Study on herbs linked to liver injury ignores wide safety margins, stakeholders say

A new study raises a red flag concerning the use of botanical supplements associated with liver problems. Industry stakeholder groups countered that the huge number of Americans using these products daily without problems demonstrates their large margin of safety.

The new paper, styled as an “original investigation,” was published in JAMA (Journal of the American Medical Association) Network Open earlier this week. It was the work of three medical doctors associated with the University of Michigan.

The paper, titled “Estimated Exposure to 6 Potentially Hepatotoxic Botanicals in US Adults,” compared the usage of products containing the botanicals in question to the usage of hypolipidemic drugs, NSAIDs (non-steroidal anti-inflammatory drugs) and antidepressants.

To arrive at this number, the researchers used data culled from NHANES (National Health and Nutrition Examination Survey) surveys conducted between 2017 and 2020. Data from more than one survey cohort was used for the analysis because the global pandemic interrupted some of the NHANES data collection, the authors said.

Authors focus in on six popular botanicals

The researchers looked at the usage of six botanicals: turmeric or curcumin, green tea, ashwagandha, Garcinia cambogia, red yeast rice and black cohosh.

Turmeric products are used by consumers for many reasons, including to reduce inflammation and improve joint health. Green tea and Garcinia cambogia are most often used in weight management formulations.

Ashwagandha has gained popularity recently for its use as an adaptogen. Consumers often use it for its calming or mood support benefits. Red yeast rice supplements are associated with cholesterol-lowering benefits, whereas black cohosh has long been a mainstay of menopause symptom relief formulations.

The authors said these six botanicals are near the top of the list when it comes to products mentioned in liver injury case reports. The reports of liver injury came from the Drug Induced Liver Injury Network (DILIN) and the Acute Liver Failure Study Group.

Study authors: Prevalence of use seen as alarming

The percentage of cases in the DILIN database linked to herbal products increased from 7% in 2003-2004 to 20% in 2013-2014, and the Acute Liver Failure Study Group’s data showed a similar rise, according to the research paper.

The authors concluded use of herbal supplements roughly matches the use of hypolipidemic drugs, NSAIDs and antidepressants — and this was an alarming finding, considering the risks they said the herbal products pose.

“In light of the lack of regulatory oversight on the manufacturing and testing of botanical products, it is recommended that clinicians obtain a full medication and HDS use history when evaluating patients with unexplained symptoms or liver test abnormalities,” the authors wrote. “Considering widespread and growing popularity of botanical products, we urge government authorities to consider increasing the regulatory oversight on how botanicals are produced, marketed, tested and monitored in the general population.”

ABC and CRN: Overall case numbers are tiny, and safety margins are high

However, the American Botanical Council (ABC) and the Council for Responsible Nutrition (CRN) were quick to cite statistical and methodological flaws in the paper, which they said reached conclusions not fully supported by the data.

ABC, in a press release issued Wednesday, noted the authors did not delve into the issues the industry often has raised with how DILIN classifies dietary supplements. The group’s HDS (Herbal and Dietary Supplements) designation includes bodybuilding products that may be contaminated with illegal anabolic steroids and shouldn’t properly be classified as a supplement at all. Industry representatives note such products are unapproved drugs, not dietary supplements.

ABC noted the JAMA paper also glossed over the fact that the overall case numbers in the DILIN reports are very low. Only 136 cases were linked to so-called “HDS” over a 10-year period, and 45 of those were linked to bodybuilding products.

“It’s disappointing that the authors provided only the percentage of DILIN-enrolled patients that experienced liver damage due to HDS as compared to all other medications,” said Richard Kingston, PharmD, in an email to ABC. Kingston is president of regulatory and scientific affairs at SafetyCall International, a consumer reporting service on adverse events for dietary supplements. He is also a professor in the College of Pharmacy at the University of Minnesota. 

“Although the percentage of cases looks ominous, the actual numbers add context to any potential concerns,” Kingston added. “Consider that the actual total number of patients that experienced liver damage from HDS was 136 over the 10-year period, amounting to about 14 patients a year. If you exclude the 45 bodybuilding products, that would leave about 9 patients per year with potential liver damage secondary to mainstream HDS.”

Steve Mister, president and CEO of CRN, said the authors raise an alarm where none is warranted. While it is important to be aware of potential risks, especially for those few consumers who might have genetic predispositions or pre-existing conditions, it is crucial to recognize the long history of safe use of these products, according to CRN.

“This analysis of existing NHANES survey data doesn’t appreciate that the overall risk these ingredients pose is exceedingly low,” Mister said in a statement. “Revealing that more than 15 million Americans use at least one of these herbal supplements, when compared to their actual reported risks, only strengthens the case for their safety.”