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Report overlooks evidence of generally safe herb use

Austin, Texas, Aug. 09, 2024 (GLOBE NEWSWIRE) — A new paper¹ published in JAMA Network Openreports estimated percentages of US adults who have used six botanical dietary supplements linked to case reports of hepatotoxicity. These include ashwagandha, black cohosh, garcinia, green tea, red yeast rice, and turmeric (including curcumin-based formulations). Much of the dietary supplement usage information in the paper is based on the US government-sponsored National Health and Nutrition Examination Survey (NHANES) data from 2017-2020.

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Shortly after the JAMA Open Network publication on August 5, the paper generated coverage in various media outlets with misleading and even alarmist headlines such as: “Botanicals like turmeric, green tea are harming Americans’ livers,”² “More than 15 million US adults consume botanicals with liver harming potential: Study,”³ “Study estimated millions in US risk liver damage from herbal remedies,”⁴ and more.

The concern over safety of botanical ingredients is certainly a very important topic. Therefore, the authors’ initiative to raise awareness of the liver-toxic potential of botanicals is reasonable. However, the nonprofit American Botanical Council (ABC) takes issue with several aspects of the study. Most importantly, ABC emphasizes the fact that the number of case reports for each of the six botanicals included are very small compared to the estimated number of people using these supplements. For example, there were 23 global case reports of liver injury associated with ashwagandha based on a review published in 2023 — only eight of which were from people in the United States — and an estimated 1.25 million US users of ashwagandha in 2020, according to data that was cited in the JAMA Network Open paper.¹ Additionally, these case reports not only include dietary supplements, but also — in the case of ashwagandha — herbal jams, syrups, and powders of unclear composition from unbranded producers selling at local markets in India.⁵

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The article also mentions that the percentage of liver injury associated with herbal dietary supplements (HDS) relative to liver injury caused by all medications (except the over-the-counter (OTC) drug acetaminophen*) increased from 7% in 2004/2005 to 20% in 2013 according to data from the Drug Induced Liver Injury Network (DILIN). However, the authors do not report that the overall number of HDS-induced liver injury cases over the 10-year period was only 136, including 45 cases linked to bodybuilding products, many of which were found to contain illegal anabolic steroids masquerading as HDS.⁶

“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,” wrote Richard Kingston, PharmD, in an email to ABC. Dr. Kingston is President of Regulatory and Scientific Affairs at SafetyCall International (a leading consumer reporting service on adverse events for dietary supplements, OTC drugs, and household products) and Clinical Professor in the Department of Experimental and Clinical Pharmacology at the College of Pharmacy, University of Minnesota. 

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Dr. Kingston continued: “Although the percentage of cases looks ominous, the actual numbers add context to any potential concerns. 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 body-building products, that would leave about 9 patients per year with potential liver damage secondary to mainstream HDS.” 

Besides the exaggerated data on the hepatotoxicity risk, the manuscript contains several inaccuracies. The authors misstate the number of HDS users. In the abstract, they write that “The overall prevalence of HDS product use was 57.6%,” while later they explain that “in total, 731 of 9685 US adults assessed (7.5%) used a botanical-containing HDS product within the last 30 days.” The initial number of 57.6% refers to all users of dietary supplements, including non-herbal vitamins, minerals, and fatty acids.⁷ 

Another important point is the reported number of people in the US that are exposed to the “potentially liver toxic” botanicals. This estimated number of 15 million people in the US is based on the authors’ erroneous use of the number 329,484,123 for US residents over 18 years old. The number in the 2020 census is actually 256,662,010⁸; hence the entire estimate is based on erroneous data and thus should be re-written and re-published. However, this error does not eliminate the fact that botanical dietary supplement use is common in the US, and that hepatotoxic side effects, although very rare, can happen in people with sensitivities to certain botanicals and/or other conditions.

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The authors extrapolated the dietary supplement use data for the six botanicals and wrote that ”An estimated 15,584,599 … US adults used at least 1 of the 6 botanical products within the past 30 days, which was similar to the estimated number of patients prescribed potentially hepatotoxic drugs, including simvastatin (14,036,024…) and nonsteroidal anti-inflammatory drugs (14,793 837…).”¹ What the authors didn’t provide is a comparison of the relative hepatotoxicity risk of the botanical ingredients and the OTC and prescription medications. Without the relative risk, it is difficult to determine the potential harm that these ingredients may cause.

