INTRODUCTION — Products containing vitamins, minerals, botanicals, live microorganisms, protein powders, and amino acids are marketed in the United States as dietary supplements [1]. Although these products may be referred to as nutraceuticals or food supplements outside of the United States, they will be referred to as dietary supplements or supplements in this chapter.
Some dietary supplements, including those containing individual vitamins and minerals, are essential components of evidence-based medical care. The efficacy and safety of vitamins, minerals, and certain botanical agents in adults are reviewed elsewhere:
●(See "Overview of water-soluble vitamins".)
●(See "Vitamin intake and disease prevention".)
●(See "Lipid management with diet or dietary supplements".)
●(See "Nutritional and non-medication supplements permitted for performance enhancement".)
●(See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)
●(See "Treatment of vitamin B12 and folate deficiencies".)
●(See "Treatment of iron deficiency anemia in adults".)
●(See "Clinical use of St. John's wort".)
●(See "Clinical use of echinacea".)
●(See "Clinical use of saw palmetto".)
●(See "Clinical use of ginkgo biloba".)
●(See "Overview of herbal medicine and dietary supplements".)
●(See "Hepatotoxicity due to herbal medications and dietary supplements".)
●(See "Nephropathy induced by aristolochic acid (AA) containing herbs".)
Although many dietary supplements lack evidence of efficacy or safety, patients may turn to these unproven supplements without seeking medical advice [2], and many use these products in combination with prescription medications [3]. Dietary supplements taken without medical advice may pose health risks.
In this chapter, we address the care of patients who use supplements that lack evidence of efficacy and may pose health risks, supplements we term “high-risk supplements.” The health risks from these supplements may be direct, due to adverse effects of the products themselves, or indirect, contributing to patients’ delaying or foregoing effective care. The use of high-risk supplements is important for clinicians to identify as it might contribute to a patient’s illness, may increase the risks of future adverse events, or may interfere with evidence-based care. The high-risk dietary supplements we review in this topic are not inclusive, and other supplements containing botanical (and other naturally derived) ingredients may also pose health risks.
DEFINITION OF HIGH-RISK DIETARY SUPPLEMENTS — We define high-risk supplements as those supplements that have the highest likelihood of containing listed ingredients or adulterants with unknown or inadequate safety data, as well as supplements that lead to a disproportionate number of adverse effects, emergency department (ED) visits, and hospitalizations.
The US Food and Drug Administration (FDA) has identified more than 1000 supplement products adulterated with pharmaceuticals, predominantly supplements marketed for weight loss, sexual enhancement, and muscle building [4]. In one surveillance study conducted by the Centers for Disease Control and Prevention (CDC) involving 63 sentinel EDs, investigators estimated that approximately 23,000 ED visits and more than 2100 hospitalizations per year in the United States can be attributed to the use of dietary supplements [5]. Supplements promoted for specific health benefits were responsible for 66 percent of supplement-related ED visits, with the most common including supplements marketed for weight loss, increased energy, and sexual enhancement (26, 10, and 3 percent, respectively). Supplements marketed for other specific health claims, including cardiovascular health, sleep, and bodybuilding, were also associated with an increased number of ED visits.
REGULATION OF DIETARY SUPPLEMENTS — In the United States, dietary supplements are regulated as a subcategory of food under the Dietary Supplement Health and Education Act of 1994 (DSHEA) [1]. Dietary supplements can be formulated with active pharmacologic ingredients and marketed with a variety of health claims [6]. Several aspects of the regulatory framework for dietary supplements increase the potential health risks for consumers.
Regulatory deficiencies and challenges — The US Food and Drug Administration (FDA) does not approve supplements prior to sale, nor does the agency test products to confirm labeling accuracy prior to marketing. Manufacturers are entrusted with ensuring the safety of supplements and the accuracy of the label [1].
Untested health claims — Traditional over-the-counter medications are pharmaceutical products that must include detailed and accurate information regarding quantity and safety on the label. Any health claims beyond those demonstrated in large clinical trials are not permitted on over-the-counter medications. By contrast, dietary supplements may be advertised as providing a wide variety of health benefits even if the product has never been tested in humans. For example, manufacturers are permitted to claim that a supplement “maintains normal glucose levels” even if evidence from human trials to support this claim are lacking [6].
Although health claims on supplement labels must be accompanied by a disclaimer that the product has not been approved by the FDA, studies have demonstrated that disclaimers are not effective in educating consumers. As examples:
●In one study, 359 consumers were shown a variety of supplement labels; some labels included the required FDA disclaimer and some did not. The consumers exposed to both labels reported similar levels of agreement that the FDA appropriately evaluated the product claims [7].
●In another study, 262 college students were randomly assigned to read two different supplement labels, one with the disclaimer and one without. The presence of the disclaimer had no effect on the college students’ perceptions of effectiveness ratings of the supplement [8].
