SUPPLEMENTS PART 2

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A SCIENTIFIC LOOK AT ALTERNATIVE MEDICINE

Dietary Supplements

Part 2. Some Items Marketed as Dietary Supplements

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.

CONTENTS OF OTHER PARTS

PART 1 General aspects. Includes overview, regulation and labeling, adverse effects, scientific critique, conventional nutrition, antioxidants, phytochemicals, and reviews and major trials of multiple supplements

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.  Supplements primarily used for weight loss are discussed in the Diets and Weight Loss article.

ALPHABETICAL LIST OF SUPPLEMENTS AND TOPICS

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. 

Acai - "The acai palm tree, native to tropical Central and South America, produces a deep purple fruit. The acai fruit has long been an important food source for indigenous peoples of the Amazon region" (National Center for Complementary and Integrative Health (NCCIH) 2020. Acai).

Promoted for: weight loss, anti-aging, antioxidant

Possible adverse effects: "drinking unprocessed acai juice has been linked to an illness called American trypanosomiasis (also known as Chagas disease). Consuming acai might affect MRI test results" (Ibid.).

Notes: "There’s no definitive scientific evidence based on studies in people to support the use of acai for any health-related purpose" (Ibid.).

Acetyl cysteine - see N-acetyl cysteine

Acidophilus (Lactobacillus acidophilus)

Promoted for: aid digestion, restore healthy balance of microorganisms to digestive tract

Notes: in supplements, milk, yogurt. See also probiotics.

Activated charcoal - "Manufacturers make activated charcoal by heating common charcoal in the presence of a gas. This process causes the charcoal to develop lots of internal spaces or 'pores'" (MedlinePlus 2020. Activated charcoal).

Promoted for: "Activated charcoal is commonly taken by mouth to treat poisonings. It is also used for intestinal gas (flatulence), high cholesterol, hangovers, upset stomach, and bile flow problems (cholestasis) during pregnancy" (Ibid.).

Presumed mechanism of action: chemicals are trapped in the pores of the charcoal

Possible adverse effects: "Activated charcoal is LIKELY SAFE for most adults when taken by mouth, short-term. Taking activated charcoal long-term by mouth is POSSIBLY SAFE. Side effects taking activated charcoal by mouth include constipation and black stools. More serious, but rare, side effects are a slowing or blockage of the intestinal tract, regurgitation into the lungs, and dehydration...Activated charcoal absorbs substances in the stomach and intestines. Taking activated charcoal along with medications taken by mouth can decrease how much medicine your body absorbs, and decrease the effectiveness of your medication" (Ibid.).

Notes: "Activated charcoal is useful for trapping chemicals to stop some types of poisoning when used as part of standard treatment" (Ibid.). Insufficient evidence to rate effectiveness for other uses.

Airborne - a line of products containing vitamins, minerals, and herbs (especially echinacea and ginger)

Promoted for: enhancing immune system, fighting colds

Notes: claims for enhancing the immune system are unsupported. In 2008 the company agreed to pay $23 million in a class action lawsuit regarding false claims concerning prevention and treatment of colds.

Alfalfa

Promoted for: "kidney conditions, bladder and prostate conditions, and to increase urine flow. It is also used for high cholesterol, asthma, osteoarthritis, rheumatoid arthritis, diabetes, upset stomach, and a bleeding disorder called thrombocytopenic purpura. People also take alfalfa as a source of vitamins A, C, E, and K4; and minerals calcium, potassium, phosphorous, and iron" (MedlinePlus 2019. Alfalfa).

Presumed mechanism of action: prevents absorption of cholesterol

Possible adverse effects: "...taking alfalfa seeds long-term is LIKELY UNSAFE. Alfalfa seed products may cause reactions that are similar to the autoimmune disease called lupus erythematosus. Alfalfa might also cause some people's skin to become extra sensitive to the sun" (Ibid.). May decrease effectiveness of warfarin and birth control pills. May interfere with absorption of iron and vitamin E.

Notes: Insufficient evidence to rate effectiveness for any condition.

Algae - see Spirulina

Amino acids (general)

Possible adverse effects: excess of one may interfere with absorption and utilization of others.

Antioxidants - see section on antioxidants in SUPPLEMENTS PART 1, as well as other individual items in this section

Androstenedione - precursor of testosterone and estrogen

Possible adverse effects: Studies found no increase in strength or testosterone in men, but rather increases in estrogen and unfavorable changes in blood lipid profiles. Numerous other side effects and potential risks have been reported.

Notes: in 2004, the FDA ordered companies to stop selling it unless they can prove that it is safe.

Anthocyanins - polyphenols that cause red, blue, and purple colors in some plants

Promoted for: antioxidant effects, prevention of heart disease, improved cholesterol levels, reduction in blood pressure

Review: Zhu et al. 2016. Medicine (Baltimore). 95(15):e3380: "results from this meta-analysis do not favor any clinical efficacy of supplementation with anthocyanins in improving blood pressure."

Apple cider vinegar

Promoted for: "to curb appetite and help weight loss, support healthy blood sugar and cholesterol, aid digestive health, and boost the immune system" (Department of Defense Dietary Supplement Resource 2020. Apple cider vinegar in dietary supplements).

Presumed mechanism of action: effects are attributed to acetic acid.

Possible adverse effects: "low potassium, skin irritation, chemical burns, and possible tooth erosion. In addition, acetic acid in concentrations greater than 20% could be considered 'poisonous'” (Ibid.).

Notes: "So far, however, no research supports any health benefit from ACV as a food or a dietary supplement...ACV dietary supplements are usually sold as a powder or extract in the form of capsule, tablet, gummy, or powder. Some of these supplements also include other plant-based ingredients—such as Garcinia cambogia, ginger, or cayenne" (Ibid.).

Arginine - a nonessential amino acid (considered "conditionally essential," needed in the diet in some circumstances).

Promoted for: enhance “vascular health” and sexual function, stimulate growth hormone release, enhance athletic performance, angina

Presumed mechanism of action: "First, some arginine is converted to nitric oxide, a potent vasodilator that can increase blood flow and the delivery of oxygen and nutrients to skeletal muscle. Second, increased vasodilation can speed up the removal of metabolic waste products related to muscle fatigue, such as lactate and ammonia, that the body produces during exercise. Third, arginine serves as a precursor for the synthesis of creatine, which helps supply muscle with energy for short-term, intense activity. Fourth, arginine may increase the secretion of human growth hormone (HGH), which in turn increases insulin-like growth factor-1 (IGF-1) levels, both of which stimulate muscle growth" (NIH Office of Dietary Supplements 2019. Dietary supplements for exercise and athletic performance).

Possible adverse effects: "abdominal pain, bloating, diarrhea, gout, allergies, worsening of asthma, and low blood pressure...L-arginine can cause an allergic response or make swelling in the airways worse" (MedlinePlus 2020. L-Arginine), can make herpes worse and lower blood pressure, should not be used with cirrhosis or after a recent heart attack, interactions with many medications.

Review: Viribay et al. 2020. Nutrients. 12(5):1300: “Results revealed that Arg supplementation could improve aerobic...and anaerobic...performance tests. In conclusion, acute Arg supplementation protocols to improve aerobic and anaerobic performance should be adjusted to 0.15 g/kg of body weight ingested between 60-90 min before. Moreover, chronic Arg supplementation should include 1.5-2 g/day for 4-7 weeks in order to improve aerobic performance, and 10-12 g/day for 8 weeks to enhance anaerobic performance.”

Notes: Natural Medicines Comprehensive Database rates as "possibly effective" for: angina, erectile dysfunction, hypertension, necrotizing enterocolitis, peripheral arterial disease, and pre-eclampsia; "possibly ineffective" for: chronic kidney disease, prevention of heart attack, high cholesterol, tuberculosis, and wound healing; insufficient evidence for numerous other conditions. "The research to support supplemental arginine as a performance enhancer is limited and conflicting...Arginine supplementation’s ability to enhance strength, improve exercise or athletic performance, or promote muscular recovery after exercise has little scientific support" (Office of Dietary Supplements 2019. Op. cit.).  Zand et al. (2011. Nutr Res. 31(4):262-9) noted that "strategies to restore NO homeostasis by supplementing L-arginine and antioxidants have consistently failed in clinical trials. This is because L-arginine-NO pathway is dysfunctional in patients with endothelial dysfunction."

Ascorbic acid (vitamin C) - see Vitamin C below and section on water-soluble vitamins in SUPPLEMENTS PART 1 

ASEA - a solution of various salts treated to allegedly produce a collection of "redox molecules" surrounded by clusters of water.

Promoted for: enhanced immune function, enhanced cellular communication, antioxidant

Notes: No evidence in support of claims. "Asea, however, is still a fantastical and unbelievable claim supported by nothing but hype, sales copy, and empty promises. It is salt water. The hand-waving nonsense about redox reactions is incoherent technobabble – the very essence of pseudoscience" (Novella 2012. Neurologica blog).

Ashwagandha - see HERBS article

Astragalus - see HERBS  article

Aspartic acid (aspartate) - nonessential amino acid

Promoted for: aiding mineral absorption and athletic performance

Possible adverse effects: “Aspartic acid is LIKELY SAFE when consumed in food amounts. Aspartic acid is POSSIBLY SAFE when taken for a short time. There isn't enough reliable information to know if aspartic acid is safe when used long-term or what the side effects might be” (WebMD 2020. Aspartic acid).

Notes: “Taking D-aspartic acid does not seem to improve muscle strength in trained male athletes. The effect of D-aspartic acid in untrained athletes or women is not known...More evidence is needed to rate the effectiveness of aspartic acid for these [other] uses” (Ibid.).

Barley green, barley grass

Promoted for: source of vitamins, amino acids, minerals (such as calcium), antioxidants, fiber, superoxide dismutase, chlorophyll. Treatment for arthritis, cancer, other diseases. Enhanced athletic performance.

Presumed mechanism of action: calcium promotes healthy bones and teeth. Soluble fiber may absorb cholesterol.

Notes: From young barley plants. See below concerning chlorophyll. “BG promoters exhibit a remarkable ignorance of the biological sciences when describing their product...Nearly all orally ingested enzymes are digested and have no enzymatic activity in the eater...BG promoters falsely claim that superoxide dismutase, an enzyme allegedly present in BG, can survive digestion when taken by mouth” (Jarvis 2000. Barley green. Quackwatch).

Bee pollen (see also propolis, royal jelly)

Promoted for: source of protein, vitamins, minerals. Enhanced stamina and athletic performance. Treatment for hair loss, faulty memory, alcoholism, diabetes, other.

Presumed mechanism of action: Alleged claims include "antioxidant, anti-inflammatory, anticariogenic, antibacterial, antifungicidal, hepatoprotective, anti-atherosclerotic, immune enhancing potential" due to "A variety of primary and secondary metabolites" (Denisow and Denisow-Pietrzyk 2016. J Sci Food Agric. 96(13):4303-9). "Some people say that the enzymes in bee pollen act like medicines. However, these enzymes are broken down in the stomach" (MedlinePlus 2020. Bee pollen).

Possible adverse effects: may cause allergic reactions. Should be avoided in pregnancy and lactation. May be contaminated with insect and rodent debris.

Notes: Nutrient content is small, can be obtained from regular food. Controlled studies show no effect on performance. No evidence for other claimed benefits.

Beetroot or beet juice - rich source of nitrate. See also nitrate and nitric oxide supplements.

Promoted for: enhance exercise and athletic performance; source of vitamins and minerals

Presumed mechanism of action: Ingested nitrate can be converted to nitrite in the saliva and then to nitric oxide in the stomach. This raises the body level of nitric oxide, a vasodilator that increases blood flow to the muscles.

Possible adverse effects: pigments can lead to a red color in the urine, but this is harmless. Nitrate is found in many fruits and vegetables so moderate amounts of beetroot are not a safety concern. However, Zamani et al. (2021. Crit Rev Food Sci Nutr. 61(5):788-804) wrote: “Drinking BRJ may easily increase nitrate intake above the acceptable daily intake, which is known to stimulate the endogenous formation of N-nitroso compounds (NOC's), a class of compounds that is known to be carcinogenic and that may also induce several other adverse effects.”

Notes: "In a position statement, the Academy of Nutrition and Dietetics (AND), the Dietitians of Canada (DoC), and the American College of Sports Medicine (ACSM) state that nitrate sources, such as beetroot juice, enhance exercise tolerance and economy and they improve endurance exercise performance in recreational athletes. The Australian Institute of Sport supports the use of beetroot juice for improving sports performance in suitable athletic competitions under the direction of an expert in sports medicine, but it notes that more research might be required to understand how the supplement should be used for best results" (NIH Office of Dietary Supplements 2019. Dietary supplements for exercise and athletic performance).

Berberine - see HERBS article

Beta-alanine - an amino acid but not one of the ones used to make protein. It is formed naturally in the body and is also present in some foods.

Promoted for: ergogenic aid

Presumed mechanism of action: It is the rate-limiting precursor compound in the formation of carnosine, which helps buffer the muscle from drops in pH during exercise.

Possible adverse effects: paresthesia (a tingling or prickling sensation), itchy skin

Notes: "There is insufficient expert consensus on the value of taking beta-alanine to enhance performance in intense, short-term activities or its safety, particularly when users take it regularly for at least several months" (NIH Office of Dietary Supplements 2019. Dietary supplements for exercise and athletic performance). Some athletic organizations support its use to improve performance. A position stand of the International Society of Sports Nutrition stated that "Daily supplementation with 4 to 6 g of beta-alanine for at least 2 to 4 weeks has been shown to improve exercise performance, with more pronounced effects in open end-point tasks/time trials lasting 1 to 4 min in duration...Beta-alanine attenuates neuromuscular fatigue, particularly in older subjects..." (Trexler et al. 2015. J Int Soc Sports Nutr. 12:30).

Beta carotene a red-orange pigment found in vegetables and fruits. It is the major chemical converted to vitamin A in the body. See discussion of vitamin A in the section on fat-soluble vitamins (SUPPLEMENTS PART 1) and also below. Supplements are promoted for antioxidant effects. Many studies of beta carotene supplements for this purpose have been in combination with other vitamins and are listed in the section on antioxidants (SUPPLEMENTS PART 1).

Possible adverse effects: "Unlike preformed vitamin A, beta-carotene is not known to be teratogenic or lead to reproductive toxicity. And even large supplemental doses (20–30 mg/day) of beta-carotene or diets with high levels of carotenoid-rich food for long periods are not associated with toxicity. The most significant effect of long-term, excess beta-carotene is carotenodermia, a harmless condition in which the skin becomes yellow-orange. This condition can be reversed by discontinuing beta-carotene ingestion. Supplementation with beta-carotene, with or without retinyl palmitate, for 5–8 years has been associated with an increased risk of lung cancer and cardiovascular disease in current and former male and female smokers and in male current and former smokers occupationally exposed to asbestos" (NIH Office of Dietary Supplements 2021. Vitamin A).

Reviews:

• • • Christen et al. 2007. Arch Ophthalmol. 125(3):333-9 [Physicians' Health Study I]: "Long-term supplemental use of beta carotene neither decreases nor increases the risk of ARM [age-related macular degeneration]."

    • Grodstein et al. 2007. Arch Intern Med. 167(20):2184-90 [Physicians’ Health Study II]: “We did not find an impact of short-term beta carotene supplementation on cognitive performance, but long-term supplementation may provide cognitive benefits.”

Beta-hydroxy-beta-methylbutyrate (HMB) - a breakdown product of leucine

Promoted for: decreased protein breakdown in exercise

Presumed mechanism of action: "HMB has important effects in activating protective and anticatabolic mechanisms and, at the same time, it has been shown to directly influence protein synthesis. HMB has been demonstrated to stabilize the muscle cell membrane, to downregulate protein degradation, and to upregulate protein synthesis...It is the active leucine metabolite that consistently activates the mTOR signal pathway...In addition, HMB selectively hinders intracellular inflammation attenuating protein degradation pathways. In fact, HMB inhibits the activation of caspase-8, thereby reducing protein degradation" (Landi et al. 2019. Curr Opin Clin Nutr Metab Care. 22(1):37-43). It may increase the production of mitochondria.

Reviews:

• Molfino et al. 2013. Amino Acids. 45(6):1273-92: "The indexed studies support that HMB is effective in preventing exercise-related muscle damage in healthy trained and untrained individuals as well as muscle loss during chronic diseases."

• Fitschen et al. 2013. Nutrition. 29(1):29-36: "Recently, HMB has been shown to attenuate muscle loss in the elderly and in clinical populations such as patients with AIDS and those with cancer; however, a limited number of studies have investigated this question, with relatively small samples."

• Rahimi et al. 2018. J Am Coll Nutr. 37(7):640-9: "The current evidence revealed a time-dependent effect of HMB in reducing LDH [lactate dehydrogenase] and CK [creatine kinase] serum levels among adults. HMB, therefore, may be seen as a priority muscle damage recovery agent in interventions."

Notes: "There is general agreement that HMB helps speed up recovery from exercise of sufficient amount and intensity to induce skeletal muscle damage...Some studies suggest that HMB use has additional benefits, including an ability to enhance strength, power, skeletal muscle hypertrophy, and aerobic performance in both trained and untrained people." However, "There is no expert consensus on the value of taking HMB for several months or longer or its safety" (NIH Office of Dietary Supplements 2019. Dietary supplements for exercise and athletic performance). Several sports organizations do not include it among their recommended evidence-based ergogenic aids.

Betaine (trimethylglycine) - can participate as a donor of methyl groups in metabolism, but is not required in the diet

Promoted for: treatment of liver disease, ergogenic aid

Proposed mechanism of action: can be used in the conversion of homocysteine to methionine, thus helping restore levels of methionine and S-adenosylmethionine while reducing the level of homocysteine. Also, "Betaine functions as an organic osmolyte to protect cells from stress" (Hanje et al. 2006. Nutr Clin Pract. 21(3):255-72).

Review: Ismaeel 2017. J Strength Cond Res. 31(8):2338-46: "This review highlights the lack of evidence for a clear ergogenic effect of BET supplementation on strength and power performance."

Bioflavonoids - chemicals based on flavone structure, include rutin and some compounds from citrus fruits

Promoted for: antioxidants; treatment or prevention of herpes, cancer, diabetic cataracts, abnormal bleeding, allergies, other.

Notes: Shown not to help resistance to colds and flu.

Biotin - see water-soluble vitamins (SUPPLEMENTS PART 1)

Promoted for: "Signs of biotin deficiency include skin rashes, hair loss, and brittle nails. Therefore, biotin supplements are often promoted for hair, skin, and nail health" (NIH Office of Dietary Supplements 2020. Biotin).

Possible adverse effects: "Very high intakes of biotin may interfere with diagnostic assays that use biotin-streptavidin technology and are commonly used to measure levels of hormones (such as thyroid hormone) and other analytes such as 25-hydroxyvitamin D, producing falsely normal or abnormal results" (Ibid.). Interactions with some medications.

Notes: "Only case reports are available to support claims that biotin supplements can promote hair health, and these reports were only in children" (Ibid.).

Blueberry

Promoted for: aging, cognitive benefits, other

Presumed mechanism of action: "Blueberry, like its relative the cranberry, might help prevent bladder infections by stopping bacteria from attaching to the walls of the bladder. Blueberry fruit is high in fiber which could help normal digestive function. It also contains vitamin C and other antioxidants. Blueberry also contains chemicals that might reduce swelling and destroy cancer cells" (MedlinePlus 2020. Blueberry).

Review: Miraghajani et al. 2020. Complement Ther Med. 53:102389: "Current evidence is insufficient to show a benefit of blueberry supplements in modifying CVD [cardiovascular disease] risk factors across a variety of adult populations."

Notes: According to Natural Medicines Comprehensive Database, evidence generally shows lack of benefit for hypertension and insufficient evidence to rate effectiveness for other benefits.

Blue-green algae - see Spirulina

Boron - see trace minerals (SUPPLEMENTS PART 1). "Boron is not classified as an essential nutrient for humans because research has not yet identified a clear biological function for boron. However, it might have beneficial effects on such functions as reproduction and development, calcium metabolism, bone formation, brain function, insulin and energy substrate metabolism, immunity, and the function of steroid hormones (including vitamin D and estrogen)" (NIH Office of Dietary Supplements 2020. Boron).

