SUPPLEMENTS PART 1

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A SCIENTIFIC LOOK AT ALTERNATIVE MEDICINE

Dietary Supplements

Part 1: General Aspects

Thomas J. Wheeler, Ph.D.

Associate Professor (retired), Department of Biochemistry and Molecular Biology,

University of Louisville School of Medicine, Louisville KY

thomas.wheeler@louisville.edu

Revised 2021

This material was originally part of a handout for an elective course given to medical students at the University of Louisville.

Copyright 2021. Permission to copy for non-profit uses is granted as long as proper citation of the source is given.

DISCLAIMER: The material presented here is not medical advice. It represents the author's summary of scientific evidence concerning various topics. For medical advice, see your physician.

LINKS TO OTHER SECTIONS

PART 2 Some items marketed as dietary supplements. Discusses 175 individual topics, arranged alphabetically.

REFERENCES for Parts 1 and 2, with links to on-line articles and abstracts

A pdf file (120 pages), including both parts and references, is available at this site: Supplements2021.pdf

Note: Herbs are regulated along with dietary supplements in the U.S., so their regulation is included in Part 1. For discussion of other aspects of herbs, as well as individual herbal products, see the HERBS article.

CONTENTS OF PART 1

Overview: definition and marketing; nutraceuticals and functional foods; usage

Regulation and labeling: overview; definitions ; structure and function claims; health claims; enforcement; other aspects

Adverse effects

Scientific critique

Conventional nutrition: vitamins and minerals; fat-soluble vitamins; water-soluble vitamins; macrominerals; trace minerals; other requirements; not required in the diet; multivitamin-multimineral supplements

Antioxidants

Phytochemicals

Reviews and major trials of multiple supplements

OVERVIEW

Definition and marketing

Dietary supplements “are substances taken by mouth in any form (gel, capsule, tablet, powder, and so on). Sold without a prescription, they can contain vitamins, minerals, botanicals (such as herbs and other plant extracts), amino acids, enzymes, or other ingredients - natural or synthetic or something in between - in any combination. They are called supplements because they are supposed to provide something the diet doesn’t supply or may not supply in sufficient quantity” (Berkeley Wellness 2019 Jul 31. Supplements: We can do better). Since the passage of the Dietary Supplement Health and Education Act (DSHEA) in 1994 (see "Regulation and labeling" below), “the U.S. supplement market has grown from 4,000 products and $4 billion in annual sales to anywhere from 50,000 to 80,000 unique products and $40 billion in annual sales, the FDA estimates” (Ibid.). Supplements for weight loss, muscle building, and sexual function each account for billions of dollars in sales. Trends include soft drinks and candy bars "fortified" with herbs and supplements. Some companies combine genetic testing with recommendations for supplements allegedly targeted to individual needs (“nutrigenomics”).

Major food and pharmaceutical companies have become involved in selling supplements. “In the past decade, portfolio diversification has been an important strategy by which big pharma has addressed its burgeoning costs and declining profits. Dietary supplements, which are cheap to make and not burdened with regulatory hurdles, represent a significant and growing sector..." (Starr 2015. Am J Public Health. 105(3):478-85).

Many products are sold via multilevel marketing. Successful distributors make most of their money not by direct sales but by recruiting other distributors (whose profits they share). Individuals at lower levels of the pyramid make little money or even lose money because of the inventory they are required to purchase. Many individual distributors (who are often lay people) have web sites. Cardenas and Fuchs-Tarlovsky (2018. Clin Nutr ESPEN. 25:133-8) wrote: "Multi-level marketing (MLM) of nutrition products has experienced dramatic growth in recent decades. ‘Wellness’ is the second most popular niche in the MLM industry and represents 35% of sales among all the products in 2016...We argue that, while being a controversial business model, MLM is not fraudulent from a legal point of view. However, it is an unethical strategy obviating all the principles of beneficence, nonmaleficence and autonomy."

According to Barrett (2014. The Mirage of multilevel marketing. Quackwatch), “Many physicians are selling health-related multilevel products to patients in their offices. The companies most involved have included Amway (now doing business as Quixtar), Body Wise, Nu Skin (Interior Design), Rexall, and Juice Plus+. Doctors are typically recruited with promises that the extra income will replace income lost to managed care.”

With the onset of the COVID-19 pandemic, supplement promoters are now selling products alleged to prevent or treat coronavirus.

Nutraceuticals and functional foods

New terms include "nutraceuticals" and "functional foods." Zeisel (1999. Science. 285(5435):1853-5) wrote: "I propose to define nutraceuticals as those diet supplements that deliver a concentrated form of a presumed bioactive agent from food, presented in a nonfood matrix, and used to enhance health in dosages that exceed those that could be obtained from normal foods...'Functional foods' are similar in appearance to conventional foods and are consumed as a part of a normal diet. They deliver one or more active ingredients (that have physiological effects and perhaps enhance health) within the matrix of a food..."

According to González-Sarrías et al. (2013. Maturitas. 75(4):313-34), "The American Nutraceutical Association...uses the definition coined by De Felice: 'A nutraceutical is any substance that is a food or a part of a food and provides medical or health benefits, including the prevention and treatment of disease. Such products may range from isolated nutrients, dietary supplements and specific diets, to genetically engineered designer foods, herbal products, and processed foods such as cereals, soups and beverages.' This definition also includes dietary non-nutrient compounds. However, the direct allusion to food (cereals, soups and beverages) means that the boundary between the current concepts of ‘functional food’ and ‘nutraceutical’ is not well established in this definition."

Santini and Novellino (2017. Br J Pharmacol. 174(11):1450-63) wrote: “The difference between food/dietary supplements and nutraceuticals is quite clear; nutraceuticals are closer to pharmaceuticals, since they must have clinically proven efficacy towards a specific pathological condition and, hence, a valid help in both disease prevention and therapy. They, when looked at as pharma-foods, position themselves in the space ‘beyond the diet before the drugs’...”

Aronson (2017. Br J Clin Pharmacol. 83(1):8-19) wrote, "There are no internationally agreed definitions of ‘nutraceuticals’ and ‘functional foods’, or of similar terms, such as ‘health foods’, or of terms related to herbal products, which are sometimes referred to as ‘nutraceuticals’, compounding the confusion. ‘Nutraceuticals’ and ‘functional foods’ are vague, nondiscriminatory, unhelpful terms; the evidence suggests that they should be abandoned in favour of more precise terms...It is clear that all those who attempt definitions of these terms assume that the terms are worthy of definition, when they really go no further than the definitions of food or foodstuffs and dietary regimens."

"Describing a food item as a functional food is considered by many to be primarily a marketing term that has no specific statutory meaning in the United States. At present, functional foods are not specifically regulated by the FDA. The term has been variably defined by a number of different food and nutritional organizations, but was recently defined by the Academy of Nutrition and Dietetics as 'Foods defined as whole foods along with fortified, enriched, or enhanced foods that have a potentially beneficial effect on health when consumed as part of a varied diet on a regular basis at effective levels.' Functional foods can further be differentiated from fortified foods in that the latter are conventional foods that have been enriched with vitamins and/or minerals (eg, a breakfast cereal with added vitamin D), usually at a range up to 100 percent of the dietary reference intake for a given nutrient...The term nutraceutical is yet another term that has become somewhat of a catch-all designation for any natural foodstuff or product that, when consumed, imparts a putative health benefit. The term nutraceutical has frequently been defined synonymously with functional foods in the media and literature. However, this is a misapplication of the word, as the term more correctly refers to whole foods or parts of foods, often plant derived, that contain bioactive components that deliver a purported health benefit. In addition, nutraceuticals are commonly marketed as oral dosage forms (eg, tablets, capsules, gummies)" (Markowitz et al. 2020. Clin Ther. 42(7):1416-23).

"Fortified foods, also called ‘designer foods,' have been defined as ‘normal foods fortified with health promoting ingredients.' This definition would encompass bread with added folic acid, used to prevent neural tube defects, salt with added iodide to prevent hypothyroidism, and butter substitutes containing plant sterols as lipid-modifying agents, as well as beverages and fruit juices fortified with milk, soy, or other proteins for nutritional purposes. These are examples with good evidence of efficacy; the evidence base for other such foods is not always as good" (Ibid.).

Usage

As determined by the National Health and Nutrition Examination, "During 2017–2018, 57.6% of adults aged 20 and over reported using any dietary supplement in the past 30 days...A higher percentage of women (63.8%) reported dietary supplement use than men (50.8%). For both sexes, dietary supplement use increased with age. Among men, use increased from 35.9% among those aged 20–39 to 67.3% among those aged 60 and over. Among women, use increased from 49.0% among those aged 20–39 to 80.2% among those aged 60 and over...Among adults aged 20 and over, 42.4% used none, 22.5% used one, 13.8% used two, 7.5% used three, and 13.8% used four or more dietary supplements in the past 30 days" (Mishra et al. 2021. NCHS Data Brief. (399):1-8). The top three supplements for all age groups were multivitamin-multimineral, vitamin D, and omega-3 fatty acids. Other leading supplements, depending on age, were vitamin C, calcium, botanicals, and vitamin B12. "For all age groups, dietary supplement use increased significantly (from 34.7% in 2007–2008 to 42.5% in 2017–2018 for ages 20–39, 51.4% to 59.2% for ages 40–59, and 66.9% to 74.3% for ages 60 and over)" (Ibid.).

According to a 2001 survey, the main reasons for supplement use were to feel better (72%), prevention of illness (67%), treatment during illness (51%), longer life (50%), strength (37%), weight management (12%). 33% of adults took supplements on the advice of their physician. Another survey (Blendon et al. 2001. Arch Intern Med. 161(6):805-10) found that while “a majority...expressed support for increased government regulatory efforts to ensure that dietary supplements are not harmful and are pure, that doses are consistent, and that advertising claims are true,” most regular users said they would continue to use products even if scientific evidence showed they were not useful. Many reported that “they do not discuss the use of dietary supplements with their physicians because they believe that the physicians know little or nothing about these products and may be biased against them.” 18% of parents gave supplements to their children. A separate survey found that 62% of children with chronic illness used supplements, half of them nonprescription. For the nonprescription supplements, only 20% had been discussed with a health care provider. Another survey found that 60% of heart patients used supplements, many of them ones that could interact with their anticoagulant drugs.

Panjwani et al. (2021. J Pediatr. 231:131-40) reported that "Between 1999 and 2016, overall dietary supplement and VM [vitamin and/or mineral]-only dietary supplement use among all children remained relatively stable at ~30%; yet, NVNM [non-vitamin/non-mineral] dietary supplement use increased from 2.9% to 6.4%, mainly due to increased use of omega-3 polyunsaturated fatty acids."

Ronis et al. (2018. Annu Rev Pharmacol Toxicol. 58:583-601) noted that "53% of active-duty US Army soldiers report using at least one dietary supplement per week, and 64% of college students participating in athletics use dietary supplements to enhance performance." A survey (2010) found that " elite track and field athletes participating in world-championship competitions took one or more dietary supplements containing such ingredients as vitamins, minerals, creatine, caffeine, and amino acids...In a national survey [2014] of about 21,000 U.S. college athletes, respondents reported taking protein products (41.7%), energy drinks and shots (28.6%), creatine (14.0%), amino acids (12.1%), multivitamins with caffeine (5.7%), beta-hydroxy-beta-methylbutyrate (HMB; 0.2%), dehydroepiandrosterone (DHEA; 0.1%), and an unspecified mix of 'testosterone boosters' (1.6%)" (National Institutes of Health Office of Dietary Supplements. 2019. Dietary supplements for exercise and athletic performance).

Frenkel and Sierpina (2014. Curr Oncol Rep. 16:411) found that "The use of dietary supplements among patients affected by cancer is extensive, with an estimated 20-90% of patients using these products. Their use of these products is often not shared with the treating physician. This is because patients perceive or believe that their physicians are indifferent or negative toward the use of dietary supplements. As a result, patients may obtain information about dietary supplements from unreliable sources, exposing themselves to unnecessary risks."

REGULATION AND LABELING

Overview

FDA labeling regulation are governed by the Dietary Supplement Health and Education Act (DSHEA) of 1994. Herbs are included in these regulations. As Marcus (2016. Drug Test Anal. 8(3-4):410-2) noted, "Herbals are used worldwide as medicines, they do not supplement the diet, they may cause severe adverse events, and they should be regulated as medicines."

“Surveys show that many consumers have misconceptions about dietary supplements. They wrongly believe that supplements have been approved by the FDA and are regulated somewhat like drugs - and thus must be safe, must deliver on their advertised claims, and must contain what’s stated on the labels. Medications are strictly regulated by the FDA. They must be tested for safety and efficacy in clinical trials before they are marketed; they must contain what the label says they contain; and potential adverse effects must be stated on package inserts and in ads. Supplements are completely different. Under DSHEA, they are regulated as a class of foods, not drugs, and their manufacturers do not have to prove safety and efficacy or warn about possible adverse effects. Thus, companies don’t have to do any pre-market testing, let alone publish their results in peer-reviewed journals, which is what makes it so hard to evaluate supplements” (Berkeley Wellness 2019. Op. cit.).

Ashar (2010. Arch Intern Med. 170(3):261-3) wrote that one justification for the DSHEA "is the concept that it promotes wellness. Implied in the legislation is the notion that more open access to dietary supplements would improve the health of Americans and that 'appropriate use of safe nutritional supplements will limit the incidence of chronic diseases, and reduce long-term health care expenditures...' This certainly has not happened over the last 15 years. The incidence of chronic disease and health care expenditures continue to rise, despite as many as 70% of adults taking dietary supplements. Rather than promoting a healthful diet, exercise, weight control, and avoidance of unhealthy behaviors, it seems that ingestion of dietary supplements has given patients a more palatable, yet ineffectual, alternative to making lifestyle changes. It is certainly much easier to take a pill than to enact a plan that limits food portions and choices and requires time and effort to enhance caloric expenditure and adequately deal with stress."