Passive surveillance — The FDA relies upon a passive surveillance system to detect adverse events from supplements, depending upon consumers and clinicians to submit reports to MedWatch in case of adverse reactions suspected to be related to supplements [9]. However, only a small fraction of adverse event reports are submitted via MedWatch [10]. As a result, the FDA lacks timely, accurate information regarding hazardous supplements available to consumers.
Inadequate labeling — Supplements can be formulated with "active" pharmacologic constituents, which can be as potent as pharmaceutical agents, but essential information, such as quantity of the active compound and known adverse effects, is not required to be listed on the label.
Manufacturers may place supplement ingredients within “propriety blends,” for which there is no requirement that the specific quantity of the ingredient is listed [1]. As an example, if yohimbe is listed as part of a “proprietary blend,” there is no requirement that the quantity of yohimbe is provided on the label.
Although the name of the botanical agent is required to be listed, the amount of active constituent/s within the botanical is not required to be listed. As an example, the ingredient “red yeast rice” is required to be listed, but the quantity of the active statin-like drug (ie, monacolin K) contained within the red yeast rice is not required [11]. Similarly, the specific strain of microorganism or quantity of colony-forming units is not required on the label of probiotic supplements, which is essential to determine the efficacy and appropriateness of the product [12].
Manufacturers are not required to include known adverse effects or known supplement-drug interactions on the label. As an example, St John’s wort has important interactions with many prescription drugs (table 1) (see "Clinical use of St. John's wort", section on 'Drug interactions'), but this information is not required on St. John’s wort product labels.
In addition, dietary supplements have become a route whereby manufacturers can introduce pharmaceutical-like compounds directly to consumers without FDA review [13]. Manufacturers may formulate dietary supplements using their own proprietary methods, containing highly variable and potentially elevated concentrations of active compounds. As examples:
●In one study, some red yeast rice supplements contained high levels of monacolin K (a chemical identical to prescription lovastatin), with some evaluated products containing much higher levels than expected [11].
●In another study evaluating yohimbe supplements, products often marketed for sexual health, investigators found that some brands contained significantly greater quantities of the active ingredient than would be expected from an authentic botanical extraction, with some even higher than prescription doses [14].
Untested new ingredients — Manufacturers can also introduce new ingredients into supplements without evidence of efficacy or safety in humans [15]. Although manufacturers are expected to share evidence of safety with the FDA, there is no requirement to include clinical trial data. For example, the pharmaceutical drug vinpocetine, used to treat patients with dementia and strokes in some countries, was introduced into the United States in hundreds of supplements, bypassing the FDA drug approval process in this way [16].
More commonly, manufacturers introduce new ingredients in supplements without ever informing the FDA or providing any evidence of safety to the FDA. Loopholes in the regulations allow this; an example is a small amount of a new agent added as a minor ingredient in a sports drink, which is then considered a constituent of food, and the ingredient is marketed as a dietary supplement without notifying the FDA [13].
Compliance with regulation and enforcement — In addition to the challenges posed by the regulatory framework, supplement safety is also affected by lack of compliance and enforcement, including ineffective enforcement actions.
The FDA inspects hundreds of supplement manufacturers each year to ensure compliance with Current Good Manufacturing Practice (CGMP) regulations. In 2018, more than half of manufacturers were not in compliance with recommended manufacturing procedures, and one-quarter failed to determine the final composition of supplement products [17].
Many studies have found that supplements often do not contain the ingredient or quantity of ingredient listed on the label [18,19]. In one study evaluating 59 echinacea products, 10 percent contained no detectable echinacea, and of the 21 standardized preparations tested, only 43 percent were consistent with labelling [19].
The FDA has identified more than 1000 dietary supplements that are adulterated with prohibited pharmaceutical drugs [4]. In addition, hundreds of other supplements brands have been found to contain experimental drugs such as 1,3-dimethylamylamine (DMAA) [20].
At times, the FDA sends warning letters to companies who have violated the law; these letters are often publicly available and contain details of dozens of products labeled as containing prohibited ingredients. The FDA also maintains an advisory list of ingredients that the agency considers to present legal or safety issues.
Historically, when the FDA has taken action to remove supplements from the marketplace, the action has often been ineffective. As examples:
●Investigators analyzed 27 FDA-recalled supplements 2.9 years after the recall; of the products still available for sale, two-thirds were found to be adulterated with at least one pharmaceutical or experimental drug [21].
●In another study, supplements were tested before and after the FDA prohibited four stimulants in supplements; all four stimulants were still present in the supplements up to four years later [22].
●In a 2022 study, 29 percent of supplements subject to previous FDA warning letters regarding prohibited stimulants were still available for sale up to seven years later, with the majority containing prohibited ingredients [23].
In some instances, the FDA has appeared to not enforce the law. In one study evaluating an FDA database, 746 brands of supplement adulterated with drugs had been identified by the agency, although recalls were issued for only 48 percent of the products [24]. The reason for the FDA's failure to recall more than half of the identified adulterated products is unknown [25]. In other instances, the FDA discovered experimental drugs in supplements but failed to inform consumers or warn manufacturers to remove the experimental drug [26,27].
