Consumers continue to increase their use of herbal supplements to improve health and manage a broad range of conditions. The American Botanical Council (ABC) estimates that Americans spent $7.5 billion on supplements in 2016, making it the 13th year in a row for which there was an increase in sales.1 These supplements include herbs thought to have medicinal benefits, such as horehound (Marrubium vulgare), which has been used since ancient times to treat respiratory conditions, to “wheatgrass” (Triticum aestivum) and barley shoots (Hordeum vulgare) because of the supposed nutritional benefits of these plants at an early growth stage. Other examples include use of botanicals for cosmetic benefits, Yerba mate tea (Ilex paraguariensis) to fight fatique, and ayahuasca (Banisteriopsis caapi) as part of a personal spiritual discovery.2, 3 In its 2016 Market Report, the ABC listed 40 herbal supplements that each exceeded $2 million in sales in the U.S.
The use of herbal supplements is also widespread in Europe and Asia, where many botanical remedies have been used for millennia and are part of traditional medicine and culture.
In some countries in Asia, the use of traditional botanical remedies and Western medicine are recognized as both having value and are now being integrated into healthcare systems. For example, in 1996, Taiwan’s National Health Insurance (NHI) system began to cover Traditional Chinese Medicine (TCM) as an integrated alternative in healthcare programs.1 Within Taiwan’s healthcare reimbursement system, patients may choose to use both TCM and Western treatments. In 2012, approximately 7% of the healthcare budget was spent on TCM options.
In 2014, the Hong Kong public health agency launched the ‘Integrated Chinese-Western Medicine Pilot Programme’ an initiative to incorporate TCM into Western medicine. In 2018, a new Chinese medicine hospital was announced that will offer TCM to patients. Authorities expect the hospital to enhance the development of Chinese medicine; additionally, the government healthcare agency has established funds to facilitate research in TCM and promote public awareness of the Chinese medicine hospital.5
U.S. Regulation of Dietary Supplements
In the U.S., the regulation of botanicals and herbal supplements is governed by the Dietary Supplement Health and Education Act (DSHEA), passed by Congress in 1994.6 DSHEA provides a broad definition of “dietary supplements” that includes anything that is “an herb or other botanical,” with very few substances—such as tobacco—being explicitly excluded. DSHEA, which is administered by the Food and Drug Agency (FDA), requires that sellers of dietary supplements not make false or misleading claims. However, the burden of proof to show that a claim is false or that a product is unsafe is on the FDA. Hence in the U.S., botanical and herbal supplements are regulated in a way that more resembles food products than pharmaceutical products.
With growing interest in natural products from health conscious consumers and the relatively light regulatory burden, the number of dietary supplements available to U.S. consumers has proliferated. Manufacturers can formulate supplements in numerous ways, and various botanical extracts and herbal materials can be combined to create new products. In a February 2019 press release, the FDA estimated that there may be over 80,000 supplement products for sale in the U.S. 7
Pharmacologists have long recognized the potential for interaction effects between botanical or herbal supplements and prescription and over-the-counter (OTC) pharmaceuticals. Botanical-drug interactions (BDIs) may result from active ingredients in botanicals decreasing (i.e. inhibiting) or increasing (i.e. inducing) the metabolism rate of drugs. This can lead to drug concentrations being too high or too low, which can cause potential risks of toxicity or other adverse effects or the drug not being effective. Additionally, there may be other pharmacokinetic effects such as can occur if a botanical active ingredient is an analogue of the drug, and the botanical and drug act together to deliver a dangerously high dose.
A longitudinal study using the Taiwan National Health Insurance Research Database was used to measure prevalence of BDIs in Taiwan.8 As part of their analysis, researchers classified TCMs, many of which are mixtures of several botanicals, into their component herbs, and then analyzed BDIs. The study showed that there were 407 drug codes for TCM compounds that contain ephedrine analogues. For the period of study these ‘ephedrine analogue’ TCMs had been paired with 19 Western medicines known to have ephedrine interaction effects, and there were a total of 7733 interaction pairs. The data indicated that between 1989 and 2011, annual prevalence of BDIs with ephedra-containing TCM drugs was between 0.06% and 0.39%.