Denham (2021. Public Health Nutr. 24(9):2771-5) noted that DSHEA exempted "manufacturers from providing premarket evidence of product safety and efficacy" to the FDA. "Ostensibly, this exemption would allow manufacturers to avoid delays in marketing supplements to consumers whose diets lacked certain nutrients. In practice, DSHEA has facilitated sales of adulterated and mislabeled products," which often contain hazardous ingredients.

Definitions:

label - anything on the product

labeling - anything that is written, printed, or graphic which accompanies the purchase of the product. Subject to same rules as label.

health claim - refers to prevention or treatment of a specific disease

structure and function claim - related to general ideas (e.g., bones, energy, immune system) but not to a specific disease

Structure and function claims

Structure and function claims must have scientific support, but need not be approved by FDA. Consumers do not generally understand this provision, and tend to think that claims have been approved. Because of confusion over allowed claims, clarifications were issued by the FDA in 2000. Claims for dealing with minor symptoms associated with life stages (e.g., menopausal symptoms) are allowed. Structure and function claims on the labels must be accompanied by a disclaimer: “This statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease.”

“Here are some examples: A label can say ‘helps improve mood’ but not ‘reduces depression.’ It can say ‘maintains a healthy circulatory system’ but not ‘prevents cardiovascular disease.’ It can say ‘maintains cholesterol in a healthy range’ but not ‘lowers cholesterol.’ It can say ‘supports the immune system’ but not ‘prevents colds and flu’” (Berkeley Wellness 2019. Op. cit.).

Avery et al. (2017. Prev Med. 97:86-92) examined structure-function claims during 2003-2009. "A significant number of the specific verbs used in these S-F claims are indicative of disease treatment/cure effects, thereby possibly mimicking health claims to the average consumer. The strength of the clinical associations made are largely unsubstantiated in the medical literature. Claims that a product is 'scientifically proven' or 'guaranteed' were largely unsubstantiated by clinical literature. Ads carrying externally validating seals of approval were highly prevalent." Furthermore, "Symbols or logos of 'independent' organizations paid to conduct product testing...that appear in supplement ads may lead consumers to incorrectly infer that the organization provides an unbiased expert opinion supporting product claims...However, these symbols only verify good manufacturing practices, not S-F claim validity."

A study of hypothetical product labels with and without the disclaimer described above "found no effect of the presence or absence of the disclaimer on consumers’ belief that the product would have the effect it claimed to have, nor on their belief that the FDA had evaluated the manufacturer’s claims of effectiveness - despite the DSHEA disclaimer clearly stating that the FDA did not review the claims" (Kesselheim et al. 2015. Health Aff (Millwood). 34(3):438-46).

In an editorial, Fontanarosa et al. (2003. JAMA. 289(12):1568-70) wrote, “...these products nearly always include at least one ‘structure/function’ claim...Yet the only way such claims can be valid is if the dietary supplement actually promotes or has inherent biological activity...If dietary supplements have or promote such biological activity, they should be considered to be active drugs. On the other hand, if dietary supplements are claimed to be safe because they lack or have minimal biological activity, then their ability to cause physiologic changes to support ‘structure/function’ claims should be challenged, and their sale and distribution as products to improve health should be curtailed. Manufacturers of dietary supplements are trying to have it both ways. They claim that their products are powerfully beneficial, on the one hand, but harmless on the other. To claim both makes no sense, and to claim either without trials demonstrating efficacy and safety is deceptive. The public should wonder why dietary supplements have effectively been given a free ride.”

Health claims

Health claims (see definition above) must be approved by FDA. According to Ellwood et al. (2010. Nutr Rev. 68(2):114-21), "health claims are limited to claims about risk reduction and cannot be about the diagnosis, cure, mitigation, or treatment of disease...The NLEA [Nutrition Labeling and Education Act of 1990] required that the FDA issue regulations for authorizing the use of a health claim about a substance/disease relationship only when the significant scientific agreement standard was met. The significant scientific agreement standard represents the agency's best judgment as to whether qualified experts would likely agree that the scientific evidence supports the substance/disease relationship that is the subject of a proposed health claim. This standard is intended to be a strong one that provides a high level of confidence in the validity of the substance/disease relationship. Significant scientific agreement means the validity of the relationship is not likely to be reversed by new and evolving science, although the exact nature of the relationship may need to be refined."

An investigation by Truth in Advertising (TINA) (2016 Nov 6. Is the DSA ignoring illegal health claims?) found that "Despite declarations by the Direct Selling Association (DSA) that it is committed to business ethics, a TINA.org investigation has found that 97 percent of DSA member companies selling nutritional supplements have distributors marketing their products with illegal health claims...The disease-treatment claims used to market these MLM supplements are not hard to find. Simply by Googling the name of one of the MLM companies and 'cancer,' or 'arthritis,' or 'eczema,' or 'diabetes,' or any other disease of one’s choosing, a plethora of websites and social media posts making false and deceptive claims pop up. From autism, Alzheimer’s and HIV/AIDS, to eczema, Ebola and epilepsy, there is an MLM supplement that is being marketed to cure, treat, mitigate, or prevent almost any disease or disorder one can think of. And for most product lines, distributors claim the product(s) are a cure-all for a variety of diseases."

Qualified health claims: A 1999 court ruling required that the FDA also issue qualified health claims "that would be misleading without such qualification. These qualified claims are based on the weight of the scientific evidence. An example of this type of claim is 'supportive but not conclusive research shows that consumption of EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) omega-3 fatty acids may reduce the risk of coronary heart disease'” (FDA Consumer. 2005 Jan-Feb). “In 2004, bowing to pressure from industry via freedom-of-speech court cases, the FDA started allowing more questionable, ‘qualified’ health claims, which are hedged with qualifiers and based on ‘very limited,’ ‘preliminary,’ and possibly even poor-quality evidence. Because the qualifiers must be on the labels, supplement makers rarely use such claims” (Berkeley Wellness 2019. Op. cit.).

Sissung et al. (2021. Lancet Oncol. 22(7):915-6) pointed out that “the costly and time-consuming process of obtaining FDA approval for qualified health claims is of little interest to most companies,” since such approval has little effect on consumer beliefs concerning the products and it is simpler to make structure-function claims.

Third party literature making health claims may be disseminated in a store, as long as it is not in direct conjunction with the product (which would be labeling), is not false or misleading, and doesn't promote a particular brand.

Enforcement

Products do not need to be shown to be safe; they just have to give “reasonable assurance” that they are not a significant risk of harm. The burden is on FDA to show that they are unsafe. It has been estimated that there are 30,000 products, with 1000 new ones each year. Aciman (2017 Jan 27. Quartz) reported that "to address this $40 billion industry the FDA must rely on a team of 24 people and a budget of less than $5 million."

“Federal law requires manufacturers to notify the FDA at least 75 days before marketing a supplement that contains a 'new dietary ingredient' (one that was not marketed in the U.S. before 1994). Supplements containing a new ingredient that has not been submitted to the FDA are considered adulterated and thus illegal. However, despite the fact that several thousand new supplements are marketed each year, the FDA received only about 750 notifications about new ingredients in total between 1994 and 2015" (Berkeley Wellness 2019. Op. cit.).

Beginning in 2010, the FDA issued “good manufacturing practices” (GMPs) for dietary supplements. These relate to issues of quality control, not to whether the products are effective. “Since DSHEA went into effect, supplements have been regulated under the category of food - and as such, they’ve been covered by GMPs that basically check for sanitary conditions and consistency in production. The newer GMPs, however, are specific for dietary supplements and add higher standards for the manufacture of these products than food GMPs do...But the final rules were watered down from the original proposals. Not surprisingly, manufacturers fought against measures that would increase costs. In particular, the provision to test finished products was weakened by various loopholes. Notably, products for which there are no validated testing methods, such as herbs, are exempt from testing. In effect, manufacturers can still cut corners and make poor-quality products and get away with it, even if they meet GMPs. What’s more, the FDA, despite a pledge to substantially increase inspections, lacks the resources to fully monitor compliance, which is often done through inspection of paperwork, not facilities. Thus, more than half of 656 FDA inspections of manufacturing facilities conducted in 2017 resulted in letters indicating GMP violations” (Berkeley Wellness 2019. Op. cit.).

"The FDA does not test dietary supplement products for validation of the amount of active ingredients specified on the label. Furthermore, if the company chooses to have a 'proprietary blend,' they only list the ingredients in descending order of weight and the total weight of all the ingredients in the blend" (White 2020. Ann Pharmacother. 54(8):815-9).

"There are currently 3 different highly regarded independent laboratories that verify dietary supplements: the USP, the NSF, and ConsumerLabs.com. Whereas USP and NSF are nonprofit organizations, they charge manufacturers for their verification services and allow companies with high-quality products (inclusion of the active ingredient, absence of pesticide and heavy metal contamination) to use the USP seal or 1 of 2 NSF seals (NSF Contents Certified for nonathletes and NSF Certified for Sport for products used by athletes subject to drug testing for banned substances). They post verified products on their websites as well. ConsumerLab.com is a for-profit company that not only regularly tests and certifies supplements in a funding process similar to USP and NSF, but also proactively assesses products without being paid by the manufacturers; but consumers or stores selling the products have to pay to see the individual results. Recently, UL, a for-profit company known for testing electronics, has begun certifying dietary supplements, but it is unclear if their results are reliable. Some manufacturers go to third-party laboratories for quality testing, and the manufacturers then post the certificates of analysis on their websites; but it is not clear how much you can trust the results. ConsumerLabs.com reports that sometimes the laboratories will select a testing method with low sensitivity to detect an issue, intentionally or unintentionally not perform the test correctly, test a different product and cross-report the results, or simply make up the results. In addition, manufacturers might use different ingredients or processes when they know they are making a batch that will be tested" (Ibid.).

Tucker et al. (2018. JAMA Netw Open. 1(6):e183337) found that "From 2007 through 2016, 776 adulterated dietary supplements were identified by the FDA and 146 different dietary supplement companies were implicated. Most of these products were marketed for sexual enhancement..., weight loss..., or muscle building..., with 157 adulterated products (20.2%) containing more than 1 unapproved ingredient. The most common adulterants were sildenafil for sexual enhancement supplements...sibutramine for weight loss supplements...and synthetic steroids or steroid-like ingredients for muscle building supplements...Of products that were found to be adulterated more than once, 19 (67.9%) had new drug ingredients reported in their second or third warning. This indicates that these products continue to be sold and are potentially dangerous even after FDA warnings. This is alarming, especially considering that the FDA is only able to test a portion of products available on the market."

A study by Cohen et al. (2014. JAMA. 312(16):1691-3) found that "66.7% of recalled supplements still available for purchase at least 6 months after FDA recalls remained adulterated with banned ingredients." Another study (Cohen et al. 2018. JAMA Intern Med. 178(12):1721-3) determined that for twelve products given notices in 2014 that were still available in 2017, nine continued to have detectable levels of prohibited stimulants. They concluded that "our study provides further evidence that a regulatory system that relies on postmarket enforcement activities is insufficient to ensure the safety of dietary supplements."

Cohen and Bass (2019. N Engl J Med. 381(25):2387-9) wrote: "We have become particularly concerned about the risks associated with newly discovered, sophisticated, and potentially potent biologic and botanical ingredients that are routinely introduced as new ingredients in supplements. The great majority of these ingredients are never reviewed by the Food and Drug Administration (FDA), even though review is mandated by the New Dietary Ingredients provision in DSHEA...We recommend reforming DSHEA such that all new ingredients, rather than only a small subset, are reviewed by the FDA and effective systems are implemented to track the safety of all supplements...The New Dietary Ingredients provision was designed to address the safety of newly introduced ingredients in supplements. For every new ingredient introduced into the market after 1994, manufacturers were expected to provide the FDA with a 75-day advance notice containing safety data establishing that the ingredient 'will reasonably be expected to be safe.' Instead, a number of loopholes, vague language in the law, and lack of industry compliance have led to the majority of new ingredients being introduced without any safety evaluation by the FDA. The FDA has also failed to enforce this provision...An estimated 75,000 new supplement products have been introduced since 1994, while the FDA has received adequate safety data for fewer than 250 new ingredients. The agency has no system for determining how many new ingredients are contained in the tens of thousands of new products on the market...The law provides an exemption for ingredients that have been 'present in the food supply as an article used for food in a form in which the food has not been chemically altered,' and manufacturers have used this provision to justify not submitting safety data to the FDA...The exemption was not meant to apply to new chemicals, combinations, or synthetic compounds. Nonetheless, the FDA has appeared to condone the use of this loophole to permit countless substances to be introduced in the absence of submitted safety data...After the ingredient has been in the 'food supply' for a few months, the manufacturer claims that it can market the new ingredient, at any dose, in dietary supplements."