DETERMINING IF YOUR PATIENT IS USING A HIGH-RISK SUPPLEMENT
Inquire about supplement use — Clinicians may not routinely inquire about the use of supplements, and patients frequently do not fully disclose their use of supplements to their providers.
●In one study, only 26 percent of patients disclosed their use of dietary supplements to their primary care provider [28].
●In a study of 299 hospitalized patients in Israel, 27 percent used herbal or dietary supplements, but a review of hospital charts revealed documentation of their use in only 23 percent of users [29].
●In another study, 78 outpatients reported using a total of 466 supplement products but had disclosed only 156 (33 percent) to their providers [30].
How to elicit an accurate supplement use history — Although there are a lack of high-quality data on the efficacy of approaches to eliciting patients' supplement use, in our clinical experience, a supportive, nonjudgmental approach encourages open communication and increases patients’ willingness to share this information. It is of particular importance to specifically ask about supplement use when patients have symptoms and conditions for which high-risk supplements are typically marketed, such as overweight/obesity, sexual dysfunction, and memory/cognitive difficulties. We use questions such as:
●“Many of my patients are trying to [lose weight/improve sexual function/enhance memory, etc] and frequently use over-the-counter supplements to help. Have you tried any over-the-counter supplements to help with this?” [31]
●“I’m interested in learning about the products you have tried to [control your weight/help with sexual function/improve your memory, etc] that were not prescribed by a doctor, including over-the-counter products such as pills, powders, and liquids” [32].
In patients who routinely exercise, sports supplements are likely to be one of the most commonly consumed high-risk supplements [33]. Asking all patients who exercise about the use of sports supplements in a nonjudgmental fashion is advised. A variant of the following question can be effective:
●“Many of my patients who exercise use over-the-counter protein powders and pre-workout and muscle-building supplements to help them exercise; have you tried any of these?”
When a patient reports using an over-the-counter product, it can often be difficult to determine if it is marketed as a medication, dietary supplement, or traditional food. The "facts panel" on the label should be examined: “Supplement Facts” panels are required on labels for products sold as a dietary supplements, “Drug Facts” panels on labels for products sold as over-the-counter drugs, and “Nutrition Facts” panels on labels for products sold as traditional food.
Once supplement use is established, explore further; ask why your patient is using supplements and use this information to tailor counseling. The same supplement product can be used for a variety of different purposes by different patients. For example, a patient might use a specific supplement product to lose weight, while another patient may use the same product to improve endurance or enhance mental acuity.
Determining if a supplement is high-risk — While there is no absolute way to determine if a dietary supplement contains potentially harmful ingredients, there is some guidance to help consumers determine supplement safety based upon the label (table 2). In general, safer products are those with fewer ingredients; products that have certain third-party verification seals (ie, Banned Substances Control Group [BSCG] Certified Drug Free, NSF Certified for Sport, United States Pharmacopeia [USP], or Informed Sport); products with less than 200 mg of caffeine per serving; products with all listed ingredients <200 percent of the daily value (DV); labels that are free of words such as "proprietary," "blend," "matrix," or "complex"; and products that are free of questionable health claims [34].
SPORTS SUPPLEMENTS — Sports supplements are commonly used by athletes at all levels of skill and competition (see "Nutritional and non-medication supplements permitted for performance enhancement" and "Use of androgens and other hormones by athletes" and "Prohibited non-hormonal performance-enhancing drugs in sport" and "Prescription and non-prescription medications permitted for performance enhancement"). In one survey including 557 collegiate athletes, 45 percent reported using a dietary supplement on at least two of the prior seven days, and 8 percent used sports supplements considered high risk [33].
Sports supplements may be organized into three general categories to understand risk and counsel patients.
Protein, amino acids, creatine, and similar supplements (lower risk) — Some sports supplements contain only protein powder, creatine, beta-alanine, amino acids or carnitine, and some athletes use these products to increase the amount of protein or protein precursors in their diet. The efficacy and safety profiles of these ingredients vary, and consumers using these sports supplements containing these individual ingredients may be counseled based on the potential benefits and risks of the ingredients; this is reviewed in detail elsewhere (see "Nutritional and non-medication supplements permitted for performance enhancement"). While this category is relatively low risk compared with other sports supplements, the use of these products may still pose certain risks, such as excessive protein intake in patients with kidney dysfunction [35]. Use of these supplements is common in young adults, especially males [36].
Pre-workout supplements with proprietary blends (higher risk) — Pre-workout supplements are those marketed to be used prior to exercise to improve energy, strength, or endurance. Many pre-workout supplements contain complex mixtures of ingredients, frequently listed on the label as “proprietary blends,” without quantities of individual ingredients provided (table 3). There are several potential risks associated with pre-workout supplements:
●The labels of sports supplements often do not provide accurate information about the content of caffeine or other stimulants [37,38]. In particular, caffeine is particularly problematic for athletes and clinicians when trying to understand how much is being ingested when using pre-workout supplements. Although caffeine can provide benefits to athletes [39], unpredictable dosages may be counterproductive. (See "Nutritional and non-medication supplements permitted for performance enhancement", section on 'Caffeine'.)