A recent in vivo rat study investigated interaction effects between aspirin (ASA) and clopidogrel (CLP), which are frequently prescribed for managing coronary artery disease, and the following four TCMs that have been used to prevent cardiovascular disease, as well improve health in other ways:
- Dan Shen Root (Radix Salvia Miltiorrhiza)
- Ge Gen (aka Kudzu Root) (Pueraria lobata)
- Danggui or Dong quai (Angelica sinensis)
- Chuanxiong (Ligusticum chuanxiong)
Study data indicated that ge gen and danggui significantly altered the pharmacokinetics of ASA and CLP, and predicted that co-administration of ASA and CLP with these herbs would result in increased systemic exposure.
Botanicals that are perceived to be exotic may have an allure to some Western consumers, especially when they are thought to be transformative in some fashion.9 These consumers may be at even higher risk of BDIs because of limited knowledge about the pharmacology of the botanicals and the risks of co-administration of the botanical and a drug regimen. For example, there is evidence that ayahuasca, a psychoactive botanical, may significantly alter the pharmacokinetics of SSRI antipsychotic drugs, resulting in serious adverse reactions.10
There is an increasing volume of published evidence of BDIs, although most BDI concerns are hypothetical, inferred from animal studies, cellular assays, or based on other indirect means, with limited rigorous clinical research on potential risks. It is difficult to obtain clinical BDI data in part because patients deliberately refuse to disclose their use of herbal remedies to their physicians, making it likely that BDIs are under reported.11 Additionally, there are ethical challenges to designing a clinical study to investigate BDIs, it is difficult to ascertain plasma levels of botanical substances, botanicals are complex mixtures making it hard to identify the phytochemicals responsible for an interaction, there is no standard BDI assessment instrument and physicians are not motivated to report BDIs.12
Nevertheless, to help patients and their physicians avoid potential drug interactions, toxicities and related risks, organizations such as the NIH National Center for Complementary and Integrative Health publish lists of potential BDIs and provide other resources.13 Websites like drugs.com publish lists of common supplements that may have a risk of drug interactions.14
A New Regulatory Focus
The FDA has signaled an increased focus on identifying and managing BDI risks and other concerns associated with herbal supplements. While the dietary supplement industry has broad latitude to create and market products, the FDA has established the “Dietary Supplement Ingredient Advisory List,” – a list compounds that are prohibited from being included in dietary supplements.15 With recent actions the agency has indicated a willingness to enforce compliance. On April 16, 2019, the FDA issued warning letters to 12 companies for including prohibited ingredients.16 Per data collected by wizmed.com, the FDA’s Center for Food Safety and Applied Nutrition has issued over 30 warning letters between January 1 and August 13, 2019 to herbal and dietary supplement companies for numerous violations.17
On February 11, 2019, FDA Commissioner Dr. Scott Gottlieb announced a new plan to modernize dietary supplement regulation.18 The announcement confirmed the FDA’s priorities to: 1) ensure safety and protect consumers from harmful products; 2) ensure product integrity so that consumers can be certain that dietary supplements contain the ingredients claimed on the label; and 3) foster an environment of informed decision making.
As part of the FDA’s renewed focus on dietary supplements, Dr. Gottlieb announced new initiatives to develop a “rapid response tool” to alert the public of unlawful or dangerous ingredients, enhance the process to notify the FDA of new dietary ingredients and increase enforcement of laws to protect public health. He also announced the formation of a Botanical Safety Consortium, which was described as “a public-private partnership that will gather leading scientific minds from industry, academia and government to promote scientific advances in evaluating the safety of botanical ingredients and mixtures in dietary supplements.” The consortium will be charged with evaluating novel methodologies to assess toxicology, risks and promote the goals of safety and effectiveness.