Bellamy (2019 Feb 14. Science-Based Medicine blog) reported that "FDA Commissioner Scott Gottlieb, MD, announced 'a new plan for policy advancements with the goal of implementing one of the most significant modernizations of dietary supplement regulation and oversight in more than 25 years'...According to Dr. Gottlieb, the FDA will focus on collaring the 'bad actors,' those who market potentially dangerous products and make unproven or misleading claims about their products’ health benefits. While this is laudable, by narrowly defining the terms 'potentially dangerous' and 'unproven or misleading claims' in a manner suitable to the dietary supplement industry, the FDA fails to address the legally authorized health dangers and misleading claims baked into the dietary supplement regulatory scheme by DSHEA...'Potentially dangerous' apparently does not include, however, products sold to consumers as beneficial to health but which are, in fact, not tested for safety or efficacy prior to their going on the market, a deficiency that necessarily eliminates any real risk/benefit calculation. That is because DSHEA does not require such testing....Thus, in the schema of Dr. Gottlieb, the FDA’s job is to ratchet up its pursuit of the 'bad actors' who 'exploit the halo created by quality work of legitimate manufacturers' and other players in the industry 'most of whom act responsibly'...Lest the supplement industry be alarmed by this newly energized FDA, Dr. Gottlieb’s statement contains assurances that the FDA will be 'flexible enough' in evaluating product safety so as not to discourage 'innovation'...As it currently stands, 'innovation' in the dietary supplement industry seems to me to consist of figuring out how to combine the same ingredients in different ways and sell the results as a new product."

See the next section ("Adverse effects") for enforcement actions related to adverse effects. Numerous actions related to labeling and safety are taken by the FDA and FTC every year.

Other aspects

Bellamy (2017 Aug 17. Science-Based Medicine blog) noted that there "is an official organization of the U.S. Congress, called the Congressional Dietary Supplement Caucus, and it is devoted, in every sense of the word, to the dietary supplement industry. Its job is feeding your elected representatives a steady diet of industry-friendly talking points and protecting the industry from meaningful regulation, all skillfully orchestrated by the industry itself." She argued that "Any organization that is essentially part of Congress and operated with taxpayer-funded resources should not function as the in-house lobbying arm of an industry special interest group, nor should Congressional rules allow this to happen."

"Medical foods are generally defined as foodstuffs that are formulated to be consumed or administered internally while under the supervision of a physician. Medical foods not only encompass various infant formulas, edible bars, and modified low-protein foods that have the expected appearance and taste of a foodstuff but are also available as specialized nutritional products including, but not limited to, high doses of vitamins and amino acids formulated as tablets and/or capsules that may be indistinguishable from conventional pharmaceutical dosage formulations in terms of dosage formulation elegance and packaging...Not surprisingly, some manufacturers of dietary supplements would much prefer to market their products as medical foods since they are exempt from the disease-statement limitations that are applied to them" (Markowitz et al. 2020. Clin Ther. 42(7):1416-23).

ADVERSE EFFECTS

A general consideration is that patients may substitute ineffective supplements for effective conventional medicine or dietary modification. In addition, supplements may interact with conventional medicines taken concurrently, either interfering with or enhancing their effectiveness. Despite this, a study of hospitalized patients by Gardiner et al. (2015. Patient Educ Couns. 98(4):512-7) found that "Among patients in a general internal medicine and geriatric service, 75% reported that no physician asked about dietary supplement use during admission. Research has indicated that many inpatient medical teams are unaware of patient’s herbal remedies and dietary supplement use."

"The more pertinent and significant pharmacodynamic interactions to be aware of in the intensive care setting are those whose pharmacological effects include blood clotting (e.g., antiplatelet and anticoagulant effects), CNS depression, hypoglycemic effects, blood pressure, stimulant effects, and those which may affect serotonin levels. There are more than 90 dietary supplements that may interact with blood clotting alone, and this can be a significant issue in the intensive care setting" (Kay 2014. Crit Care Med. 42(4):1014-6 ).

Direct harm from the supplement ingredients themselves (either stated ingredients or adulterants) is a more serious problem. Dietary supplements cause an estimated 20,000 emergency room visits and thousands of hospitalizations per year in the US. Many of these involve children. "U.S. Poison Control Centers receive a call every 24 minutes, on average, due to exposures to dietary supplements. The rate of calls increased by almost 50 percent from 2005 to 2012, with a total of 274,998 incidents reported from 2000 through 2012. About 4.5 percent - more than 12,300 cases - resulted in serious medical complications" (Miller and Bloom 2019 Jun 17. Genetic Literacy Project). "The FDA has estimated that dietary supplements cause 50 000 adverse events annually" (Marcus 2016. Drug Test Anal. 8(3-4):410-2). Especially common have been incidents from weight loss and athletic performance supplements. Gavura (2016 Nov 17. Science-Based Medicine blog) pointed out that there is "no routine collection of adverse event (side effect) information. The consequence is that we’re effectively conducting a massive, uncontrolled, unmonitored clinical trial in millions, with products of unknown quality. Only when products kill (e.g., ephedra) or harm in a unique way (e.g., aristolochia) is the link more obvious" (ephedra and aristolochia are discussed in the Herbs article).

Toxicity to the liver and kidney are the most common problems. Many of the most severe cases of liver damage have been among middle-age women using supplements for weight loss.

A database maintained by the FDA is the Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS), which "is a collection of complains about dietary supplements and other products submitted by consumers, healthcare practitioners, and manufacturers. Consumers and doctors submit the reports voluntarily. Manufacturers must submit them whenever they receive reports about consumers who experienced serious adverse events, including death or hospitalization, after taking one of their products. The reports can’t, on their own, establish a cause-and-effect link between an incident and a product. Rather, the agency periodically scours the database using algorithms to detect signals of potential safety problems. But the system is plagued by problems, starting with under-reporting. The agency receives just an estimate 2 percent of adverse event reports related to supplements annually. As a result, it can take years for the FDA to build a case that a supplement is unsafe and, as with cesium chloride, even consider getting it removed from the market. Unlike with drug monitoring, the FDA doesn’t have to alert the public when it investigates a potential problem with a supplement. In only a few cases has CAERS clearly played a major role in the recall of dietary supplements...Harvard's [Pieter] Cohen says the agency isn't doing enough to follow up. 'Year after year there has been no substantial enforcement action by the FDA to remove dangerous supplements from the marketplace based on adverse event reports,' he says. 'Rational consumers and their physicians could reasonably conclude that it is fruitless to submit more reports to an agency that is not following up on reports'" (Felton 2020 May 27. FDA's supplement warning system has deadly limitations. Consumer Reports).

Supplements may be adulterated with conventional drugs, producing dangerous side effects. As Gavura (2018 Oct 18. Science-Based Medicine blog) pointed out, "Adulterated dietary supplements are particularly problematic for consumers, because it is impossible to safely take a prescription drug if you don’t know you’re taking it at all. And if you have medical conditions, or take other prescription drugs, your risk of harm from adulterated supplements is even greater."

"Many supplements for the enhancement of athletic performance contain analogues of amphetamines, and supplements for sexual health frequently contain sildenafil or other phosphodiesterase-5 (PDE-5) inhibitors. To escape detection by regulatory agencies, many PDE-5 analogues have been synthesized. Seventy-five percent of sexual enhancement supplements seized in the Netherlands contained PDE-5 analogues. There are eleven different families of phosphodiesterases that are active in a variety of metabolic processes. The FDA-approved PDE-5 medications inhibit only one family, but less specific analogues may inhibit receptors found in many organs, and their safety has not been studied" (Marcus 2016. Op. cit.).

Mathews (2018. Sports Health. 10(1):19-30) described the re-emergence of nasal decongestants and stimulants, previously abandoned due to safety concerns, beginning with "dimethylamylamine (DMAA), also known as 'geranium oil extract,' a potent vasopressor in a class known as phenylethylamines. As reports of cardiac arrests, cerebral hemorrhages, and other adverse events started to appear, DMAA was banned in 2012 after it was determined it was a new dietary ingredient and was not found in geraniums. What followed was a succession of chemically related compounds with structures and effects similar to DMAA and methamphetamines, with initials like DMBA, BMPEA, NADEP, and NN-DMPAA, each claiming to be occurring naturally from sources but later disproven as being created synthetically."

A prominent example of supplement toxicity is OxyELITE Pro, used for weight loss and increased energy. The original product contained DMAA (see above). After it was reformulated, more than 40 cases of liver toxicity in 2013 were linked to the new product. A synthetic version of the herbal compound aegeline was implicated.

"Sport or performance-enhancing supplements pose risks that are unique to the growing athlete. The developing endocrine and nervous systems are sensitive to the presence of hormones, anabolic-androgenic steroids, and stimulants...Anabolic agents can also cause premature epiphyseal closure (which is permanent), brain remodelling, and an increased risk of maladaptive behaviors and neurological disorders. For stimulants, increases in blood pressure, loss of appetite, emotional instability, nervousness, jitteriness, and social withdrawal are common side-effects in youth, and prolonged exposure to stimulants can also negatively affect growth" (Eichner and Tygart 2016. Drug Test Anal. 8(3-4):304-6). Cohen et al. (2021. Clin Toxicol (Phila). 23:1-7) found that "Weight loss and sports supplements listing deterenol as an ingredient contained 9 prohibited stimulants and 8 different mixtures of stimulants, with as many as 4 experimental stimulants per product. These cocktails of stimulants have never been tested in humans and their safety is unknown."

Zamil et al. (2020. Dermatol Online J. 26(8):13030/qt9rp7t2p2) noted that some dietary supplements have been "linked to acne, including those containing vitamins B6/B12, iodine, and whey, as well as 'muscle building supplements' that may be contaminated with anabolic-androgenic steroids (AAS)." A study by Deldicque and Francaux (2016. Curr Opin Clin Nutr Metab Care. 19(6):439-45) found that "90% of sports supplements contain trace of estrogenic endocrine disruptors, with 25% of them having a higher estrogenic activity than acceptable."

Considerations especially important with herbal supplements are discussed in the HERBS article. Adverse effects of individual supplements are discussed in the descriptions of the supplements in SUPPLEMENTS PART 2.

SCIENTIFIC CRITIQUE

Research

"During the past 2 decades, a steady stream of high-quality studies evaluating dietary supplements has yielded predominantly disappointing results about potential health benefits, whereas evidence of harm has continued to accumulate... even supplements that are useful in treating certain conditions are frequently overused among the general population to 'improve' or 'maintain' health, and only about one-quarter of consumers use supplements based on the advice of their clinicians. For the majority of adults, supplements likely provide little, if any, benefit...Moreover, even after high-quality studies that show no meaningful clinical differences between supplements and placebos are published, the law provides manufacturers latitude to continue advertising their products based on earlier, low-quality data. For example, Ginkgo biloba continues to be sold 'to support mental sharpness' despite a large, high-quality NIH-funded study that found evidence to the contrary" (Cohen 2016. JAMA. 316(14):1453-4).

There is often reliance on testimonials, anecdotal evidence, and preliminary research such as animal studies or poorly designed human trials. “There is little or no incentive for supplements companies to fund well-designed, placebo-controlled studies, which are expensive to carry out. For one thing, any positive research findings would also benefit the sponsoring company’s competitors, since most supplements are substances found in nature and thus can’t be patented. In addition, studies - particularly those conducted by independent researchers - may produce disappointing or even worrisome results” (Berkeley Wellness 2019 Jul 31. Supplements: We can do better).

Unscientific claims

Disparaging claims are made about the quality of food due to poor soils, food processing, pesticides, etc. But plants won't grow properly if they don't have the necessary minerals, and they make vitamins themselves. As noted by Davis et al. (2004. J Am Coll Nutr. 23(6):669-82), "Plant cells require most human nutrients for their own needed levels of a broad range of nutrients. Thus, no whole plant food can be as broadly depleted of nutrients as are refined sugars and separated fats and oils." These authors reviewed changes in food composition of 43 garden crops from 1950 to 1999, and found declines in six nutrients (protein, calcium, phosphorus, iron, riboflavin, and ascorbic acid) but "no statistically reliable changes for 7 other nutrients" (some of them appeared to increase). Moreover, the reported declines could well have been due to improvements in measurements.

Rationales show ignorance of principles of digestion and metabolism (e.g., selling enzymes that will be degraded before they can be of use).

There is promotion of products that are not needed in the diet (e.g., carnitine) or have no role in human metabolism (e.g., chlorophyll), or for nutrient content (e.g., royal jelly, blue-green algae) that can be obtained much more easily from normal food.

Marketing

Promoters of dietary supplements use invalid diagnostic methods for nutritional deficiencies (questionnaires, applied kinesiology, iridology, live cell analysis, hair analysis, etc.). Applied kinesiology and live cell analysis are described in the article on "Chelation therapy; allergy and arthritis treatments; other miscellaneous topics." Iridology is described in the article on "Homeopathy, naturopathy, energy medicine, and other 'holistic' approaches."

Promoters may boast of degrees from non-accredited institutions.

Aggressive marketing techniques are employed. These may involve lay people who are not knowledgeable in nutrition.

Hall (2020 Aug 4. Science-Based Medicine blog) described some of the typical tactics used in advertising videos. "The presenter wears a white coat and is shown standing in a pristine laboratory, so you are supposed to think he’s a reputable doctor or scientist, but he is not identified." A moving story is told of someone who only found relief when using the product. It is claimed that the pharmaceutical industry is trying to suppress the product, and that thousands of people have successfully used the product. The product is on sale for a special price today only. Supplies are running out and you may have to wait months for more to be produced. You can buy the individual components of the product but they will be more expensive and won't work as well.

Hall and Barrett (2016. Puritan's Pride's "Vitamin Advisor" wants to sell you something. Quackwatch) investigated an on-line "Vitamin Advisor." They found that "no matter how you answer the questions, you will be advised to buy at least one product. EVERYONE is advised to buy a multivitamin...All of these products include some ingredients that are unnecessary and others that exceed standard recommended amounts... In a few instances, one or two ingredients might be useful but the product provides too much of them or contains other substances that are not. Some ingredients are found in more than one product. For this reason, when several products are recommended, the total amount of these ingredients may be way too high...In proper professional hands, a well-designed questionnaire that includes a detailed dietary history can identify areas of overall diet that could use improvement. However, no questionnaire can be customized to make appropriate supplement recommendations, either for dietary improvement or for treatment."