In one study evaluating 31 sports supplements, the products were analyzed for caffeine content and compared with the information provided on the label [38]. Twenty products listed caffeine, but less than half provided accurate amounts. There is no legal limit of amount of caffeine in dietary supplements, and further, even if caffeine is declared as part of a "proprietary blend," the specific quantity is not required to be listed.
●A number of experimental stimulants, including analogs of ephedrine, amphetamine, and methamphetamine, have been found in sports supplements [26,40,41]. Consuming these agents may lead to increases in blood pressure and cardiac demand, potentially leading to complications such as hemorrhagic stroke and sudden death [42-44].
Anabolic (muscle-building) supplements (higher risk) — Supplements marketed as natural testosterone replacements may list proprietary blends or a single ingredient on the label. However, analyses of these products have found a wide range of steroid-like compounds with a variety of anabolic and other endocrine effects [45,46] and may include agents such as selective androgen receptor modulators (SARMs) [47], selective estrogen receptor modulators (SERMs), and aromatase inhibitors (table 4) [48]. These products may pose a variety of significant health risks such as gynecomastia, lipid abnormalities, hypogonadism, and hepatocellular injury, which may be severe [49-52]. (See "Hepatotoxicity due to herbal medications and dietary supplements", section on 'Androgenic anabolic steroids' and "Use of androgens and other hormones by athletes", section on 'Side effects and complications'.)
In one study of muscle-building supplements, none of the products evaluated was accurately labeled; less than half of labeled ingredients were present, and less than one-third of listed quantities were accurate [45]. Further, ingredients detected included those with potential anabolic effects (7-keto dehydroepiandrosterone and ecdysterone), an unapproved drug with abuse potential (phenibut), and a designer steroid that may function as an aromatase inhibitor (arimistane). No ingredients carried an FDA-approved indication.
Counseling patients who use sports supplements — For patients who elect to use sports supplements, we provide the following information and advice:
●We emphasize that eating a healthy well-balanced diet is more important than consuming supplements, and there are several ways for an athlete to improve their diet. Excellent nutritional resources for athletes are available from the US Anti-Doping Agency (USADA) as well as from other organizations.
●If a patient strongly desires to take a sports supplement, we advise choosing products that list well-studied ingredients, such as protein powder, amino acids, or creatine, and avoid pre-workout and muscle-building supplements. When selecting sports supplements, patient should use products which have been evaluated by a high-quality third party such as NSF International for Sport [53]. Before consuming any supplement product, the patient should check the ingredient with the USADA high-risk list as well as the Department of Defense’s Operation Supplement Safety program.
●If a patient chooses to use caffeine to enhance exercise performance, the best-studied dose is 100 to 200 mg (see "Nutritional and non-medication supplements permitted for performance enhancement", section on 'Caffeine'). This can be accurately dosed using over-the-counter caffeine tablets instead of consuming dietary supplements (the latter of which may contain unpredictable quantities of caffeine combined with other stimulants). Use of caffeine is not advised for children or adolescents.
●To learn more about safety of supplements, athletes should be directed to the USADA Supplement Connect program, including their guide to reducing supplement risk [54].
WEIGHT LOSS SUPPLEMENTS — Weight loss supplements are commonly used by adults in the United States. In one cross-sectional telephone survey including over 9400 adults, 15 percent of respondents reported having ever used a weight loss supplement (20 percent of females and 10 percent of males), and the majority of users reported not having discussed this with their health care provider [32]. Use of weight loss supplements may be even higher among certain groups. As an example, in another survey of 1444 adults, 34 percent of those who had made a serious weight loss attempt reported the use of weight loss supplements [55]. Despite the high prevalence of use, there is no high-quality evidence that any ingredient sold as a dietary supplement can lead to safe, long-term weight loss. (See "Obesity in adults: Drug therapy", section on 'Therapies not recommended'.)
In the 1990s, ephedra was the most common ingredient in weight loss supplements. Ephedra was eventually linked to thousands of adverse effects, including myocardial infarction and sudden death [56]. The US Food and Drug Administration (FDA) banned ephedra alkaloids from supplements in 2004, and since then, ephedra has been replaced with experimental stimulants in weight loss supplements (table 3) [57]. These include synthetic variants of ephedrine, amphetamine, and methamphetamine [26,40,41]. One example is 1,3-dimethylamylamine (DMAA), originally marketed in the 1940s as an over-the-counter nasal inhaler, but DMAA was withdrawn from the market by the 1970s [20,58,59]. DMAA began to appear in supplements shortly after ephedra was banned, and became available in hundreds of brands of supplements until the FDA prohibited its sale in 2008 due to potential health risks including heart disease and sudden death [60]. DMAA continues to be available in supplements despite the FDA’s prohibition [27,61].