Retailers and manufactures are showing increased concern about assessing the safety of the dietary supplement products they are marketing. They want to continue to supply herbal and botanical remedies to their customers, while also providing high quality products and ensuring customers are aware of interaction effects. As an example of retailers’ commitment to quality and safety, in May 2019, CVS Health announced that it will require independent third party testing of all supplements that it sells to ensure accuracy of the ingredients listed on the label.19
Increased vigilance and better processes to ensure the quality of supplements will reduce risk to consumers. However, there are significant challenges to develop evidence that can be used to mitigate the risks of BDIs. Evaluation of drug-drug interaction (DDI) risks is a standard part of the preclinical and clinical development process for new pharmaceuticals. But it would be very time consuming and prohibitively expensive to conduct clinical studies of all possible BDIs because there is such a vast array of herbal supplements, each with numerous formulations in different mixtures with each other, and a very high number of possible combinations with drugs.
Researchers have used various test species to investigate potential BDIs. While these in vivo studies can provide useful information, they do not always accurately predict BDI risks in humans because of the different metabolism profiles between the test species and humans.20 In vitro human hepatic models, using microsomes and plated hepatocyte cultures, have also been used to predict BDIs. These models have the advantages of using human liver cells, rather than a test species, and the benefit that studies can be conducted relatively quickly using fewer resources. However, conventional models are limited because hepatic cells in an in vitro culture may not have the same clearance, regulatory and metabolism function as a human liver.
Conventional DDI models typically evaluate one test article in the presence of known controls. Because botanical supplements are complex mixtures of multiple compounds, BDI evaluations must account for synergistic, additive, competing and other interaction effects among the phytochemical constituents and capture clinically relevant pathways.
A new paradigm is needed to evaluate risks of BDIs using a model that takes advantage of the efficiency of in vitro human hepatocytes but is better at predicting effects in humans.
BioIVT and P&G Collaborate on BDI Research
The Procter and Gamble Company (P&G) collaborated with BioIVT to investigate potential BDI effects of several botanicals. The studies were implemented with an in vitro model that uses TRANSPORTER CERTIFIED™ hepatocytes in sandwich culture. TRANSPORTER CERTIFIED hepatocytes are evaluated to ensure they have physiologically relevant transporter uptake and efflux function. In sandwich culture, TRANSPORTER CERTIFIED hepatocytes form bile pockets that are analogous to bile canaliculi in the liver. In these culture conditions, the hepatocytes have been shown to more closely replicate the clearance, metabolism and regulatory function of hepatocytes in the liver as compared to conventional models. For some compounds, this model better predicts effects in humans.
Schisandra species have been used in traditional Chinese medicine and are reported to have a broad range of medicinal benefits, including anti-inflammatory effects. In China, Schisandra sphenanthera extract (SSE) is often co-administered with midazolam (MDZ) before surgery, and with tacrolimus in the treatment of renal and liver transplant recipients.21 Separate clinical studies have shown that SSE can reduce clearance of MDZ and tacrolimus, thus increasing the systemic concentration of these drugs.22,23
In their collaboration, BioIVT and P&G sought to predict the SSE-MDZ and SSE-tacrolimus interactions observed in the clinical study using the in vitro TRANSPORTER CERTIFIED hepatocytes in sandwich culture model. The pharmacokinetics of MDZ and tacrolimus is well characterized, and both drugs are metabolized by liver enzymes (CYPs). The model has been effective at predicting CYP-mediated metabolism. Results from the in vitro study accurately predicted (e.g. net effect and relative strength) the clinically observed BDIs across a range of doses.24 The study results support the use of the model for BDI assessments to predict clinically relevant clearance interactions. Dr. Amy Roe, Principal Toxicologist at P&G and co-author of a publication about the study (Jackson, et al (2017) DMD), was the lead presenter on a webinar in which she discussed the study design and benefits of this “whole-cell” model to investigate BDIs. She emphasized that whole-cell models can account for the complexity of the herbal mixture. You can watch the webinar here.