Promoted for: "osteoarthritis, bone health, and cancer" (Ibid.).

Notes: evidence in support of these uses is limited.

Branched-chain amino acids (BCAA) - the essential amino acids leucine, isoleucine, and valine

Promoted for: ergogenic aids

Presumed mechanism of action: "Unlike other essential amino acids, the BCAAs can be metabolized by mitochondria in skeletal muscle to provide energy during exercise. The BCAAs, especially leucine, might also stimulate protein synthesis in exercised muscle" (NIH Office of Dietary Supplements 2019. Dietary supplements for exercise and athletic performance).

Notes: "Studies have not consistently shown that taking supplements of BCAAs or any of their three constituent amino acids singly enhances exercise and athletic performance, builds muscle mass, or aids in recovery from exercise. Consuming animal foods containing complete proteins - or a combination of plant-based foods with complementary proteins that together provide all essential amino acids - automatically increases consumption of BCAAs" (Ibid.).

Bromelain - "a group of enzymes found in the fruit and stem of the pineapple plant" (NCCIH 2020. Bromelain).

Promoted for: "reducing pain and swelling, especially of the nose and sinuses, gums, and other body parts after surgery or injury. It is also promoted for osteoarthritis, cancer, digestive problems, and muscle soreness" (Ibid.).

Possible adverse effects: upset stomach, diarrhea, allergic reactions

Notes: "There is not enough high-quality research to say whether bromelain should be recommended for sinusitis" (Ibid.). Conflicting or insufficient evidence in support of other uses.

Caffeine - see also coffee

Promoted for: stimulant, ergogenic aid

Presumed mechanism of action: binds to adenosine receptors, preventing sedative actions of adenosine

Possible adverse effects: "Heavy caffeine use (500 mg/day or more) might diminish rather than enhance physical performance and could also disturb sleep and cause irritability and anxiety. Other adverse effects of caffeine include insomnia, restlessness, nausea, vomiting, tachycardia, and arrhythmia" (NIH Office of Dietary Supplements 2019. Dietary supplements for exercise and athletic performance).

Notes: found naturally in coffee, tea, and several other plant sources. Used as a component of energy drinks and other supplement products. Recognized value in enhancing athletic performance, although sports authorities place limits on the concentrations that can be detected in the urine.

Calcium - see macrominerals (SUPPLEMENTS PART 1

Promoted for: bone health and osteoporosis, prevention of cancer, cardiovascular disease, hypertension, preeclampsia

Presumed mechanism of action: “Calcium makes up much of the structure of bones and teeth and allows normal bodily movement by keeping tissue rigid, strong, and flexible. The small ionized pool of calcium in the circulatory system, extracellular fluid, and various tissues mediates blood vessel contraction and dilation, muscle function, blood clotting, nerve transmission, and hormonal secretion” (NIH Office of Dietary Supplements 2021. Calcium). "Although the exact mechanism by which calcium may help reduce the risk of colorectal cancer is unclear, researchers know that, at the biochemical level, calcium binds to bile acids and fatty acids in the gastrointestinal tract to form insoluble complexes known as calcium soaps. This reduces the ability of the acids (or their metabolites) to damage cells in the lining of the colon and stimulate cell proliferation to repair the damage. Calcium may also act directly to reduce cell proliferation in the lining of the colon or cause proliferating colon cells to undergo differentiation, which, in turn, leads to a reduction in cell proliferation. Calcium also may improve signaling within cells and cause cancer cells to differentiate and/or die" (National Cancer Institute 2009.Calcium and cancer prevention).

Possible adverse effects: "High intake of calcium from supplements, but not foods, has been associated with increased risk of kidney stones" (NIH Office of Dietary Supplements 2020. Calcium). Other possible risks include increased risk of prostate cancer or cardiovascular disease, and interactions with some medications.

Reviews and major trials (see also Reviews and major trials of multiple supplements for specific diseases or conditions, and Reviews and major trials of multiple supplements for multiple outcomes, for trials of calcium combined with vitamin D):

• Prince et al. 2006. Arch Intern Med. 166(8):869-75 [trial of 1460 women over 70]: "Supplementation with calcium carbonate tablets supplying 1200 mg/d is ineffective as a public health intervention in preventing clinical fractures in the ambulatory elderly population owing to poor long-term compliance, but it is effective in those patients who are compliant."

• Warensjö et al. 2011. BMJ. 342:d1473 [Swedish Mammography Cohort]: " Gradual increases in dietary calcium intake above the first quintile in our female population were not associated with further reductions in fracture risk or osteoporosis."

• Xiao et al. 2013. JAMA Intern Med. 173(8):639-46 [National Institutes of Health-AARP diet and health study]: "Our findings suggest that high intake of supplemental calcium is associated with an excess risk of CVD [cardiovascular disease] death in men but not in women."

• Reid 2013. Nutrients. 5(7):2522-9: "we recently conducted a meta-analysis of trials of calcium supplements, and found a 27%-31% increase in risk of myocardial infarction, and a 12%-20% increase in risk of stroke...Thus, the non-skeletal risks of calcium supplements appear to outweigh any skeletal benefits, and are they appear to be unnecessary for the efficacy of other osteoporosis treatments. "

• Rautiainen et al. 2013. Curr Atheroscler Rep. 15(11):362: "To date there is no randomized clinical trial that has been designed specifically to test the effect of calcium supplementation on the risk of CVD [cardiovascular disease] as the primary end point...The average daily intake of calcium is low in many populations; however, the evidence for a potential role of dietary or supplemental calcium in the prevention of CVD remains insufficient and inconclusive."

• Bolland et al. 2015. BMJ. 351:h4580: "Dietary calcium intake is not associated with risk of fracture, and there is no clinical trial evidence that increasing calcium intake from dietary sources prevents fractures. Evidence that calcium supplements prevent fractures is weak and inconsistent."

• Chung et al. 2016. Ann Intern Med. 165(12):856-66: "Calcium intake within tolerable upper intake levels (2000 to 2500 mg/d) is not associated with CVD risk in generally healthy adults."

• Kopecky et al. 2016. Ann Intern Med. 165(12):867-8: "The National Osteoporosis Foundation and American Society for Preventive Cardiology adopt the position that there is moderate-quality evidence (B level) that calcium with or without vitamin D intake from food or supplements has no relationship (beneficial or harmful) to the risk for cardiovascular and cerebrovascular disease, mortality, or all-cause mortality in generally healthy adults at this time."

• Myung et al. 2021. Nutrients. 13(2):368: “The current meta-analysis found that calcium supplements increased a risk of CVD by about 15% in healthy postmenopausal women.”

• Michos et al. 2021. J Am Coll Cardiol. 77(4):437-49: "...some (but not all) observational and RCT studies of calcium supplementation have suggested potential for cardiovascular harm. Therefore, calcium supplementation should be used cautiously, striving for recommended intake of calcium predominantly from food sources."

Notes: "The results of epidemiologic studies regarding the relationship between calcium intake and colorectal cancer risk have not always been consistent...The results of some studies suggest that a high calcium intake may decrease the risk of one or more types of cancer, whereas other studies suggest that a high calcium intake may actually increase the risk of prostate cancer" (National Cancer Institute 2009. Calcium and cancer prevention). "Although the preponderance of evidence does not support cardiovascular adverse effects, dietary sources of calcium are preferable to supplements for other reasons" (such as the risk of kidney stones) (Margolis and Manson 2016. Ann Intern Med. 165(12):884-5).

Cannabinoids, cannabidiol (CBD) - "The word 'cannabis' refers to all products derived from the plant Cannabis sativa...Cannabinoids are a group of substances found in the cannabis plant...The main cannabinoids are THC [tetrahydrocannabinol] and cannabidiol (CBD)...The FDA has not approved the cannabis plant for any medical use. However, the FDA has approved several drugs that contain individual cannabinoids" (NCCIH 2019. Cannabis (Marijuana) and Cannabinoids: What You Need To Know).

Promoted for: pain, epilepsy, nausea, glaucoma, cancer, heart disease, hypertension, Alzheimer's disease, reducing opioid addiction, other

Possible adverse effects: "CBD has the potential to harm you, and harm can happen even before you become aware of it.

• CBD can cause liver injury.

• CBD can affect how other drugs you are taking work, potentially causing serious side effects.

• Use of CBD with alcohol or other drugs that slow brain activity, such as those used to treat anxiety, panic, stress, or sleep disorders, increases the risk of sedation and drowsiness, which can lead to injuries.

• Male reproductive toxicity, or damage to fertility in males or male offspring of women who have been exposed, has been reported in studies of animals exposed to CBD.

"CBD can cause side effects that you might notice. These side effects should improve when CBD is stopped or when the amount used is reduced.

• Changes in alertness, most commonly experienced as somnolence (drowsiness or sleepiness).

• Gastrointestinal distress, most commonly experienced as diarrhea and/or decreased appetite.

• Changes in mood, most commonly experienced as irritability and agitation" (FDA 2020. What you need to know (and what we’re working to find out) about products containing cannabis or cannabis-derived compounds, including CBD).

Notes: "The FDA has determined that products containing THC or CBD cannot be sold legally as dietary supplements. Foods to which THC or CBD has been added cannot be sold legally in interstate commerce. Whether they can be sold legally within a state depends on that state’s laws and regulations...Drugs containing cannabinoids may be helpful in treating certain rare forms of epilepsy, nausea and vomiting associated with cancer chemotherapy, and loss of appetite and weight loss associated with HIV/AIDS. In addition, some evidence suggests modest benefits of cannabis or cannabinoids for chronic pain and multiple sclerosis symptoms. Cannabis isn’t helpful for glaucoma. Research on cannabis or cannabinoids for other conditions is in its early stages" (NCCIH 2019. Op. cit.). Novella (2020 Sep 30. Science-Based Medicine blog) wrote, "The existing evidence is showing that there are serious drug-drug interaction (mostly because of changes to liver enzymes), and there are potentially serious side effects in certain populations. In addition, beneficial effects are mostly small and/or dubious." In 2020 the Food and Drug Administration and the Federal Trade Commission took action against promoters of CBD products for prevention or treatment of a variety of serious conditions.

Capsicum - a genus of plant including bell peppers and chili peppers. Capsaicin is the chemical contained in capsicum, responsible for the burning sensation.

Promoted for: "rheumatoid arthritis (RA), osteoarthritis, and other painful conditions. It is also used for digestion problems, conditions of the heart and blood vessels, and many other conditions" (MedlinePlus 2020. Capsicum). However, some of these are topical applications, which are not addressed here.

Possible adverse effects when taken by mouth: "Capsicum is LIKELY SAFE when consumed in amounts typically found in food. Capsicum is POSSIBLY SAFE when taken by mouth as medicine, short-term, Side effects can include stomach irritation and upset, sweating, flushing, and runny nose. Capsicum is POSSIBLY UNSAFE to take by mouth in large doses or for long periods of time. In rare cases, this can lead to more serious side effects like liver or kidney damage, as well as severe spikes in blood pressure" (Ibid.).

Notes: insufficient evidence to rate effectiveness of any non-topical use.

Cardamom

Review: Shekarchizadeh-Esfahani et al. 2020. Phytother Res. 34(3):475-85: "Meta-analysis of data from five eligible RCTs [randomized controlled trials] showed that cardamom supplementation did not significantly change the concentrations of total cholesterol...low-density lipoprotein cholesterol...or high-density lipoprotein cholesterol...However, a significant reduction was observed in serum triglyceride."

Carnitine - part of normal human metabolism but not required in diet. "Carnitine occurs in two forms, known as D and L, that are mirror images (isomers) of each other. Only L-carnitine is active in the body and is the form found in food" (NIH Office of Dietary Supplements 2017. Carnitine). May be provided as an ester such as acetyl-L-carnitine or propionyl-L-carnitine.

Promoted for: weight control and athletic performance, to prevent heart disease and aging, cognitive performance, claudication, diabetes

Proposed mechanism of action: carnitine enables fatty acids to enter the mitochondria, where they can be oxidized to provide cellular energy.

Possible adverse effects: deficiency of L-carnitine if D-carnitine also taken. "At doses of approximately 3 g/day, carnitine supplements can cause nausea, vomiting, abdominal cramps, diarrhea, and a 'fishy' body odor. Rarer side effects include muscle weakness in uremic patients and seizures in those with seizure disorders. Some research indicates that intestinal bacteria metabolize carnitine to form a substance called TMAO that might increase the risk of cardiovascular disease. This effect appears to be more pronounced in people who consume meat than in vegans or vegetarians" (Ibid.). Interactions with some antibiotics.

Reviews:

• Marx et al. 2017. Nutrients. 9(11):1224: "Results from studies with lower risk of bias do not support the use of carnitine supplementation for cancer-related fatigue."

• Askarpour et al. 2019. J Hum Hypertens. 33(10):725-34: "L-carnitine supplementation decreased DBP [diastolic blood pressure]...without changing SBP [systolic blood pressure] levels..."

• Askarpour et al. 2020. Arch Med Res. 51(1):82-94: "L-carnitine supplementation showed beneficial hepato-protective effects on circulating liver enzymes."

• Asadi et al. 2020. Clin Nutr. 39(1):110-22: “This meta-analysis showed that l-carnitine supplementation could improve lipid profile levels, particularly in doses more than 1500 mg/day.”

• Choi et al. 2020. Nutrients. 12(9):2795: “ In conclusion, L-carnitine supplementation is correlated with a significant reduction of WC [waist circumference] and BP [blood pressure]. A dose of 1-3 g/d could improve the biomarkers of MetSyn [metabolic syndrome] by reducing FBS [fasting blood sugar] and TG [triglyceride] and increasing HDLc [high-density lipoprotein cholesterol].”

Notes: "...twenty years of research finds no consistent evidence that carnitine supplements can improve exercise or physical performance in healthy subjects" (NIH-ODS 2017. Op. cit.). Meta-analyses support some benefits for cognitive deterioration in older adults and Alzheimer's disease; for reduction of mortality following myocardial infarction but not risk of heart failure or reoccurrence; increased walking distance in patients with claudication. Preliminary research suggests benefits in diabetes and for HIV-infected individuals.

Carnosine - a dipeptide of beta-alanine and histidine. Found naturally in the body and also in meat and fish.

Promoted for: numerous conditions including Alzheimer's disease, autism, diabetes, cancer, hypertension, kidney problems, cataracts, enhanced immunity

Presumed mechanism of action: antioxidant, reduced inflammation

Review: Peng et al. 2020. Complement Ther Med. 48:102241: "Carnosine supplementation results in a decrease in HbA1C [hemoglobin A1C] , but elicits no effect on HOMA-IR [Homeostatic Model Assessment for Insulin Resistance], Cholesterol, fasting blood sugar, TG [triglycerides] and HDL-C [high-density lipoprotein cholesterol]."

Catalase - see superoxide dismutase

Chaga tea - tea made from the chaga mushroom, Inonotus obliquus, a parasite of birch and some other trees.

Promoted for: "It is thought to boost immunity (which you can’t do) and improve overall health. It has also been used for cancer, diabetes, tuberculosis, digestive diseases, and heart disease. It is said to provide a boost of energy" (Hall 2020 Apr 28. Science-Based Medicine blog).

Presumed mechanism of action: antioxidant effects, reduce inflammation, promote formation of beneficial cytokines and inhibit formation of harmful cytokines

Possible adverse effects: "It contains high levels of oxalates and is contraindicated in people with kidney disease or who are at risk of kidney stones. Its safety in pregnancy and breastfeeding is not known. It may interfere with blood clotting and should be used with caution in patients on blood thinners. It might cause hypoglycemia in patients who are being treated for diabetes" (Ibid.).

Notes: "there is little or no scientific evidence that it has any health benefits for humans” (Ibid.).

Cherry - see tart or sour cherry

Chlorella - “Chlorella is a type of algae that grows in fresh water. The whole plant is used to make nutritional supplements and medicine. Most of the chlorella that is available in the U.S. is grown in Japan or Taiwan. It is processed and made into tablets and liquid extracts. These extracts contain ‘chlorella growth factor,’ which is described as a water-soluble extract of chlorella containing chemicals including amino acids, peptides, proteins, vitamins, sugars, and nucleic acids” (WebMD 2020. Chlorella).

Promoted for: boosting immunity, preventing cancer, anti-aging effects, hypertension, reduction of cholesterol, fibromyalgia, premenstrual syndrome, provide iron in pregnancy, depression, other

Proposed mechanism of action: provision of various nutrients, including vitamins, minerals (including iron), omega-3 fatty acids, and carotenoids. Antioxidant effects; conversion of carotenes to vitamin A

Possible adverse effects: “Chlorella is LIKELY SAFE when taken by mouth, short-term (up to 29 weeks). The most common side effects include diarrhea, nausea, gas (flatulence), green discoloration of the stools, and stomach cramping, especially in the two weeks of use. Chlorella can cause skin to become extra sensitive to the sun” (Ibid.).

Notes: “Be aware that chlorella products can vary significantly depending on the way ‘the crop’ used to make them was cultivated, harvested, and processed. Investigators have found that dried preparation of chlorella can contain from 7% to 88% protein, 6% to 38% carbohydrate, and 7% to 75% fat...Early research shows that taking chlorella during pregnancy does not reduce the risk of high blood pressure.” (Ibid.). Insufficient evidence of effectiveness for other purposes.

Chlorogenic acid - "The term 'chlorogenic acids' refers to a related polyphenol family of esters, including hydroxycinnamic acids (caffeic acid, ferulic acid and p-coumaric acid) with quinic acid. Despite the 'chloro' of the name, chlorogenic acids contain no chlorine." Rather, the name refers to "the green color produced when chlorogenic acids are oxidized" (Wikipedia 2021. Chlorogenic acid). The compounds are abundant in coffee and are also found in many other plants. The term "chlorogenic acid" is applied to a specific compound in this group, 5-O-caffeoylquinic acid (5-CQA) (also referred to as 3-CQA in an older nomenclature).

Promoted for: "hepatoprotective, cardioprotective, anti-inflammatory, antipyretic, neuroprotective, anti-obesity, antiviral, anti-microbial, anti-hypertension, free radicals scavenger and a central nervous system stimulator" (Ibid.).; cognitive benefits, metabolic syndrome

Presumed mechanism of action: protection against oxidative stress, promotion of neural differentiation. "CGAs have been postulated to decrease glucose absorption in the intestines through inhibition of glucose 6 phosphatase and decreasing the sodium gradient of apical cells" (Onakpoya et al. 2015. J Hum Hypertens. 29(2):77-81). “CGA protects vascular health by inhibiting ED [endothelial dysfunction]. Several mechanisms explain its effects on LPC [lysophosphatidylcholine] injury and atherosclerosis, modulation of dual PPAR α/γ agonist, AMPK phosphorylation, adiponectin, and adiponectin receptors. It plays a role in reducing proinflammatory cytokine concentration that contribute to atherosclerosis development and progression. Furthermore, it suppresses the expression of E-selectin, VCAM-1, and ICAM-1, as well as decreases HOCl-induced oxidative damage in endothelial cells. In addition, CGA induces hemeoxygenase-1 and antiplatelet activity through thromboxane A2 (TXA2) reduction, and attenuates ROS [reactive oxygen species] by decreasing the production of NAD(P)H-dependent superoxide. Furthermore, it inhibits the activity of ACE [angiotensin-converting enzyme] and the proliferation of smooth muscle cells. Finally, it has been shown to block the HIF-1a/AKT signalling pathway, which plays a crucial role in the activation of VEGF [vascular endothelial growth factor] and angiogenesis” (Lukitasari et al. 2020. F1000Res. 9:1462).

Review: Onkpoya et al. 2015. Op. cit. "The evidence from published RCTs suggests that CGA intake causes statistically significant reductions in systolic and diastolic blood pressures. The size of the effect is moderate and the clinical relevance is uncertain. Few clinical trials have been conducted; they vary in design and methodology and are all confined to Asian population."

Chlorophyll -  a group of pigments that enable plants to absorb and utilize solar energy.