The health risks of these stimulants are poorly understood. These agents may increase blood pressure, heart rate, and cardiac output. Case reports have linked these stimulants to hemorrhagic stroke and sudden cardiac death [42,43,59,62,63]. As these supplements may contain complex mixtures of chemicals never tested together in humans, they may also lead to unexpected adverse effects: a hepatitis outbreak following the use of a weight loss/workout supplement affected 69 consumers, of whom 32 were hospitalized, three required liver transplants, and two died [49,64,65]. (See "Hepatotoxicity due to herbal medications and dietary supplements", section on 'Weight loss products'.)
In addition to novel and experimental stimulants, withdrawn prescription pharmaceutical agents are commonly found as adulterants in weight loss supplements (table 3) [66,67]. The most commonly detected adulterant is sibutramine [24], a drug that was previously available by prescription [68,69] until evidence demonstrated that it increased the risk of nonfatal stroke and myocardial infarction among those at increased risk for cardiovascular disease [70]. The FDA has identified hundreds of weight loss supplement products that contain sibutramine, often in combination with the withdrawn laxative phenolphthalein. Some of these products contain greater-than-prescription-strength quantities of sibutramine, and dry mouth, anxiety, and insomnia have been reported as common side effects [71].
2,4-dintrophenol is an industrial chemical used as a raw material for explosives. The agent uncouples mitochondrial oxidative phosphorylation, with the energy that would have been stored in the cell released as heat. Initially used in the 1930s as a potent weight loss medication, it was banned by the FDA within a decade due to a variety of significant toxicities including agranulocytosis, neuropathy, hearing loss, and associated fatalities [72]. Since the 1980s, 2,4-dintrophenol has been sporadically identified as the cause of death among teenagers and young adults using the drug to lose weight [73-75]. Since 2011, the use of the 2,4-dintrophenol has increased globally [76], with products containing the agent typically sold illicitly, often on the "dark web"; in 2015, Interpol issued a global ‘imminent threat’ advisory [77]. In a 2021 study including 204 cases of 2,4-dintrophenol exposures, confusion/agitation, tachycardia, hyperpyrexia, and acidosis at presentation were associated with higher mortality rates [78].
Counseling patients who use weight loss supplements — Although the FDA advises consumers to avoid any supplement with unrealistic weight loss claim such as “guaranteed weight loss” [79], we recommend that patients not use any weight loss dietary supplements since none are proven safe or effective for weight loss. However, counseling patients regarding this can be challenging. Our approach with patients who use weight loss supplements includes:
●When a patient shares with us that they are using, or considering using a weight loss supplement, we use this as an opportunity to counsel the patient on healthy weight loss strategies and engage them in evidence-based weight management approaches (algorithm 1). (See "Obesity in adults: Overview of management".)
●If a patient is unwilling to consider discontinuing weight loss supplements, we counsel against the use of supplements listing many ingredients in a “proprietary blend,” which can pose serious health risks and may be adulterated with unapproved drugs. Instead, patients should use a product listing a single ingredient. Selecting an ingredient based on a reliable source such as the National Institute of Health fact sheet on dietary supplements for weight loss can be helpful.
MALE SEXUAL ENHANCEMENT SUPPLEMENTS — Many dietary supplements products are sold with the claim that they will improve male sexual function; however, we are unaware of any supplement with proven benefits for sexual dysfunction [80]. Some consumers may try these supplements rather than seek medical advice because it is more convenient than seeing a clinician, or they might be embarrassed discussing their concerns. Other consumers may have contraindications to phosphodiesterase-5 (PDE-5) inhibitors (table 5) and turn to these supplements after they have been counseled by their provider to avoid prescription erectile dysfunction medications.
The prevalence of use of male sexual enhancement supplements in the United States is unknown, although indirect evidence that their use is common; a single manufacturer in the United States produced more than one million capsules per month of adulterated male sexual enhancement supplements [80,81]. In fact, the US Food and Drug Administration (FDA) has identified hundreds of brands of sexual enhancement products adulterated with prescription and experimental drugs [4].
Of the botanical ingredients commonly found in male sexual enhancement supplements, yohimbe is one of the most likely to cause adverse effects (table 6). The most active compound in yohimbe is yohimbine, which was formerly available as a prescription drug for erectile dysfunction. Yohimbine may increase blood pressure and cause panic attacks [14]. Some male sexual enhancement products are formulated with larger-than-pharmaceutical quantities of yohimbine, increasing the risks of adverse events [14,82].
In addition to botanical ingredients, pharmaceutical adulterants are also found in sexual enhancement supplements, most frequently the prescription PDE-5 inhibitors sildenafil and tadalafil, as well as novel analogues of these prescription drugs (table 6). More than 80 different analogues of PDE-5 inhibitors have been identified in sexual enhancement supplements [83]. Many products have been found to contain multiple PDE-5 analogues [84].