In an additional collaboration, BioIVT and P&G investigated BDIs with Boswellia serrata (Indian Frankincense), a botanical used as an anti-inflammatory supplement. B serrata saw U.S. sales of $14.7 million in 2017, making it one of the top 40 botanical supplements in the U.S.25 The study compared two in vitro methods–a conventional pooled human liver microsomes model and a whole cell model using TRANSPORTER CERTIFIED™ hepatocytes in sandwich culture–to evaluate the inhibitory effects of B. serrata on CYP enzymatic activity. It focused specifically on CYP2C9 and CYP3A4/5, as those enzymes had been shown in in vitro studies to be the most potently inhibited by B. serrata. While the microsomal liver method predicted potent CYP inhibition by B. serrata, the sandwich cultured whole cell model predicted much less inhibition potential.26 Dr. Kenneth Brouwer, VP Research, ADME-Tox at BioIVT and co-author of a publication on the research (Roe et al. (2019) AIVT) commented, “Although we are not aware of any clinical studies investigating potential BDIs with B. serrata, the large volume of sales of this botanical, seemingly without adverse events, tends to suggest that the microsomal model may be overly conservative, potentially leading to false positives.” He added, “The microsomal studies may overestimate the interaction potential because they lack the full complement of metabolic enzyme and transporter functions. Therefore, we believe that the sandwich cultured human hepatocytes model, which incorporates cellular uptake, efflux, metabolism and regulatory function, serves as a more accurate predictor of in vivo effects. It can also be employed to investigate both potential drug-drug interactions and BDIs.”
Dr. Roe presented the study results at a symposium at the 12th International ISSX Meeting in July 2019. As part of her presentation, Dr. Roe emphasized that B. serrata extract supplements have numerous chemical components, so it is important to use an integrated whole cell system, such as the TRANSPORTER CERTIFIED hepatocytes in sandwich culture to model potential hepatic effects. View the presentation slides here.
BioIVT supports regulatory and research initiatives to better understand BDIs and is committed to developing products and methods that will help researchers predict potential risks and benefits of dietary supplements and enable consumers to make informed decisions about these products.
1 Smith, T et. al., (2017) Herbal Supplement Sales in US Increase 7.7% in 2016. Market Report 115. http://cms.herbalgram.org/herbalgram/issue115/images/HG15-Mktrpt.pdf
2 Callicott, C. (2016) Introduction to the Special Issue: Ayahuasca, Plant-Based Spirituality, and the Future of Amazonia. Anthropology of Consciousness 27(2): 113 – 120. DOI: 10.1111/anoc.12059
3 America is Getting a (Legal) Ayahuasca Retreat. (2017, January 21). Retrieved from https://www.travelandleisure.com/articles/first-legal-ayahuasca-retreat-opens
4 Chen Chen, K. et al (2015) Interactions between traditional Chinese medicine and western drugs in Taiwan: A population-based study. Computer Methods and Programs in Biomedicine. 122(3). http://dx.doi.org/10.1016/j.cmpb.2015.09.006
5 Traditional but unconventional: Hong Kong’s first Chinese medicine hospital signals a change in gov’t attitude (2019, April 20). Retrieved from Hong Kong Free Press https://www.hongkongfp.com/2019/04/20/traditional-unconventional-hong-kongs-first-chinese-medicine-hospital-signals-change-govt-attitude/
6 Dietary Supplement Health and Education Act of 1994 Public Law 103-417. National Institutes of Health Office of Dietary Supplements. https://ods.od.nih.gov/About/DSHEA_Wording.aspx#sec3