ABC chief science officer Stefan Gafner, PhD, commented: “In my opinion, the main issue is that the paper implies that 15 million US adults are exposed to potentially hepatotoxic botanicals. This sounds like a huge problem, even if the actual risk of liver injury from the six botanicals in question is low. The authors provide some information to support the hepatotoxic potential of botanicals, but these data are provided without proper context and suggest that the risk of liver injury is much greater than it actually is.”

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The authors also incorrectly contend that the dietary supplement industry is largely “unregulated.” Unfortunately, this notion of an unregulated industry is too often repeated in medical journals and mainstream media. Dietary supplement products are subject to various federal regulations including the requirement to be made according to current good manufacturing practices (cGMPs) and to be tested for identity, purity, strength, composition, and absence of contaminants by appropriate analytical methods.⁹ The FDA is carrying out hundreds of inspections of manufacturers each year in its attempt to ensure that the regulations are followed, although admittedly, the agency is inadequately resourced to inspect all facilities as often as might be optimal.

The use of botanical dietary supplements has steadily increased over the past years, and at the same time, several case reports of liver injury, especially for the most popular ingredients such as turmeric and ashwagandha, have appeared in the literature. Liver toxicity is a serious health issue, and causative agents need to be identified promptly and be monitored closely. However, the actual number of liver injury case reports for botanicals is very low.¹⁰ Therefore, suggesting that 15 million US adults may be at risk of liver injury is an exaggeration of the fact that may grab media attention but contributes little to a rational discussion of the hepatotoxic potential of botanical ingredients.

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*Acetaminophen is an OTC analgesic and antipyretic drug and the most common cause of drug-induced hepatotoxicity. However, it is often excluded from statistical analyses related to dietary supplements and OTC and prescription drugs with hepatotoxic potential.

 References

1.     Likhitsup A, Chen VL, Fontana RJ. Estimated exposure to 6 potentially hepatotoxic botanicals in US adults. JAMA Netw Open. 2024;7(8):e2425822. doi:10.1001/jamanetworkopen.2024.25822.

2.     Mundell E. Botanicals like turmeric, green tea are harming Americans’ livers [online]. Medical Xpress. Available at: Botanicals like turmeric, green tea are harming Americans’ livers (medicalxpress.com). Accessed August 6, 2024.

3.     Sunny S. More than 15 million US adults consume botanicals with liver harming potential: Study [online]. Medical Daily. Available at: https://www.medicaldaily.com/more-15-million-us-adults-consume-botanicals-liver-harming-potential-study-472066. Accessed August 6, 2024.

4.     Koumoundouros T. Study estimates millions in US risk liver damage from herbal remedies [online]. ScienceAlert. Available at: https://www.sciencealert.com/study-estimates-millions-in-us-risk-liver-damage-from-herbal-remedies?utm_source=ScienceAlert+-+Daily+Email+Updates&utm_campaign=0dc9b35b89-RSS_EMAIL_CAMPAIGN&utm_medium=email&utm_term=0_fe5632fb09-0dc9b35b89-365670825. Accessed August 7, 2024.

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5.     Philips CA, Valsan A, Theurvath AH, et al. Ashwagandha-induced liver injury—A case series from India and literature review. Hepatol Commun. 2023;7(10):e207.

6.     Navarro VJ, Barnhart H, Bonkovski HL, et al. Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network. Hepatology. 2014;60(4):1399-1408.

7.     Mishra S, Gahche J, Ogden C, Dimeler M, Potischman N, Ahluwalia N. Dietary Supplement Use in the United States: National Health and Nutrition Examination Survey, 2017–March 2020. National Center for Health Statistics. 2023. Available at: https://doi.org/10.15620/cdc:124677. Accessed August 7, 2024.

8.     Estimates of the total resident population and resident population age 18 years and older for the United States, the District of Columbia, and Puerto Rico: July 1, 2020. Available at: https://census.hawaii.gov/wp-content/uploads/2020/12/sc-est2020-18pop-res.pdf. Accessed August 6, 2024.

9.     Soller RW, Bayne HJ, Shaheen C. The Regulated Dietary Supplement Industry: Myths of an Unregulated Industry Dispelled. HerbalGram. 93;2012:42-57.

10.  Teschke R, Frenzel C, Glass X, Schulze J, Eickhoff A. Herbal hepatotoxicity: A critical review. Br J Clin Pharmacol. 2013;75(3):630-636.

About the American Botanical Council

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