A new clinical trial suggests there are still ongoing questions about the safety of even low doses of cannabidiol, even as CBD capsules, gummies, edibles, oils and lotions have become increasingly omnipresent in the United States in recent years.
Scientists from the Food and Drug Administration’s Division of Applied Regulatory Science carried out a randomized double-blind placebo-controlled trial last year to assess how low-dose CBD affects liver function in a group of healthy middle-aged men and women.
Over the course of four weeks, 201 volunteers received either 5 mg per kilogram of body weight (approximately 2.3 mg per pound or the equivalent of 350 mg for a 154-pound individual) of oral CBD, or a placebo. The goal was to give them a typical amount that might be used by consumers. Participants also underwent weekly laboratory assessments.
While the vast majority of people in the trial were unaffected, 5% showed greatly elevated levels of the liver enzyme aminotransferase, a known marker of liver cell damage or inflammation, according to the study published Monday in JAMA Internal Medicine. Women appeared to be more vulnerable than men. The liver enzyme returned to normal within one or two weeks of stopping CBD.
Seven participants withdrew from the trial because they were showing clinical signs of potential drug-induced liver injury.
The FDA didn’t respond immediately to a request for comment.
“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,” says Amir Englund, a researcher at King’s College London who studies cannabinoid psychopharmacology, and was not involved in the new 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.”
Between 2014 and 2022, CBD product sales in the U.S. increased from $108 million to $1.9 billion, after a landmark bill passed by the Trump administration in 2018 enabled the unrestricted sale of cannabis products containing less than 0.3% THC, the psychoactive element which gets users high.
According to various surveys in recent years, 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.
While CBD products have become a popular way to self-medicate for conditions including pain, anxiety, insomnia and depression, especially among older adults, there’s been little evidence on how well they work or guidance on how to use the products safely.
Symptoms of liver injury
Signs of liver injury include abdominal discomfort, jaundice or yellowing of the skin and eyes, and fatigue.
However, research has shown that drug-induced liver injuries don’t always become immediately apparent. In the FDA trial, only one of the participants with elevated liver enzymes noticed any symptoms within four weeks. The authors suggested that users may not realize that they are incurring harm and that doctors should ask about regular CBD use as part of routine medical screening.
“This was an important observation from the study,” said Paul Watkins, professor of pharmacy at the University of North Carolina at Chapel Hill. “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.”
The new trial is not the first study to suggest potential health risks relating to cannabidiol and its effects on the liver. Such 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.
“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 said “However, those participants were concurrently taking other anti-epileptic medications, which could have contributed to the observed liver effects.”
Watkins was subsequently involved in research investigating why CBD can affect liver cells, and he said that certain doses seem to have an effect similar to acetaminophen, or paracetamol.
“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 said.
In the U.S., acetaminophen, when taken in excess, is among the most common causes of drug-induced liver injury, also called toxic hepatitis.
In the last few years, research 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. There have still been reports of drug-induced liver injuries in some healthy individuals taking moderate doses of anywhere between 300 mg and 1000 mg per day.
Relatively little is known about why some people are more susceptible than others, but it is thought that 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 an immune condition called eosinophilia, which is when the body produces an excess of a type of white blood cell called eosinophils.
The new results emphasize the importance of tracking liver safety as a potential, unintended adverse effect, Englund said.
“Given the growing interest in CBD as a potential treatment for conditions such as psychosis and cannabis use disorder, these findings underscore the importance of monitoring liver enzyme levels in future clinical trials,” he said.
Overall, Watkins — who co-chairs the Drug-Induced Liver Injury Network, a research group backed by the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health — still believes CBD is relatively safe.
While over-the-counter supplements are becoming a growing potential cause of significant liver injuries, CBD has yet to be flagged as a source of concern, he said.
“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.”
