low for THC/CBD). THC plus CBD is probably associated with large increased risk of nausea (SOE: moderate).
• Other key adverse event outcomes (psychosis, cannabis use disorder, cognitive deficits) and outcomes on the impact on opioid use were not reported or evidence was insufficient to draw conclusions.
• We did not identify any evidence on other plant-based compounds such as kratom that met criteria for this review.

Structured Abstract

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 June 30, 2024.

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) in four publications (n=134, 86, and 60) and two new observational studies (N=296 and 32,332) were added for this annual update; no study addressed subacute pain or adolescents. One new RCT compared high THC, low THC, and combination THC to CBD ratio products versus placebo in patients with neuropathic pain; one new RCT evaluated oral CBD plus paracetamol versus paracetamol alone for knee osteoarthritis; and one new RCT evaluated a topical (intraoral) THC to CBD product versus placebo for temporomandibular disorders. Since the inception of this living review, from 5,894 total abstracts identified, 26 RCTs (in 27 publications) (N=2,315) and 12 observational studies (N=48,468) assessing different cannabinoids have been included; no study evaluated kratom. Studies were primarily short term, and 53 percent enrolled patients with neuropathic pain. Comparators were primarily placebo or usual care. Strength of evidence (SOE) 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 small (negative values for function indicate improved function; 6 RCTs, N=616, 0 to 10 scale, MD −0.42, 95% CI −0.73 to −0.16, I2=32%; SOE: moderate) versus placebo. There was no effect on 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, with no effect on overall function or disability. There was a moderate increase in risk of WAEs, a moderate increase in sedation, and a large increase in risk of nausea (pain: 8 RCTs, N=507, 0 to 10 scale, MD −0.78, 95% CI −1.59 to −0.08, I2=64%; WAEs: 6 RCTs, N=487, RR 1.92, 95% CI 1.10 to 4.80, I2=0%; sedation: 5 RCTs, N=458, RR 1.57, 95% CI 1.11 to 2.29, I2=0%; 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 increased 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, comparisons with active noncannabis treatments or between cannabis-related products, and impact 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.