Retail sales

Gotay and Dumitriu (2000. Arch Fam Med. 9(8):692-9) surveyed health food stores, with a researcher pretending to be a daughter of a cancer patient. “Store personnel readily provided information and product recommendations.” 18% “directly or indirectly counseled against the use of orthodox cancer therapies.”

In another study, Consumer Reports sent undercover shoppers to retail pharmacy departments, where they asked employees about products that contained potentially dangerous ingredients. "Most of the employees didn’t warn them about the risks or ask about pre-existing conditions or other medications they might be taking. Many gave information that was either misleading or flat-out wrong." When asked about a product with yohimbe (which is linked to serious side effects), a clerk "said it was safe because it was 'natural'" (Interlandi 2016 Sep. Consumer Reports).

Other points

Supplement manufacturers have sued critics for defamation when they question the safety and/or effectiveness of their products.

Aronson (2017. Br J Clin Pharmacol. 83(1):8-19) has criticized the DSHEA definition of dietary supplement as being so broad that it "opens the door to inappropriate description of any other substance as a dietary supplement: if you label it as a dietary supplement, it is one! For example, melatonin is often marketed as a nutritional or dietary supplement but it is in fact formulated as medicinal products that are claimed to aid sleep and may have efficacy in preventing or ameliorating jet lag."

As noted above ("Regulation and Labeling"; "Adverse Effects"), dietary supplements are frequently mislabeled, containing ingredients (sometimes dangerous ones) not listed on the label, and/or not containing listed ingredients. As another example, Crawford et al. (2020. J Altern Complement Med. 26(4):265-72) examined 12 supplements marketed for brain heath and cognitive performance. Ten contained ingredients not listed, and 8 had undetectable level of a listed ingredient. Moreover, "The average number of ingredients in the products overall (~12: range 6–24) begs the question of why do manufacturers believe that more ingredients make a product more enticing, when in fact the risk of problems increases given the greater number of possible interactions."

Denham (2021. Public Health Nutr. 24(9):2771-5) noted that raw powders "containing anabolic steroids and steroid precursors" can be "purchased inexpensively" (frequently from China) "and then mixed with fillers to increase volume," facilitating the "home brewing" of adulterated supplements.

Branson (2016 Nov 22. HealthNewsReview.org) pointed out the "broader problems with the way many journalists cover supplements. Inconclusive research is characterized as conclusive, the larger evidence context is ignored, and important marketing influences may get overlooked."

CONVENTIONAL NUTRITION: VITAMINS AND MINERALS

Before looking at individual dietary supplements (SUPPLEMENTS PART 2 , the following sections review standard views of the need for various nutrients, as well as the potential benefits of dietary antioxidants and phytochemicals. Requirements of nutrients for age 14 and older are listed, as well as possible toxic effects of taking doses in large excess of the recommended levels. Discussion of their promotion for effects other than preventing deficiency diseases are discussed later (Part 2) along with other dietary supplements.

In general, small excesses of water-soluble vitamins are excreted; larger excesses can be harmful. Excesses of fat-soluble vitamins are more likely to be toxic because these accumulate in fatty tissues.

Dietary Reference Intakes (DRI) "is the general term for a set of reference values used to plan and assess nutrient intakes of healthy people. These values, which vary by age and sex, include:

• Recommended Dietary Allowance (RDA): average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%-98%) healthy people.

• Adequate Intake (AI): established when evidence is insufficient to develop an RDA and is set at a level assumed to ensure nutritional adequacy.

• Tolerable Upper Intake Level (UL): maximum daily intake unlikely to cause adverse health effects"

(National Institutes of Health Office of Dietary Supplements, Nutrient Recommendations: Dietary Reference Intakes (DRI)). (Quotes in the following sections are from this source.)

Fat-soluble vitamins

Vitamin A (retinol): RDA 700 μg (women), 900 μg (men). RDA values are expressed as "retinol activity equivalents (RAEs). 1 RAE = 1 µg retinol, 12 µg β-carotene, 24 µg α-carotene, or 24 µg β-cryptoxanthin. The RAE for dietary provitamin A carotenoids is two-fold greater than retinol equivalents (REs), whereas the RAE for preformed vitamin A is the same as RE."

UL: 2800 μg (14-18), 3000 μg (>18) vitamin A

Toxic effects of megadoses: birth defects, liver damage, skin problems, hea­d­ache, fatigue, bone problems, nausea, diarrhea, hair loss. High dietary intake linked to hip fractures in women.

Notes: Many diets may be deficient. Made from beta carotene (much less toxic in large amounts).

Vitamin D (D₃ or chole­cal­cif­erol): RDA 15 μg (14-70), 20 μg (>70). "As cholecalciferol. 1 µg cholecalciferol = 40 IU vitamin D." "Under the assumption of minimal sunlight."

UL: 100 μg

Toxic effects of megadoses: hy­percalcemia, bone demineralization, hype­r­calcuria, nausea, vomiting, other. Various prob­lems in in­fants, includ­ing retardation and kid­ney dam­age.

Notes: “Some professional organizations recommend 1000 to 2000 IU/d [25-50 μg], but it has been widely debated whether doses above the RDA offer additional benefits. Ongoing large-scale randomized trials...should help to resolve continuing uncertainties soon” (Manson and Bassuk 2018. JAMA. 319(9):859-60).

Vitamin E (α-tocopher­ol): RDA 15 mg

UL: 800 mg (14-18), 1000 mg (>18)

Toxic effects of megadoses: bleeding problems, diar­rhea, head­ache, muscle weak­ness, oth­er.

Notes: Natural (d) appears superior to synthetic (dl). Can increase effect or bioavailability of aspirin, digoxin, warfarin.

Vitamin K: AI women: 75 μg (14-18), 90 μg (>18)

AI men: 75 μg (14-18), 120 μg (>18)

Toxic effects of megadoses: could be hazardous if getting antico­agulants

Notes: deficiency rare ex­cept in newborns

Water-soluble vitamins

Thiamine (B₁): RDA 1.0 mg (women 14-18), 1.1 mg (women >18), 1.2 mg (men)

Toxic effects of megadoses: nausea, vomiting, anorexia

Riboflavin (B₂): RDA 1.0 mg (women 14-18), 1.1 mg (women >18), 1.3 mg (men)

Niacin: RDA ("As niacin equivalents (NE). 1 mg of niacin = 60 mg of tryptophan"): 14 mg (women), 16 mg (men)

UL: 30 mg (14-18), 35 mg (>18)

Toxic effects of megadoses: GI upset, ab­normal liver function tests, hyperglyce­mia, atrial fibril­lation, flush­ing of skin, itching, oth­ers

Pyridoxal phos­ph­ate (B₆): RDA women: 1.2 mg (14-18), 1.3 mg (19-50), 1.5 mg (>50)

RDA men: 1.3 mg (14-50), 1.5 mg (>50)

UL: 80 mg (14-18), 100 mg (>18)

Toxic effects of megadoses: peripheral neuropathy, depression, headache.

Notes: Many diets may be deficient. *see below

Pantothenic acid: AI 5 mg, 6 mg (pregnancy), 7 mg (lactation)

Notes: Made by intes­tinal bacteria. Defi­ciency known only in severe malnutrition.

Biotin: AI 25 μg (14-18), 30 μg (>18), 35 μg (lactation)

Notes: Made by intes­tinal bacteria. Deficien­cy only in unusual sit­uations.

Folate: RDA ("As dietary folate equivalents (DFE). 1 DFE = 1 µg food folate = 0.6 µg of folic acid from fortified food or as a supplement consumed with food = 0.5 µg of a supplement taken on an empty stomach") 400 μg, 600 μg (pregnancy), 500 μg (lactation). "In view of evidence linking folate intake with neural tube defects in the fetus, it is recommended that all women capable of becoming pregnant consume 400 µg from supplements or fortified foods in addition to intake of food folate from a varied diet."

UL: 800 μg (14-18), 1000 μg (>18)

Toxic effects of megadoses: increases neurologi­cal problems of B₁₂ deficiency while masking its symp­toms.

Possible toxic effects of the synthetic form, which at high doses cannot all be converted to the active form.

Notes: Grains are now sup­ple­mented to prevent birth defects. *see below.

Vitamin B₁₂ (cobalamine): RDA 2.4 μg, 2.6 μg (pregnancy), 2.8 μg (lactation). "Because 10 to 30 percent of older people may malabsorb food-bound B12, it is advisable for those older than 50 years to meet their RDA mainly by consuming foods fortified with B12 or a supplement containing B12."

Notes: Deficiencies ex­tremely rare. Sev­eral year supply stored in liver. *see below

Ascorbic acid (vitamin C): RDA women 65 mg (14-18), 75 mg (>18), 80 mg (pregnancy 14-18), 85 pregnancy >18), 115 mg (lactation 14-18), 120 mg (lactation >18)

RDA men: 75 mg (14-18), 90 mg (>18)

UL: 1800 mg (14-18), 2000 mg (>18)

Toxic effects of megadoses: diarrhea, interference with test for colon cancer, reduced effectiveness of anticoagulant therapy, impaired immune function. Could worsen arthritis. Possibly prooxidant if iron levels high.

Choline: AI women: 400 mg (14-18), 425 mg (>18), 450 mg (pregnancy), 550 mg (lactation)

AI men: 550 mg

UL: 3000 mg (14-18), 3500 mg (>18)

Toxic effects of megadoses: hypotension, sweating, diarrhea, fishy odor

*The combination of folate, B₆, and B₁₂ is important in maintaining low homocysteine, implicated as a risk factor in heart disease.

Macrominerals

Calcium: RDA 1300 mg (9-18), 1000 mg (women 19-50 and men 19-70), 1200 mg (women >50, men >70)

UL: 3000 mg (14-18) 2500 mg (>18)

Toxic effects of megadoses: constipation, kidney problems. Can cause decreased absorption of several drugs and minerals.

Phosphorus: RDA 1250 mg (9-18), 700 mg (>18)

UL: 4000 mg (14-70), 3000 mg (>70)

Magnesium: RDA women: 360 mg (14-18), 310 mg (19-30), 320 mg (>30)

RDA men: 410 mg (14-18), 400 mg (19-30), 420 mg (>30)

UL: 350 mg

Toxic effects of megadoses: diarrhea, kidney failure, neurological and other metabolic effects. Can decrease digoxin absorption.

Sodium: AI 1500 mg

Potassium: AI women: 2300 mg (14-18), 2600 mg (>18)

AI men: 3000 mg (14-18), 3400 mg (>18)

Chloride: AI 2300 mg (9-50), 2000 mg (51-70), 1800 mg (>70)

UL: 3600 mg

Sulfur: no RDA; however, there is a requirement for sulfur-containing amino acids

Notes: Methylsulfonylmethane (MSM) (see SUPPLEMENTS PART 2 ) is promoted as a sulfur source.

Trace minerals

Iron: RDA women: 15 mg (14-18), 18 mg (19-50), 8 mg (>50), 27 mg (pregnant), 9 mg (lactating)

RDA men: 11 mg (14-18), 8 mg (>18)

UL: 45 mg

Toxic effects of megadoses: "acute intakes of more than 20 mg/kg iron from supplements or medicines can lead to gastric upset, constipation, nausea, abdominal pain, vomiting, and faintness, especially if food is not taken at the same time. Taking supplements containing 25 mg elemental iron or more can also reduce zinc absorption and plasma zinc concentrations. In severe cases (e.g., one-time ingestions of 60 mg/kg), overdoses of iron can lead to multisystem organ failure, coma, convulsions, and even death" (NIH Office of Dietary Supplements 2020. Iron). Interactions with some drugs.

Fluoride: AI women 3 mg; men 3 mg (14-18), 4 mg (>18)

UL: 10 mg

Iodine: RDA 150 μg

UL: 900 μg (14-18), μg (>18)

Toxic effects of megadoses: "High intakes of iodine can cause some of the same symptoms as iodine deficiency - including goiter, elevated TSH levels, and hypothyroidism—because excess iodine in susceptible individuals inhibits thyroid hormone synthesis and thereby increases TSH stimulation, which can produce goiter. Iodine-induced hyperthyroidism can also result from high iodine intakes, including when iodine is administered to treat iodine deficiency. Studies have also shown that excessive iodine intakes cause thyroiditis and thyroid papillary cancer. Cases of acute iodine poisoning are rare and are usually caused by doses of many grams. Acute poisoning symptoms include burning of the mouth, throat, and stomach; fever; abdominal pain; nausea; vomiting; diarrhea; weak pulse; and coma" (NIH Office of Dietary Supplements 2020. Iodine).

Zinc: RDA 9 mg (women 14-18), 18 mg (women >18), 11 mg (men)

UL: 40 mg

Toxic effects of megadoses: blocks copper absorption. Increases magnesium excretion. Bone marrow depression, anemia, weaken immunity, reduce HDL, other. Can decrease absorption of some drugs.

Copper: RDA 890 μg (14-18), 900 μg (>18)

UL: 8 mg (14-18), 10 mg (>18)

Toxic effects of megadoses: liver damage

Selenium: RDA 55 μg

UL: 400 μg

Toxic effects of megadoses: damage to liver, nervous system, skin, nails, teeth. Gastrointestinal upset.

Notes: functions in glutathione peroxidase and at least 14 other selenoproteins

Manganese: AI women: 1.6 mg (14-18), 1.8 mg (>18)

AI men: 2.2 mg (14-18), 2.3 mg (>18)

UL: 11 mg

Toxic effects of megadoses: neurological problems. People with liver disease are more sensitive.

