A new clinical trial conducted by the Food and Drug Administration has revealed potential liver safety concerns with cannabidiol (CBD) use, even at low doses typically consumed by the general public. The randomized double-blind placebo-controlled study, published in JAMA Internal Medicine, found that 5% of healthy participants developed significantly elevated liver enzymes after four weeks of CBD treatment.
Study Design and Findings
Scientists from the FDA's Division of Applied Regulatory Science enrolled 201 healthy middle-aged men and women in the trial. Participants received either 5 mg per kilogram of body weight of oral CBD (approximately 350 mg for a 154-pound individual) or a placebo over four weeks, with weekly laboratory assessments to monitor liver function.
While the vast majority of participants remained unaffected, 5% showed greatly elevated levels of the liver enzyme aminotransferase, a known marker of liver cell damage or inflammation. Women appeared to be more vulnerable than men to these effects. The liver enzyme levels returned to normal within one or two weeks of stopping CBD treatment.
Seven participants withdrew from the trial because they were showing clinical signs of potential drug-induced liver injury. Notably, only one of the participants with elevated liver enzymes noticed any symptoms within the four-week period, suggesting that liver damage may occur without immediate awareness.
Clinical Implications and Expert Perspectives
"This is a significant finding, as it suggests that CBD itself, even in the absence of other drugs, may pose a risk to liver health," said Amir Englund, a researcher at King's College London who studies cannabinoid psychopharmacology and was not involved in the trial. "The results have important implications for individuals using over-the-counter CBD supplements. Many may be unaware of the potential for liver injury and assume that CBD is entirely benign."
Paul Watkins, professor of pharmacy at the University of North Carolina at Chapel Hill, emphasized the clinical relevance of these findings: "When doctors get liver chemistry results back and they're out of whack, they should be aware to ask, 'Were you taking CBD?' Because a lot of people are."
Market Context and Usage Patterns
The study comes amid explosive growth in the CBD market. Between 2014 and 2022, CBD product sales in the U.S. increased from $108 million to $1.9 billion, following a landmark bill passed in 2018 that enabled the unrestricted sale of cannabis products containing less than 0.3% THC. According to various surveys, the majority of people in the U.S. have now heard of CBD, and around 20% have reported using CBD products in the past 12 months.
CBD products have become a popular way to self-medicate for conditions including pain, anxiety, insomnia and depression, especially among older adults. However, there has been little evidence on how well they work or guidance on how to use the products safely.
Previous Safety Concerns
This trial is not the first to suggest potential liver risks with CBD. Previous concerns were initially described following an FDA review of clinical trial data on CBD-based prescription drugs for childhood epilepsy, with raised liver enzymes being observed in 14% of participants. However, those participants were concurrently taking other anti-epileptic medications, which could have contributed to the observed liver effects.
"In clinical trials involving epilepsy patients, elevated levels of liver enzymes were among the leading causes of withdrawal from the trials due to serious adverse events," Englund noted.
Mechanism and Risk Factors
Research has shown that CBD can affect liver cells in a manner similar to acetaminophen. "It's interesting because it's also been shown that healthy adults, when they get recurrent therapeutic doses of paracetamol, also have these liver chemistry abnormalities," Watkins explained.
In recent years, studies have shown that people most at risk of liver injury are those taking very high oral doses of CBD, exceeding 1000 mg per day. However, there have been reports of drug-induced liver injuries in some healthy individuals taking moderate doses between 300 mg and 1000 mg per day.
Relatively little is known about why some people are more susceptible than others, but genetic factors may play a role. According to Englund, CBD can inhibit certain enzymes in the liver which are needed for metabolizing medications.
In the new FDA trial, the majority of participants who experienced the most serious liver problems also developed signs of eosinophilia, an immune condition characterized by excess production of eosinophils, a type of white blood cell.
Safety Assessment and Future Monitoring
Despite these findings, experts maintain that CBD appears relatively safe overall. Watkins, who co-chairs the Drug-Induced Liver Injury Network backed by the National Institute of Diabetes and Digestive and Kidney Diseases, noted that CBD has yet to be flagged as a major source of concern for serious liver injuries.
"Overall, the liver is very good at adjusting to sources of drug stress [indicated by elevated enzymes]," Watkins said, noting the network hasn't detected a case of serious liver injury attributed to CBD. "There could be people out there whose liver doesn't adjust very well, and as companies compete for market share, you might start getting more potent CBD which could push people into the ranges where they're getting into trouble, but the data we've got suggests it's very safe."
The researchers emphasized the importance of monitoring liver enzyme levels in future clinical trials, particularly given the growing interest in CBD as a potential treatment for conditions such as psychosis and cannabis use disorder. They also recommended that doctors ask about regular CBD use as part of routine medical screening, as symptoms of liver injury—including abdominal discomfort, jaundice, and fatigue—don't always become immediately apparent.
