Samara Soghoian and Lewis S. Nelson
In 1994, the Dietary Supplement and Health Education Act (DSHEA) (accessible online at http://www.fda.gov/Food/DietarySupplements) was enacted to amend the Federal Food, Drug, and Cosmetic Act with respect to dietary supplements. DSHEA defines dietary supplements as products other than tobacco that are intended to supplement the diet and that contain a vitamin, mineral, amino acid, herb, or other botanical, enzyme, or animal derivative such as glandular or organ tissues. Americans spend more than $28 billion on dietary supplements and they are consumed by more than 100 million Americans (1).
Dietary supplements may not be represented as conventional food items, but they are regulated as a special subcategory of food and not as medication. This distinction has important consequences for the types of evidence documenting safety and efficacy that are required of the manufacturers of dietary supplements. Unlike medications, dietary supplements need not be proven safe or effective prior to marketing, and most have never been studied in controlled trials.
Nevertheless, there is a common public misperception that dietary supplements are safe, in large part because they are “natural.” Yet the implication that they contain one or more active ingredients should logically raise concerns for the possibility of adverse effects. As with any pharmacologically active substance, the dose defines the poison and while low doses may be safe, high doses may lead to exaggerated or unexpected clinical effects.
Unlike the case of pharmaceuticals, if the US Food and Drug Administration (FDA) wants to restrict sale or use of a dietary supplement, it must prove that the product is dangerous (2). Unfortunately, no formal postmarketing safety-review mechanism exists, but if the FDA does find a product unsafe, it can warn the public, suggest changes in the formulation, urge the manufacturer to recall the product, recall the product, or ban it entirely. This last option has only been exercised once, when sales of ephedra-containing products were banned in light of hundreds of reported adverse events, including 10 deaths. The FDA has also issued warnings about hepatotoxicity from comfrey and kava, renal failure from products containing aristolochic acid, and the risk of stroke or myocardial infarction from tiratricol (thyroxine), the stimulant DMAA, or 1,3-dimethylamylamine, in geranium extract, and the presence of potentially dangerous anabolic steroids in vitamin supplements. Despite these dangers, none of these products have been removed from the market.
Assurance of quality control in the manufacture of dietary supplements falls under the Current Good Manufacturing Practices (CGMPs) standard. This requires that production be done under sanitary conditions and manufacturers have the responsibility to substantiate the safety of their products and to ensure the identity, purity, quality, strength, and composition of their ingredients. Unfortunately, the FDA has few resources available to enforce these standards.
Contamination of products is an important cause of toxicity from dietary supplements. In 1990, L-tryptophan was pulled from the US market when a Japanese brand was associated with more than 1,500 cases of eosinophilia myalgia syndrome (EMS), including 30 fatalities. It is believed that this epidemic was caused by inadvertent contamination with an impurity, 1,1′-ethylidenebis[tryptophan], also called EBT or “Peak E,” during the manufacturing process.
Herbal supplements may be particularly prone to contamination during the harvest and storage of wild plants. Investigation of two cases of cardiac glycoside exposure reported to the FDA in 1997 revealed that a bulk shipment of plantain imported from Germany had been contaminated with Digitalis lanata. The contaminated plantain had been shipped to more than 150 manufacturers in the United States over a period of about 2 years before this was discovered and the products could be tested and recalled.
Misuse of herbal supplements may also be due to confusion between species with similar common names but very different pharmacologic properties. An epidemic of renal fibrosis occurred in Belgium in the 1990s when the manufacturers of a Chinese weight-loss supplement confused two products with similar common names and substituted the nephrotoxic Aristolochia westlandi (guang fang ji) for Stephania tetandra (han fang ji). Similarly, there have been multiple reported deaths from hepatic veno-occlusive disease after chronic use of teas from Senecio longilobus, a shrub containing hepatotoxic pyrrolizidine alkaloids. In Mexico, where “gordolobo” (big wolf) tea is used as an expectorant and anti-inflammatory, Gnaphallium species are generally implied. However, numerous plants are called by this name throughout Latin America, including the highly toxic S. longilobus.