Notes: Deficiency is unknown.

Molybdenum: RDA 43 μg (14-18), 45 μg (>18)

UL: 2 mg

Cobalt: no RDA established. Contained in vitamin B₁₂.

Chromium: AI women: 24 μg (14-18), 25 μg (19-50), 20 μg (>50)

AI men: 35 μg (14-50), 30 μg (>50)

Boron: UL 17 mg (14-18), 20 mg (>18)

Toxic effects of megadoses: nausea, vomiting, diarrhea, dermatitis, lethargy

Notes: no requirement established in humans.

Silicon: no RDA or UL determined

Vanadium: UL not determined (14-18), 1.8 mg (>18)

Notes: role unknown

Nickel: UL 1 mg

Notes: role unknown

Other requirements

Essential amino acids: phenylalanine, valine, threonine, tryptophan, methionine, leucine, isoleucine, lysine, and histidine. "Six other amino acids are considered conditionally essential in the human diet, meaning their synthesis can be limited under special pathophysiological conditions, such as prematurity in the infant or individuals in severe catabolic distress. These six are arginine, cysteine, glycine, glutamine, proline, and tyrosine" (Wikipedia 2020. Essential amino acids).

Fatty acids: linoleic acid and linolenic acid are considered essential.

Protein: RDA 0.8 g per kg body weight.

Toxic effects of megadoses: kidney damage

Not required in the diet

The following organic compounds are essential in human metabolism, but can be synthesized by the body and thus are not needed in the diet: betaine, biopterin, carnitine, coenzyme Q10 (ubiquinone), creatine, inositol, lipoic acid, para-aminobenzoic acid (PABA), and pyruvate. They are, however, marketed as dietary supplements. These products are discussed below in the section "Some items marketed as dietary supplements" (SUPPLEMENTS PART 2).

Note on research studies and reviews: because of the immense number of individual research studies on dietary supplements, the following sections generally cite only reviews or meta-analyses rather than individual clinical trials. Exceptions are some large trials with thousands of participants.

Multivitamin-multimineral supplements

The value of supplements of multiple vitamins and minerals, as well as various combinations of vitamins (such as antioxidants) has been assessed in many observational studies and controlled trials. Some of these have involved tens of thousands, or even more than 100,000, participants.

"In 2006, researchers published a comprehensive evidence-based review of the relationship between studies on nutrients that most strongly suggested potential impacts on health and on conditions (cancer; age-related sensory loss; and cardiovascular, endocrine, neurologic, musculoskeletal, gastroenterologic, renal, and pulmonary diseases) on which experts believe that nutrient supplements have the most potential influence. Considering only published randomized, controlled clinical trials, the investigators found that use of MVMs [multivitamin/minerals] ]did not reduce the risk of any chronic disease. (The authors defined MVMs as products containing three or more vitamins and minerals at levels below the UL and no herbs). An expert panel that reviewed this report and participated in a state-of-the-science conference on MVMs in chronic disease prevention at the National Institutes of Health in 2006 concluded that 'the present evidence is insufficient to recommend either for or against the use of MVMs by the American public to prevent chronic disease'. An earlier assessment of the evidence by the U.S. Preventive Services Task Force came to a similar conclusion: the evidence for or against the use of MVMs to prevent cancer or cardiovascular disease was insufficient. A comprehensive evaluation of research by the World Cancer Research Fund and the American Institute for Cancer Research [2007] recommended against the use of dietary supplements for cancer prevention by the public because of the unpredictability of potential benefits and risks, as well as the possibility of unexpected adverse events" (National Institutes of Health Office of Dietary Supplements 2019. Multivitamin/mineral supplements).

"Because people with healthier diets and lifestyles are more likely to use dietary supplements, attributing potential health benefits that are distinct from the proven and predictable benefits of health-promoting behaviors to the use of supplements is difficult. Furthermore, whether studies find any benefits (or risks) depends on the combinations and amounts of nutrients in the MVMs used as well as the populations studied and duration of follow-up, and these results are not generalizable to the enormous variety of MVMs available in the marketplace" (Ibid.).

In a more recent assessment, Manson and Bassuk (2018. JAMA. 319(9):859-60) wrote: “Multivitamin/multimineral supplementation is not recommended for generally healthy adults. One large trial in US men found a modest lowering of cancer risk, but the results require replication in large trials that include women and allow for analysis by baseline nutrient status, a potentially important modifier of the treatment effect. An ongoing large-scale 4-year trial...is expected to clarify the benefit-risk balance of multivitamin/multimineral supplements taken for primary prevention of cancer and cardiovascular disease.”

A contrasting view was offered by Frei et al. (2014. Ann Intern Med. 160(11):807): "Although a well-balanced diet is the best way to get essential nutrients (except vitamin D and, for vegans and many older adults, vitamin B12), few persons in the United States follow the Dietary Guidelines for Americans. Consequently, most persons in the United States are not 'well-nourished' and do not meet the Institute of Medicine's recommendations for the dietary intake of all vitamins and essential minerals." Noting some positive studies, they continued: "Therefore, taking a daily multivitamin and mineral supplement not only helps fill known nutritional gaps in the diet of most persons in the United States (thereby ensuring normal body function and supporting good health) but may have the added benefit of helping to reduce the risk for some chronic diseases."

Reviews and major trials

• Neuhouser et al. 2009. Arch Intern Med. 169(3):294-304 [Women's Health Initiative]: "After a median follow-up of 8.0 and 7.9 years in the clinical trial and observational study cohorts, respectively, the Women's Health Initiative study provided convincing evidence that multivitamin use has little or no influence on the risk of common cancers, CVD [cardiovascular disease], or total mortality in postmenopausal women."

• Gaziano et al. 2012. JAMA. 308(18):1871-80 [Physicians' Health Study II]: " In this large prevention trial of male physicians, daily multivitamin supplementation modestly but significantly reduced the risk of total cancer." However, an accompanying editorial by Bach and Lewis (2012. JAMA. 308(18):1916-7) noted that " this report is a single entry in a crowded field of studies. The majority of these studies...suggest no effect of vitamin supplementation on cancer risk and some, notably, show evidence of harm. Given this context, the marginal statistical significance and the perplexing and somewhat counterintuitive nature of the study findings make drawing any firm conclusion premature. Thus, it may be inappropriate to recommend that men take multivitamins to prevent cancer...the biological plausibility of the study hypothesis - that a multivitamin would be protective in a well-nourished population - is also limited...The plausibility of a protective effect is reduced by the absence of a clear path through which 30 different vitamins and minerals would cause a decline in the risk of multiple cancers and, especially, by the negative pattern of prior results." Demark-Wahnefried (2013. Evid Based Med. 18(6):214-5) wrote, "it is questionable whether a difference of 1.3 events/1000 patient-years is clinically significant especially when supplementation would cost roughly $1800 over the balance of an average life..."

• Alexander et al. 2013. J Am Coll Nutr. 32(5):339-54: "Based upon the available scientific evidence to date, supplementation with MVMs does not appear to increase all-cause mortality, cancer incidence or mortality, or CVD incidence or mortality and may provide a modest protective benefit."

• Singal et al. 2013. Can Fam Physician. 59(8):847: "Current evidence does not support the routine use of multivitamins to reduce mortality, CVD, or cancer for people in developed countries."

• Grodstein et al. 2013. Ann Intern Med. 159(12):806-14 [Physicians' Health Study II]: " In male physicians aged 65 years or older, long-term use of a daily multivitamin did not provide cognitive benefits."

• Christen et al. 2014. Ophthalmology. 121(2):525-34 [Physicians' Health Study II]: "long-term daily multivitamin use modestly and significantly decreased the risk of cataract but had no significant effect on visually significant AMD [age-related macular degeneration]."

• Zhao et al. 2014. Nutrients. 6(3):931-49: "There is sufficient evidence to support the role of dietary multivitamin/mineral supplements for the decreasing the risk of age-related cataracts."

• Rautiainen et al. 2015. Am J Clin Nutr. 101(1):144-52 [Women's Health Study]: " In this study of middle-aged and elderly women, neither baseline nor time-varying multivitamin use was associated with the long-term risk of major CVD events, MI [myocardial infarction], stroke, cardiac revascularizations, or CVD death."

• Bailey et al. 2015. J Nutr. 145(3):572-8: " In this nationally representative data set with detailed information on supplement use and CVD mortality data ~20 y later, we found an association between MVM use of >3 y and reduced CVD mortality risk for women when models controlled for age, race, education, body mass index, alcohol, aspirin use, serum lipids, blood pressure, and blood glucose/glycated hemoglobin."

• Rautiainen et al. 2016. J Nutr. 146(6):1235-40 [Physicians' Health Study I]: " In this long-term prospective study in initially healthy men, multivitamin use for ≥20 y was associated with a lower risk of major CVD events.

• Kim et al. 2018. Circ Cardiovasc Qual Outcomes. 11(7):e004224: "Our meta-analysis of clinical trials and prospective cohort studies demonstrates that MVM supplementation does not improve cardiovascular outcomes in the general population."

• Beeram et al. 2021. Arch Osteoporos. 16(1):29: "Our meta-analysis indicates that multivitamin use is significantly protective against osteoporotic hip fracture."

• Simsek et al. 2021. Clin Nutr ESPEN. 42:1-14: "Vitamin supplementation does not improve clinical cardiovascular outcomes in general population."

ANTIOXIDANTS

Traditional research on vitamins has dealt with levels needed to prevent deficiency diseases. Increasing attention is being placed on their possible uses, at much higher levels, in preventing other diseases. Of special interest is the roles of vitamins E, C, and A as antioxidants. Selenium, which is needed for glutathione peroxidase, has also been the focus of attention. Various other supplements are also proposed to provide benefits as antioxidants.

During normal metabolism, some dangerous products (reactive oxygen species, such as hydrogen peroxide and superoxide anion) are made from oxygen. Molecules that fight these oxidizing compounds are antioxidants (conversely, molecules that help generate them are prooxidants).

Gutteridge and Hilliwell (2010. Biochem Biophys Res Commun. 393(4):561-4) noted, "the assay procedures widely used to measure antioxidant activity in vitro often depend on the generation and trapping of non-biological radicals. Such assays are useful when comparing the alleged in vitro antioxidant activities of berries or tea extracts but the results are usually biologically irrelevant. Rarely do they translate into physiological effects. Almost any chemical could affect the in vitro test systems currently used, leading to that chemical being classified as an antioxidant or pro-oxidant."

Reactive oxygen species can damage proteins, DNA, and lipids. "Denham Harman developed his Free Radical Theory of Aging, which suggested that an accumulation of oxygen-derived radicals (namely superoxide) causes or contributes to the cellular damage associated with progressive aging. Over time, this theory has been expanded to encompass additional reactive species that function as pro-oxidants, and has been supported by studies from a number of independent laboratories...nearly six and half decades of research built upon Dr. Harman’s original hypothesis has led to a general consensus that oxidative stress contributes to aging and pathological conditions such as cancer, neurodegeneration, diabetes, and cardiovascular disease" (Quiles 2018 Oct 23. Science-Based Medicine blog). The leading hypothesis of atherosclerotic plaque formation proposes a critical role for oxidation of low-density lipoprotein (LDL); thus, antioxidants are proposed to protect against atherosclerosis.

"Despite promising results in lower organisms such as Caenorhabditis elegans (roundworms) and Drosophila melanogaster (fruit flies), overexpressing endogenous antioxidants in mice...didn’t help them live longer. However, the overexpression of particular endogenous antioxidants was sufficient to improve health outcomes in mouse models of myocardial infarction (heart attack), diabetes, stroke, and Alzheimer’s disease (among others) suggesting that strategies designed to increase antioxidant abundance during these disease processes could potentially provide a level of protection in humans" (Ibid.).

However, free radicals are a part of normal cellular metabolism and have many positive roles as well. "Some examples of the positive biological roles of free radicals:

• Are used by the immune system to defend against viruses, bacteria, and fungi.

• Are signaling molecules regulating our physiologic processes, e.g., muscles adaptation to exercise, regulation of blood pressure, and even production of cellular antioxidants.

• Participate in apoptosis, 'programmed cell death,' which lessens the risk of cancer cells' proliferation" (Lightsey 2020 Nov 24. American Council on Science and Health).

Many large clinical trials and retrospective studies of antioxidants have been performed. "Sadly, despite massive efforts involving thousands of patients and millions of dollars in grant money, the outcome of these trails [sic] was emphatically abysmal. As summarized by the National Institutes of Health (NIH), the primary funding agency for much of this work, antioxidant supplementation did not reduce risk of heart attack, stroke, cataracts, and age-dependent cognitive decline. In fact, in two separate studies, exogenous antioxidant supplementation actually increased the incidence of lung and prostate cancer" (Quiles 2018. Op. cit.).

Novella (2016 Jan 27. Science-Based Medicine blog) pointed out that "organisms already possess powerful antioxidants (more powerful than any supplement) that keep the ROS in balance. Evolution is very efficient at optimizing systems. It therefore makes sense that we would have evolved an optimal balance between ROS and antioxidants. If there were a clear health benefit to additional antioxidants, our bodies would just make more."

Murphy (2014. Free Radic Biol Med. 66:20-3) proposed that the negative results in trials are due to the problem of delivering antioxidants to precise locations in sufficiently high amounts. He wrote that "it may be helpful to stop thinking of antioxidant therapy as a branch of nutrition and instead view it as a drug discovery and development program following the same approaches that we use for other new medicines...we need to move away from seeing antioxidants as a general, nonspecific panacea and instead use them to target specific 'druggable' redox processes using the tools of medicinal chemistry and pharmacology."