Promoted for: treatment for ulcers, hypertension, allergies, infections, other

Notes: No role in human metabolism. While chlorophyll is chemically similar to heme, it is not be converted to heme. It is digested, not absorbed intact (though there may be some uptake of digestion products).

Chocolate

Promoted for: "Historically, cocoa products have been used as antidiarrheals, antiseptics, diuretics, and parasiticides. In recent years, dark chocolate has been recognized as a significant source of antioxidant polyphenol compounds, which have been suggested to have beneficial effects for many diseases, including coronary artery disease, hypercholesterolemia, hypertension, skin conditions, and vascular disorders" (Haber and Gallus 2012. Am J Health Syst Pharm. 69(15):1287-8, 1290, 1292-3).

Presumed mechanism of action: "Cocoa flavonoids, found in the highest concentrations in dark chocolate, exhibit antioxidative and cardioprotective properties, inhibit platelet activity, and activate endothelial nitric oxide synthase. Although the exact mechanism is not clear, results from mechanistic and clinical studies suggest that the blood-pressure-lowering effects of dark chocolate may be due to activation of endothelial nitric oxide synthase, which results in arterial vasodilation" (Ibid.). Regulation of interleukins and nuclear factor-κB have been proposed.

Possible adverse effects: "Due to the caffeine content of chocolate, significant adverse effects such as tachyarrhythmias and sleep disturbances may occur when excessive doses of chocolate are consumed. It has been suggested that chocolate may raise blood glucose levels and cause altered bowel habits, bloating, and nausea...Patients with an allergy or hypersensitivity to chocolate, cocoa, or any of its components should not consume dark chocolate. Dark chocolate may be a trigger for migraine headache, but this effect was not demonstrated in all trials...The caffeine in chocolate may theoretically contribute to interactions with medications, though additive effects from other sources would likely need to be involved to be clinically evident" (Ibid.).

Reviews and major trials:

• Jansky et al. 2009. J Intern Med. 266(3):248-57 [Stockholm Heart Epidemiology Program]: "Chocolate consumption was associated with lower cardiac mortality in a dose dependent manner in patients free of diabetes surviving their first AMI [acute myocardial infaction]."

• Haber and Gallus 2012. Op. cit.: "Polyphenols in dark chocolate may lower blood pressure in patients with hypertension, but trials have found mixed results."

Choline - see section on water-soluble vitamins (SUPPLEMENTS PART 1)

Promoted for: improve memory, prevent aging, protect liver, reduce cholesterol, ergogenic aid, cardiovascular benefits, neurological disorders, nonalcoholic fatty liver disease (NAFLD).

Presumed mechanism of action: "choline might protect cardiovascular health by reducing blood pressure, altering lipid profiles, and reducing levels of plasma homocysteine" (NIH Office of Dietary Supplements 2020. Choline). As a precursor to acetylcholine and phosphatidylcholine, "it might help support the structural integrity of neurons and thus might promote cognitive function in elderly adults" (Ibid.). Phosphatidylcholine is needed to transport lipids from the liver, and thus choline might help with NAFLD.

Possible adverse effects: "High intakes of choline are associated with a fishy body odor, vomiting, excessive sweating and salivation, hypotension, and liver toxicity" (Ibid.). Similarly to carnitine (see above), choline might be converted by intestinal bacteria to the harmful compound trimethylamine-N-oxide (TMAO).

Notes: "Despite the hypothesis that choline might affect heart health, several large observational studies have found no significant associations between choline intakes and cardiovascular or peripheral artery disease risk" (Ibid.). Some studies support benefits in cognitive performance. Only limited data concerning NAFLD.

Chondroitin - see glucosamine

Chromium - see trace minerals (SUPPLEMENTS PART 1)

Promoted for: Conditions in which chromium might have beneficial effects include "impaired glucose tolerance and diabetes, metabolic syndrome, polycystic ovary syndrome, dyslipidemia, and weight and lean body mass" (NIH Office of Dietary Supplements 2020. Chromium).

Proposed mechanism of action: "Chromium might play a role in carbohydrate, lipid, and protein metabolism by potentiating insulin action. Although the precise mechanism for this activity has not been identified, scientists have proposed that chromium binds to an oligopeptide to form chromodulin, a low-molecular-weight, chromium-binding substance that binds to and activates the insulin receptor to promote insulin action. Chromium might also have antioxidant effects...Because chromium might amplify insulin action, some scientists have proposed that chromium supplementation could reduce the amount of glucose converted to fat and increase protein synthesis and, hence, muscle mass" (Ibid.).

Possible adverse effects: "According to isolated case reports, chromium supplements might cause weight loss, anemia, thrombocytopenia, liver dysfunction, renal failure, rhabdomyolysis, dermatitis, and hypoglycemia...Several types of medications have the potential to interact with chromium supplements."

Reviews:

• Althuis et al. 2002. J Clin Nutr. 76(1):148-55: "Data from RCTs [randomized controlled trials] show no effect of chromium on glucose or insulin concentrations in nondiabetic subjects. The data for persons with diabetes are inconclusive."

• Balk et al. 2007. Diabetes Care. 30(8):2154-63: "No significant effect of chromium on lipid or glucose metabolism was found in people without diabetes. Chromium supplementation significantly improved glycemia among patients with diabetes"; however, "Larger effects were more commonly observed in poor-quality studies. The evidence was limited by poor study quality, heterogeneity in methodology and results, and a lack of consensus on assessment of chromium status."

• Suksomboon et al. 2015. J Clin Pharm Ther. 39(3):292-306: "The available evidence suggests favourable effects of chromium supplementation on glycaemic control in patients with diabetes. Chromium monosupplement may additionally improve triglycerides and HDL-C [high-density lipoprotein cholesterol] levels. Chromium supplementation at usual doses does not increase the risk of adverse events compared with placebo."

• McIver et al. 2015. J Nutr. 145(12):2675-82: "The odds of having T2D [type 2 diabetes] were lower in those who, in the previous 30 d, had consumed supplements containing chromium."

• Costello et al. 2016. Nutr Rev. 74(7):455-68: "On the basis of the low strength of existing evidence, chromium supplements have limited effectiveness, and there is little rationale to recommend their use for glycemic control in patients with existing T2DM [type 2 diabetes mellitus]."

• Lari et al. 2021. High Blood Press Cardiovasc Prev. 28(4):333-42: “The current meta-analysis, indicated that supplementation with chromium significantly decrease SBP [systolic blood pressure] and DBP [diastolic blood pressure].”

• Asbaghi et al. 2021. Complement Ther Med. 60:102755: "The present systematic review and meta-analysis shows that supplementation with chromium at dose of 200-1000 µg/day may reduce DBP and MDA [malondialdehyde] in T2DM patients."

Notes: "recent research has suggested that although chromium might have benefits at pharmacologic amounts (e.g., in the hundreds of mcg), it is not an essential mineral because an absence or deficiency of chromium does not produce abnormalities that can be reversed with the addition of chromium" (NIH ODS 2020. Chromium). Although the dietary requirement not known, it has been alleged by promoters that 90% of Americans are deficient. However, deficiency is difficult to detect, and is thought to be unlikely; the typical American diet meets or exceeds the AI. Supplements are often sold as chromium picolinate; picolinate is an organic molecule to complex the chromium and aid its absorption. It is controversial whether picolinate is toxic. The American Diabetes Association 2015 position statement concluded that "evidence is insufficient to support the routine use of supplements containing chromium and other micronutrients for glycemic control in people with diabetes" (Ibid.).

"Overall, limited research suggests that chromium supplements do not significantly benefit people with metabolic syndrome...Overall, the evidence on whether chromium supplementation reduces the risk of PCOS [polycystic ovary syndrome] or is beneficial for women with this condition is mixed, making it difficult to draw firm conclusions...meta-analyses examining the effects of chromium supplementation in people with diabetes and PCOS have shown no significant changes in total cholesterol and LDL cholesterol levels. However, some have shown that chromium supplementation increases HDL cholesterol levels by 1.73–4.64 mg/dL and decreases triglyceride levels by 11.71–26.57 mg/dL...research suggests that supplementation with chromium, mainly in the form chromium picolinate, reduces body weight and body fat percentage to a very small, but statistically significant, extent. However, these effects have little clinical significance" (Ibid.)

The Federal Trade Commission in 1997 ordered companies to stop making claims that chromium "reduces body fat, causes body mass loss without exercise, and increases muscle mass," but decades later "continues to write letters requesting a halt to these and related claims. During the last 2 decades, the scientific support for most of these claims has completely eroded" (Vincent 2017.  J Nutr. 147(12):2212-9). Meta-analyses showing statistically significant but clinically insignificant effects of chromium on body mass and muscle development are heavily influenced by studies funded by a supplier of chromium picolinate. "...Chromium nutritional supplements are now primarily marketed for potential beneficial effects associated with glucose metabolism and diabetes. However, clinical studies of chromium supplements have failed to unambiguously establish the generation of beneficial effects in diabetic or healthy subjects, in stark contrast to studies with rodent models" (Ibid.).

Cinnamon - "Used as a spice for thousands of years, cinnamon comes from the bark of various species of cinnamon trees. The leaves, flowers, fruits, and roots of cinnamon trees have also been used in cooking and for medicinal purposes. There are differences in the chemical composition of cinnamon products produced from different species or parts of cinnamon trees" (NCCIH 2020. Cinnamon).

Promoted for: "cinnamon is promoted as a dietary supplement for diabetes or for irritable bowel syndrome or other gastrointestinal problems, as well as other conditions" (Ibid.); the latter include hypertension, toothache, fever, colds, headache, and cancer.

Presumed mechanism of action: The most important components are cinnamaldehyd and cinnamic acid. However, a hydroxychalcone has been proposed to be important in affecting insulin action. Actions of cinnamon are thought to include stimulation of insulin release, improved sensitivity to insulin, activation of insulin receptor kinase, and activation of glycogen synthase; "antitumor, antioxidant, immunomodulatory, and anti-diabetic and lipid-lowering properties" (Jamali et al. 2020. Complement Ther Med. 55:102571). The mechanisms concerning "cardiometabolic disorders are still unknown, but it might be related to its effects on CRP [C-reactive protein], IL-6 [interleukin-6], MDA [malondialdehyde], and total antioxidant capacity (TAC), which are biomarkers of inflammation and oxidative stress" (Zhu et al. 2020. Complement Ther Med. 53:102517).

Possible adverse effects: "Use in larger amounts or for long periods of time is sometimes associated with side effects, most commonly gastrointestinal problems or allergic reactions. Cassia cinnamon contains a chemical called coumarin, which can be harmful to the liver. Some cassia cinnamon products contain high levels of this substance...prolonged use of cassia cinnamon could be an issue for sensitive people, such as those with liver disease" (Ibid.).

Reviews:

• Costello et al. 2016. J Acad Nutr Diet. 116(11):1794-1802: "We conclude that the evidence to date does not suggest that the addition of a cinnamon supplement achieve hypoglycemic treatment goals nor cause a reliable and clinically significant drop in FPG [fasting plasma glucose] or HbA1c [hemoglobin A1c] in patients with T2DM [type 2 diabetes mellitus].

• Namazi et al. 2019. Complement Ther Med. 43:92-101: "Supplementation with cinnamon can reduce serum levels of glucose with no changes in other glycemic parameters and anthropometric indices. However, due to high heterogeneity findings should be interpreted with great caution."

• Zhu et al. 2020. Op. cit.: "Cinnamon supplementation may be an adjuvant for reducing inflammation and oxidative stress levels in humans."

• Jamali et al. 2020. Op. cit.: "Cinnamon supplementation significantly decreased serum TG [triglyceride], TC [total cholesterol], and LDL-C [low-density lipoprotein cholesterol] concentrations, but did not change HDL-C [high-density lipoprotein cholesterol] levels, in patients with type 2 diabetes."

• Shekarchizadeh-Esfahani et al. 2021. Complement Ther Med. 58:102699: “In summary, cinnamon supplementation had no significant effect on liver enzymes in adults. However, the effect of cinnamon on ALT [alanine aminotransferase] levels was significant at the dosages of <1500 mg/day, in trials lasting>12 weeks, and in trials conducted of both gender.”

• Ghavami et al. 2021. Endocr Metab Immune Disord Drug Targets. 21(5):956-65: "Our findings revealed that cinnamon supplementation has favorable effects on DBP [diastolic blood pressure] although results of SBP [systolic blood pressure] were not the same."

Notes: "There have been many studies of cinnamon, especially for diabetes. However, the results of the studies are difficult to interpret because it’s often unclear what type of cinnamon and what part of the plant were used...Studies done in people don’t clearly support using cinnamon for any health condition. A 2019 review of 18 studies of cinnamon supplementation in people with diabetes suggested that cinnamon could reduce blood sugar but didn’t have a significant effect on hemoglobin A1C, which reflects blood sugar levels over a longer period of time...It’s uncertain whether cinnamon is helpful for weight loss or for controlling blood levels of cholesterol and related lipids. There’s not enough evidence to show whether cinnamon is helpful for irritable bowel syndrome" (NCCIH 2020. Cinnamon). Gavura (2012, reposted 2019 Jun 27. Science-Based Medicine blog) wrote: "Cinnamon’s effectiveness as a treatment for diabetes has not been established. A prescription drug as ineffective as cinnamon likely wouldn’t pass FDA muster. Existing drug treatments for diabetes, on the other hand, are cheap, effective, and generally well tolerated. Compared to drug therapy, we don’t know if cinnamon can reduce the risk of mortality due to diabetes, or the progression to any of the other serious outcomes of diabetes."

Citrulline - a compound found in normal human metabolism (part of the urea cycle). It is present in high levels in watermelon.

Promoted for: ergogenic aid

Presumed mechanism of action: since arginine is another member of the urea cycle, citrulline can lead to production of arginine. "The subsequent conversion of arginine to nitric oxide, a potent dilator of blood vessels, might be the mechanism by which citrulline could serve as an ergogenic aid. In fact, consumption of citrulline might be a more efficient way to raise blood arginine levels than consumption of arginine because more citrulline is absorbed from the gut than arginine. Most studies have used citrulline malate, a combination of citrulline with malic acid (a constituent in many fruits that is also produced endogenously), because malate, an intermediate in the Krebs cycle, might enhance energy production" (NIH Office of Dietary Supplements 2019. Dietary supplements for exercise and athletic performance). Effects on calcium in the sarcoplasmic reticulum and glucose uptake have also been proposed.

Reviews:

• Trexler et al. 2019. Sports Med. 49(5):707-18 [high-intensity strength and power performance]: "  The effect size was small (0.20), and confidence intervals for each individual study crossed the line of null effect. However, the results may be relevant to high-level athletes, in which competitive outcomes are decided by small margins."

• Rhim et al. 2020. J Sport Health Sci. 9(6):553-61: "Citrulline supplements significantly reduced post-exercise RPE [rating of perceived exertion] and muscle soreness without affecting blood lactate levels."

• Aubertin-Leheudre and Buckinx 2020. Curr Opin Clin Nutr Metab Care. 23(1):8-16: "CIT supplementation seems to be able to improve muscular and physical factors in frail elderly people (malnourished, hypertensive, obese, dynapenic-obese) compared to placebo. More importantly, CIT combined to exercise is more efficient than exercise or CIT alone. However, because of the small number (six) and heterogeneity (dose, duration, population) of the studies realized in older adults, further studies are needed to confirm its promising potential.”

Notes: "The research to support supplemental citrulline as an ergogenic aid is limited and conflicting at best...The research to date does not provide strong support for taking citrulline or citrulline malate to enhance exercise or athletic performance" (NIH 2019. Op. cit.).

Clove

Promoted for: "Clove is most commonly applied directly to the gums for toothache, pain control during dental work, and other dental-related issues" (MedlinePlus 2020. Clove). Other uses include hangover, prediabetes, diarrhea, indigestion, and nausea and vomiting.

Presumed mechanism of action: eugenol may be responsible for some effects

Possible adverse effects: "When taken by mouth: Clove is LIKELY SAFE for most people when taken by mouth in amounts commonly found in food. There isn't enough reliable information to know if taking clove in larger medicinal amounts is safe or what the side effects might be...Clove contains chemicals that might lower blood sugar...Taking clove along with diabetes medications might cause your blood sugar to go too low" (Ibid.).

Notes: Natural Medicines Comprehensive Database states "insufficient evidence to rate effectiveness" for all claimed benefits.

Coconut oil

Promoted for: "It is alleged to reverse Alzheimer’s disease, improve heart health, raise good HDL [high-density lipoprotein] cholesterol, reduce bad LDL [low-density lipoprotein] cholesterol, improve diabetes, treat epilepsy, re-grow damaged hair, heal many skin diseases, provide peak performance energy, kill candida fungus, remove stress on the pancreas, increase metabolic rate, support healthy functioning of the thyroid and endocrine system..." and provide numerous other benefits (Hall 2019. Skeptic Magazine. 24(3):4-5).

Presumed mechanism of action: contains some medium chain triglycerides found in caprylidene, a medical food that has been used for treatment of Alzheimer’s disease (AD). The triglycerides in caprylidene are thought to induce ketosis in the brain, which in turn is thought to provide some benefits in AD. Medium chain triglycerides are thought to be used more directly by the liver for fuel rather than being circulated and deposited as fat.

Possible adverse effects: coconut oil is very high in saturated fat, which is considered a risk factor for heart disease. "Regular use tends to increase calorie intake and promote weight gain" (Ibid.) "The side effects from coconut oil include increased low density lipoprotein (LDL), triglycerides, hypocalcemia, insulin resistance, and carcinogenesis" (Varteresian and Lavretsky 2014. Curr Psychiatry Rep. 16(8):456).

Notes: " Despite popular reports in the media regarding coconut oil and treatment of AD, the data are not available to support such use. The assumed clinical effect comes partly from the fact that caprylidene has some ingredients from coconut oil as well as the highly publicized Newport Story. In the Newport Story, a physician Dr. Mary Newport, had given her husband large amounts of coconut oil and saw a benefit. In this case study, there were other interventions that were used with the coconut oil including exercise, which could have accounted for the improvement" (Ibid.). Concerning the variety of alleged benefits, Hall (2019. Op. cit.) wrote, "The problem with these claims is that there is little or no evidence from human studies to support them...How could a single treatment produce all the broad spectrum of diverse health benefits that are claimed? When treatments are claimed to cure everything it usually means they cure nothing." Researcher Richard Veech noted that "while cells produce ketones when they metabolize the medium-chain triglycerides in coconut oil, 'that doesn’t lead to levels anywhere near high enough in the brain to do much good'" (Schardt 2017 Jul 17. Nutrition Action).

Coenzyme Q10 - a compound found in normal human metabolism (component of mitochondrial respiratory chain), one of a group of similar compounds known as coenzyme Q or ubiquinone. Made in body, not required in diet.

Promoted for: improve heart and other muscle function, antioxidant, counteract possible decreases in coenzyme Q10 due to statin use, other (see below) 

Presumed mechanism of action: as part of the respiratory chain, coenzyme Q10 is necessary for the process by which most cellular energy is made. Statins inhibit a step which is used in the synthesis of coenzyme Q10 as well as that of cholesterol, so they can produce lower levels of CoQ10 in the body; thus supplements might restore the level of Q10. Concerning reducing blood pressure, "one theory is that it reduces peripheral resistance by preserving nitric oxide" (Wyman et al. 2010. Cleve Clin J Med. 77(7):435-42). Antioxidant effects may protect lipids from oxidative damage. Regulation of gene expression to produce anti-inflammatory effects has also been proposed.

Possible adverse effects: "No serious side effects of CoQ10 have been reported. Mild side effects such as insomnia or digestive upsets may occur. CoQ10 may interact with the anticoagulant (blood thinner) warfarin and the diabetes drug insulin, and it may not be compatible with some types of cancer treatment" (NCCIH 2019. Coenzyme Q10). "Gastrointestinal effects include abdominal discomfort, nausea, vomiting, diarrhea, and anorexia. Allergic rash and headache have also been reported" (Wyman et al. 2010. Op. cit.).

Reviews:

• Jankowski et al. 2016. Pharmacol Rep. 68(5):1015-9: "Current data from clinical trials indicate that CoQ10 can significantly reduce morbidity and mortality of heart failure patients in addition to guideline recommended pharmacotherapy."

