Dietary Supplements
Abstract & Commentary
The Drawbacks of Retrospective Dietary Supplement Monitoring
By David Kiefer, MD
Synopsis: This study reviews a recent example of hepatotoxicity from a dietary supplement and discusses the issues related to retroactively monitoring nutritional supplements for adverse effects.
Source: Cohen PA. Hazards of hindsight — Monitoring the safety of nutritional supplements. N Engl J Med 2014;370:1277-1280.
This article tracks the chronology of adverse effects to OxyElite Pro, a dietary supplement containing caffeine and four herbal ingredients (Bauhinia purpurea, Bacopa monnieri, Cirsium oligophyllum, and yohimbe, Pausinystalia johimbe), that was marketed to help people "burn fat." The product, which has since been recalled, was first noted to cause hepatitis and, sometimes, liver failure in May 2013, but it took the FDA 4 months to learn of the problem and start an investigation. All told, 97 cases were linked to OxyElite Pro, including 47 hospitalizations, three liver transplantations, and one fatality.
The author accurately reviews the ultimate origin of the reporting delay in this case example. Due to 1994 legislation (the Dietary Supplement Health and Education Act, abbreviated DSHEA and often pronounced "deh shay"), the 85,000 dietary supplement products in the United States can be released for sale to the public without the phases of proof of safety or efficacy that are required for pharmaceuticals. All monitoring for dietary supplements takes place retroactively, and the FDA relies on MedWatch, a voluntary reporting system. Of note, attempts to change this arrangement repeatedly have failed due to outcry from industry and the public, due, in part to the desire to have unfettered access to vitamins and herbs in the over-the-counter or online environments, where most of these products are sold.
This article is not a clinical trial nor meta-analysis, but rather a commentary type review, and it mentions concerns about adulteration. For example, over an undisclosed time period, 500 supplements have been found to be adulterated, including two with "new" stimulants that were found in 2013. The author also mentions one stimulant adulterant that was identified in the author’s laboratory. In addition, the article provides a table of potential adverse reactions to "legal ingredients and adulterants in dietary supplements" (see abbreviated Table), although no sources were given for the information provided. Twice, NSAIDs were listed, though it was unclear if those are known adulterants or "legal ingredients" in dietary supplements.
Mention is made of the confusion surrounding this topic on the part of clinicians or the concerned public, how reports are sometimes made to local poison control centers, and how investigations may begin with other governmental groups such as public health departments, the Department of Defense, or the Centers for Disease Control and Prevention. With so many people and organizations involved, the author posits that it is easy to understand why a delay might occur in the reporting of an adverse dietary supplement effect.
The Dietary Supplement Labeling Act, pending in Congress, may lead to some improvement through required product registration with the FDA and lists of known adverse effects. Other suggestions for going forward include the sharing of databases between the groups mentioned above; a central clearinghouse where all of that data are combined, stored, and accessible; and a team of experts to assist health care providers with their supplement questions and concerns.
The author’s parting comments make clear the main point of the article: "But even these ambitious changes would not prevent dangerous supplements from reaching consumers. If consumers and physicians are to have confidence that all supplements are safe, the law regulating supplements must be reformed. Every supplement ingredient should undergo rigorous safety testing before marketing."
Table. Summary of Potential Adverse Dietary Supplement Reactions Noted by Author
The following information appears in the table in the article reviewed. The information is both potentially accurate but also misleading.
Symptoms |
Ingredients possibly responsible |
Arrhythmias |
Ephedra spp, Epimedium spp (Horny goat weed) |
Bleeding |
Ginkgo biloba, NSAIDs |
Gynecomastia, acne, hirsutism, infertility |
DHEA |
Hepatotoxicity |
Symphytum officinale (comfrey), Piper methysticum (kava kava), Larrea tridentata (chaparral) |
Mood alterations |
Panax ginseng |
Nausea, vomiting, diarrhea, anorexia |
Crataegus spp (hawthorn) |
Nephrolithiasis |
Calcium |
Rash |
Hypericum perforatum |
Adapted from: Cohen PA. Hazards of hindsight — Monitoring the safety of nutritional supplements. N Engl J Med 2014;370:1277-1280.
Commentary
This article received media coverage and seems to nudge (push?) the consumer and health care providers toward feeling like it is dangerous to drink bottled herbal tea, take vitamin C, or ingest any of the 85,000 dietary supplements available in the marketplace; the current climate of retrospective dietary supplement monitoring is dangerous, replete with adverse effects and pharmaceutical interactions, so beware! A more balanced view of this topic would agree with some, but not all, of the author’s points.