Shen et al. (2007. Biochem Biophys Res Commun. 362(3):543-5) wrote, "the distribution of exogenous antioxidants is not very selective. As a result, the antioxidants do not always emerge in the 'right' place and at the 'right' time in vivo, which results in the frequent miss between antioxidants and ROS. Second, the in vivo redox status is usually in good balance. The exogenous antioxidants are only expected to exert preventive effects when the balance is broken."

Concerning the use of vitamins C and E for brain health, Spector (2019. Skeptical Inquirer. 43(2):46-50) wrote: "oral megavitamins C and E do not increase brain vitamin C or E much if at all."

Woolston (2007 Mar 5. A palm reading that’s fruitful? Los Angeles Times) reviewed commercial tests for measuring antioxidant levels. Laser scans of the palm might give some indication of the level of carotenoids in the diet, but “Carotenoids are just one part of the antioxidant arsenal...Mail-order urine tests would provide even less complete measures of one’s antioxidant status, says nutrition professor Garry Handelman of the University of Massachusetts...Anyone who eats anything remotely resembling a normal American diet will likely have enough antioxidants to prevent the kind of damage measured by the mail-order tests, Handelman says. Only people with certain serious conditions such as kidney failure or diabetes should expect unusual readings.”

According to the U.S. Department of Agriculture (2012 May 16. Oxygen radical absorbance capacity (ORAC) of selected foods, release 2 (2010)), "There is no evidence that the beneficial effects of polyphenol-rich foods cans be attributed to the antioxidant properties of these foods. The data for antioxidant capacity of foods generated by in vitro (test-tube) methods cannot be extrapolated to in vivo (human) effects and the clinical trials to test benefits of antioxidants have produced mixed results. We know now that antioxidant molecules in food have a wide range of functions, may of which are unrelated to the ability to absorb free radicals. For this reasons, the ORAC table, previously available on this web site has been withdrawn."

Studies of the individual vitamins and other antioxidant supplements are discussed in the section below ("Some items marketed as dietary supplements") (SUPPLEMENTS PART 2 ).

Reviews and major trials of multiple antioxidant vitamins

Athletic performance:

• Mason et al. 2020. Redox Biol. 35:101471 [endurance exercise]: “N-acetyl cysteine may be of benefit over the days prior to an endurance event; while chronic intake of combined 1000 mg vitamin C + vitamin E is not recommended during periods of heavy training associated with adaptations in skeletal muscle. Melatonin, vitamin E and a-lipoic acid appear effective at decreasing markers of exercise-induced oxidative stress. However, evidence on their effects on endurance performance are either lacking or not supportive. Catechins, anthocyanins, coenzyme Q10 and vitamin C may improve vascular function, however, evidence is either limited to specific sub-populations and/or does not translate to improved performance.”

Cancer:

• Bjelakovic et al. 2004. Lancet. 364(9441):1219-28: "We could not find evidence that antioxidant supplements can prevent gastrointestinal cancers; on the contrary, they seem to increase overall mortality." (However, selenium might be protective.)

• Coulter et al. 2006. J Gen Intern Med. 21(7):735-44: "The systematic review of the literature does not support the hypothesis that the use of supplements of vitamin C or vitamin E in the doses tested helps prevent and/or treat cancer in the populations tested."

• Kirsh et al. 2006. J Natl Cancer Inst. 98(4):245-54 [PLCO Trial]: "Our results do not provide strong support for population-wide implementation of high-dose antioxidant supplementation for the prevention of prostate cancer. However, vitamin E supplementation in male smokers and beta-carotene supplementation in men with low dietary beta-carotene intakes were associated with reduced risk of this disease."

• Hercberg et al. 2007. J Nutr. 137(9):2098-105 [Supplementation in Vitamins and Mineral Antioxidants study]: "In women, the incidence of SC [skin cancer] was higher in the antioxidant group...in men, incidence did not differ between the 2 treatment groups."

• Lippman et al. 2009. JAMA. 301(1):39-51 [SELECT]: "Selenium or vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men."

• Gaziano et al. 2009. JAMA. 301(1):52-62 [Physicians' Health Study II]: " In this large, long-term trial of male physicians, neither vitamin E nor C supplementation reduced the risk of prostate or total cancer."

• Lin et al. 2009. J Natl Cancer Inst. 101(1):14-23 [Women's Antioxidant Cardiovascular Study]: "Supplementation with vitamin C, vitamin E, or beta carotene offers no overall benefits in the primary prevention of total cancer incidence or cancer mortality."

• Asgari et al. 2009. Arch Dermatol. 145(8):879-82 [SUVIMAX]: "Antioxidants taken in nutritional doses do not seem to increase melanoma risk."

• Neuhouser et al. 2009. Cancer Epidemiol Biomarkers Prev. 18(8):2202-6 [CARET]: "Neither the CARET nor other supplements were associated with total prostate cancer risk. For aggressive prostate cancer, men in the CARET intervention arm who used additional supplements had a relative risk for aggressive prostate cancer (Gleason ≥7 or stage III/IV) of 1.52...relative to all others."

• Vance et al. 2013. Nutr Cancer. 65(6):793-801: "Different forms of vitamin E appear to exert different effects on prostate cancer, with alpha-tocopherol potentially increasing and gamma-tocopherol potentially decreasing risk of the disease. There is no strong evidence for a beneficial effect of selenium, vitamin C, or beta-carotene, whereas lycopene appears to be negatively associated with risk of the disease. The effect of dietary antioxidants on prostate cancer remains undefined and inconclusive, with different antioxidants affecting prostate cancer risk differentially."

• Wang et al. 2014. Am J Clin Nutr. 100(3):915-23 [Physicians' Health Study II]: "In this large-scale randomized trial in men, vitamin E and C supplementation had no immediate or long-term effects on the risk of total cancers, prostate cancer, or other site-specific cancers."

• Pantavos et al. 2015. Int J Cancer. 136(9):2178-86 [Rotterdam Study]: " These results suggest that high overall dietary antioxidant capacity is associated with a lower risk of breast cancer. Individual effects of dietary carotenoids and dietary flavonoids may be restricted to subgroups such as smokers and elderly."

Cardiovascular disease:

• Heart Protection Study Collaborative Group 2002. Lancet. 360(9326):23-33 [MRC/BHF Heart Protection Study]: "...although this regimen increased blood vitamin concentrations substantially, it did not produce any significant reductions in the 5-year mortality from, or incidence of, any type of vascular disease, cancer, or other major outcome."

• Muntwyler et al. 2002. Arch Intern Med. 162(13):1472-6 [Physicians' Health Study]: "In this large cohort of apparently healthy US male physicians, self-selected supplementation with vitamin E, vitamin C, or multivitamins was not associated with a significant decrease in total CVD [cardiovascular disease] or CHD [coronary heart disease] mortality."

• Cook et al. 2007. Arch Intern Med. 167(15):1610-8 [Women's Antioxidant Cardiovascular Study]: "There were no overall effects of ascorbic acid, vitamin E, or beta carotene on cardiovascular events among women at high risk for CVD."

• Sesso et al. 2008. JAMA. 300(18):2123-33 [Physicians' Health Study II]: "In this large, long-term trial of male physicians, neither vitamin E nor vitamin C supplementation reduced the risk of major cardiovascular events. These data provide no support for the use of these supplements for the prevention of cardiovascular disease in middle-aged and older men."

• Ye et al. 2013. PLoS One. 8(2):e56803: "Antioxidant vitamin supplementation has no effect on the incidence of major cardiovascular events, myocardial infarction, stroke, total death, and cardiac death."

• Wang et al. 2013. Nutrients. 5(8):2969-3004: "Although antioxidant supplement use was reported to have no effect or an adverse effect on cardiovascular events by several large randomized controlled trials, cohort studies still supported the protective effects of dietary antioxidants on preventing CVD."

• Ali-Hassan-Sayegh et al. 2014. Interact Cardiovasc Thorac Surg. 18(5):646-54: "In conclusion, perioperative antioxidant supplementations with NAC [N-acetylcysteine], PUFA [polyunsaturated fatty acids] and vitamin C prevent atrial fibrillation after cardiac surgery. Moreover, PUFA and vitamin C are capable to reduce hospital stay, whereas NAC lacks this capacity."

• Kim et al. 2016. Nutrients. 8(1):15 [NHANES]: "The findings of this study support the hypothesis that an antioxidant-rich diet and intake of supplements are beneficial to reduce CVD risk."

Cognitive function:

• Masaki et al. 2000. Neurology. 54(6):1265-72 [Honolulu-Asia Aging Study]: "These results suggest that vitamin E and C supplements may protect against vascular dementia and may improve cognitive function in late life...No protective effect was found for Alzheimer's dementia."

• Englehart et al. 2002. JAMA. 287(24):3223-9 [Rotterdam Study]: "High dietary intake of vitamin C and vitamin E may lower the risk of Alzheimer disease." No benefit was found for supplements.

• Luchsinger et al. 2003. Arch Neurol. 60(2):203-8 [Washington Heights-Inwood Columbia Aging Project]: "Neither dietary, supplemental, nor total intake of carotenes and vitamins C and E was associated with a decreased risk of AD [Alzheimer's disease] in this study."

• Zandi et al. 2004. Arch Neurol. 61(1):82-8 [Cache County Study]: "Use of vitamin E and vitamin C supplements in combination is associated with reduced prevalence and incidence of AD."

• Devore et al. 2010. Arch Neurol. 67(7):819-25 [Rotterdam Study]: " Higher intake of foods rich in vitamin E may modestly reduce long-term risk of dementia and AD... Dietary intake levels of vitamin C, beta carotene, and flavonoids were not associated with dementia risk."

• Basambombo et al. 2017. Pharmacother. 51(2):118-24: "This analysis suggests that the use of vitamin E and C supplements is associated with a reduced risk of cognitive decline."

• Kryscio et al. 2017. JAMA Neurol. 74(5):567-73 [PREADViSE]: "Neither supplement [vitamin E and selenium] prevented dementia."

Eye health:

• Grover and Samson 2014. Mol Cell Biochem. 388(1-2):173-83: "The literature indicates that antioxidant supplements plus lutein have a reasonable probability of retarding AMD. For glaucoma, such supplements were ineffectual in some studies but useful in others. In some studies, antioxidant rich fruits and vegetables were also useful for protection against glaucoma. For diabetic retinopathy, antioxidant supplements may have a small benefit, if any, but only as an adjunct to glycemic control. In very high-risk premature retinopathy and retinitis pigmentosa, antioxidant supplements may be beneficial but those with excess Vitamin E should be avoided. For cataract, there is no evidence for an advantage of such nutritional supplements. However, lubricant drops containing N-acetylcarnosine may be helpful in initial stages of the disease. For eye infections and other causes of uveitis, antioxidants have not been found useful."

• Christen et al. 2015. JAMA Ophthalmol. 133(1):17-24 [SELECT]: "These data from a large cohort of apparently healthy men indicate that long-term daily supplementation with selenium and/or vitamin E is unlikely to have a large beneficial effect on age-related cataract."

• Evans and Lawrensen 2017. Cochrane Database Syst Rev. CD000253: "Taking vitamin E or beta-carotene supplements will not prevent or delay the onset of AMD [age-related macular degeneration]. The same probably applies to vitamin C and the multivitamin (Centrum Silver) investigated in the one trial reported to date. There is no evidence with respect to other antioxidant supplements, such as lutein and zeaxanthin."

• Evans and Lawrensen 2017. Cochrane Database Syst Rev. CD000254: "People with AMD may experience some delay in progression of the disease with multivitamin antioxidant vitamin and mineral supplementation...Supplements containing lutein and zeaxanthin are heavily marketed for people with age-related macular degeneration but our review shows they may have little or no effect on the progression of AMD."

Mortality:

• Bjelakovic et al. 2012. Cochrane Database Syst Rev. CD007176: " We found no evidence to support antioxidant supplements for primary or secondary prevention. Beta-carotene and vitamin E seem to increase mortality, and so may higher doses of vitamin A. Antioxidant supplements need to be considered as medicinal products and should undergo sufficient evaluation before marketing."

• Bjelakovic et al. 2013. PLoS One. 8(9):e74558: "Beta-carotene and vitamin E in doses higher than the RDA seem to significantly increase mortality, whereas we lack information on vitamin A. Dose of vitamin A was significantly associated with increased mortality in meta-regression. We lack information on doses below the RDA."

• Paganini-Hill et al. 2015. Am J Epidemiol. 181(2):120-6 [Leisure World Cohort Study]: "Neither dietary nor supplemental intake of vitamin A or vitamin C nor supplemental intake of vitamin E was significantly associated with mortality after multivariate adjustment."

Parkinson's disease:

• Zhang et al. 2002. Neurology. 59(8):1161-9 [Nurses' Health Study]: "Neither intake of total vitamins E or C or use of vitamin E or vitamin C supplements or multivitamins was significantly associated with risk of PD [Parkinson's disease]. The risk of PD, however, was significantly reduced among men and women with high intake of dietary vitamin E (from foods only)...The reduction in risk of PD associated with high dietary vitamin E intake suggests that other constituents of foods rich in vitamin E may be protective."

Preeclampsia:

• Rumbold et al. 2006. N Engl J Med. 354(17):1796-806: " Supplementation with vitamins C and E during pregnancy does not reduce the risk of preeclampsia in nulliparous women, the risk of intrauterine growth restriction, or the risk of death or other serious outcomes in their infants."

Quality of life:

• Briançon et al. 2011. Int J Epidemiol. 40(6):1605-16 [SU.VI.MAX trial]: "Long-term supplementation with antioxidant vitamins and minerals had no beneficial effect on HRQoL [health-related quality of life] in this trial."