Adulterated male sexual enhancement supplements may pose risks to consumers. While drugs such as sildenafil and tadalafil are designed to inhibit only one family of phosphodiesterases and selectively target the penile corpus cavernosum, less selective inhibitors may affect other organ systems such as the brain, heart, kidney, and liver and have unpredictable adverse effects [80]. Most of these experimental PDE-5 inhibitors in sexual enhancement supplements have not been studied in humans, and their health risks remain unknown.
Some products might contain mixtures of different experimental PDE-5 inhibitors or other prescription drugs. Life-threatening hypoglycemia due to adulteration with sulfonylureas has occurred with adulterated sexual enhancement products [85]. It is not understood why prescription hyperglycemia medications are sometimes included in sexual enhancement supplements, but sulfonylureas have been found in multiple brands in the United States and elsewhere [85-87].
It is often difficult for clinicians to determine if an adulterant is present based upon a patient’s reported side effects. Common adverse effects of PDE-5 inhibitors such as flushing, lightheadedness, or dyspepsia can be identical to those of niacin and yohimbe, ingredients often listed on sexual enhancement supplement labels. Given the frequency of adulteration, patients experiencing any of these side effects should be counseled to immediately discontinue use of the product.
Counseling patients who use sexual enhancement supplements — Given their wide availability, all patients with sexual dysfunction should be queried if they are using, or have used, over-the-counter sexual enhancement supplement products.
We counsel patients who use sexual enhancement supplements as follows:
●We advise patients that sexual enhancement supplements should be avoided as they are unlikely to be effective and, if they have efficacy, may be adulterated with unlabeled, untested, and potentially unsafe drugs.
●We also acknowledge the patient’s desire to improve their sexual function. We evaluate the patient and offer evidence-based treatment (figure 1). (See "Evaluation of male sexual dysfunction" and "Treatment of male sexual dysfunction".)
●Patient may find the FDA advisory on sexual enhancement supplements to be a useful resource [88]. Consumers and clinicians can search for specific brands of supplements in the FDA’s list of tainted sexual enhancement products [89], although if a brand is not listed on the website, it may nonetheless be adulterated but not yet identified as such.
COGNITIVE ENHANCEMENT (“NOOTROPIC”) SUPPLEMENTS — Dietary supplements may be marketed with claims that suggest benefit for brain health or memory, such as “maintains brain health” or “maintains brain performance.”
A large market for cognitive enhancement supplements exists in the United States. Americans were estimated to spend more than USD $600 million on this category of supplements in 2015 [90], and a 2019 American Association of Retired Persons (AARP) survey found that 13 percent of adults 70 years of age or older take a supplement to treat memory loss or dementia [91].
Manufacturers may target their supplements to younger consumers interested in improving their cognitive function in the workplace or to older consumers concerned by lapses in memory due to aging or illness. Unfortunately, these supplements may be used by patients in lieu of evaluation and treatment for illnesses such as depression, strokes, and dementia.
However, no large clinical trials have provided robust, consistent evidence that dietary supplements, including botanical ingredients such as ginkgo biloba, can improve memory or cognition [92,93] (see "Mild cognitive impairment: Prognosis and treatment", section on 'Herbs and nutritional supplements'). Despite these negative results, ginkgo biloba and other botanical supplements are nonetheless permitted to be marketed to maintain cognitive health [6].
While no supplement product has been proven effective for improving cognition, cognitive enhancement supplements may pose health risks, particularly for older adults. The risks may be due to labeled ingredients, such as levodopa and vinpocetine [94,95], as well as the presence of adulterants (table 7). Dozens of cognitive enhancement supplement products have been found to contain unapproved or experimental drugs; several drugs such as phenibut, centrophenoxine, and piracetam, used in Russia and elsewhere for the treatment of several neurologic and psychiatric conditions, have been found in cognitive enhancement supplements (table 7) [96-98]. These unapproved drugs have the potential to cause adverse effects including changes in blood pressure, insomnia, agitation, dependence, sedation, and respiratory arrest [99-101].
Counseling patients who use cognitive enhancement supplements — For all patients who have memory or cognitive concerns, we ask about the use of cognitive support or memory supplements. For patients using such supplements:
●We perform a comprehensive cognitive assessment with particular attention to screening for mood disorders and careful evaluation of sleep patterns. (See "Evaluation of cognitive impairment and dementia" and "Mental status scales to evaluate cognition" and "Clinical features and diagnosis of Alzheimer disease".)
●We advise the avoidance of all cognitive enhancement dietary supplements; we counsel that there is no high-quality evidence that any ingredient sold as a dietary supplement can improve memory or prevent the development of dementia, and that some supplements may pose health risks. (See "Prevention of dementia", section on 'Ineffective therapies' and "Prevention of dementia", section on 'Interventions with unproven benefit'.)