A significant portion of both Chinese and Indian traditional remedies—more than 90% in one study—contain metals such as arsenic, lead, cadmium, copper, thallium, or mercury. This may not be inadvertent because therapy with metals has been an accepted part of these medical traditions and the inclusion of metals in patent medicines may be deliberate. Yet cases of heavy-metal toxicity have been clearly linked to such preparations.
Herbal preparations may also be adulterated with pharmaceutical medications. Chinese patent medicines have also been particularly implicated in this regard. Patent medicines are standard herbal preparations manufactured and sold in pill form. Analyses of Chinese patent medicines being sold internationally have estimated that between 7% and 24% of these products contain undeclared pharmaceutical medicines such as corticosteroids, ephedrine, benzodiazepines, and nonsteroidal anti-inflammatory drugs (NSAIDs). Numerous analyses of this type have been published (3). Drug–herb interactions are another source of adverse actions (Table 356.1) (4). For example, St. John wort is a potent inducer of CYP3A4. Patients taking medications that are metabolized by this enzyme have decreased therapeutic effectiveness. Common medication classes include antiretrovirals, antidepressants, and antineoplastics (5).
TABLE 356.1
Dietary Supplement/Herb–Drug Interactions
A 1-year observational study in 14 US poison centers found that of 1,466 calls reporting ingestion of dietary supplements, 489 had symptoms that were likely to have been caused by the exposure. Of these, 31% (149 cases) were considered moderate to severe reactions, including 5 deaths (6). Although these numbers suggest that the adverse effects are uncommon, harm is well demonstrated. Given the undefined, but likely relatively small benefit of dietary supplements on improving human health, the risk–benefit relationship is highly unclear (7).
Much remains to be learned about the specific pharmacology, toxicology, and clinical utility of most dietary supplements (8). Very few supplements have been tested in randomized controlled trials. In 1991, the National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health (NIH) was created with the explicit mission to explore complementary and alternative medicine in the context of rigorous science. Billions of dollars in grant monies have been disbursed through this program to fund all complementary health practices (including body manipulation and energetic healing techniques), and clinical trials of dietary supplements comprise only a small portion of this work. Recently, the result of the NCCAM-funded, highly controversial, and negative study of chelation therapy for heart disease called “Trial to Assess Chelation Therapy,” or TACT, was published (9).
CLINICAL PRESENTATION
Dietary supplements form a category that is broadly unified in terms of intended use but not by any equivalence of biochemical composition or physiologic effect. Manifestations of toxicity are therefore varied. Acute effects may include allergy, any of the toxidromes, cardiac dysrhythmias, gastrointestinal distress, hepatitis, hepatic veno-occlusive disease, renal impairment, metabolic or electrolyte disturbance, hemorrhage, nervous system (CNS) stimulation or depression (see Table 356.2). Detailed information about specific agents and central potential interactions can be found at the NCCAM website (http://nccam.nih.gov). The Natural Medicines Comprehensive Database (http://www.naturaldatabase.com) is also a credible source of information.
TABLE 356.2
Toxic Manifestations of Selected Dietary Supplements by Presenting Complaint
DIFFERENTIAL DIAGNOSIS
The toxic effects of various herbal preparations are varied, and an appropriate differential diagnosis should be constructed with respect to these specific signs and symptoms. Conversely, because herbal preparations can affect every organ system, toxicity from dietary supplements should be considered in the differential diagnosis of any unexplained metabolic aberration or organ dysfunction. Inquiring about herbal and dietary supplements is the only way to increase the likelihood of considering these products as contributors to the patient’s symptoms.