• Qu et al. 2018. J Am Heart Assoc. 7(19):e009835: "CoQ10 supplementation ameliorated statin-associated muscle symptoms, implying that CoQ10 supplementation may be a complementary approach to manage statin-induced myopathy."

• Sharifi et al. 2018. Curr Pharm Des. 24(23):2729-42: " CoQ10 supplementation may significantly reduce serum triglycerides levels, and help to improve lipid profiles in patients with metabolic disorders."

• Tabrizi et al. 2018. High Blood Press Cardiovasc Prev. 25(1):41-50: "CoQ10 supplementation may result in reduction in SBP [systolic blood pressure] levels, but did not affect DBP [diastolic blood pressure] levels among patients with metabolic diseases."

• Taylor 2018. Am J Cardiovasc Drugs. 18(2):75-82: "data supporting the efficacy of CoQ10 are equivocal, with some studies showing that CoQ10 supplementation reduces the incidence and severity of SAMS [statin-associated muscle symptoms] and others finding no beneficial effects of supplementation...In addition, the effectiveness of oral CoQ10 supplementation to increase mitochondrial CoQ10 in human skeletal muscle is not well established."

• Zaleski et al. 2018. Adv Nutr. 9(4):519S-523S: "CoQ10 is popular as a form of adjuvant therapy for the treatment of SAMS. However, the data evaluating the efficacy of CoQ10 supplementation has been equivocal, with some, but not all, studies suggesting that CoQ10 supplementation mitigates muscular complaints."

• Jorat et al. 2018.Lipids Health Dis. 17(1):230: "This meta-analysis demonstrated the promising effects of CoQ10 supplementation on lowering lipid levels among patients with CAD [coronary artery disease], though it did not affect triglycerides, LDL-cholesterol [low-density lipoprotein cholesterol] and Lp(a) [lipoprotein (a)] levels."

• Jorat et al. 2019. Inflammopharmacology. 27(2):233-48 [biomarkers of inflammation and oxidative stress]: " CoQ10 supplementation increased SOD [superoxide dismutase] and CAT [catalase], and decreased MDA [malondialdehyde] and diene levels, but did not affect CRP [C-reactive protein], TNF-a [tumor necrosis factor alpha], IL-6 [interleukin-6], and GPx [glutathione peroxidase] levels among patients with CAD."

• Mehrabani et al. 2019. Complement Ther Med. 43:181-7: "CoQ10 supplementation could alleviate fatigue...It seems CoQ10 has better therapeutic effects in statin-related fatigue and fibromyalgia patients compared with the other disease related fatigue."

• Dludla et al. 2020. Int J Mol Sci. 21(9):3247: "Results from the current meta-analysis, involving 318 participants, showed that CoQ10 supplementation in individuals with metabolic syndrome increased adiponectin levels when compared to those on placebo...Moreover, CoQ10 supplementation significantly lowered inflammation markers in individuals with metabolic syndrome in comparison to those on placebo...Such benefits with CoQ10 supplementation were related to its ameliorative effects on lipid peroxidation by reducing malondialdehyde levels, concomitant to improving glucose control and liver function. The overall findings suggest that optimal regulation of adipokine function is crucial for the beneficial effects of CoQ10 in improving metabolic health."

• Kennedy et al. 2020. Atherosclerosis. 299:1-8: "This systematic review and meta-analysis did not demonstrate that CoQ10 supplementation was beneficial for patients with statin-associated muscle pain or improved adherence to statin therapy."

• Akbari et al. 2020. Eur J Clin Pharmacol. 76(11):1483-99: "CoQ10 supplementation, in the tested range of doses, was shown to reduce MDA concentrations, and increase TAC [total antioxidant capacity] and antioxidant defense system enzymes. However, there were no significant effects of CoQ10 on NO [nitric oxide], GSH [glutathione] concentrations, or CAT activity."

• Sazali et al. 2021. BMJ Open. 11(1):e039358: " CoQ10 appears to have beneficial effects in reducing duration and frequency of migraine attack."

Notes: The following "Bottom Line" is given by NCCIH (2019. Op. cit.):

• CoQ10 has not been shown to be of value in treating cancer, but it may reduce the risk of heart damage caused by one type of cancer chemotherapy drug.

• Only a few studies have looked at whether CoQ10 might help prevent heart disease, and their results are inconclusive. Research on the effects of CoQ10 in heart failure is also inconclusive. However, there is evidence that CoQ10 may reduce the risk of some complications of heart surgery.

• Although results of individual studies have varied, the overall scientific evidence does not support the idea that CoQ10 can reduce muscle pain caused by the cholesterol-lowering drugs known as statins.

• The small amount of evidence currently available suggests that CoQ10 probably doesn’t have a meaningful effect on blood pressure.

• Guidelines from the American Academy of Neurology and the American Headache Society say that CoQ10 is “possibly effective” in preventing migraines, but this conclusion is based on limited evidence.

• A major National Institutes of Health-funded study showed that CoQ10, even in higher-than-usual doses, didn’t improve symptoms in patients with early Parkinson’s disease. A 2017 evaluation of this study and several other, smaller studies concluded that CoQ10 is not helpful for Parkinson’s symptoms.

• CoQ10 has also been studied for a variety of other conditions, including amyotrophic lateral sclerosis (Lou Gehrig’s disease), Down syndrome, Huntington’s disease, and male infertility, but the research is too limited for any conclusions to be drawn.

Coffee, green coffee bean extract. See also article on diet and weight loss. The discussion below considers aspects other than coffee's stimulant effects.

Promoted for: "In recent years, numerous meta-analyses have come up with positive health outcomes associated with habitual coffee consumption in the general population...Positive health outcomes include lower incidences of type 2 diabetes mellitus, kidney stones, Parkinson’s disease, gout, liver fibrosis, non-alcoholic fatty liver disease, liver cirrhosis, liver cancer and of chronic liver disease" (Kolb et al. 2020. Nutrients. 12(6):1842).

Presumed mechanism of action: "We argue here that coffee as a plant food has similar beneficial properties to many vegetables and fruits. Recent studies have identified a health promoting mechanism common to coffee, vegetables and fruits, i.e., the activation of an adaptive cellular response characterized by the upregulation of proteins involved in cell protection, notably antioxidant, detoxifying and repair enzymes...it is the major dietary source of phenolic acids and polyphenols in the developed world. A possible supportive action may be the modulation of the gut microbiota by non-digested prebiotic constituents of coffee" (Ibid.).

Possible adverse effects: According to WebMD (2018. Coffee), "Coffee is LIKELY SAFE for most healthy adults when consumed in moderate amounts (about 4 cups per day). Coffee containing caffeine can cause insomnia, nervousness and restlessness, stomach upset, nausea and vomiting, increased heart and breathing rate, and other side effects. Caffeinated coffee is POSSIBLY UNSAFE when taken by mouth for a long time or in high doses (more than 4 cups per day). Drinking large amounts of caffeinated coffee might cause headache, anxiety, agitation, ringing in the ears, and irregular heartbeats. Larger doses might cause headache, anxiety, agitation, and chest pain."

Reviews:

• Ding et al. 2020.  Nutr Metab Cardiovasc Dis. 30(1):1-10: "The evidence from available studies suggests that the GCBE [green coffee bean extract] supplementation leads to significant reductions in total cholesterol, HDL-C [high density lipoprotein cholesterol], and LDL-C [low-density lipoprotein cholesterol] levels, and has modest, but, non-significant effects on triglycerides levels."

• Zhao, LG et al. 2020. BMC Cancer. 20(1):101: "There is highly suggestive evidence for an inverse association between coffee intake and risk of liver and endometrial cancer."

Notes: According to WebMD (2018. Coffee), Natural Medicines Comprehensive Database considers effective for mental alertness; possibly effective for Impaired movement of food through the intestines after surgery, diabetes, death from any cause, and Parkinson disease; insufficient evidence of effectiveness for other conditions.

Collagen - a protein found in connective tissue. Made by the body, not needed in the diet.

Promoted for: "Smoother skin, shinier hair, stronger nails, healthier joints, and more lean muscle mass - these are just a few of the benefits proponents claim collagen powders, pills, and foods can deliver...Collagen is promoted as an anti-aging compound, as well as a beauty and performance enhancer" (Wadyka 2020 Oct 13. Consumer Reports).

Presumed mechanism of action: With aging and sun exposure, there is less collagen in the skin, leading to wrinkles and sagging. "In many of these supplements, the bioactive ingredients are collagen peptides, which are peptides rich in the amino acids proline, glycine, and hydroxyproline. Upon digestion, these peptides are cleaved into di- and tri-peptides, which are claimed to be used by the body as building blocks for proteins, such as collagen. It has been theorized that the availability of these protein peptides can help to maintain and increase the collagen in the skin. It is also believed that the peptides may increase hyaluronic acid production in skin fibroblasts, induce migration of fibroblasts, promote stronger collagen fibrils, and increase water content of the stratum corneum" (Jhawar et al. 2020. J Cosmet Dermatol. 19(4):910-2). It has also been proposed that glycine will stimulate growth hormone, leading to more collagen synthesis.

Possible adverse effects: Some products have been found to contain toxic elements such as arsenic, lead, and cadmium. "Collagen supplements that come from marine sources instead of the more common bovine-sourced collagen have become popular as many people lessen their beef intake, but they've brought with them a host of new issues. Experts report that they are more likely to ignite allergic reactions because of potential shellfish contamination. Since collagen can lead to increased fullness and satieity, which is common with any protein source, some companies have attempted to frame it as a weight loss tool...In some cases these products can actually have the opposite effect because of their often high sugar and carbohydrate content, as well as a tendency to cause bloating" (Schiffer 2021 May 12. Buzzy new collagen products are risky business. New York Times).

Reviews:

• Asserin et al. 2015. J Cosmet Dermatol. 14(4):291-301: "The oral supplementation with collagen peptides is efficacious to improve hallmarks of skin aging."

• Choi et al. 2019. J Drugs Dermatol. 18(1):9-16: "Preliminary results are promising for the short and long-term use of oral collagen supplements for wound healing and skin aging. Oral collagen supplements also increase skin elasticity, hydration, and dermal collagen density."

Notes: Supportive research is preliminary. Ernst (2019 Feb 28. Edzard Ernst blog) wrote that "most studies are small and not as rigorous as one would hope. But the existing evidence is nevertheless intriguing." Jhawar et al. (2020. Op. cit.) wrote, "While there were many different types of objective measurements, it is unclear how each translates into clinical appearance or why each was affected by collagen supplements. There is also no reliable evidence to suggest that orally digested collagen becomes preferentially localized to the dermis as opposed to other parts of the body...There are additionally many other vital proteins, other than collagen, that contribute to the appearance and properties of skin. While some proponents may rely on the body of evidence from animal studies, these findings cannot necessarily be extrapolated to humans due to differences in digestion, enzyme activity, and metabolism." In recent years many "functional foods" such as energy bars and smoothies have included collagen. "But even if eating collagen directly does lead to more collagen in your body, you don’t need special collagen foods or supplements to get it. Collagen is found in meat, poultry, fish, egg whites, and gelatin, as well as in stock or bone broth" (Wadyka 2020. Op. cit.).

Colloidal minerals - “Colloidal minerals are taken from clay or shale deposits” (WebMD 2020. Colloidal minerals).

Promoted for: being a more efficiently absorbed form of minerals, source of trace minerals, treatment of numerous diseases

Possible adverse effect: “When taken by mouth: Colloidal minerals are POSSIBLY UNSAFE for use. The content of these products varies, depending on the source of the clay. Some products might contain metals such as aluminum, arsenic, lead, barium, nickel, and titanium in potentially harmful amounts. There is also concern that some products might contain radioactive metals” (Ibid.).

Notes: Promoted by Joel Wallach, who has made dubious statements about nutrition and disease. Claims of superior absorption are unfounded. “There is no good scientific evidence to support any of its uses” (Ibid.).

Colostrum (bovine) - the first milk produced by cows after the birth of the calf

Promoted for: antimicrobial action, suppression of inflammation and promotion of tissue repair in the gut

Presumed mechanism of action: contains antimicrobial enzymes, immune-regulating cytokines, and growth factors

Reviews:

• Rathe et al. 2014. Nutr Rev. 72(4):237-54: "Studies suggesting clinical benefits of colostrum supplementation were generally of poor methodological quality, and results could not be confirmed by other investigators. Bovine colostrum may provide gastrointestinal and immunological benefits, but further studies are required before recommendations can be made for clinical application."

• Davison 2021. Nutrients. 13(6):1789: "Although some studies have shown protection against performance decrements caused by periods of intensified training, there is limited evidence for effects on body composition and physical performance. There is stronger evidence for benefit on gut permeability and damage markers and on immune function and illness risk, especially during periods of intensified training."

Conjugated linoleic acid (CLA) - a group of linoleic acid isomers

Promoted for: weight loss, bodybuilding; prevention of heart disease, diabetes, cancer

Possible adverse effects: Animal studies showed enlarged livers and insulin resistance. Human studies have shown adverse effects on blood lipids and C-reactive protein.

Notes: found in milk and meat of some ruminant animals. Some benefits found in animal studies but not yet with humans.

Coral calcium - derived from coral of Okinawa

Promoted for: alleged to be better absorbed than other forms of calcium; to prevent numerous diseases; and be responsible for longevity of Okinawans

Notes: in 2003-4 the FTC and FDA took action against leading marketers for making false and unsubstantiated claims.

Cranberry

Promoted for: "Historically, cranberry fruits or leaves were used for bladder, stomach, and liver disorders, as well as diabetes, wounds, and other conditions. Today, cranberry is most commonly promoted for urinary tract infections (UTIs)" (NCCIH 2020. Cranberry).

Presumed mechanism of action: "Initially, cranberry juice was explored as an approach to treating UTI following the observation that it could lower urine pH. This is attributed to formation of hippuric acid through metabolism of the quinic acid present in cranberry juice. Later studies reported that the concentration of hippuric acid in the urine was insufficient for an antibacterial effect unless very large volumes of cranberry juice were ingested. Subsequently, some lectins (proanthocyanidins) present in cranberries as well as blueberries were reported to inhibit binding of the type 1 P-fimbriae of Escherichia coli to uroepithelial cells, preventing bacterial adherence within the urinary tract. This proposed mechanism for a beneficial effect of cranberries has not yet been shown to have a role in human infection" (Nicolle 2016. JAMA. 316(18):1873-4).

Possible adverse effects: "Cranberry products are generally thought to be safe. However, if consumed in very large amounts, they can cause stomach upset and diarrhea, particularly in young children...There is conflicting evidence about whether cranberry interacts with the anticoagulant (blood thinner) warfarin" (NCCIH 2020. Cranberry). Drinking cranberry juice (which is usually sweetened) to prevent UTIs involves adding considerable sugar to the diet.

Reviews:

• Jepson et al. 2012. Cochrane Database Syst Rev. CD001321: "Given the large number of dropouts/withdrawals from studies (mainly attributed to the acceptability of consuming cranberry products particularly juice, over long periods), and the evidence that the benefit for preventing UTI is small, cranberry juice cannot currently be recommended for the prevention of UTIs. Other preparations (such as powders) need to be quantified using standardised methods to ensure the potency, and contain enough of the 'active' ingredient, before being evaluated in clinical studies or recommended for use."

• Gbinigie et al. 2020. Antibiotics (Basel). 10(1):12: "The current evidence base for or against the use of cranberry extract in the management of acute, uncomplicated UTIs is inadequate; rigorous trials are needed."

Notes: "In general, studies in people who are at increased risk for UTIs or those who have had recurrent UTIs show that cranberry products decrease the risk of UTIs by about one-third. However, there’s still some uncertainty about the effectiveness of cranberry because some of the research has not been of high quality. Also, studies in certain populations at increased risk of UTIs, such as elderly people in long-term care and pregnant women, have had inconsistent results, and studies in other high-risk populations, such as women undergoing gynecological surgeries or people with multiple sclerosis, have not found cranberry to be beneficial. In 2020, the U.S. Food and Drug Administration announced that it would permit manufacturers to claim on product labels that there is 'limited' evidence that daily consumption of specified amounts of cranberry dietary supplements may reduce the risk of recurrent UTI in healthy women who have had a UTI. A similar claim may be made for cranberry juice beverages, but the evidence must be described as 'limited and inconsistent.' Cranberry hasn’t been shown to be effective as a treatment for an existing UTI" (NCCIH 2020. Cranberry). "The evidence...is convincing that cranberry products should not be recommended as a medical intervention for the prevention of UTI...Clinicians who encourage such use are doing their patients a disservice" (Nicolle 2016. Op. cit.). Concerning the proposed inhibition of bacterial adhesion, Gavura (2016 Dec 15. Science-Based Medicine blog) wrote, "But these 'fimbriated' bacteria are uncommon in species isolated from urinary tract infections. So even if the theoretical mechanism of action is correct (which remains unproven), the real-world effect, based on this assumption, should be minimal." Hall (2019 Dec 24. Science-Based Medicine blog) discussed Ellura, a cranberry product with 36 mg A-type proanthocyanidins per capsule: "the existing studies are very promising. In my opinion, the evidence is sufficient to warrant trying Ellura as a replacement for antibiotic prophylaxis in patients with recurrent UTIs, as long as proper precautions are taken."

Creatine - part of normal human metabolism, not required in diet. "Creatine monohydrate powder has been the most extensively studied and commonly used form of creatine in dietary supplements since the early 1990s...A number of different forms of creatine (e.g., creatine salts, creatine complexed with other nutrients, creatine dipeptides, etc.) have been marketed as more effective sources of creatine than creatine monohydrate" (Antonio et al. 2021. J Int Soc Sports Nutr. 18(1):13).

Promoted for: muscle strength and athletic performance, cognitive performance, improved glucose metabolism

Presumed mechanism of action: creatine phosphate (phosphocreatine) acts as a reserve of energy for short-term bursts of muscular activity. "Creatine might improve muscle performance in four ways: by increasing stores of phosphocreatine used to generate ATP at the beginning of intense exercise, accelerating the re-synthesis of phosphocreatine after exercise, depressing the degradation of adenine nucleotides and the accumulation of lactate, and/or enhancing glycogen storage in skeletal muscles" (NIH Office of Dietary Supplements 2019. Dietary supplements for exercise and athletic performance). Antioxidant effects have also been proposed. "The exact action mechanism of creatine as an antioxidant is not known. However, it has been shown to increase the activity of antioxidant enzymes and the capability to eliminate ROS [reactive oxygen species] and reactive nitrogen species (RNS)" (Arazi et al. 2021. Nutrients. 13(3):869).

Possible adverse effects: "Studies have found no consistent set of side effects from creatine use, except that it often leads to weight gain, because it increases water retention and possibly stimulates muscle protein synthesis...Anecdotal reactions to creatine use include nausea, diarrhea and related gastrointestinal distress, muscle cramps, and heat intolerance. Creatine supplementation may reduce the range of motion of various parts of the body (such as the shoulders, ankles, and lower legs) and lead to muscle stiffness and resistance to stretching" (Ibid.). A meta-analysis by de Souza E Silva et al. (2019. J Ren Nutr. 29(6):480-9) found that creatine supplementation did not produce kidney damage. Dehydration caused by creatine has been linked to risk of thrombosis.

Reviews:

• Laners et al. 2017. Sports Med. 47(1):163-73: "Creatine supplementation is effective in upper limb strength performance for exercise with a duration of less than 3 min, independent of population characteristics, training protocols, and supplementary doses or duration."

• Avgerinos et al. 2018. Exp Gerontol. 108:166-73: "Oral creatine administration may improve short-term memory and intelligence/reasoning of healthy individuals but its effect on other cognitive domains remains unclear."

• Mielgo-Ayuso et al. 2019. Nutrients. 11(4):757: "In conclusion, creatine supplementation...presents positive effects on improving physical performance tests related to anaerobic metabolism, especially anaerobic power, in soccer players."

• Solis et al. 2021. Nutrients. 13(2):570: "Although preliminary findings from small-scale trials involving patients with type 2 diabetes mellitus are promising, the efficacy of creatine for improving glycemic control is yet to be confirmed."