●The safety and efficacy of ginkgo biloba for prevention of cognitive decline has been extensively studied. Although this supplement is safe, it has no effect on cognitive function. Issues pertaining to the use of ginkgo biloba are presented elsewhere. (See "Clinical use of ginkgo biloba", section on 'Dementia, cognitive impairment, memory enhancement'.)
●If a patient elects to use dietary supplements for memory, we encourage use of single-ingredient vitamin, fish oil, or botanical products that have been certified by a high-quality third-party certification program such as US Pharmacopeia (USP) or NSF International.
●For patients who elect to use a single-ingredient botanical supplement, potential adverse effects can be obtained from a reputable resource such as the NIH botanical supplement fact sheets.
OTHER CATEGORIES — Other dietary supplements may be marketed to treat or prevent many different conditions, and patients should be counseled to avoid all such supplements. For example, supplements targeting patients with cancer, diabetes, hyperlipidemia, thyroid disease, rheumatological conditions, substance use disorders, coronavirus disease 2019 (COVID-19), and other infections are common. Although not comprehensively studied, these supplements may be more likely to be adulterated with pharmaceutically active drugs than other supplements. As examples:
●Supplements marketed to patients with substance use disorders have been found to contain drugs such as kratom, tianeptine and phenibut, with potential for dependency and overdose [102-104].
●Supplements marketed for treatment of rheumatologic disorders and joint symptoms have been found to contain dexamethasone, diclofenac, indomethacin, and methocarbamol [105,106].
●Supplements marketed for "adrenal support" or "thyroid support" have been found to contain thyroid hormone and a variety of steroid hormones [107].
Clinicians should counsel patients regarding the possible presence of active, potentially harmful drugs in these products while addressing the patient’s underlying concerns and medical issues.
IF YOU SUSPECT A DIETARY SUPPLEMENT HAS HARMED YOUR PATIENT — There are several important steps to take if a clinician suspects that a patient has experienced an adverse effect from a dietary supplement. In order of importance:
●Manage the patient as clinically appropriate, including emergency department (ED) evaluation if necessary. Immediate guidance can be obtained by contacting a regional poison control center. (See 'Regional poison control centers' below.)
●Counsel patients to immediately discontinue the product. Advise the patient about the potential connection between supplement product use and the adverse effect. We have found it helpful to explain that dietary supplements can contain compounds as potent as prescription medications but are not evaluated by the US Food and Drug Administration (FDA) before they are sold to consumers.
●If appropriate, contact the local department of public health; for example, if you suspect multiple patients may have been harmed by the same product.
●When possible, obtain and save the supplement product(s) in question. Store the product in a secure, cool, dry location.
●Report the case to the FDA via MedWatch along with detailed product information (eg, manufacturer, name, and lot number) if available. The FDA lacks an active surveillance system and must rely upon consumers, health care providers, and others to report adverse effects to MedWatch. The agency is particularly reliant on detailed reports of suspected harm submitted by clinicians. A clinician need not be absolutely convinced that the supplement led to an adverse event prior to submitting a report. Rather, the report serves as a notification to the FDA of a possible reaction related to a supplement, and the agency can monitor and assess if additional signals of harm exist.
If a clinician is interested in more detailed information about supplements in general or an individual product, we advise referencing available databases to get further information or to determine if the product has been subjected to a recall or previously found to be adulterated [4,108]:
●NIH: Dietary supplements for exercise and athletic performance
●NIH: Dietary supplements for weight loss
●MedlinePlus: Drugs, Herbs and Supplements
●Dietary Supplement Label Database
●US FDA Recalls, Market Withdrawals, & Safety Alerts
ADDITIONAL RESOURCES
Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)
Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Performance-enhancing substances" and "Society guideline links: General measures for acute poisoning treatment" and "Society guideline links: Treatment of acute poisoning caused by specific agents other than drugs of abuse".)
SUMMARY AND RECOMMENDATIONS
●What is a "high-risk" dietary supplement? – We define high-risk supplements as those supplements that have the highest likelihood of containing listed ingredients or adulterants with unknown or inadequate safety data, as well as supplements that lead to a disproportionate number of adverse effects, emergency department (ED) visits, and hospitalizations. (See 'Introduction' above and 'Definition of high-risk dietary supplements' above.)
●Regulatory issues with dietary supplements – The US Food and Drug Administration (FDA) does not approve supplements prior to sale, nor does the agency test products to confirm labeling accuracy prior to marketing. Dietary supplements may be advertised as providing a wide variety of health benefits even if the product has never been tested in humans. Supplements can be formulated with active pharmacologic constituents which can be as potent as pharmaceutical agents, but information such as quantity of the active compound and known adverse effects are not required to be listed on the label. Manufacturers may place supplement ingredients within “propriety blends,” for which there is no requirement that the specific quantity of the ingredient is listed. In addition to these challenges, supplement safety is also affected by ineffective enforcement actions. (See 'Regulation of dietary supplements' above.)