Stroke:

• Rautiainen et al. 2012. Stroke. 43(2):335-40 [Swedish Mammography Cohort]: " These findings suggest that dietary TAC [total antioxidant capacity] is inversely associated with total stroke among CVD [cardiovascular disease]-free women and hemorrhagic stroke among women with CVD history."

Potential hazards of these antioxidant vitamin combinations (see also individual listings above for toxic effects of megadoses, and individual sections below):

• In a study of smokers in Finland (Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group 1994. N Engl J Med. 330(15):1029-35), beta carotene increased the incidence of lung cancer. The study also suggested an increased risk of stroke from vitamin E. The beta carotene danger to smokers was confirmed in a National Cancer Institute study (which used beta carotene and vitamin E together).

• Brown et al. (2001. N Engl J Med. 345(22):1583-92) found that a combination of antioxidant vitamins plus selenium interfered with the benefits of cholesterol-lowering drugs.

• Because antioxidant vitamins protect against apoptosis, they may interfere with chemotherapy or radiation treatment. (However, some papers indicate that antioxidants can be useful when combined with certain types of chemotherapy. Also, a review by Simone et al. (2007. Altern Ther Health Med. 13(1):22-8) concluded that "non-prescription antioxidants and other nutrients do not interfere with therapeutic modalities for cancer.") Antioxidants may also interfere in other metabolic situations in which oxidizing conditions are required for desirable effects.

• A review on antioxidants noted, concerning their use in fighting oxidative stress, “Antioxidants can protect or increase injury depending on the situation and therefore their use should always be made with a full appreciation of the situation” (Azzi et al. 2004. FEBS Lett. 558(1-3):3-6).

• Studies in mice found that "antioxidants accelerate tumor growth" (Sayin et al. 2014. Sci Transl Med. 6(221):221ra15) and increase the metastasis of melanoma (Le Gal et al. 2015. Sci Transl Med. 7(308):308re8).

Morley (2014. J Am Med Dir Assoc. 15(4):229-31) wrote, "The fact that antioxidant supplements fail to extend life is not surprising. Simply put, free radicals are essential for survival. Free radicals are essential as part of the body’s defense against infections and cancer. In addition, free radicals play an important role as neurotransmitters (eg, nitric oxide) and increasing blood flow (eg, nitric oxide again) and in modulating a variety of signaling pathways. A clear example of the deleterious effect of antioxidants is that when an antioxidant is given before exercise training, it inhibits the increase in endothelial mediated vasodilation, which would normally occur with exercise. Antioxidants also prevent exercise-dependent induction of insulin sensitivity, though this may not be true for alpha-lipoic acid."

Along these lines, "Studies suggest that the use of large doses of antioxidant supplements, especially vitamins C and E, may actually reduce rather than promote some of the beneficial effects of exercise...The preponderance of research to date suggests that exercise-induced reactive oxygen species and nitric oxide are beneficial. These free radicals induce adaptive changes in muscle that lead to greater production of mitochondria and hypertrophy of myofibers. Exposure of cells to high concentrations of various antioxidant supplements (of which vitamins C and/or E have the most evidence) appears to blunt or block cell signaling and thereby inhibit some favorable physiological and physical adaptations to exercise" (NIH Office of Dietary Supplements 2019. Dietary supplements for exercise and athletic performance).

PHYTOCHEMICALS

There is great interest in roles (antioxidant and other) of various plant compounds (phytochemicals) in preventing cancer and other diseases. These include bioflavonoids (such as quercetin and rutin), allicin (in garlic), lutein (in spinach, kale, and other vegetables), lycopene (in tomatoes), genistein (in soybeans), resveratrol (in grapes), anthocyanins (in blueberries), flavonols (in cocoa, chocolate, red wine, and green tea), and sulforaphane (in broccoli). Of particular interest are compounds that can exert estrogen-like effects (phytoestrogens). Among these are isoflavones (such as genistein) and coumestans. See SUPPLEMENTS PART 2 for discussion of the individual compounds, and of soy products.

"In fruits and vegetables, vitamin C contributes only ~14% of the total antioxidant capacity and phenolic phytochemicals such as flavonoids contribute the most. The phenolic compounds that are the major sources of total antioxidant capacity and prevent LDL [low-density lipoprotein] oxidation are quercetin in apples and onions; catechin, procyanidin, quercetin, and kaempferol in grapes and wines; and genistein in soybeans" (Chun et al. 2010. J Nutr. 140(2):317-24).

An alternative view to the antioxidant hypothesis is that some of these compounds are potentially toxic, yet confer advantages by inducing detoxifying enzymes. These in turn help dispose of carcinogens.

Schewe et al. (2008. Arch Biochem Biophys. 476(2):102-6) proposed that “dietary flavonoids may act as antioxidants in vivo in a more broad sense by interfering with prooxidant processes or by inhibition of prooxidant enzymes such as NADPH oxidases...lipoxygenases and myeloperoxidase-mediated modifications of LDL.”

The xanthophylls lutein, zeaxanthin, and meso-zeaxanthin are thought to concentrate in neural tissue, so there is interest in their possible effects on cognitive function.

Reviews:

• Lem et al. 2021. Nutrients. 13(6):1949: "The data suggest that carotenoid vitamin therapy exerts synergic neuroprotective benefits and has the capacity to serve adjunctive therapy in the management of glaucoma."

• Chen et al. 2019. Nutrients. 11(11):2649: "We found that isoflavones reduce hot flashes even accounting for placebo effect, attenuate lumbar spine bone mineral density (BMD) loss, show beneficial effects on systolic blood pressure during early menopause, and improve glycemic control in vitro. There are currently no conclusive benefits of isoflavones on urogenital symptoms and cognition."

REVIEWS AND MAJOR TRIALS OF MULTIPLE SUPPLEMENTS FOR PARTICULAR DISEASES OR CONDITIONS

(see also reviews in next section)

Alzheimer's disease:

• Otaegui-Arrazola et al. 2014. Eur J Nutr. 53(1):1-23: "Data from observational studies point to a protective role for certain nutrients, such as omega-3 fatty acids, antioxidants or B vitamins, and dietary patterns (Mediterranean diet). However, data from randomized controlled trials do not show a consistent effect."

Athletic performance:

• Harty et al. 2018. J Int Soc Sports Nutr. 15(1):41: “In conclusion, it appears that multi-ingredient pre-workout supplements [which typically contain a blend of ingredients such as caffeine, creatine, beta-alanine, amino acids, and nitric oxide agents] have promise as an ergogenic aid for active individuals, though further information is required regarding long-term efficacy and safety in a wider variety of populations. “

Cancer:

• Lawson et al. 2007. J Natl Cancer Inst. 99(10):754-64 [NIH-AARP Diet and Health Study]: "No association was observed between multivitamin use and risk of localized prostate cancer. However, we found an increased risk of advanced and fatal prostate cancers...among men reporting excessive use of multivitamins (more than seven times per week) when compared with never users...The positive associations with excessive multivitamin use were strongest in men with a family history of prostate cancer or who took individual micronutrient supplements, including selenium, beta-carotene, or zinc."

• Zhang et al. 2008. JAMA. 300(17):2012-21 [Women's Antioxidant and Folic Acid Cardiovascular Study]: "Combined folic acid, vitamin B₆, and vitamin B₁₂ treatment had no significant effect on overall risk of total invasive cancer or breast cancer among women during the folic acid fortification era."

• Satia et al. 2008. Epidemiol. 169(7):815-28 [VITAL Study]: "Longer duration of use of individual β-carotene, retinol, and lutein supplements (but not total 10-year average dose) was associated with statistically significantly elevated risk of total lung cancer and histologic cell types...There was little evidence for effect modification by gender or smoking status. Long-term use of individual β-carotene, retinol, and lutein supplements should not be recommended for lung cancer prevention, particularly among smokers."

• Song et al. 2012. J Natl Cancer Inst. 104(20):1562-75 [Women's Antioxidant and Folic Acid Cardiovascular Study]: "Our results indicate no statistically significant effect of combined folic acid, vitamin B₆, and vitamin B₁₂ treatment on colorectal adenoma among women at high risk for cardiovascular disease."

• Harvie 2014. Am Soc Clin Oncol Educ Book. 2014:e478-86: "Large-scale, randomized cancer prevention trials have mainly been negative, with some notable adverse and beneficial effects. For example, these trials showed that beta-carotene increases the risk of lung and stomach cancer, vitamin E increases prostate cancer and colorectal adenoma, and selenium reduces gastric and lung cancer in populations with low selenium levels but increase rates in those with higher levels. Both beta-carotene and vitamin E supplementation increase overall mortality."

• Brasky et al. 2017. J Clin Oncol. 35(30):3440-8: “Use of supplemental vitamins B6, folate, and B12 was not associated with lung cancer risk among women. In contrast, use of vitamin B6 and B12 from individual supplement sources, but not from multivitamins, was associated with a 30% to 40% increase in lung cancer risk among men...This sex- and source-specific association provides further evidence that vitamin B supplements are not chemopreventive for lung cancer and may be harmful.”

Cardiovascular disease:

• Lonn et al. 2006. N Engl J Med. 354(15):1567-77 [HOPE-2]: "Supplements combining folic acid and vitamins B₆ and B₁₂ did not reduce the risk of major cardiovascular events in patients with vascular disease."

• Bønaa et al. 2006. N Engl J Med. 354(15):1578-88 [Norwegian Vitamin Trial]: "Treatment with B vitamins did not lower the risk of recurrent cardiovascular disease after acute myocardial infarction. A harmful effect from combined B vitamin treatment was suggested. Such treatment should therefore not be recommended."

• Loscalzo 2006. N Engl J Med. 354(15):1629-32 [commenting on the two studies above, which were aimed at lowering homocysteine levels]: "the consistency among the results leads to the unequivocal conclusion that there is no clinical benefit of the use of folic acid and vitamin B₁₂ (with or without the addition of vitamin B₆) in patients with established vascular disease."

• Bleys et al 2006. Am J Clin Nutr. 84(4):880-7: "Our meta-analysis showed no evidence of a protective effect of antioxidant or B vitamin supplements on the progression of atherosclerosis, thus providing a mechanistic explanation for their lack of effect on clinical cardiovascular events."

• SEARCH Collaborative Group; Armitage et al. 2010. JAMA. 303(24):2486-94: "Substantial long-term reductions in blood homocysteine levels with folic acid and vitamin B₁₂ supplementation did not have beneficial effects on vascular outcomes but were also not associated with adverse effects on cancer incidence."

• Desai et al. 2014. Clin Cardiol. 37(9):576-81: "Unfortunately, the current evidence suggests no benefit exists with vitamin supplementation in the general US population."

• Writing Group for the AREDS2 Research Group 2014. JAMA Intern Med. 174(5):763-71: "Dietary supplementation of long-chain ω-3 polyunsaturated fatty acids or macular xanthophylls in addition to daily intake of minerals and vitamins did not reduce the risk of CVD in elderly participants with age-related macular degeneration."

• Thaipitakwong and Aramwit 2017. Am J Cardiovasc Drugs. 17(1):27-35: “...some dietary supplements exert protective effects on cardiovascular health beyond lipid-improving activities. These include soy protein, green tea, sesame, probiotics, flaxseed, garlic, red yeast rice, fish oil, and krill oil.”

• Jenkins et al. 2018. J Am Coll Cardiol. 71(22):2570-84: "...systematic reviews and meta-analyses showed generally moderate- or low-quality evidence for preventive benefits (folic acid for total cardiovascular disease, folic acid and B-vitamins for stroke), no effect (multivitamins, vitamins C, D, β-carotene, calcium, and selenium), or increased risk (antioxidant mixtures and niacin [with a statin] for all-cause mortality). Conclusive evidence for the benefit of any supplement across all dietary backgrounds (including deficiency and sufficiency) was not demonstrated; therefore, any benefits seen must be balanced against possible risks."

• Khan et al. 2019. Ann Intern Med. 171(3):190-8: "Reduced salt intake, omega-3 LC-PUFA [long-chain polyunsaturated fatty acid] use, and folate supplementation could reduce risk for some cardiovascular outcomes in adults. Combined calcium plus vitamin D might increase risk for stroke." "Other nutritional supplements, such as vitamin B6, vitamin A, multivitamins, antioxidants, and iron and dietary interventions, such as reduced fat intake, had no significant effect on mortality or cardiovascular disease outcomes (very low- to moderate-certainty evidence)." In commenting on the review, Gavura (2019 Sep 19. Science-Based Medicine blog) wrote, "If dietary supplements or specific dietary approaches had substantial effects on cardiovascular disease, we should have seen them consistently in the medical evidence. We do not. Consequently, it’s reasonable to assume that the overall benefit of individual dietary supplements or dietary interventions for cardiovascular disease has not been demonstrated, and that there is no solid evidence to support their use."

Cognition:

• Forbes 2015. Can Geriatr J. 18(4):231-45: " Omega-3 fatty acids, B vitamins, and vitamin E supplementation did not affect cognition in non-demented middle-aged and older adults."

Depression:

• Sarris et al. 2016. Am J Psychiatry. 173(6):575-87: “Current evidence supports adjunctive use of SAMe, methylfolate, omega-3, and vitamin D with antidepressants to reduce depressive symptoms.”

Dermatology:

• Schlichte et al. 2016. Dermatol Pract Concept. 6(3):23-9: “Based on trials to date, no dietary supplements can be recommended for routine use in the treatment of AD [atopic dermatitis]. However, some promising results have been noted from the use of probiotics and prebiotics taken in combination...Studies of vitamin D have been limited and have produced conflicting results...Very limited data is available on fish oil supplements, while future studies on Chinese herbal medicine would require evaluation of comparable herbs and formulations. Finally, multiple trials of evening primrose oil and borage seed oil have shown improvement similar to placebo, and neither is currently recommended in eczema therapy.”