Notes: evidence for benefit in sports requiring short bursts of intense activity, but not for sustained aerobic exercise. Some increase in muscle mass may be water retention. The International Society of Sports Nutrition position stand stated "Creatine is one of the most popular nutritional ergogenic aids for athletes. Studies have consistently shown that creatine supplementation increases intramuscular creatine concentrations which may help explain the observed improvements in high intensity exercise performance leading to greater training adaptations. In addition to athletic and exercise improvement, research has shown that creatine supplementation may enhance post-exercise recovery, injury prevention, thermoregulation, rehabilitation, and concussion and/or spinal cord neuroprotection. Additionally, a number of clinical applications of creatine supplementation have been studied involving neurodegenerative diseases (e.g., muscular dystrophy, Parkinson’s, Huntington’s disease), diabetes, osteoarthritis, fibromyalgia, aging, brain and heart ischemia, adolescent depression, and pregnancy. These studies provide a large body of evidence that creatine can not only improve exercise performance, but can play a role in preventing and/or reducing the severity of injury, enhancing rehabilitation from injuries, and helping athletes tolerate heavy training loads" (Kreider et al. 2017. J Int Soc Sports Nutr. 14:18).

Crocin - see also saffron. Crocin is "a carotenoid chemical compound that is found in the flowers crocus and gardenia. Crocin is the chemical primarily responsible for the color of saffron" (Wikipedia 2021. Crocin). (Note: do not confuse with the brand name Crocin for a pain reliever, paracetamol).

Promoted for: cognitive benefits, general health, eye health

Presumed mechanism of action: antioxidant, moderation of serotonin receptors, antidepressant properties

Review: Naserizadeh et al. 2020. Complement Ther Med. 52:102500: "crocin supplementation can decrease significantly FBS [fasting blood sugar] and TC [total cholesterol] without any beneficial effects on TG [triglyceride], LDL-C [low-density lipoprotein cholesterol], and HDL-C [high-density lipoprotein cholesterol] levels."

Curcumin - see HERBS article (under turmeric)

Cysteine - a nonessential amino acid (considered "conditionally essential," needed in the diet in some circumstances). Marketed as N-acetyl cysteine (NAC). See also hangover remedies and N-acetyl cysteine below.

Promoted for: antioxidant, hangover cure, support immune system

Presumed mechanism of action: antioxidant effects, enhance metabolism of ethanol to acetate without buildup of acetaldehyde

Deer antler velvet - "consists of cartilage and epidermis from growing deer or elk antlers before ossification. It is used as a general health aid in traditional Chinese medicine" (NIH Office of Dietary Supplements 2019. Dietary supplements for exercise and athletic performance).

Promoted for: ergogenic aid

Presumed mechanism of action: "Several growth factors have been detected in deer antler velvet, such as IGF-1, that could promote muscle tissue growth in a similar way to the quick growth of deer antlers" (Ibid.).

Notes: studies found little or no evidence of benefits. "An evaluation of six deer-antler-velvet dietary supplements that were commercially available in 2013 found that five of them contained no deer IGF-1, and four were adulterated with human IGF-1...The research to date does not support taking deer-antler-velvet supplements to enhance exercise or athletic performance" (Ibid.). Like other proteins, growth factors in deer antler velvet would be digested and are unlikely to be absorbed intact.

Dehydroepiandrosterone (DHEA) - a natural steroid hormone which declines in age

Promoted for: anti-aging effects, ergogenic aid, cognitive enhancement, adrenal insufficiency, immune benefits, improve ovarian function, prevention of cardiovascular disease and cancer, obesity

Presumed mechanism of action: "The body can convert DHEA to the male hormone testosterone; testosterone’s intermediary, androstenedione; and the female hormone estradiol. Testosterone is an anabolic steroid that promotes gains in muscle mass and strength when combined with resistance training" (NIH Office of Dietary Supplements 2019. Dietary supplements for exercise and athletic performance).

Possible adverse effects: "Most side effects appear to be mild and often temporary. The most common is acne, but a variety of other side effects have been noted. Women might develop masculine features, and men might experience breast tenderness or enlargement, aggression, or testicular wasting..." (Department of Defense Dietary Supplement Resource. 2020. DHEA: Can I use it?).

Reviews:

• Qin et al. 2020. Nutr Metab Cardiovasc Dis. 30(9):1465-75: "supplementation with DHEA did not change circulating values of TC [total cholesterol], LDL-C [low-density lipoprotein cholesterol] and TG [triglycerides], whereas it may decrease HDL-C [high-density lipoprotein cholesterol] levels. Further long-term RCTs are required to investigate the effects of DHEA particularly on major adverse cardiac events."

• Wang et al. 2020. Complement Ther Med. 55:102583: "This systematic review evaluated the association between FPG [fasting plasma glucose] and DHEA, revealing that the administration of DHEA reduces FPG levels. However, we found no association between DHEA administration and IN [insulin] levels or insulin resistance."

• Wang et al. 2020. Steroids. 163:108710: "Our findings demonstrate that DHEA supplementation increased lean body mass and decreased fat mass, but debate persists when translating the results into clinical benefit. Lastly, DHEA supplementation had a neutral effect on BP [blood pressure]."

• Hu et al. 2021. Complement Ther Med. 56:102620: "The results of the current meta-analysis support the use of DHEA supplementation for increasing testosterone concentrations in elderly women."

Notes: "The research to date does not support taking DHEA supplements to enhance exercise or athletic performance" (NIH 2019. Op. cit.). Lobbying for the supplement industry resulted in DHEA being exempted from being a controlled substance like other steroids. However, it is prohibited in sports by the World Anti-Doping Agency.

Diatomaceous earth - a sedimentary rock formed form the fossilized remains of diatoms

Promoted for: "Proponents of diatomaceous earth suggest that its high silicon dioxide content helps with weight loss, detoxification and cleansing, energy levels, joint pain, teeth and gums, cholesterol and blood pressure, and food absorption" (Department of Defense Dietary Supplement Resource. 2019. Diatomaceous earth: Is it a useful supplement?). Numerous other benefits have been claimed.

Presumed mechanism of action: source of silicon. "Consumers and some retailers of diatomaceous earth supplements also claim that its abrasive (rough) and absorptive properties improve digestive health by ridding the intestines of bacteria and parasites and regulating bowel movements" (Ibid.).

Notes: "there hasn’t been enough research conducted on diatomaceous earth as a dietary supplement to support these claims. In addition, the biological role of silicon in humans is uncertain, so there is no recommended dietary intake amount" (Department of Defense 2019. Op. cit.). Hall (2016 Jul 12. Science-Based Medicine blog) wrote, "As far as I was able to determine, there have never been ANY controlled clinical trials in humans to test the effects of supplementing the diet with silicon or diatomaceous earth."

Dihydrohonokiol-B (DHH-B) - a chemical made from magnolia bark

Promoted for: anxiety, stress, obesity, cognitive performance

Presumed mechanism of action: effects on GABA receptors

Possible adverse effects: "There is no information about DHH-B, but magnolia bark has been reported to cause side effects. It may cause bleeding and should not be used prior to surgery or when taking anticoagulants. Due to lack of information, it should be avoided during pregnancy and breast-feeding" (Hall 2020 Jun 23. Science-Based Medicine blog).

Notes: supportive evidence cited by one promoter consists of an animal study from 2000.

1,3-Dimethylamylamine (DMMA, methylhexanamine) - a synthetic drug marketed as a nasal decongestant but later withdrawn. Falsely claimed to be found in geranium and thus a natural compound (some studies have found traces in geranium extract, but most have not, and the amount detected is negligible).

Promoted for: stimulant, ergogenic aid

Presumed mechanism of action: "an indirect sympathomimetic drug that constricts blood vessels and thus has effects on the heart, lungs, and reproductive organs. It also causes bronchodilation, inhibits peristalsis in the intestines, and has diuretic effects. Most studies have been done on pharmacological effects when the drug is inhaled; the understanding of what methylhexanamine does when taken orally are mostly based on extrapolating from the activities of similar compounds" (Wikipedia 2021. Methylhexanamine).

Possible adverse effects: "The FDA has stated that methylhexanamine 'is known to narrow the blood vessels and arteries, which can elevate blood pressure and may lead to cardiovascular events ranging from shortness of breath and tightening in the chest to heart attack.' Numerous adverse events and at least five deaths have been reported in association with methylhexanamine-containing dietary supplements" (Ibid.).

Notes: "Methylhexanamine-containing supplements sometimes list 'geranium oil' or 'geranium extract' as a source of methylhexanamine. However, geranium oils do not contain methylhexanamine, and the methylhexanamine in these supplements is added in the form of synthetic material...A number of sporting authorities and countries have banned or heavily restricted the use of methylhexanamine as a dietary supplement, due to serious concerns about its safety" (Ibid.). The FDA issued warning letters to manufacturers and distributors in 2012; supplements containing DMMA are considered "adulterated."

Dimethylsulfoxide (DMSO) is discussed with arthritis remedies in the article "Chelation therapy;

allergy and arthritis treatments; other miscellaneous topics" (CHELATION AND MISC).

Dolomite - a mineral made of calcium magnesium carbonate

Promoted for: source of calcium and magnesium

Possible adverse effects: may have toxic levels of lead, mercury, arsenic

Notes: poorly absorbable form of these minerals

Emblica officinalis (EO) (Phyllanthus emblica, Indian gooseberry, amla) - an Ayurvedic medicine

Promoted for: cholesterol, diarrhea, nausea, cancer, longevity, cardiovascular disease, fever and cough, asthma, other

Proposed mechanism of action:  "The plant has shown antiatherogenic, anticoagulant, hypolipidemic, antihypertensive, antioxidant, antiplatelet, and vasodilatory effects as well as lipid deposition inhibitory properties. Moreover, it prevents from doxorubicin and isoproterenol cardiotoxicity and myocardial ischemia/reperfusion injury, and improves vascular endothelial function in animal studies" (Hashem-Dabaghian et al. 2018. J Cardiovasc Thorac Res. 10(3):118-28).

Review: Hashem-Dabaghian et al. 2018. Op. cit.: "EO influences various cardiovascular risk-factors. However, there is not sufficient evidence to confirm the plant efficacy in preventing and treating CVD [cardiovascular disease]."

Emu oil - oil from the fat of the emu, an Australian flightless bird

Promoted for: various topical uses; internal use is promoted for inflammatory diseases, high cholesterol, diabetes, arthritis

Presumed mechanism of action: effects are attributed to its content of various unsaturated fatty acids (see discussion of fatty acids below)

Energy drinks - usually contain high levels of caffeine. Other possible ingredients include sugar, guarana (which also contains caffeine), taurine, glucuronolactone, vitamins, minerals, herbal extracts, and creatine.

Promoted for: mental and physical stimulation

Presumed mechanism of action: caffeine and other stimulants stimulate mental alertness and physical performance. Sugar provides calories for physical effort. Presumed mechanisms of other components are discussed along with the individual items. However, for most of these the contents would be too small to have the purported benefits, or their effects would take too long to produce any immediate benefit.

Possible adverse effects: "Energy drinks have been associated with unwanted side effects such as headache, jitteriness, stomach upset, trouble sleeping, and chest pain" (Department of Defense Dietary Supplement Resource. 2020. Energy drinks and energy shots: What's the problem?). Many of these effects are due to the very high levels of caffeine. Caffeine contents may be as high as 500 mg per serving, compared to 30 to 40 mg in soft drinks and 145 mg in a serving of coffee. "And if 'stacked' with dietary supplements, especially ones containing other stimulants, the potential risk for serious side effects is higher than when used alone...some products might contain yohimbe or other stimulants that could be of concern...Don’t use energy drinks or energy shots immediately before, during, and after strenuous activity. Energy drinks are not sports drinks, which are designed to fuel and hydrate you during long workouts" (Ibid.). "Convenience stores now display EBs [energy beverages] next to the SDs [sports drinks], which can mislead the consumer into thinking that they are similar products" (Higgins et al. 2010. Mayo Clin Proc. 85(11):1033-41).

Review: Mora-Rodriguez and Pallarés 2014. Nutr Rev. 72 Suppl 1:108-20: "The existing data suggest that the caffeine dose given in studies of energy drinks is insufficient to enhance neuromuscular performance... Ingestion of high doses of caffeine, although ergogenic, could result in negative side effects that could counteract the caffeine's ergogenic effect."

Notes: "sales reached $12.5 billion by 2012. Emergency department visits related to caffeine-containing energy drink consumption increased nearly 14-fold between 2005 and 2011... in 2011, 35% of 8th graders and 29% of 10th and 12th graders consumed caffeine-containing energy drinks, with almost 20% of 8th grade students reporting daily use" (Sorkin et al. 2014. Nutr Rev. 72 Suppl 1(Suppl 1):1-8). By including other ingredients and calling their products dietary supplements, promoters are able to exceed FDA limits on caffeine in soft drinks.

Enzymes - various proteases, barley diatase, bile extract. See also bromelain.

Promoted for: improve digestion, prevent inflammation, enhance immunity, other. Pancreatic enzymes are promoted as a cancer cure (see Cancer article).

Notes: Not needed in the intestine (except for deficiency of pancreatic enzymes). They would be digested (like other proteins) and not contribute to metabolism elsewhere. A review by Edakkanambeth Varayil et al. (2014. Mayo Clin Proc. 89(9):1307-12) made the following points:

• There are "prescription pancreatic enzyme products that are used to treat pancreatic insufficiency, such as protease, pancrelipase, and pancreatic amylase. However, some enzymes are sold directly to consumers, including bromelain, papain, trypsin, and chymotrypsin, as well as numerous combination products...Bromelain is a group of proteolytic enzymes derived from the stem and fruit of the pineapple (Ananas comosus). Taking oral bromelain combined with trypsin and rutin may improve the symptoms of osteoarthritis (OA)."

• "Oral chymotrypsin seems to be effective for reducing the inflammation and edema associated with hand fractures."

• "Enzymes derived from plant sources are touted as remaining active over a broader pH range, whereas animal-derived enzymes function in a narrower pH range. This wider pH range may protect plant-based enzymes from being degraded in the acidic environment of the stomach."

• "The mechanism of action of OTC [over-the-counter] enzymes is not entirely clear as there are a number of studies demonstrating both pro-inflammatory and anti-inflammatory effects."

• "One of the main theories advocated by OTC enzyme proponents is that with age, natural enzyme production decreases and enzyme supplementation, therefore, becomes essential. However, enzyme production does not inherently decrease with age....No evidence indicates that exocrine pancreatic secretions decrease with age. Evidence supporting OTC enzyme supplementation in older patients is lacking."

• "Current evidence does not permit endorsement of the use of supplemental enzymes to treat common gastrointestinal tract symptoms, such as bloating, gas, and irritable bowel syndrome."

• For enzyme supplements to have an effect on systemic symptoms, such as those in OA [osteoarthritis], rheumatoid arthritis, or muscle soreness, the intact enzyme must reach the joints or muscle tissue after absorption from the gastrointestinal tract. Enzymes (proteins), if not enterically coated or supplemented with a proton pump inhibitor or histamine blocker, would essentially be denatured in the acidic environment of the stomach. However, some evidence suggests that undegraded protein can be detected in the plasma after oral intake."

• "The OTC enzymes may have a clinical role in improving symptoms of OA, but larger studies are needed to confirm these effects."

• "Currently, evidence of OTC enzymes improving muscle soreness in athletes is insufficient."

Enzyte - a supplement promoted for "male enhancement" (counteracting erectile dysfunction). It contains various herbs, such as ginseng, horny goat weed, and Ginkgo biloba, as well as other components. Prior to 2004 it also contained yohimbe. See discussion of these herbs in the HERBS article.

Notes: "An official of the Federal Trade Commission division that monitors advertising says the lack of scientific testing is 'a red flag right away. There's no science behind these claims.' The company has conceded that it has no scientific studies that substantiate any of its Enzyte claims. Ira Sharlip, a spokesman for the American Urological Association, has said, 'There is no such thing as a penis pill that works. These are all things that are sold for profit. There's no science or substance behind them'" (Wikipedia 2021. Enzyte).

Evening primrose oil (EPO) - contains omega-6 fatty acids such as gamma-linolenic acid

Promoted for: "atopic dermatitis (a type of eczema), rheumatoid arthritis, premenstrual syndrome (PMS), breast pain, menopause symptoms, and other conditions. Evening primrose oil may also be included in products that are applied to the skin" (NCCIH 2020. Evening primrose oil).

Possible adverse effects: "Evening primrose oil is probably safe for most adults. Less is known about its safety for children. Evening primrose oil may be safe for use during pregnancy and while breastfeeding, but the evidence is not conclusive. Evening primrose oil is generally well tolerated. The most common side effects are temporary gastrointestinal symptoms such as abdominal pain, fullness, or nausea. Evening primrose oil may increase the effects of the HIV medicine lopinavir" (NCCIH 2020. Op. cit.)

Reviews:

• Wong et al. 2009. Gynecol Endocrinol. 25(3):166-74: "Use of Ginseng, evening primrose, Dong Quai or vitamin E appears not to be efficacious for the relieving hot flushes."

• Bamford et al. 2013. Cochrane Database Syst Rev. CD00441: "Oral borage oil and evening primrose oil lack effect on eczema; improvement was similar to respective placebos used in trials."

Notes: "There’s not enough evidence to support the use of evening primrose oil for any health condition. Evening primrose oil, taken orally (by mouth), has not been shown to be helpful for relieving symptoms of atopic dermatitis. Studies of evening primrose oil for breast pain have not found it to be more effective than a placebo (an inactive substance). There’s insufficient evidence to show whether evening primrose oil is helpful for other conditions, such as PMS and menopause symptoms" (NCCIH 2020. Op. cit.).

Fatty acids and fish oil - see also evening primrose oil, flaxseed oil.

General aspects

Fatty acids are carboxylic acids with long chains of carbon and hydrogen. They play important roles in the body, such as in storage and generation of energy, as components of membranes, and in cellular signaling. Because of the generally beneficial role of unsaturated fatty acids (compared to saturated), there is considerable interest in the value of various fatty acids in the diet and in supplements. Since many studies involve fish oil as a source of beneficial fatty acids, these are also considered in this section.

A triglyceride (triacylglycerol) consists of three fatty acids linked to a glycerol molecule. They are the main components of fats and oils. Fats are solid at room temperature; oils, which contain more unsaturated fatty acids, are liquid.

Nomenclature and types:

By length: short-chain fatty acids have 6 or fewer carbons; medium-chain 7-13; long-chain 14-22; very long chain more than 22

Saturated fatty acids have no double bonds in the carbon chain. Unsaturated fatty acids have one or more double bonds. Monounsaturated fatty acids (MUFAs) have one double bond, while polyunsaturated fatty acids (PUFAs) have two or more double bonds.

Numbers of carbons and double bonds: a fatty acid may be designated with the number of carbon atoms, a colon, and the number of double bonds, for example, 14:0 and 18:1. The carbons are numbered starting with the carboxyl carbon as number 1, and double bonds are designated with Δ (delta). For example, Δ8 indicates a double bond between carbons 8 and 9. Another method is based on the furthest double bond from the carboxyl group. The furthest carbon atom is designated omega (ω) (the last letter of the Greek alphabet) or n (which stands for the number of carbon atoms). For example, in an 18-carbon fatty acid, a double bond between the third carbon from the end (carbon 15) and the second from the end (carbon 16) is designated ω-3 (omega-3) or n-3. There could be additional double bonds. For example, α-linolenic acid has three double bonds, but the one closest to the end is at the ω-3 position, so it is referred to as an ω-3 fatty acid.

Some important fatty acids

Monounsaturated: palmitoleic acid (ω-7, 16:1), oleic acid (ω-9, 18:1).

Polyunsaturated:

• ω-3: alpha-linolenic acid (ALA) (18:3) (essential), eicosapentaenoic acid (EPA) (20:5), docosahexaenoic acid (DHA) (22:6), docosapentaenoic acid (DPA) (22:5).

• ω-6: linoleic acid (18:2) (essential), arachidonic acid (20:4)

Omega-3 fatty acids (ALA, EPA and DHA) and fish oils. ALA is found in plant oils (flaxseed, soy, canola), EPA and DHA in fish oils (especially from cold-water fatty fish).