●Importance of asking about supplement use – Clinicians may not routinely inquire about the use of supplements, and patients frequently do not fully disclose their use. A supportive, nonjudgmental approach encourages open communication and increases patients’ willingness to share this information. It is important to specifically ask about supplement use when patients have symptoms and conditions for which high-risk supplements are typically marketed, such as overweight/obesity, sexual dysfunction, and memory/cognitive difficulties.
Once supplement use is established, explore further; ask why your patient is using the supplement and use this information to tailor counseling. (See 'Determining if your patient is using a high-risk supplement' above.)
●Sports supplements – Sports supplements may be organized into three general categories to understand risk and counsel patients: Supplements containing only protein powder, creatine, beta-alanine, amino acid or carnitine (lower risk); pre-workout supplements, typically marketed to improve energy, strength, or endurance (higher risk) (table 3); and anabolic (muscle-building) supplements (higher risk) (table 4). (See 'Sports supplements' above.)
•Patient counseling – For patients who use sports supplements, we emphasize that eating a healthy, well-balanced diet is more important than supplements. We recommend against using pre-workout or muscle building supplements (Grade 1C). If a patient strongly desires to take a sports supplement, we advise them to choose products that list well-studied ingredients, such as protein powder, amino acids, or creatine. We direct athletes to the US Anti-Doping Agency (USADA) Supplement Connect program to learn more about safety of sports supplements. (See 'Counseling patients who use sports supplements' above.)
●Weight loss supplements – Weight loss supplements may contain experimental stimulants (including synthetic variants of ephedrine, amphetamine, and methamphetamine), as well as withdrawn pharmaceutical agents such as sibutramine and phenolphthalein (table 3). (See 'Weight loss supplements' above.)
•Patient counseling – We recommend against all weight loss dietary supplements (Grade 1B). None are proven effective for weight loss, and these supplements often contain ingredients that increase the risk of cardiovascular events. We also use this as an opportunity to counsel the patient on healthy weight loss strategies and engage them in evidence-based weight management approaches (algorithm 1). (See 'Counseling patients who use weight loss supplements' above.)
●Male sexual enhancement supplements – Some consumers may try these supplements rather than seek medical advice because of convenience or embarrassment. Others may have contraindications to phosphodiesterase-5 (PDE-5) inhibitors (table 5) and turn to supplements after they have been counseled to avoid these medications. Yohimbe (of which the most active compound is yohimbine) and pharmaceutical adulterants are commonly found in sexual enhancement supplements, most frequently the prescription PDE-5 inhibitors sildenafil and tadalafil, as well as novel analogues of these drugs (table 6). (See 'Male sexual enhancement supplements' above.)
•Patient counseling – We suggest not using sexual enhancement supplements (Grade 2C), since these supplements generally lack efficacy and have potential harm. We acknowledge the patient’s desire to improve sexual function and offer evidence-based treatment for male sexual dysfunction (figure 1). (See 'Counseling patients who use sexual enhancement supplements' above.)
●Cognitive enhancement ("nootropic") supplements – No supplement product has been proven effective for improving cognition, and dozens of cognitive enhancement supplement products have been found to contain unapproved or experimental drugs (table 7). (See 'Cognitive enhancement (“nootropic”) supplements' above.)
•Patient counseling – For all patients who have memory or cognitive concerns, we ask about the use of cognitive support or memory supplements. We perform a comprehensive cognitive assessment with particular attention to screening for mood disorders and careful evaluation of sleep patterns.
The safety and efficacy of ginkgo biloba for prevention of cognitive decline has been extensively studied. Although this supplement is safe, it has no effect on cognitive function. Issues pertaining to the use of ginkgo biloba are presented elsewhere. (See "Clinical use of ginkgo biloba", section on 'Dementia, cognitive impairment, memory enhancement'.)
Other (non-ginkgo) cognitive enhancement dietary supplements are not effective, may cause harm, and should generally be avoided. These agents are discussed separately. (See "Prevention of dementia", section on 'Interventions with unproven benefit' and "Prevention of dementia", section on 'Ineffective therapies' and 'Counseling patients who use cognitive enhancement supplements' above.)
●If you suspect a supplement has caused harm (see 'If you suspect a dietary supplement has harmed your patient' above):
•Manage the patient as clinically appropriate, including ED evaluation or poison control center consultation as necessary. (See 'Regional poison control centers' above.)
•Advise the patient of your concern and counsel them to immediately discontinue the product. Obtain, save, and store any unused supplement product if possible.
•Contact the local health department if you suspect multiple individuals may have been harmed by the product
•Report the case to the FDA via MedWatch along with detailed product information (eg, manufacturer, name, and lot number) if available. A clinician need not be absolutely convinced that the supplement led to an adverse event; the report serves as a notification to the FDA of a possible reaction related to a supplement, and the agency can monitor and assess if additional signals of harm exist.
