Cannabis products with high levels of tetrahydrocannabinol (THC) were associated with a small improvement in chronic pain but also increased risk of adverse events (AEs), according to a newly updated systematic review.

The review of more than two dozen randomized controlled trials (RCTs) with 2300 participants showed that products with a high or comparable THC-to-cannabidiol (CBD) ratio were linked to a “slight” reduction in the severity of mostly neuropathic pain, but that relief was accompanied by an increase in dizziness, nausea, and sedation. 

Products with a low THC-to-CBD ratio showed no significant harms and, surprisingly to the researchers, resulted in almost no improvements.

“Conventional wisdom was that CBD was promising because it doesn’t have euphoric effects like TCH, and it was thought to have medicinal properties. But at least in our analysis, it didn’t have an effect on pain,” lead author Roger Chou, MD, Oregon Health and Science University, Portland, Oregon, said in a release.

“It’s complicated because cannabis products are complicated,” Chou added.

The findings were published online on December 23 in the Annals of Internal Medicine.

Updated Review

The current systematic review is an update to a previous review published in 2022. It includes 25 placebo-controlled trials involving 2303 participants with chronic pain, 64% of whom had neuropathic pain. The mean age ranged from 24 to 68 years, and baseline pain scores on a 10-point scale ranged from 2.5 to 8.5. The trial duration ranged from 4 to 16 weeks.

Cannabinoids were categorized by THC-to-CBD ratio as high (evaluated in 10 studies), comparable (seven studies), or low (seven studies); by source (synthetic, purified, or extracted); and by method of administration. Three studies also evaluated other cannabis-based products considered to be non-THC or non-CBD.

Bias was rated high for five trials, moderate for 14, and low for six.

Results showed that oral synthetic/purified high THC-to-CBD (THC-only) products had a pooled difference in reduction of pain severity of -0.78 points on a 10-point pain scale vs placebo (95% CI, -1.59 to -0.08). Oromucosal, extracted products with comparable THC-to-CBD ratios had a pooled difference of -0.54 points (95% CI, -0.95 to -0.19).

These small effects were less than the moderate effects found in the original review, which was likely due to the addition of two new THC-only RCTs, investigators noted.

In stratified analysis, investigators found that nabilone was associated with a moderate reduction in pain severity, while dronabinol was not, with a significant difference between products (P for trend = .03). Both are approved by the FDA for the treatment of chemotherapy-related nausea and vomiting; dronabinol is also approved for HIV wasting syndrome.

Synthetic or purified THC-only products vs placebo were associated with a moderate-to-large increased risk for any AE, as well as for dizziness, nausea, and sedation. Extracted THC-only products were linked to a higher risk for any AE and dizziness.

Extracted comparable THC-to-CBD ratio products were also associated with increased risks for dizziness, nausea, and sedation compared to placebo, but had a low risk for any AE.

Applicability of Findings ‘Challenging’ 

Low THC-to-CBD synthetic or purified products were associated with “no or trivial” likelihood of a pain response compared to placebo. They also showed no or trivial difference in risk for any AE and sedation, as well as a slight decrease in risk for dizziness.

Combined purified THC and synthetic CBD had no effect on pain or function, but the number of relevant trials was low, the investigators noted. It was associated with an increased risk for nausea, dizziness, and sedation. 

There was insufficient evidence on efficacy or AEs for other low TCH-to-CBD ratio products.

Chou noted that classifying cannabis products is complicated because their properties can differ depending on where they are grown and how they are cultivated and prepared for sale.

“Many people use these products, and they think it helps. Our goal is to provide some scientific basis to help people make their decisions,” he said.

Study limitations included the inconsistent and unstandardized reporting of product details. Also, harms such as psychosis or cannabis use disorder were not addressed, and data on long-term outcomes were unavailable.

“Understanding applicability of findings is challenging because the availability of studied cannabis products varies, depending on local regulatory and other factors,” the researchers wrote.

‘Lacks Compelling Evidence’

The study is the most comprehensive review of cannabinoids for chronic pain to date, wrote Ziva D. Cooper, PhD, Center for Cannabis and Cannabinoids at the University of California, Los Angeles, in an accompanying editorial.

Cooper noted that the findings of little-to-no effect on pain outcomes for CBD products were notable, but they highlighted that only seven studies were included in that evaluation, with most having moderate to high risk of bias. She also questioned the generalizability of the overall results.

“Can findings from standardized formulations inform real-world use of diverse, cannabis-derived, state-regulated products?” she questioned.

Still, Cooper noted the review showed that while THC-containing products were associated with some pain relief, they were tempered by AEs. And despite widespread use, “CBD lacks compelling evidence as a standalone treatment,” she added.

“Although the studies to date fail to demonstrate a consistent, positive signal of cannabinoids for chronic pain across preparations and chronic pain conditions, the work is just beginning,” she wrote.

New studies and research approaches in the future will help clinicians “navigate this complex and rapidly evolving landscape,” Cooper added.

The study was funded by the Agency for Healthcare Research and Quality. Chou reported having received research and guideline development funding from the FDA. The other investigators reported no relevant financial relationships. Cooper reported receiving grant/contract, travel, and data and safety monitoring funding from various organizations, which are fully listed in the original article.