Promoted for: cardiovascular health, infant health and development, depression, anxiety, cancer prevention, cognitive function, eye health, rheumatoid arthritis, traumatic brain injuries, eczema, psoriasis, asthma, and several other conditions

Proposed mechanism of action: Mechanisms related to heart disease include antiarrhythmic, antithrombotic, antiatherosclerotic, and anti-inflammatory effects; enhanced endothelial function; reduction in blood pressure; and reduction in triglycerides. Also proposed are antioxidant effects, effects on membrane environment and fluidity, formation of cellular mediators (resolvins and protectins) derived from DHA and EPA, and activation of nuclear receptors and transcription factors.

Possible adverse effects: "Commonly reported side effects of omega-3 supplements are usually mild. These include unpleasant taste, bad breath, heartburn, nausea, gastrointestinal discomfort, diarrhea, headache, and odoriferous sweat" (NIH Office of Dietary Supplements 2020. Omega-3 fatty acids). Other possible effects include increased cholesterol, impaired blood clotting, vitamin E deficiency, and drug interactions. Fish liver oils may result in excess levels of vitamin A if supplements with vitamin A are also being taken.

Reviews and major trials, omega-3 supplements (fish oil or other forms):

• Kromhout et al. 2011. Diabetes Care. 34(12):2515-20 [Alpha Omega Trial]: “Our results suggest that low-dose supplementation of n-3 fatty acids exerts a protective effect against ventricular arrhythmia-related events in post-MI [myocardial infarction] patients with diabetes.”

• Rizos et al. 2012. JAMA. 308(10):1024-33: “Overall, omega-3 PUFA supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke based on relative and absolute measures of association.”

• Rogers et al. 2013. Pharmacol Res. 70(1):13-9: “Given the overall benefits of DHA, maternal and infant supplementation may improve neurological outcomes especially in vulnerable populations.”

• Mariani et al. 2013. J Am Heart Assoc. 2(1):e005033: “Published clinical trials do not support n-3 PUFAs as agents aimed at preventing either postoperative or recurrent AF [atrial fibrillation].”

• Hegarty and Parker 2013. Curr Opin Psychiatry. 26(1):33-40: “Although early studies evaluating the role of omega-3 preparations as treatments of depression were generally positive, the rate of negative or nondifferential studies has increased in recent years. Recent meta-analyses provide an explanation in suggesting that docosahexaenoic acid-weighted preparations may be ineffective while finding support for eicosapentaenoic acid (EPA)-weighted preparations...There is sufficient indicative data favouring EPA-weighted omega-3 supplementation for those with a depressive mood disorder, particular when fish oil is viewed by patients as 'natural,' it has few side effects and is neuroprotective.”

• Xin et al. 2013. Am J Clin Nutr. 97(5):926-35: “Short-term fish-oil supplementation may favorably influence the frequency domain of heart rate variability, as indicated by an enhanced vagal tone, which may be an important mechanism underlying the antiarrhythmic and other clinical effects of fish oil.”

• Varteresian and Lavretsky 2014. Curr Psychiatry Rep. 16(8):456: "for the general adult population, evidence supports a role for Ω3 supplementation in treating depression. The data supporting Ω3 supplementation in geriatric depression is less extensive."

• Zhang et al. 2014. BMC Public Health. 14:204: “Omega-3 fatty acid supplementation does not have an effect on cancer incidence, nonvascular death, or total mortality.”

• Anon. 2014. JAMA. 312(8):839-40 [from The Medical Letter]: “Omega-3 polyunsaturated fatty acids can lower high plasma triglycerides, but they have not been shown to reduce the risk of pancreatitis. The results of recent studies do not offer any convincing evidence that fish oil supplements prevent cardiovascular disease.”

• Boe and Vangsness 2015. Am J Orthop. 44(7):302-5: “Results of human clinical trials have not been consistently significant. Well-designed clinical trials are needed to substantiate or refute the potential benefit of fish oils in OA [osteoarthritis] treatment.”

• Cooper et al. 2016. J Affect Disord. 190:474-82 [attention-deficit/hyperactivity disorder]: “These results exclude the possibility of moderate to large effects. They provide suggestive evidence of small effects of n-3 PUFA on reducing EL [emotional lability] and oppositional behaviour in subgroups of children with ADHD.”

• Balk and Lichtenstein 2017. Nutrients. 9(8):865: "There is high strength of evidence, based on numerous trials, of no significant effects of marine oils on systolic or diastolic blood pressures, but there are small, yet statistically significant increases in high density lipoprotein and low density lipoprotein cholesterol concentrations. The clinical significance of these small changes, particularly in combination, is unclear...In observational studies, there is low strength of evidence that increased marine oil intake lowers ischemic stroke risk. Among randomized controlled trials and observational studies, there is evidence of variable strength of no association with increased marine oil intake and lower CVD event risk...There is moderate strength of evidence of no effect on blood pressure or lipoprotein concentrations and low strength of evidence of no association with coronary heart disease, atrial fibrillation and congestive heart failure."

• Aung et al. 2018. JAMA Cardiol. 3(3):225-34: "This meta-analysis demonstrated that omega-3 fatty acids had no significant association with fatal or nonfatal coronary heart disease or any major vascular events. It provides no support for current recommendations for the use of such supplements in people with a history of coronary heart disease."

• Su et al. 2018.  JAMA Netw Open. 1(5):e182327: "This review indicates that omega-3 PUFAs might help to reduce the symptoms of clinical anxiety. Further well-designed studies are needed in populations in whom anxiety is the main symptom."

• Canhada et al. 2018. Nutr Neurosci. 21(8):529-38: "The effects of omega-3 fatty acids supplementation in mild AD [Alzheimer's disease] corroborate epidemiological observational studies showing that omega-3 fatty acids may be beneficial in disease onset, when there is slight impairment of brain function. Although some studies have shown changes in scales of cognitive function in more severe cases, they are not enough to support omega-3 fatty acids supplementation in the treatment of AD."

• Dupont et al. 2019. Aging Clin Exp Res. 31(6):825-36: "We conclude that there is growing evidence for a beneficial effect of omega-3 PUFAs supplementation in sarcopenic older persons, which may add to the effect of exercise and/or protein supplementation."

• Manson et al. 2019. N Engl J Med. 380(1):23-32 [Vitamin D and Omega-3 Trial (VITAL)]: "Supplementation with n-3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo."

• Bhatt et al. 2019. N Engl J Med. 380(1):11-22 [REDUCE-IT trial]: “Among patients with elevated triglyceride levels despite the use of statins, the risk of ischemic events, including cardiovascular death, was significantly lower among those who received 2 g of icosapent ethyl [an EPA supplement] twice daily than among those who received placebo.”

• Li et al. 2020. BMJ. 368:m456 [trial with over 400,000 participants]: "Habitual use of fish oil seems to be associated with a lower risk of all cause and CVD mortality and to provide a marginal benefit against CVD events among the general population."

• Bakouei et al. 2020. Taiwan J Obstet Gynecol. 59(1):8-15: "The meta-analysis of the 14 comparisons demonstrated that n-3 fatty acids supplementation played a protective role against the risk of preeclampsia...The analysis of the 10 comparisons revealed that n-3 fatty acid supplements for pregnant women did not mitigate the risk of pregnancy-induced hypertension...The n-3 fatty acid supplements are an effective strategy to prevent the incidence of preeclampsia in women with low-risk pregnancies."

• Balachandar et al. 2020. Eur J Clin Pharmacol. 76(5):639-48: " Current pieces of evidence do not support the role of DHA supplementation, in preventing/retarding ARCD [age-related cognitive decline] of memory, executive function, attention, and working memory."

• Watson and Stackhouse 2020. Cochrane Database Syst Rev. CD002201: "This review found that regular omega-3 supplements may provide some limited benefits for people with cystic fibrosis with relatively few adverse effects: however, the quality of the evidence across all outcomes was very low."

• Gao et al. 2020. J Matern Fetal Neonatal Med. 33(10):1767-73: "Omega-3 fatty acids supplementation can provide substantially beneficial effects on glycemic control and inflammatory response for gestational diabetes."

• Araya-Quintanilla et al. 2020. Neurologia. 35(2):105-14: "There is no consistent evidence to support the effectiveness of omega-3 supplementation in improving cognitive function in AD [Alzheimer's disease] patients in the short and medium term."

• Zhang et al. 2020. Eur J Clin Nutr. 74(4):548-54: "Our results provided further evidence that n-3 LC-PUFAs may have beneficial effect in elderly with MCI [mild cognitive impairment]."

• Nicholls et al. 2020. JAMA. 324(22):2268-80 [STRENGTH trial]: “Among statin-treated patients at high cardiovascular risk, the addition of omega-3 CA, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients.”

• Christen et al. 2020. JAMA Ophthalmol. 138(12):1280-9 [VITAL]: "Neither vitamin D3 nor marine ω-3 fatty acid supplementation had a significant overall effect on AMD [age-related macular degeneration] incidence or progression."

• Gao et al. 2020. Lipids Health Dis. 19(1):87: "This meta-analysis shows that among patients with T2DM [type 2 diabetes mellitus], fish oil supplementation leads to a favorable blood lipids profile but does not improve glucose control."

• Hoang and Kim 2020. Nutrients. 12(8):2218: "The findings of this study suggest that pravastatin and atorvastatin may be more beneficial than omega-3 supplementation in reducing the risk of total cardiovascular disease, coronary heart disease, and myocardial infarction."

• Lee et al. 2020. Nutrients. 12(9):2769: "The current evidence supports the effects of n-3 PUFAs supplementation in improving fatty liver. n-3 PUFAs supplementation may also improve blood lipid levels and obesity."

• van der Wurff et al. 2020. Nutrients. 12(10):3115: "In conclusion, daily supplementation of ≥450 mg DHA + EPA per day and an increase in the O3I [omega-3 index] to >6% makes it more likely to show efficacy on cognition in children and adolescents."

• Lewis et al. 2020. Adv Nutr. 11(5):1300-14 [athletic performance]: "We report consistent effects for FS [fish oil supplementation] on reaction time, mood, cardiovascular dynamics in cyclists, skeletal muscle recovery, the proinflammatory cytokine TNF-a, and postexercise NO responses. No clear effects on endurance performance, lung function, muscle force, or training adaptation were evident."

• Wang et al. 2020. J Int Med Res. 48(12):300060520953684: "Omega-3 fatty acid supplementation might be associated with reduced mortality in patients with sepsis, especially those with gastrointestinal dysfunction. Furthermore, omega-3 fatty acid administration could shorten DMV [duration of mechanical ventilation] and ICU LOS [length of stay]."

• Rizos et al. 2021. Heart. 107(2):150-8: "Omega-3 supplementation at <2 1 g capsules/day showed no association with CVD outcomes; this seems unlikely to change from future research. Compared with the robust scientific evidence available for low doses, the evidence for higher doses (2-4 1 g capsules/day) is weak. The emerging postulated benefit from high-dose supplementation needs replication and further evaluation as to the precise formulation and indication."

• Mullin et al. 2021. Gastroenterol Clin North Am. 50(1):169-82: "Although RCTs have identified possible benefit of fish oil supplements for induction of remission in UC [ulcerative colitis], there was no benefit found for maintenance of remission in UC."

• Händel et al. 2021. Nutrients. 13(4):1226: "For now, there seems to be no benefit of PUFA in ADHD [attention deficit hyperactivity disorder] treatment; however, the certainty of evidence is questionable, and thus no conclusive guidance can be made."

• Serra et al. 2021. Nutrients. 13(5):1704: "We conclude that omega 3 supplementation during pregnancy does not reduce the risk of PTB [preterm birth] and ePTB [early preterm birth]."

• Chu et al. 2021. Nutr Metab Cardiovasc Dis. 31(5):1339-48: "The current study showed that fish oil supplementation had a beneficial effect on pulse wave velocity [a measure of arterial stiffness]."

Reviews, supplemental and dietary omega-3:

• Hooper et al. 2006. BMJ. 332(7544):752-60: “Long chain and shorter chain omega 3 fats do not have a clear effect on total mortality, combined cardiovascular events, or cancer.”

• Yang et al. 2013. PLoS One. 8(11):e80048: “Epidemiological data to date indicate that fish or LCn3PUFA intake may be beneficial to prevent asthma in children.”

• Johnsen et al. 2018. Nutr J. 17(1):56 [Tromsø study]: "We found no protective effect of fatty fish eating or fish oil supplements on atherosclerotic plaque formation or plaque area in a general population. Lean fish consumption was associated with a reduced risk for plaque in cross-sectional analysis, suggesting that the beneficial effects of fish consumption on atherosclerosis may be mediated through other mechanisms than n-3 PUFAs."

• Abdelhamid et al. 2020. Cochrane Database Syst Rev. CD003177: "This is the most extensive systematic assessment of effects of omega-3 fats on cardiovascular health to date. Moderate- and low-certainty evidence suggests that increasing LCn3 [long chain omega 3 fatty acids] slightly reduces risk of coronary heart disease mortality and events, and reduces serum triglycerides (evidence mainly from supplement trials). Increasing ALA slightly reduces risk of cardiovascular events and arrhythmia."

• Wu et al. 2020. J Clin Endocrinol Metab. 105(4):1030–45: "While replacement of dietary saturated fat with unsaturated fat, polyunsaturated fat in particular, or intake of LC n-3 PUFA-rich seafood has generally shown benefit for ASCVD [atherosclerotic cardiovascular disease] prevention and is recommended for cardiovascular benefits, data on effects of n-3 PUFA products on ASCVD health are inconsistent. However, recent clinical trials support benefits of prescription EPA in ASCVD prevention. n-3 PUFAs may contribute to ASCVD prevention through multiple mechanisms, including lowering plasma triglyceride levels, anti-inflammatory effects, antithrombotic effects, and effects on endothelial function."

Notes: There is considerable evidence associating intake of oily fish with reduced incidence of heart disease, cancer, stroke, and Alzheimer’s. There is less evidence in support of supplements. There is an FDA-allowed qualified health claim that ω-3 fatty acids from fish oil may reduce the risk of heart disease, and the American Heart Association supports the use of supplements for heart patients.

Among the points made in the NIH Office of Dietary Supplements article on omega-3 fatty acids (2020) are:

• "Some researchers propose that the relative intakes of omega-6s and omega-3s - the omega-6/omega-3 ratio - may have important implications for the pathogenesis of many chronic diseases, such as cardiovascular disease and cancer, but the optimal ratio - if any - has not been defined. Others have concluded that such ratios are too non-specific and are insensitive to individual fatty acid levels. Most agree that raising EPA and DHA blood levels is far more important than lowering linoleic acid or arachidonic acid levels.”

• “Overall, research indicates that consuming fish and other types of seafood as part of a balanced diet promotes heart health, especially when the seafood is consumed in place of less healthy foods. Fish oil and other LC omega-3 supplements lower triglyceride levels and might reduce the risk of some cardiovascular endpoints, especially among people with low dietary omega-3 intakes. Evidence of a protective effect for omega-3 supplementation is stronger for people with existing coronary heart disease than for healthy individuals.”

• “Overall, data from observational studies show no consistent relationship between omega-3s and overall cancer risk.”

• “Overall, the findings indicate that LC omega-3 supplementation does not affect cognitive function in healthy older adults or in people with Alzheimer’s disease compared to placebo. For people with mild cognitive impairment, omega-3s may improve certain aspects of cognitive function, including attention, processing speed, and immediate recall. However, these findings need to be confirmed in additional clinical trials.”

• “The Cochrane review authors concluded that LC omega-3 supplementation for up to 5 years in people with AMD [age-related macular degeneration] does not reduce the risk of progression to advanced AMD or of moderate to severe vision loss.”

• “Overall, the evidence to date shows no consistent relationship between omega-3s and dry eye disease.”

• “Findings to date suggest that LC omega-3s may be helpful as an adjunctive treatment to pharmacotherapy for ameliorating the symptoms of RA [rheumatoid arthritis]. However, more research is needed to confirm this finding.”

• “The benefits of omega-3 supplementation are being investigated for several other conditions, including depression, inflammatory bowel disease, attention-deficit/hyperactivity disorder (ADHD), childhood allergies, and cystic fibrosis...The potential benefits of omega-3s for these and other conditions require further study.”

Conflicting results in different studies could be due to differences in the bioavailability of the fatty acids in the supplements used, or to the choice of fat in the control group. Promoters of krill oil as a source of fatty acids claim that it is less contaminated with mercury and other toxic chemicals, and that the fatty acids are more readily absorbed. Grey and Bolland (2014. JAMA Intern Med. 174(3):460-2) found that in the mid-2010's “Sales of ω-3 FAs steadily increased despite contemporaneous accrual of high-level evidence that the supplements lack efficacy across a range of health outcomes for which their use is advocated.” More recently, Curfman (2020. JAMA. 324(22):2280-1) wrote, “Given the current uncertain state of knowledge, neither patients nor physicians can be confident that omega-3 fatty acids have any health benefits, yet in 2019 the global market for omega-3 fatty acids reached $4.1 billion and is expected to double by 2025.”

Omega-6 fatty acids include linoleic acid and arachidonic acid. "Some types are found in vegetable oils, including corn, evening primrose seed, safflower, and soybean oils. Other types of omega-6 fatty acids are found in black currant seed, borage seed, and evening primrose oils" (MedlinePlus 2020. Omega-6 fatty acids).

Promoted for: heart disease, infant development, multiple sclerosis, cognitive function, attention deficit-hyperactivity disorder, diabetes, diarrhea, eye health, cholesterol levels, prevention of cancer

Possible adverse effects: high intakes possibly unsafe in pregnancy, can make breathing more difficult in chronic obstructive pulmonary disease, can increase risk of hypertension in diabetes, can raise triglyceride levels

Reviews:

• Hooper et al. 2018. Cochrane Database Syst Rev. CD011094: "We found no evidence that increasing omega-6 fats reduces cardiovascular outcomes other than MI [myocardial infarction]...Although benefits of omega-6 fats remain to be proven, increasing omega-6 fats may be of benefit in people at high risk of MI. Increased omega-6 fats reduce serum total cholesterol but not other blood fat fractions or adiposity."

• Kim and Kim 2020. Nutrients. 12(9):2523: "Evidence from prospective studies indicated that intake of n-6 PUFAs was not significantly associated with risk of cancer, but blood levels of n-6 PUFAs were inversely associated with risk of cancer."

Notes: "...the best information that science can provide is that putting arachidonic acid, a particular omega-6 fatty acid, in infant formula doesn't improve infant development. Not enough research has been done on omega-6 fatty acids to judge whether or not they are effective for other uses" (MedlinePlus 2020. Op. cit.). There is some controversy over the relative amounts of omega-3 and omega-6 fatty acids that should be in the diet. Omega-6 levels have increased in recent years, due to changes such as an increased use of soybean oil. The relative amounts of omega-3 and omega-6 affect the distribution of eicosanoids, which have both pro- and anti-inflammatory effects.

Omega-7 fatty acids

Promoted for: " if you search for omega-7 supplements on the Internet, you’ll find pages of results of articles and online retailers purporting the beneficial effects of omega-7 fatty acids (particularly from sea buckthorn oil), such as for heart, digestive, and liver health, immune support, weight loss, detoxification, glucose (blood sugar) metabolism, hydration of mucous membranes, and healthy skin, hair, and nails" (Department of Defense Dietary Supplement Resource. 2019. Omega 7 supplements).

Notes: "a limited amount of research using isolated cells and animals suggests that an external source of palmitoleic acid (by mouth in a dietary supplement or by injection) can increase fatty-acid breakdown and energy expenditure, reduce weight gain and food intake, and improve insulin sensitivity and glucose metabolism. But there hasn’t been enough research on either omega-7 or palmitoleic acid supplements in humans to determine if they’re effective. As a result, no recommended dose or source of omega-7s or palmitoleic acid has been established so far" (Ibid.). According to Retraction Watch (2021 Apr 16. Palmitoleic acid paper pulled for data concerns), "A journal has retracted the 2014 report of a clinical trial of a supplement touted as a way to reduce the risk of cardiovascular disease after beginning to suspect that the data were not reliable." The palmitoleic acid product was promoted by Dr. Mehmet Oz.