• Thompson and Kim 2021. J Am Acad Dermatol. 84(4):1042-50: “The most promising evidence exists for the use of nicotinamide in preventing nonmelanoma skin cancers. There is some evidence for the role of vitamin D in decreasing melanoma risk and progression in some individuals and for the photoprotective role of Polypodium, although additional high-quality studies are needed to determine appropriate dosing. Current evidence is insufficient to recommend the use of biotin or zinc supplements in dermatology.”

Diabetes:

• Derosa et al. 2014. Arch Med Sci. 10(2):336-44: “Monounsaturated fatty acids such as olive oil and other vegetable oils are recommended. L-carnitine, α-lipoic acid, berberine and ω-3 fatty acids can be useful supplements.”

• Yan and Khalil 2017. Diabetes Metab Syndr. 11 Suppl 2:S589-95: "No clear evidence supporting the beneficial role of any specific vitamin in the treatment of T2DM [type 2 diabetes mellitus] was found."

Dyslipidemia:

• Hunter and Hegele 2017. Nat Rev Endocrinol. 13(5):278-88: "Those with good evidence for a biochemical effect on plasma lipid levels include soy protein, green tea, plant sterols, probiotic yogurt, marine-derived omega-3 fatty acids and red yeast rice. Other products such as seaweed, berberine, hawthorn and garlic might confer some limited benefit in certain patient groups...Natural health products marketed at individuals with dyslipidaemia, such as policosanol, guggulsterone and resveratrol, have minimal definitive evidence of a biochemical benefit."

Dysmenorrhoea:

• Pattanittum et al. 2016. Cochrane Database Syst Rev. CD002124: "There was no high quality evidence to support the effectiveness of any dietary supplement for dysmenorrhoea, and evidence of safety was lacking. However, for several supplements there was some low quality evidence of effectiveness. Supplements for which there was some very limited evidence to suggest a potential benefit were fenugreek, ginger, valerian, zataria, zinc sulphate, fish oil, and vitamin B1. There was no strong evidence of benefit for melatonin compared to placebo for dysmenorrhoea secondary to endometriosis."

Eye health:

• Christen et al. 2009. Arch Intern Med. 169(4):335-41 [Women's Antioxidant and Folic Acid Cardiovascular Study]: "These randomized trial data from a large cohort of women at high risk of cardiovascular disease indicate that daily supplementation with folic acid, pyridoxine, and cyanocobalamin may reduce the risk of AMD [age-related macular degeneration]."

• Kolber et al. 2013. Can Fam Physician. 59(5):503: "Ocular vitamins only slow visual loss in AMD patients with intermediate and severe retinal findings...Progression to advanced AMD is rare in patients with minimal AMD, and ocular vitamins do not prevent AMD in those without AMD. Components of ocular vitamins are potentially harmful and should be used only in selected patients."

• Evans and Lawrenson 2014. Ophthalmic Physiol Opt. 34(4):390-6: "There is no high quality experimental evidence that nutritional supplementation is beneficial for the primary prevention of AMD. However, people with AMD may benefit from supplementation with antioxidant vitamins. There is currently no evidence to support increasing levels of omega 3 long chain polyunsaturated fatty acids in the diet for the explicit purpose of preventing or slowing the progression of AMD."

• Kohn 2015. J Acad Nutr Diet. 115(9):1548: Summarized results of the Age-Related Eye Disease Studies (AREDS and AREDS2). In the first, "Supplementation with zinc plus the antioxidants significantly reduced the risk of vision loss and the risk of AMD progressing to the advanced stage, but only in the groups that were considered to be at highest risk...The second study (AREDS2) incorporated lutein and zeaxanthin and the n-3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), but a further reduction in the progression of AMD was not realized."

Fertility:

• Kuchakulla et al. 2020. Urology. 136:133-41: “Many male fertility supplements claim to improve fertility; however, their products are rarely backed by evidence and their efficacy remains unproven. Few ingredients used in popular fertility supplements have positive evidence in randomized clinical trials and should therefore be used cautiously.”

Fractures:

• Moyer and U.S. Preventive Services Task Force. 2013. Ann Intern Med. 158(9):691-6: "The USPSTF concludes that the current evidence is insufficient to assess the balance of the benefits and harms of combined vitamin D and calcium supplementation for the primary prevention of fractures in premenopausal women or in men...that the current evidence is insufficient to assess the balance of the benefits and harms of daily supplementation with greater than 400 IU of vitamin D3 and greater than 1000 mg of calcium for the primary prevention of fractures in noninstitutionalized postmenopausal women."

Hypertension:

• Cicero and Colletti 2015. High Blood Press Cardiovasc Prev. 22(3):203-13: "...relatively large body of evidence support the use of potassium, L-arginine, vitamin C, cocoa flavonoids, beetroot juice, coenzyme Q10, controlled-release melatonin, and aged garlic extract."

Inflammatory bowel disease:

• Hur et al. 2012. Nutr Res. 32(11):801-16: "The natural products having anti-IBD actions included phytochemicals, antioxidants, microorganisms, dietary fibers, and lipids. The literature revealed that many of these natural products exert anti-IBD activity by altering cytokine production. Specifically, phytochemicals such as polyphenols or flavonoids are the most abundant, naturally occurring anti-IBD substances. The anti-IBD effects of lipids were primarily related to the n-3 polyunsaturated fatty acids."

• Parian et al. 2015. Nutr Clin Pract. 30(4):551-8: "Several nutraceuticals show promising results for the treatment of inflammatory bowel disease with minimal to no side effects...Prebiotics and probiotics appear to alter the gut microbiome by increasing biodiversity and increasing the production of butyrate, an anti-inflammatory and antineoplastic agent of the gut. Fish oil acts as a direct anti-inflammatory agent as well as an immune regulator. Curcumin and Boswellia both are anti-inflammatory agents that act on a variety of receptors, and vitamin D affects cell growth and immune system regulation."

Menopause-related symptoms:

• Carroll 2006. Am Fam Physician. 73(3):457-64: "Soy isoflavones reduced hot flashes by 9 to 40 percent in some trials, but most trials showed no difference compared with placebo. Black cohosh and red clover also have had inconsistent results, with some trials showing benefit and some no difference compared with placebo...Other agents that have been used to alleviate hot flashes include belladonna/ergotamine tartrate/phenobarbital combination, dong quai, evening primrose oil, gabapentin, ginseng, mirtazapine, trazodone, vitamin E, and wild yam, but few data regarding their effectiveness have been published."

• LeBlanc et al. 2015. Maturitas. 81(3):377-83 [Women's Health Initiative Trial]: "Our data suggest that supplementation with 1000 mg of calcium plus 400 IU of vitamin D does not influence menopause-related symptoms over an average of 5.7 years of follow-up among postmenopausal women with an average age of 64 at the WHI baseline visit."

Metabolic syndrome:

• Sirtori et al. 2017. Ann Med. 49(8):678-97: "Pro- and pre-biotics, that are able to modify intestinal microbiome, reduce absorption of specific nutrients and improve the metabolic handling of energy-rich foods. Finally, specific nutraceuticals have proven to be of benefit, in particular, red-yeast rice, berberine, curcumin as well as vitamin D."

Mortality:

• Mursu et al. 2011. Arch Intern Med. 171(18):1625-33 [Iowa Women's Health Study]: "In older women, several commonly used dietary vitamin and mineral supplements may be associated with increased total mortality risk; this association is strongest with supplemental iron. In contrast to the findings of many studies, calcium is associated with decreased risk." The supplements associated with higher risk were "multivitamins, vitamins B6 and folic acid, and minerals iron, magnesium, zinc and copper." An accompanying commentary (Bjelakovic and Gluud 2011. Arch Intern Med. 171(18):1633-4) noted "We cannot recommend the use of vitamin and mineral supplements as a preventive measure, at least not in a well-nourished population. Those supplements do not replace or add to the benefits of eating fruits and vegetables and may cause unwanted health consequences."

Osteoarthritis:

• Nieves 2013. Osteoporos Int. 24(3):771-86: "Results regarding soy compounds on bone density and bone turnover are inconclusive perhaps due to differences in dose and composition or in study population characteristics. The skeletal benefit of black cohosh and red clover are unknown. Dehydroepiandrosterone (DHEA) use may benefit elderly individuals with low serum dehydroepiandrosterone-sulfate levels, but even in this group, there are inconsistent benefits to bone density (BMD)...The skeletal benefit of flavonoids, carotenoids, omega-3-fatty acids, and vitamins A, C, E and K are limited to observational data or a few clinical trials, in some cases investigating pharmacologic doses. Given limited data, it would be better to get these nutrients from fruits and vegetables. Potassium bicarbonate may improve calcium homeostasis but with little impact on bone loss. High homocysteine may relate to fracture risk, but the skeletal benefit of each B vitamin is unclear. Magnesium supplementation is likely only required in persons with low magnesium levels. Data are very limited for the role of nutritional levels of boron, strontium, silicon and phosphorus in bone health."

Premenstrual syndrome:

• Whelan et al. 2009. Can J Clin Pharmacol. 16(3):e407-29: "Sixty-two herbs, vitamins and minerals were identified for which claims of benefit for PMS were made, with RCT [randomized controlled trial] evidence found for only 10...Data supports the use of calcium for PMS, and suggests that chasteberry and vitamin B6 may be effective. Preliminary data shows some benefit with ginkgo, magnesium pyrrolidone, saffron, St. John's Wort, soy and vitamin E. No evidence of benefit with evening primrose oil or magnesium oxide was found."

Pressure ulcers:

• Langer and Fink 2014. Cochrane Database Syst Rev. CD003216: "There is currently no clear evidence of a benefit associated with nutritional interventions for either the prevention or treatment of pressure ulcers."

Skeletal muscle and exercise:

• Deane et al. 2017. Am J Physiol Endocrinol Metab. 312(4):E282-99: "Regarding novel nutraceuticals, we show that the following ones in particular may have effects in relation to 1) muscle mass/protein metabolism: leucine, hydroxyl β-methylbutyrate, creatine, vitamin-D, ursolic acid, and phosphatidic acid; and 2) exercise performance: (i.e., strength or endurance capacity): hydroxyl β-methylbutyrate, carnitine, creatine, nitrates, and β-alanine."

Stroke:

• Hankey 2012. Lancet Neurol. 11(1):66-81: "Reliable evidence suggests that dietary supplementation with antioxidant vitamins, B vitamins, and calcium does not reduce the risk of stroke."

Tinnitus:

• Coelho et al. 2016. Am J Audiol. 25(3):184-205: “It is likely that some supplements will help with sleep for some patients. However, they are generally not effective, and many produced adverse effects.”

REVIEWS AND MAJOR TRIALS OF MULTIPLE SUPPLEMENTS FOR MULTIPLE OUTCOMES

• Ebbing et al. 2009. JAMA. 302(19):2119-26 [Norwegian Vitamin Trial and Western Norway B Vitamin Intervention Trial]: "Treatment with folic acid plus vitamin B12 was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease in Norway, where there is no folic acid fortification of foods."

• Tice 2010. Arch Intern Med. 170(18):1631-3 [commentary]: "...randomized trials of vitamin therapy with folate, vitamin B₆ (pyridoxine hydrochloride), vitamin B₁₂ (cyanocobalamin), vitamin C, vitamin E (tocopherol compounds), and beta carotene demonstrated that none of these therapies are effective for preventing cardiovascular disease and cancer in the general population."

• Avenell et al. 2012. J Clin Endocrinol Metab. 97(2):614-22 [RECORD Trial]: "Daily vitamin D or calcium supplementation did not affect mortality, vascular disease, cancer mortality, or cancer incidence."

• Prentice et al. 2013. Osteoporos Int. 24(2):567-80 [Women's Health Initiative]: "Though based primarily on a subset analysis, long-term use of calcium and vitamin D appears to confer a reduction that may be substantial in the risk of hip fracture among postmenopausal women." "Supplementation effects were not apparent on the risks of myocardial infarction, coronary heart disease, total heart disease, stroke, overall cardiovascular disease, colorectal cancer, or total mortality, while evidence for a reduction in breast cancer risk and total invasive cancer risk among calcium plus vitamin D users was only suggestive."

• Fortmann et al. 2013. Ann Intern Med. 159(12):824-34: "Limited evidence supports any benefit from vitamin and mineral supplementation for the prevention of cancer or CVD [cardiovascular disease]."

• Schwingshackl et al. 2017. Adv Nutr. 8(1):27-39: "Supplements containing vitamin E...significantly reduced cardiovascular mortality risk, whereas supplements with folic acid reduced the risk of CVD ...Vitamins D, C, and K; selenium; zinc; magnesium; and eicosapentaenoic acid showed no significant risk reduction for any of the outcomes. On the contrary, vitamin A was linked to an increased cancer risk...Supplements with β-carotene showed no significant effect; however, in the subgroup with β-carotene given singly, an increased risk of all-cause mortality by 6%...was observed. Taken together, we found insufficient evidence to support the use of dietary supplements in the primary prevention of cause-specific death, incidence of CVD, and incidence of cancer."

• Marra and Bailey 2018. J Acad Nutr Diet. 118(11):2162-73: "It is the position of the Academy of Nutrition and Dietetics that micronutrient supplements are warranted when requirements are not being met through the diet alone...However, the routine and indiscriminate use of micronutrient supplements for the prevention of chronic disease is not recommended, given the lack of available scientific evidence."