For example, there is no doubt that there are some unsafe products for sale, but in context, many botanical medicines have years of safe and effective traditional use, some mounting clinical evidence, Good Manufacturing Practice (GMP) oversight that is now legally mandated, and third-party certification efforts (such as ConsumerLab and the United States Pharmacopeia) that are addressing the issue of safety. One could argue that some of the energy of safety vigilance should be turned to a greater public health concern — the morbidity, mortality, and polypharmacy associated with pharmaceutical use, not an insignificant concern.1,2,3
Perhaps the author’s recent discovery of an adulterant in a popular sports supplement scared him. And, it seems, for good reason; he reports finding an analog of methamphetamine that has never been used nor studied in humans, potentially a serious, if not dangerous, situation. Such products are unacceptable and should never be found on the store shelves. His suggested improvements via labeling legislation, database sharing, and a team of experts whose sole purpose is to guide confused clinicians faced with a possible adverse effect all seem like good ideas and worth government funding. And, the author is right about the inadequacies of the MedWatch system to thoroughly characterize possible adverse dietary supplement effects. Product name, lot numbers, chronology, and dose are some key pieces of information required to pin an effect on a given substance, and to leave that detective work up to busy clinicians volunteering their time to access an online report form is a recipe for incomplete reporting. The proposed legislation may function to improve this situation, but it begs the question of how registering safety information with the FDA will occur when many products have little to no data, and there is little to no incentive, if it isn’t mandated, to do the expensive studies necessary to determine safety. Partnerships between researchers, industry, and government seem crucial to providing information necessary to making all of these decisions.
It is all too easy to fan the negative media fire about dietary supplements, but more useful to clinicians is a discussion grounded in scientific articles and high-quality references. The misinformation in the Table provided by the author is anything but scientific: lacking references, correct botanical nomenclature, or relevance to the topic of adverse effect reporting. For example, arrhythmias, myocardial infarction, and stroke are listed as being caused by ephedra, true, but ephedra (Ephedra sinica) and ephedrine alkaloids have been banned since the early 2000s due to their adverse cardiovascular effects; the inclusion of "illegal" substances in a table labeled as "legal" seems unnecessary and misleading, perhaps representing the author’s bias. The inclusion of NSAIDs seems equally irrelevant and not very useful to clinicians trying to learn about the topic. Also, well-known adverse effects, such as a few possible case reports of bleeding from Ginkgo biloba or the photo-induced rash from Hypericum perforatum, and adverse gastrointestinal effects from numerous dietary supplements, are no surprise, and don’t really seem relevant to the topic of surveillance. These latter adverse effects and those of other dietary supplements seem better addressed through improved patient and provider education and increased rates of disclosure of use.4,5,6 Again, to include such a table here seems to unnecessarily feed hysteria.
In summary, it is extremely important that safe, high-quality dietary supplements, free of adulteration, be available for use in the United States, and that all clinicians get in the habit of checking for adverse effects or supplement-pharmaceutical interactions for each patient. This article makes some useful suggestions about improving surveillance and marketing of dietary supplements in the United States at the same time that some of the data provided are misleading, out of useful context, and distracting, a reminder of the importance of an evidence-based discourse about dietary supplements and other integrative therapeutics.
References
1. Miguel A, et al. Frequency of adverse drug reactions in hospitalized patients: A systematic review and meta-analysis. Pharmacoepidemiol Drug Saf 2012;21:1139-1154.
2. Lazarou J, et al. Incidence of adverse drug reactions in hospitalized patients: A meta-analysis of prospective studies. JAMA 1998;279:1200-1205.
3. Nisly NL, et al. Dietary supplement polypharmacy: An unrecognized public health problem. Evid Based Complement Alternat Med 2010;7:107-113.
4. Kiefer D, et al. The overlap of dietary supplement and pharmaceutical use in the MIDUS National Study. Evid Based Comp Alternat Med April 2014. Article ID 823853. http://dx.doi.org/10.1155/2014/823853.
5. Gardiner P, et al. Factors associated with herbal therapy use by adults in the United States. Altern Ther Health Med 2007;13:22-29.
6. Barnes PM, et al. Complementary and alternative medicine use among adults and children: United States, 2007. National Health Statistics Report 2009;12:1-23.
Summary Points
- Dietary supplement monitoring takes place retroactively and involves several different groups, which can delay the removal of unsafe supplements from store shelves.
- A recent example of this is well-documented hepatotoxicity from OxyElite Pro, a supplement marketed to help burn fat.
- Some solutions to the problems associated with retroactive surveillance are new labeling legislation, database sharing, and an advisory team of experts.
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