Fennel

Promoted for: "Fennel is used by mouth for excessive crying in infants (colic), indigestion (dyspepsia), menstrual cramps (dysmenorrhea), and symptoms of menopause" (WebMD 2020. Fennel).

Presumed mechanism of action: "Fennel might relax the colon. Fennel also appears to contain an ingredient that may act like estrogen in the body" (Ibid.).

Possible adverse effects: "Fennel is LIKELY SAFE in the amounts commonly found in food. It is POSSIBLY SAFE when used at appropriate doses for a short period of time. There isn't enough reliable information to know whether fennel is safe when used as medicine for longer periods of time. Although rare, side effects might include stomach upset. Seizures have occurred when taking fennel essential oil by mouth" (Ibid.).

Reviews:

• Lee et al. 2020. Nutrients. 12(11):3438: "This systematic review concludes that fennel is as effective as conventional drug therapies in alleviating pain in primary dysmenorrhea."

• Shahrahmani et al. 2021. J Complement Integr Med. 18(2):261-9: "The F. vulgare alleviates dysmenorrhea. Regarding the same effect of F. vulgare with NSAIDs [nonsteroidal anti-inflammatory drugs], it is highly recommend to the women suffered from dysmenorrhea specifically the ones who have high tendency toward herbal medicine."

Notes: According to Natural Medicines Comprehensive Database, as cited by WebMD, there is insufficient evidence of effectiveness for any use. 

Fibers, soluble (e.g., psyllium)

Promoted for: "Aid intestinal cleansing by pulling heavy metals and toxins out of the body." Aid dieting, due to feeling of fullness.

Notes: soluble fibers may lower cholesterol.

Fish oils - see fatty acids

“Flavocoxid is a medical food consisting of plant derived flavonoids which have anti-inflammatory activity and are used to provide nutritional support to people with chronic osteoarthritis. Flavocoxid has been approved for use as a medical food in the United States since 2004 and is available by prescription for use in chronic osteoarthritis in tablets of 500 mg under the commercial name Limbrel. Flavocoxid has been linked to occasional minor elevations in serum enzyme levels during therapy and to rare instances of clinically apparent liver injury” (Wikipedia 2021. Flavocoxid). “The standardized formula of Limbrel is primarily comprised of two groups of flavonoid constituents: baicalin (from Scutellaria baicalensis) and catechin (from Acacia catechu)” Moyer 2006 Feb 21. Medscape).

Flaxseed and flaxseed oil (with the ω-3 fatty acid alpha-linolenic acid (ALA))

Promoted for: high cholesterol, inflammation, prevention of cancer, premenstrual syndrome, constipation, diabetes, hot flashes, arthritis

Presumed mechanism of action: fiber in flaxseed might help with constipation. Source of alpha linolenic acid, phytoestrogens, and lignans.

Possible adverse effects: diarrhea, interference with vitamin absorption. “Don’t eat raw or unripe flaxseeds, which may contain potentially toxic compounds...Flaxseed may be unsafe during pregnancy as it may have mild hormonal effects..Some research suggests that flaxseed oil taken in the second or third trimester of pregnancy may increase the chance of premature births. Little is known about whether it’s safe to use flaxseed while breastfeeding. Flaxseed, like any fiber supplement, should be taken with plenty of water, as it could worsen constipation or, in rare cases, cause an intestinal blockage” (NCCIH 2020. Flaxseed and flaxseed oil).

Review:  Sahebkar et al. 2021. Altern Ther Health Med. 27(3):50-3: "...the results suggested a significant decrease in plasma Lp(a) [lipoprotein(a), a risk factor for premature cardiovascular disease] levels...following supplementation with flaxseed-containing products. Conclusions: This finding highlights the potential clinical significance of flaxseed supplementation for patients who are at risk of a high residual CVD [cardiovascular disease] despite intensive statin therapy, patients with hyperlipoproteinemia(a), and patients who prefer natural remedies for CVD prevention in the context of a healthy lifestyle."

Notes: “Flaxseed contains fiber, which may relieve constipation. However, there’s little research on the effectiveness of flaxseed for this condition. Authors of a 2019 review article suggest that flaxseed may be helpful for some people diagnosed with heart and blood vessel diseases. (It is not known whether flaxseed oil might have a similar effect.) Research suggests that flaxseed may help with blood sugar levels in some people with type 2 diabetes. (It is not known whether flaxseed oil might have a similar effect.) Studies have had conflicting results on whether flaxseed helps with symptoms of menopause” (NCCIH 2020. Op. cit.).

Fluoride - see trace minerals (SUPPLEMENTS PART 1)

Promoted for: prevention of dental caries and bone fractures

Presumed mechanism of action: “ inhibits or reverses the initiation and progression of dental caries (tooth decay) and stimulates new bone formation” (NIH Office of Dietary Supplements 2020. Fluoride).

Possible adverse effects: Excess early in life can lead to dental fluorosis. “Chronic, excess intakes of fluoride are also associated with skeletal fluorosis...Its effects can range from occasional joint pain or stiffness to osteoporosis, muscle wasting, and neurological defects” (Ibid.).

Reviews:

• Vestergaard et al. 2008. Osteoporos Int. 19(3):257-68: “Fluoride treatment increases spine and hip BMD [bone mineral density], depending on treatment duration. Overall there was no effect on hip or spine fracture risk. However, in subgroup analyses a low fluoride dose (< or =20 mg/day of fluoride equivalents) was associated with a significant reduction in fracture risk.”

• Tubert-Jeannin et al. 2011. Cochrane Database Syst Rev. CD007592: “This review suggests that the use of fluoride supplements is associated with a reduction in caries increment when compared with no fluoride supplement in permanent teeth. The effect of fluoride supplements was unclear on deciduous teeth.”

• Chou et al. 2013. Pediatrics. 132(2):332-50: “Evidence previously reviewed by the US Preventive Services Task Force found oral fluoride supplementation effective at reducing caries incidence...”

Notes: “Overall, the available evidence suggests that dietary supplements containing fluoride can reduce rates of dental caries in children who lack access to fluoridated drinking water. No studies have assessed the impact of fluoride supplements on caries development in adults...Clinical trials have also had conflicting findings about the efficacy of fluoride dietary supplements to prevent bone fractures” (NIH-ODS 2020. Fluoride).

Folate, folic acid - see water-soluble vitamins (SUPPLEMENTS PART 1)

Promoted for: prevention of congenital abnormalities, autism, cancer, heart disease, stroke, and Alzheimer’s disease; cognitive performance; depression

Presumed mechanism of action: some potential benefits are thought to arise from the effects of folate to lower homocysteine levels.

Possible adverse effects: see section on water-soluble vitamins.

Reviews:

• Wald et al. 2006. BMJ. 333(7578):1114-7: "Since folic acid reduces homocysteine concentrations, to an extent dependent on background folate levels, it follows that increasing folic acid consumption will reduce the risk of heart attack and stroke by an amount related to the homocysteine reduction achieved."

• Bazzano et al. 2006. JAMA. 296(22):2720-6: "Folic acid supplementation has not been shown to reduce risk of cardiovascular diseases or all-cause mortality among participants with prior history of vascular disease."

• Clarke et al. 2010. Arch Intern Med. 170(18):1622-31: "Dietary supplementation with folic acid to lower homocysteine levels had no significant effects within 5 years on cardiovascular events or on overall cancer or mortality in the populations studied."

• Vollset et al. 2013. Lancet. 381(9871):1029-36: "Folic acid supplementation does not substantially increase or decrease incidence of site-specific cancer during the first 5 years of treatment. Fortification of flour and other cereal products involves doses of folic acid that are, on average, an order of magnitude smaller than the doses used in these trials."

Notes: “Dietary supplements containing 5-methyl-THF (also called methylfolate), a reduced form of folate, are also available. For some people, supplementation with 5-methyl-THF might be more beneficial than with folic acid...The bioavailability of 5-methyl-THF in supplements is the same as or greater than that of folic acid” (NIH Office of Dietary Supplements 2020. Folate). This article also makes the following points:

• “Emerging evidence suggests that periconceptional folic acid supplementation might reduce the risk of ASD [autism spectrum disorder] or mitigate the potentially increased risk of ASD from prenatal exposure to certain drugs and toxic chemicals.”

• Concerning prevention of cancer: “Results from clinical trials involving folic acid supplementation have been mixed. In addition, most trials have included other B-vitamins (frequently at doses well above RDA levels) and sometimes other nutrients, making it difficult to disentangle the effects, if any, of folic acid alone...Overall, the evidence to date indicates that adequate dietary folate intake might reduce the risk of some forms of cancer. However, the effects of supplemental folic acid on cancer risk are unclear, especially among individuals with a history of colorectal adenomas or other forms of cancer.”

• “Overall, the available evidence suggests that supplementation with folic acid alone or in combination with other B-vitamins reduces the risk of stroke, especially in populations with low folate status, but does not affect other cardiovascular endpoints.”

• “...most clinical trial research has not shown that folic acid supplementation affects cognitive function or the development of dementia or Alzheimer’s disease, even though supplementation lowers homocysteine levels...Several large reviews have evaluated the effect of B vitamins on cognitive function. Most of the authors concluded that supplementation with folic acid alone or in combination with vitamins B12 or B6 does not appear to improve cognitive function in individuals with or without cognitive impairment. Some noted, however, that when researchers took baseline homocysteine and B-vitamin status into account, B-vitamin supplementation slowed cognitive decline in individuals at high risk of cognitive decline.”

The relationship of folate to cancer is complex. Supplementation might protect from mutations that initiate cancer; on the other hand, it might also promote proliferation of cancer once it has been initiated.

Gamma-hydroxybutyrate (GHB)

Promoted for: bodybuilding, recreational drug

Possible adverse effects: vomiting, dizziness, tremors, seizures, severe withdrawal symptoms

Notes: Has caused several deaths. Banned by FDA, but illegal use continues. There are similar problems with gamma-butyrolactone (GBL) and butanediol (BD).

Gamma-linolenic acid (GLA) - an omega-6 fatty acid from black currant seed, evening primrose, and other oils

Promoted for: “People use GLA for conditions such as nerve pain in people with diabetes (diabetic neuropathy), eczema (atopic dermatitis), arthritis, high blood pressure, and other conditions” (WebMD 2020. Gamma-linolenic acid (Gla)).

Possible adverse effect: “GLA is POSSIBLY SAFE for most adults when taken in a dose of up to 2.8 grams daily for up to a year. It can cause some gastrointestinal side effects, such as soft stools, diarrhea, belching, and gas. It can also make blood take longer to clot” (Ibid.).

Presumed mechanism of action: benefits may arise from its role as a precursor to prostaglandins.

Notes: According to WebMD (2020. Op. cit.), it is possibly effective for diabetic neuropathy; possibly ineffective for eczema, scleroderma, and ulcerative colitis. For other conditions there is too little information to judge effectiveness.

Garlic

Promoted for: "Garlic is most commonly promoted as a dietary supplement for conditions related to the heart and blood vessels, including high blood cholesterol and high blood pressure" (NCCIH 2020. Garlic); also for treating the common cold and other infections, and preventing cancer.

Presumed mechanism of action: active ingredients are allicin and other sulfur-containing compounds. These may break down to produce hydrogen sulfide, which can cause relaxation of blood vessels and reduction in blood pressure. Allicin "is derived from the odorless compound alliin through the action of the enzyme alliinase. The mechanical action of crushing or cutting brings the enzyme alliinase into contact with alliin, yielding the unstable pungent principal allicin. Other bioactive compounds in garlic include ajoene, allixin, erubosides, S-allyl cysteine, and N-acetyl S-allyl cysteine...Many of these compounds have antithrombotic and antiplatelet effects, reduce LDL oxidation, and affect expression of endothelial adhesion molecules during simulated endothelial injury" (Charlson and McFerren 2007. Arch Intern Med. 167(4):325-6).

Possible adverse effects: "Side effects include breath and body odor, heartburn, and upset stomach. These side effects can be more noticeable with raw garlic. Some people have allergic reactions to garlic. Taking garlic supplements may increase the risk of bleeding. If you take an anticoagulant (blood thinner), such as warfarin (Coumadin), or if you need surgery, tell your health care provider if you’re taking or planning to take garlic supplements. Garlic supplements may interfere with the effectiveness of some drugs, including saquinavir, a drug used to treat HIV infection" (NCCIH 2020. Garlic).

Reviews:

• Hu et al. 2014. World J Gastroenterol. 20(41):15413-22: "Consumption of RC [raw and cooked] garlic or garlic supplements is not significantly associated with reduced colorectal cancer risk."

• Varshney and Budoff 2016. J Nutr. 146(2):416S-421S: "We conclude that garlic supplementation has the potential for cardiovascular protection based on risk factor reduction (hypertension and total cholesterol) and surrogate markers (CRP [C-reactive protein], PWV [pulse wave velocity], and CAC [coronary artery calcium]) of atherosclerosis. Larger studies are warranted to evaluate these effects further."

• Panjeshahin et al. 2020. Phytother Res. 2020 Aug;34(8):1947-55 [liver enzymes]: "Results showed that garlic supplementation reduced AST [aspartate transaminase] levels significantly; however, had no significant effect on ALT [alanine transaminase] levels."

• Mirzavandi et al. 2020. Diabetes Metab Syndr. 14(5):1153-61 [inflammatory markers]: "This meta-analysis showed that supplementation with garlic could reduce the level of circulating CRP [C-reactive protein] and AGE [aged garlic extract] could reduce the level of TNF-a [tumor necrosis factor α] and CRP, whereas it had no significant effect on the IL-6 [interleukin-6] level."

• Askari et al. 2021. Phytother Res. 35(6):3032-45: "Garlic supplementation appears to improve serum levels of TAC [total antioxidant capacity], MDA [malondialdehyde], and SOD [superoxide dismutase]. Garlic supplementation may be useful to reduce oxidative stress and related diseases."

Notes: The following points were made in the NCCIH article:

• While there’s conflicting evidence, the most reliable results suggest that taking garlic supplements may reduce total cholesterol and low-density lipoprotein (LDL) cholesterol levels in people with high levels of these blood lipids. If it does, the effect is small, and it may take more than 8 weeks before noting any improvement. Taking garlic doesn’t appear to improve high-density lipoprotein (HDL) levels or triglycerides (another blood lipid).”

• “Garlic supplements may be helpful for high blood pressure, but the evidence is limited.”

• “The most reliable research has found that intake of garlic as a food or supplement is not associated with a reduced risk of developing gastric cancer. However, epidemiologic studies suggest a link between higher intakes of vegetables in the garlic family (which includes onions, shallots, chives, and leeks as well as garlic) and lower risks of certain cancers, particularly gastrointestinal cancers.”

• “There’s not enough evidence to show whether garlic is helpful for the common cold."

A problem with garlic studies is that adequate blinding requires preparations lacking in distinctive taste and odor, which may remove active ingredients.

Gelatin - see also collagen above

Promoted for: "aging skin, osteoarthritis, weak and brittle bones (osteoporosis), brittle nails, obesity, and many other conditions" (MedlinePlus 2020. Gelatin).

Presumed mechanism of action: gelatin is made of collagen; as with other ingested proteins, the collagen would be digested to amino acids. Presumably these would enhance the synthesis of new collagen.

Notes: Natural Medicines Comprehensive Database found "insufficient evidence to rate effectiveness" for numerous conditions.

Genistein - an isoflavone found in soybean and some other plants

Promoted for: hot flashes and other menopausal symptoms

Presumed mechanism of action: estrogen-like effects

Possible adverse effects: can counteract the effects of aromatase inhibitors (used in breast cancer treatment)

Gerovital (GH3)

Promoted for: anti-aging remedy, prevention of many diseases

Possible adverse effects: low blood pressure, breathing problems, convulsions

Notes: major component is procaine. No benefit was seen in controlled trials. "In the United States, the FDA bans Gerovital H3 from interstate commerce as an unapproved drug and, since 1982, has prohibited its importation" (Wikipedia 2021. Gerovital).

"Glandulars" (material from animal organs)

Promoted for: alleged to treat the corresponding organ (e.g.,adrenals)

Possible adverse effects: bacterial contamination, potential spread of prion diseases

Notes: would be digested like other foods, not targeted to any particular organ

Glucosamine and chondroitin. These are considered together here because both are promoted for similar uses and are often taken together. Some studies have examined them in combination. Glucosamine is an amino sugar that is produced within the body in the form of glucosamine 6-phosphate, which is then converted to UDP-N-acetylglucosamine. UDP-N-acetylglucosamine then is the donor of glucosamine groups for the synthesis of macromolecules such as  glycosaminoglycans, proteoglycans, and glycolipids. Glucosamine is usually marketed in the form of a salt such as glucosamine sulfate or glucosamine hydrochloride. "Chondroitin sulfate is a sulfated glycosaminoglycan (GAG) composed of a chain of alternating sugars (N-acetylgalactosamine and glucuronic acid). It is usually found attached to proteins as part of a proteoglycan. A chondroitin chain can have over 100 individual sugars, each of which can be sulfated in variable positions and quantities. Chondroitin sulfate is an important structural component of cartilage, and provides much of its resistance to compression" (Wikipedia 2021. Chondroitin sulfate). As with glucosamine, it is formed naturally in the body and is not required in the diet.

Promoted for: treatment of arthritis. Benefits for preventing various diseases are also proposed.

Presumed mechanism of action: The original rationale for glucosamine was that glucosamine synthesis is rate-determining for proteoglycan synthesis, needed for restoration of cartilage, and ingested glucosamine could be used for this pathway. This seems unlikely, as discussed below, and extracellular effects such as inhibition of proteoglycan breakdown are now favored as explanations. Kucharz et al. (2016. Curr Med Res Opin. 32(6):997-1004) wrote, "When administered exogenously, glucosamine exerts specific pharmacological effects on osteoarthritic cartilage and chondrocytes. Glucosamine affects gene expression of OA cartilage, and the anti-catabolic activities of glucosamine are responsible for its therapeutic effects." These authors note that administration of glucosamine sulfate can lead to a plasma level of 9 micromolar glucosamine. "Several potential mechanisms could explain the observed protective relation between glucosamine use and CVD [cardiovascular disease] diseases. In the National Health and Nutrition Examination Survey (NHANES) study, regular use of glucosamine was associated with a statistically significant reduction in C reactive protein concentrations, which is a marker for systemic inflammation. Animal studies also reported that the anti-inflammatory properties of glucosamine might have a preventive role in the pathophysiology of CVD. In addition, a previous study found that glucosamine could mimic a low carbohydrate diet by decreasing glycolysis and increasing amino acid catabolism in mice; therefore, glucosamine has been treated as an energy restriction mimetic agent" (Ma et al. 2019. BMJ. 365:l1628). In the case of chondroitin, "Proposed mechanisms of action include restoring the extracellular matrix of cartilage, preventing further cartilage degradation, and overcoming a dietary deficiency of sulfur-containing amino acids" (Hall 2017 May 30. Science-Based Medicine blog).

Possible adverse effects: There are possible allergic reactions with products derived from shellfish. "Glucosamine sulfate can cause some mild side effects including nausea, heartburn, diarrhea, and constipation. Uncommon side effects are drowsiness, skin reactions, and headache" (MedlinePlus 2021. Glucosamine sulfate). "Glucosamine hydrochloride can cause gas, bloating, and cramps. Some glucosamine products do not contain the labeled amount of glucosamine or contain excessive amounts of manganese" (MedlinePlus 2020. Glucosamine hydrochloride). "Glucosamine and chondroitin supplements may interact with the anticoagulant (blood-thinning) drug warfarin (Coumadin)" (NCCIH 2014. Glucosamine and chondroitin for osteoarthritis).

Reviews and major trials, glucosamine:

• Kucharz et al. 2016. Op. cit.: "It is evident, from careful consideration of the evidence base, that only the pCGS [patented crystalline glucosamine sulfate] formulation of glucosamine reliably provides an effect size on pain that is higher than that of paracetamol and equivalent to that provided by non-steroidal anti-inflammatory drugs. In comparison, the effect size on pain of non-crystalline GS preparations and GH [glucosamine hydrochloride] from randomized controlled trials is repeatedly demonstrated to be zero. In addition, there is evidence that chronic administration of pCGS has disease-modifying effects, with a reduction in the need for total joint replacement surgery lasting for at least 5 years after treatment cessation."