ED EVALUATION
The initial evaluation of a patient with potential toxicity from dietary supplements should proceed as for any other emergency department patient, with immediate attention given to the stabilization of the ABCs (airway, breathing, and circulation) and vital signs. A history of exposure to dietary supplements is clearly helpful in evaluating the potential for adverse effects but patients may not connect their symptoms with supplement use. Clinicians should be aware that many patients believe that dietary supplements are benign and may not include them on a list of “medications” unless explicitly prompted. Others may be hesitant to admit their use of herbals and supplements to a physician for fear of censure or judgment. Clinicians should also be aware that products may be contaminated or that labeling may be unclear or misleading. Ultimately, the best gauge of toxicity is a focused history and physical examination in conjunction with selected ancillary tests of metabolic and organ-system dysfunction.
KEY TESTING
• Obtain sample of the product for potential testing by FDA or other analytical laboratory.
• Clinical testing is based on the patient’s symptoms and findings on history and examination.
• In the uncommon patient with a suicide attempt using a dietary supplement, a serum acetaminophen concentration and pregnancy test, as appropriate, should be performed.
ED MANAGEMENT
The acute care of a patient with actual or potential toxicity from a dietary supplement is based on the nature and severity of illness. Gastrointestinal decontamination may be appropriate for patients who present early after a significant ingestion of a potentially toxic substance. Good supportive care is sufficient to treat most overdoses, but there are some notable exceptions. For example, poisoning with cardiac glycosides warrants therapy with multidose activated charcoal or digoxin-specific Fab fragments. Cyanide toxicity warrants specific therapy with sodium thiosulfate or hydroxocobalamin. Metal poisoning may require chelation therapy. Patients with anticholinergic toxicity may benefit from judicious use of physostigmine. All patients with possible adverse effects from a dietary supplement should be advised to discontinue its use. News about contaminated herbal and dietary products are in constant flux and all toxicity from herbals and dietary supplements should be discussed with the regional poison center who may help identify products that are contaminated, misrepresented, or pose significant public health risks in addition to serving as an up-to-date informational resource for the clinician.
CRITICAL INTERVENTIONS
• Routinely ask about the use of dietary supplements while taking the medication history.
• Report all suspected drug interactions and adverse effects of dietary supplements by calling your regional poison center, or the FDA MedWatch program at 1–800-FDA-1088. (You may also report these online at http://www.fda.gov/Safety/MedWatch.)
DISPOSITION
Patient disposition depends on the presentation. Significant organ dysfunction demands admission to a higher level of care and a rigorous examination of all potential causes. Patients who take intentional overdoses should have psychiatric evaluation prior to discharge.
Common Pitfalls
• Failure to recognize that most people regard herbals and dietary supplements as benign and may not alert the clinician to their use unless specifically prompted.
• Failure to consider toxicity from herbals and dietary supplements in the differential diagnosis of unexplained organ dysfunction.
• Failure to contact knowledgeable resources for up-to-date trends on contaminated products.
• Failure to warn patients of potential interactions between medications and herbals and dietary supplements.
REFERENCES
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3. Ching CK, Lam YH, Chan AY, et al. Adulteration of herbal antidiabetic products with undeclared pharmaceuticals: A case series in Hong Kong. Br J Clin Pharmacol. 2012;73:795–800.
4. Posadzki P, Watson L, Ernst E. Herb-drug interactions: An overview of systematic reviews. Br J Clin Pharmacol. 2013;75(3):603–618.
5. Rahimi R, Abdollahi M. An update on the ability of St. John’s wort to affect the metabolism of other drugs. Expert Opin Drug Metab Toxicol. 2012;8:691–708.
6. Palmer ME, Haller C, McKinney PE, et al. Adverse events associated with dietary supplements: An observational study. Lancet. 2003;361:101–106.
7. Peng CC, Glassman PA, Trilli LE, et al. Incidence and severity of potential drug-dietary supplement interactions in primary care patients: An exploratory study of 2 outpatient practices. Arch Intern Med.2004;164:630–636.
8. Jordan SA, Cunningham DG, Marles RJ. Assessment of herbal medicinal products: Challenges, and opportunities to increase the knowledge base for safety assessment. Toxicol Appl Pharmacol.2010;243:198–216.
9. Lamas GA, Goertz C, Boineau R, et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: The TACT randomized trial. JAMA.2013;309:1241–1250.