7 Statement from FDA Commissioner Scott Gottlieb, M.D., on the agency’s new efforts to strengthen regulation of dietary supplements by modernizing and reforming FDA’s oversight. (2019, February 11). FDA. https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-agencys-new-efforts-strengthen-regulation-dietary
8 Chen Chen, K. et al (2015) Interactions between traditional Chinese medicine and western drugs in Taiwan: A population-based study. Computer Methods and Programs in Biomedicine. 122(3). http://dx.doi.org/10.1016/j.cmpb.2015.09.006
9 Callicott, C. (2016) Introduction to the Special Issue: Ayahuasca, Plant-Based Spirituality, and the Future of Amazonia. Anthropology of Consciousness 27(2): 113 – 120. DOI: 10.1111/anoc.12059
10 Calloway, JC, Grob, CS (1998) Ayahuasca Preparations and Serotonin Reuptake Inhibitors: A Potential Combination for Severe Adverse Interactions. Journal of Psychoactive Drugs. 30(4): 367-369
11 Awortwe C, Makiwane, M, Reurter H, Muller C, Louw J, Rosenkranz B L (2018) Critical evaluation of causality assessment of herb–drug interactions in patients. Br J Clin Pharmacol 84: 679–693
12 Awortwe C, Makiwane, M, Reurter H, Muller C, Louw J, Rosenkranz B L (2018) Critical evaluation of causality assessment of herb–drug interactions in patients. Br J Clin Pharmacol 84: 679–693
13 NCCIH Clinical Digest for Health Professionals. Herb-Drug Interactions. (2015) Retrieved from https://nccih.nih.gov/health/providers/digest/herb-drug
14 18 Herbal Supplements with Risky Drug Interactions. (2019) Retrieved from https://www.drugs.com/slideshow/herb-drug-interactions-1069#view-as-slideshow
15 US Food and Drug Administration Dietary Supplement Ingredient Advisory List. Retrieved from https://www.fda.gov/food/dietary-supplement-products-ingredients/dietary-supplement-ingredient-advisory-list
16 US Food and Drug Administration. FDA Acts on Dietary Supplements Containing DMHA and Phenibut. (2019, April 16) Retrieved from https://www.fda.gov/food/cfsan-constituent-updates/fda-acts-dietary-supplements-containing-dmha-and-phenibut
17 WIZMED (2019, August 13) Recent FDA Warning Letters. Retrieved from https://wizmed.com/warning
18 US Food and Drug Administration. (2019, February 11) Statement from FDA Commissioner Scott Gottlieb, M.D., on the agency’s new efforts to strengthen regulation of dietary supplements by modernizing and reforming FDA’s oversight. Retrieved from https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-agencys-new-efforts-strengthen-regulation-dietary
19 Chin, K., (2019, May 15). CVS Health to Require Third-Party Testing of Vitamins, Supplements. The Wall Street Journal. Retrieved from https://www.wsj.com
20 Bracken MB, (2009). Why Animal Studies Are Often Poor Predictors Of Human Reactions to Exposure. Journal of the Royal Society of Medicine. 102(3): 120-122
21 Jackson J., Freeman KM, Friley WW, Herman AG, Black CB, Brouwer KR, Roe AL (2017) Prediction of Clinically Relevant Herb-Drug Clearance Interactions Using a Whole Cell Approach: Schisandra sphenanthera case study. Drug Metabolism and Disposition, 45 (9): 1019-1026; DOI: https://doi.org/10.1124/dmd.117.075408
22 Xin HW, Wu XC, Li Q, Yu AR, Zhu M, Shen Y, Su D, and Xiong L (2007) Effects of Schisandra sphenanthera extract on the pharmacokinetics of tacrolimus in healthy volunteers. Br J Clin Pharmacol 64:469–475.
23 Hua-Wen Xin et al.; British Journal of Clinical Pharmacology, (2007) 64:4:469-475
24 Jackson J. et al (2017) Prediction of Clinically Relevant Herb-Drug Clearance Interactions Using a Whole Cell Approach: Schisandra sphenanthera case study. Drug Metabolism and Disposition, 45 (9): 1019-1026; DOI: https://doi.org/10.1124/dmd.117.075408
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