08.08.24
A paper published Aug. 5 in JAMA Network Open estimated percentages of U.S. 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 U.S. government-sponsored National Health and Nutrition Examination Survey (NHANES) data from 2017-2020.
Shortly after publication, 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,” “More than 15 million US adults consume botanicals with liver harming potential: Study,” “Study estimated millions in US risk liver damage from herbal remedies,” and more.
Trade associations including the American Botanical Council (ABC) and Council for Responsible Nutrition (CRN) took issue with several aspects of the study.
ABC emphasized 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 U.S. — and an estimated 1.25 million U.S. users of ashwagandha in 2020, according to data that was cited in the JAMA Network Open paper.
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.
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.
“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.
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.
“Although the percentage of cases looks ominous, the actual numbers add context to any potential concerns,” Kingston continued. “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, ABC noted. 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.
Another important point is the reported number of people in the U.S. that are exposed to the “potentially liver toxic” botanicals. This estimated number of 15 million people in the U.S. is based on the authors’ erroneous use of the number 329,484,123 for U.S. 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, ABC said.
However, this error does not eliminate the fact that botanical dietary supplement use is common in the U.S., and that hepatotoxic side effects, although very rare, can happen in people with sensitivities to certain botanicals and/or other conditions.
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…).”
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 U.S. 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.”
CRN said the biggest takeaway is that nothing present in the article's findings indicate any new risk of injury that should alarm supplement consumers.
"This analysis of existing NHANES survey data doesn't appreciate that the overall risk these ingredients pose is exceedingly low," said Steve Mister, president and CEO of CRN. "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."
Mister also noted that the article didn't investigate a causal relationship between the consumption of botanical supplements and liver injury, nor does it add any new scientific findings with respect to their potential for hepatotoxicity. These limitations largely weren't acknowledged in mainstream news coverage, suggesting that many of those who reported on the study might not have actually read it, CRN noted. "Liver injury from botanicals may occur in rare cases, especially in individuals with specific genetic predispositions or pre-existing conditions. But the vast majority of the population taking these botanical supplements uses them as directed without issue," the association stated.
CRN stated that it advocates for a balanced perspective that includes awareness of potential risks - consumers should use these products as directed, and in consultation with healthcare providers, especially when combining supplements with prescription medications.
"What consumers and healthcare practitioners should take away from this study is that there is great and growing interest in using herbal supplements to promote health and wellness," said Mister. "Practitioners should encourage candid and open-minded conversations with their patients about supplement usage. Alarmist headlines that mislead doctors and panic consumers shut down those conversations and do a disservice to the millions of people who trust and use these products safely every day."
The authors also incorrectly contend that the dietary supplement industry is largely “unregulated.” This notion of an unregulated industry is often repeated in medical journals and mainstream media.
However, 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. 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. Therefore, suggesting that 15 million U.S. 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.
Shortly after publication, 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,” “More than 15 million US adults consume botanicals with liver harming potential: Study,” “Study estimated millions in US risk liver damage from herbal remedies,” and more.
Trade associations including the American Botanical Council (ABC) and Council for Responsible Nutrition (CRN) took issue with several aspects of the study.
ABC emphasized 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 U.S. — and an estimated 1.25 million U.S. users of ashwagandha in 2020, according to data that was cited in the JAMA Network Open paper.
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.
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.
“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.
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.
“Although the percentage of cases looks ominous, the actual numbers add context to any potential concerns,” Kingston continued. “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, ABC noted. 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.
Another important point is the reported number of people in the U.S. that are exposed to the “potentially liver toxic” botanicals. This estimated number of 15 million people in the U.S. is based on the authors’ erroneous use of the number 329,484,123 for U.S. 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, ABC said.
However, this error does not eliminate the fact that botanical dietary supplement use is common in the U.S., and that hepatotoxic side effects, although very rare, can happen in people with sensitivities to certain botanicals and/or other conditions.
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…).”
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 U.S. 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.”
CRN said the biggest takeaway is that nothing present in the article's findings indicate any new risk of injury that should alarm supplement consumers.
"This analysis of existing NHANES survey data doesn't appreciate that the overall risk these ingredients pose is exceedingly low," said Steve Mister, president and CEO of CRN. "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."
Mister also noted that the article didn't investigate a causal relationship between the consumption of botanical supplements and liver injury, nor does it add any new scientific findings with respect to their potential for hepatotoxicity. These limitations largely weren't acknowledged in mainstream news coverage, suggesting that many of those who reported on the study might not have actually read it, CRN noted. "Liver injury from botanicals may occur in rare cases, especially in individuals with specific genetic predispositions or pre-existing conditions. But the vast majority of the population taking these botanical supplements uses them as directed without issue," the association stated.
CRN stated that it advocates for a balanced perspective that includes awareness of potential risks - consumers should use these products as directed, and in consultation with healthcare providers, especially when combining supplements with prescription medications.
"What consumers and healthcare practitioners should take away from this study is that there is great and growing interest in using herbal supplements to promote health and wellness," said Mister. "Practitioners should encourage candid and open-minded conversations with their patients about supplement usage. Alarmist headlines that mislead doctors and panic consumers shut down those conversations and do a disservice to the millions of people who trust and use these products safely every day."
The authors also incorrectly contend that the dietary supplement industry is largely “unregulated.” This notion of an unregulated industry is often repeated in medical journals and mainstream media.
However, 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. 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. Therefore, suggesting that 15 million U.S. 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.