• Ma et al. 2019. Op. cit. [UK Biobank study]: "Habitual use of glucosamine supplement to relieve osteoarthritis pain might also be related to lower risks of CVD [cardiovascular disease] events."

• Li et al. 2020. Ann Rheum Dis. 79(6):829-36 [UK Biobank study]: "Regular glucosamine supplementation was associated with lower mortality due to all causes, cancer, CVD, respiratory and digestive diseases."

Reviews and major trials, chondroitin:

• Reichenbach et al. 2007. Ann Intern Med. 2007 Apr 17;146(8):580-90: "Large-scale, methodologically sound trials indicate that the symptomatic benefit of chondroitin is minimal or nonexistent. Use of chondroitin in routine clinical practice should therefore be discouraged."

• Kahan et al. 2009. Arthritis Rheum. 60(2):524-33 [trial]: "The long-term combined structure-modifying and symptom-modifying effects of CS [chondroitin sulfate] suggest that it could be a disease-modifying agent in patients with knee OA [osteoarthritis]."            

• Singh et al. 2015. Cochrane Database Syst Rev. CD005614: "A review of randomized trials of mostly low quality reveals that chondroitin (alone or in combination with glucosamine) was better than placebo in improving pain in participants with osteoarthritis in short-term studies. The benefit was small to moderate..."

• Reginster et al. 2017. Ann Rheum Dis. 76(9):1537-43 [CONCEPT trial]: " A 800 mg/day pharmaceutical-grade CS is superior to placebo and similar to celecoxib in reducing pain and improving function over 6 months in symptomatic knee osteoarthritis (OA) patients. This formulation of CS should be considered a first-line treatment in the medical management of knee OA."

• Honvo et al. 2019. Adv Ther. 36(5):1085-99: "This new meta-analysis suggests that CS provides a moderate benefit for pain and has a large effect on function in knee OA, however with large inconsistency. The risks of bias, brand and study size were the factors explaining heterogeneity among the clinical trial results."

Reviews and major trials, glucosamine and chondroitin:

• Clegg et al. 2007. N Engl J Med. 354(8):795-808 [GAIT trial]: "Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee. Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain."

• Sawitzke et al. 2008. Arthritis Rheum. 58(10):3183-91 [GAIT trial]: "At 2 years, no treatment achieved a predefined threshold of clinically important difference in JSW [joint space width] loss as compared with placebo. However, knees with K/L grade 2 radiographic OA appeared to have the greatest potential for modification by these treatments."

• Sawitzke et al. 2010. Ann Rheum Dis. 69(8):1459-64 [GAIT trial]: "Over 2 years, no treatment achieved a clinically important difference in WOMAC [Western Ontario and McMaster University Osteoarthritis Index] pain or function as compared with placebo. However, glucosamine and celecoxib showed beneficial but not significant trends."

• Wandel et al. 2010. BMJ. 341:c4675: "Compared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain or have an impact on narrowing of joint space. Health authorities and health insurers should not cover the costs of these preparations, and new prescriptions to patients who have not received treatment should be discouraged."

• Henrotin and Lambert 2013. Curr Rheumatol Rep. 15(10):361: "Clinical trials, although providing conflicting and questionable results, report symptomatic and structure-modifying effects for both pharmaceutical-grade compounds."

• Yang et al. 2015. Arthritis Rheumatol. 67(3):714-23 [trial]: "Use of glucosamine/chondroitin did not appear to relieve symptoms or modify disease progression among patients with radiographically confirmed OA. Our findings are consistent with the results of meta-analyses of clinical trials and extend those results to a more general population with knee OA."

• King and Xiang 2020. J Am Board Fam Med. 33(6):842-7 [National Health and Nutrition Examination Survey]: "Regular intake of glucosamine/chondroitin is associated with lower all-cause and CVD mortality in a national US cohort and the findings are consistent with previous studies in other populations."

Notes: It has been noted that positive studies were funded by manufacturers, while negative studies were independent. Placebo effects of as large as 60% have been reported, which might explain why many supplement users feel they are receiving benefits. This also makes it more difficult to measure genuine effects beyond placebo. A 2003 paper, using cultured chondrocytes, found that exogenous glucosamine had no ability to increase chondroitin sulfate synthesis. Also, glucosamine itself is not normally used in the synthesis of macromolecules containing glucosamine groups. Biggee et al. (2006. Ann Rheum Dis. 65(2):222-6), referring to the maximum level of serum glucosamine after ingestion of supplements, wrote, "This maximum concentration of 11.5 μmol/l has previously been shown to contribute less than 2% of the galactosamine incorporated into chondroitin sulphate in incubations of glucosamine with cultured human chondrocytes, and is a much lower concentration than the glucosamine concentrations claimed by other investigators to have various significant in vitro effects. This raises questions about current biological rationales for glucosamine use that were based on in vitro effects of glucosamine at much higher concentrations." However, extracellular effects (such as the inhibition of proteoglycan breakdown) remain possible. (It has also been proposed that the sulfate is useful, not the glucosamine; the compound is usually sold as the sulfate salt.) A beneficial effect of chondroitin sulfate is less plausible, since this large molecule is unlikely to survive digestion, be absorbed, and delivered to a useful site. Conflicting results have been reported concerning the ability of chondroitin sulfate to be taken up in intact form.

MedlinePlus makes the following points concerning glucosamine sulfate (taken from Natural Medicines Comprehensive Database):

• Likely effective for osteoarthritis. "Most research shows that taking glucosamine sulfate can provide some pain relief for people with osteoarthritis, especially those with osteoarthritis of the knees...In addition to relieving pain, glucosamine sulfate might also slow the breakdown of joints and prevent the condition from getting worse if it is taken for several years...Glucosamine sulfate does not seem to prevent people from getting osteoarthritis."

• Insufficient evidence to rate effectiveness for other conditions.

Concerning glucosamine hydrochloride:

• Insufficient evidence to rate effectiveness for osteoarthritis and other conditions. "There is conflicting evidence about the effectiveness of glucosamine hydrochloride for osteoarthritis. Most of the evidence supporting the use of glucosamine hydrochloride comes from studies of a particular product (CosaminDS). This product contains a combination of glucosamine hydrochloride, chondroitin sulfate, and manganese ascorbate. Some evidence suggests that this combination can improve pain in people with knee osteoarthritis."

• "The effects of taking glucosamine hydrochloride along with only chondroitin sulfate are mixed."

• "Most research suggests that taking glucosamine hydrochloride alone does not reduce pain in people with osteoarthritis of the knee."

• "More research has been done on glucosamine sulfate...than on glucosamine hydrochloride. There is some thought that glucosamine sulfate may be more effective than glucosamine hydrochloride for osteoarthritis. Most research comparing the two forms of glucosamine showed no difference. However, some researchers have criticized the quality of some of these studies."

MedlinePlus (2020. Chondroitin sulfate) notes that "Some chondroitin sulfate products are not labeled accurately. In some cases, the amount of chondroitin has varied from none to more than 100% of the amount stated on the product's label. Also, some products contain chondroitin that is taken from multiple different animals, even though this is not always stated on the label." It also notes the following (taken from Natural Medicines Comprehensive Database):

• Possibly effective for osteoarthritis. "Clinical research shows that taking chondroitin sulfate by mouth modestly improves pain and function in some people with osteoarthritis when used for up to 6 months. It seems to work best in people with more severe pain and when a pharmaceutical-grade preparation is used. Specific products that have shown benefit in patients with osteoarthritis include Chondrosulf (IBSA Institut Biochimique SA), Chondrosan (Bioibérica, S.A.), and Structrum (Laboratoires Pierre Fabre). But pain relief is likely to be small at best. Other research shows that taking chondroitin sulfate for up to 2 years might slow the progression of osteoarthritis. Some research has evaluated the effects of chondroitin sulfate when taken by mouth in combination with glucosamine. Some research shows that taking specific products containing chondroitin sulfate and glucosamine helps reduce symptoms of osteoarthritis. Other research shows no benefit when non-commercial preparations are used. Taking chondroitin sulfate plus glucosamine long-term appears to slow the progression of osteoarthritis."

• Insufficient evidence to rate effectiveness for other conditions.

Hall (2017. Op. cit.) noted that "If a medication is truly effective, that should become more and more obvious over time as more and better studies are done. And that hasn’t happened with chondroitin." Concerning the rationale for chondroitin supplements, she quoted a pathologist stating "I doubt that dietary glucosamine or chondroitin sulfate are absorbed from the gut as such. Further, human cartilage contains N-acetyl galactosamine, not glucosamine...Finally, the cartilaginous glycosaminoglycan matrix is synthesized by the chondrocytes, and it is naive to assume that dietary supplements will 'home' to that avascular tissue." Felson (2007. Ann Intern Med. 146(8):611-2) wrote, "There are 2 other practical concerns about the potential efficacy of chondroitin sulfate. First, because chondroitin is a large macromolecule, only about 12% to 13% of ingested chondroitin is absorbed intact into the bloodstream. Second, while chondroitin therapy supposedly targets cartilage, osteoarthritis affects the whole joint, not just cartilage. Pathologies include bone sclerosis, remodeling and deformity, ligamentous stretching and loss of integrity, muscle atrophy, joint capsular stretching, and even synovial inflammation. A molecule targeted only at constituents of cartilage is unlikely to affect all manifestations of osteoarthritis. Also, any treatment targeting cartilage alone would be unlikely to alleviate pain, the predominant symptom of osteoarthritis, because cartilage is aneural. Animal studies suggest that chondroitin functions as an anti-inflammatory agent rather than being directly integrated into cartilage. If chondroitin does indeed have a modest anti-inflammatory effect, then it could alleviate pain."

Glutamate (glutamic acid) - a nonessential amino acid

Promoted for: improving memory.

Glutamine - a nonessential amino acid (except for some seriously ill patients)

Promoted for: to provide glutamate to brain; build muscle protein

Notes: "The research to date does not support taking glutamine alone to improve exercise and athletic performance" (NIH Office of Dietary Supplements 2019. Dietary supplements for exercise and athletic performance).

Glutathione - a tripeptide (γ-L-glutamyl-L-cysteinylglycine) formed within cells, where it provides antioxidant functions.

Promoted for: "Glutathione is said to protect against a wide range of health problems, including atherosclerosis, Lyme disease, Alzheimer's disease, chronic fatigue syndrome, colitis, high cholesterol, osteoarthritis, alcoholism, asthma, cataracts, diabetes, glaucoma, heart disease, hepatitis, liver disease, and Parkinson's disease" (Wong 2020. The health benefits of glutathione. Verywell Health).

In addition, glutathione is purported to reverse the aging process, prevent cancer, and preserve memory.

Presumed mechanism of action: antioxidant, neutralizing reactive oxygen species; keeps intracellular molecules such as vitamin C in a reduced state; attached to toxic molecules in order to aid in their metabolism and excretion.

Notes: oral glutathione is degraded in the intestinal tract so it is unlikely to survive and reach the inside of cells to provide any benefit. As alternatives, liposomal and inhaled forms have also been promoted. "While research on the use of glutathione supplements is fairly limited, there's some evidence that glutathione may offer certain benefits when taken in supplement form. But the benefits could be due to the increase in L-cysteine as glutathione is digested into its amino acids" (Wong 2020. Op. cit.). " Inhaled glutathione is commonly used in the CAM community to treat a number of conditions, such as asthma, chronic obstructive pulmonary disease, bronchitis, sinusitis, and chemical sensitivity" (Allen 2008. Altern Ther Health Med. 14(3):42-4).

"Glyconutrients" - an invented term used by Mannatech and disavowed by genuine researchers in glycobiology, the study of sugars found in living things (such as polysaccharides and glycoproteins). Mannatech, whose leading product is Ambrotose, markets products containing eight sugars claimed to be needed but not present in the diet in sufficient amounts. A variety of products have been formulated containing Ambrotose combined with other supplement ingredients. Ambrotose complex contains "Arabinogalactan (from Larix spp. wood), Aloe vera (inner leaf gel powder), Ghatti Gum, Gum Tragacanth" (Supplement Facts listed on us.mannatech.com 2021).

Promoted for: "Company representatives and other advocates continue to claim in seminars and on the Internet that Ambrotose helps with a variety of conditions including MS, AIDS, cancer, lupus, colitis, diabetes, fibromyalgia, cystic fibrosis, ADHD, neuralgia, wound healing, and much more" (Hall 2016 Sep 13. Science-Based Medicine blog).

Presumed mechanism of action: provide simple sugars (monosaccharides) needed to synthesize glycoproteins and other complex carbohydrates

Notes: The sugars are made from other nutrients and are not required in the diet. Schnaar and Freeze (2008. Glycobiology. 18(9):652–7) noted that "except for rare patients with certain types of congenital disorders of glycosylation (CDG)...the inference that humans can benefit clinically from ingesting these monosaccharides is unsupported by controlled clinical trials. Furthermore, the relationship between Mannatech's flagship product, Ambrotose® Complex, and vertebrate glycans is tenuous. Ambrotose® Complex consists of a mixture of partially purified polydisperse plant polysaccharides...Claims of health benefits of ingesting Ambrotose® Complex, or its components, remain untested in controlled human trials, or have been disproved in such trials, depending on the indication...one must ask whether branched plant polysaccharides are effectively digested to provide biologically meaningful concentrations of individual monosaccharides that reach human tissues". In a later article (Schnaar and Freeze 2017. Glycobiology. 27(5):383-4), these authors found that while there were additional studies related to Ambrotose, "None provide convincing evidence that lead us to change our previous conclusion...Our conclusion is that there remains insufficient evidence to conclude that 'glyconutrients' diagnose, treat, cure or prevent any disease. Further, we have not found convincing evidence to indicate that, except as a source of indigestible fiber, Ambrotose® enhances health or quality of life."  Hall (2016 Sep 13. Science-Based Medicine blog) wrote, "The company’s own magazine even admitted that there were no double-blind, placebo-controlled studies of the type used by drug companies establishing that its products work." Mannatech was the subject of a lawsuit by the state of Texas in 2007, and received FDA warnings for illegal marketing of supplement products in 2017.

Grape (see also grape seed extract below)

Promoted for: "Grape is used for poor circulation that can cause the legs to swell (chronic venous insufficiency or CVI) or for eye stress. Various grape products are also commonly used for diseases of the heart and blood vessels, other eye problems, gastrointestinal health, and many other conditions" (MedlinePlus 2021. Grape).

Presumed mechanism of action: "Grape contains flavonoids, which can have antioxidant effects, lower the levels of low density lipoproteins..., relax blood vessels, and reduce the risk of coronary heart disease. The antioxidants in grape might help to prevent heart disease and have other potentially beneficial effects" (Ibid.).

Possible adverse effects: "Eating large quantities of grapes, dried grapes, raisins, or sultanas might cause diarrhea. Some people have allergic reactions to grapes and grape products. Some other potential side effects include stomach upset, indigestion, nausea, vomiting, cough, dry mouth, sore throat, infections, headache, and muscular problems...Grape juice might increase how quickly the liver breaks down some medications. Taking grape along with some medications that are changed by the liver can decrease the effectiveness of these medications" (Ibid.).

Notes: Natural Medicines Comprehensive Database (cited in MedlinePlus 2021. Grape) considers grape to be possibly effective for chronic venous insufficiency and eye stress; possibly ineffective for hay fever, nausea and vomiting caused by chemotherapy, lower urinary tract symptoms, breast pain, and obesity; insufficient evidence to rate effectiveness for other conditions.

Grape seed extract - made from the seeds of wine grapes

Promoted for: "Grape seed extract is used for conditions related to the heart and blood vessels, such as atherosclerosis..., high blood pressure, high cholesterol, and poor circulation. Other reasons...include complications related to diabetes, such as nerve and eye damage; vision problems, such as macular degeneration...; and swelling after an injury or surgery. Grape seed extract is also used for cancer prevention and wound healing" (NCCAM 2007. Grape seed extract).

Presumed mechanism of action: antioxidant effects of proanthocyanidins

Possible adverse effects: "Grape seed extract might decrease how quickly the liver breaks down some medications. Taking grape seed extract along with some medications that are changed by the liver might increase the effects and side effects of these medications" (MedlinePlus 2021. Grape). Interactions with anticoagulants are of special concern. Also, "...people with high blood pressure should not take high doses of grape seed extract with vitamin C because the combination might worsen blood pressure" (NCCIH 2020. Grape seed extract). "Side effects that have been reported most often include headache; a dry, itchy scalp; dizziness, and nausea" (NCCAM 2007. Grape seed extract).

Notes: The following points are made in NCCIH 2020. Grape seed extract:

• "Some studies suggest that grape seed extract might help with symptoms of chronic venous insufficiency and with eye stress from glare, but the evidence isn’t strong."

• "Conflicting results have come from studies on grape seed extract’s effect on blood pressure. It’s possible that grape seed extract might help to slightly lower blood pressure in healthy people and those with high blood pressure, particularly in people who are obese or have metabolic syndrome."

• "A 2019 review of 15 studies involving 825 participants suggested that grape seed extract might help lower levels of LDL cholesterol, total cholesterol, triglycerides, and the inflammatory marker C-reactive protein. The individual studies, however, were small in size, which could affect the interpretation of the results."

Grapefruit and grapefruit seed extract. "People use the fruit, oil from the peel, and extracts from the seed as medicine. Grapefruit seed extract is processed from grapefruit seeds and pulp obtained as a byproduct from grapefruit juice production" (MedlinePlus 2020. Grapefruit).

Promoted for: "Grapefruit is commonly taken by mouth for weight loss. It is also used for asthma, high cholesterol, cancer, and many other conditions..." (Ibid.). Grapefruit seed extract "is also consumed orally based on claims that it can treat infections of the gastrointestinal tract (or elsewhere in the body). It is particularly popular for the alternative medicine treatment of what’s called 'chronic candida' infection. Chronic candida is not a real condition, but is a fake disease created out of thin air as an explanation for often non-specific gastrointestinal symptoms. In the 'treatment' of chronic candida, it’s claimed that GSE selectively kills fungi but leaves normal gastrointestinal species intact. In addition to being consumed in the belief that it can treat candida infections, it’s also claimed that GSE can treat toenail fungus, restore normal blood lipids, heal wounds, 'alkalize' the body, is an effective douche, cures warts, treat 'dysbiosis,' and more" (Gavura 2016 Mar 10. Science-Based Medicine blog).

Presumed mechanism of action: "Grapefruit is a source of vitamin C, fiber, potassium, pectin, and other nutrients. Some components might have antioxidant effects that might help protect cells from damage or reduce cholesterol. It is not clear how the oil might work for medicinal uses" (MedlinePlus 2020. Grapefruit).

Possible adverse effects: interactions with some medications. "Taking grapefruit juice along with some medications that are broken down by the liver can increase the effects and side effects of some medications" (Ibid.).

Notes: Natural Medicines Comprehensive Database (as cited by MedlinePlus 2020. Grapefruit) classifies as possibly effective for obesity, and insufficient evidence to rate effectiveness for other conditions. Gavura (2016. Op. cit.) stated "There is no evidence suggesting that actual grapefruit seed extract has any meaningful antibacterial, antifungal, or antiviral effects. Repeated testing over the past 20 years has demonstrated that any GSE efficacy is due to product adulteration with one or more synthetic chemical disinfectants. Adulterated or not, there is no reason to take GSE at all."

Hangover remedies. See also cysteine above. Ingredients may include L-cysteine, N-acetyl-L-cysteine (NAC), an extract of the Japanese raisin tree (Hovenia dulcis), milk thistle, kudzu powder, artichoke leaf extract, prickly pear cactus, and charcoal.

Presumed mechanism of action: Cysteine is thought to enhance the metabolism of alcohol. The active ingredient in Japanese raisin tree is dihydromyrcetin (DHM).

Possible adverse effects: see below

Review: Pittler et al. 2005. BMJ. 331(7531):1515-8: " No compelling evidence exists to suggest that any conventional or complementary intervention is effective for preventing or treating alcohol hangover."

Notes: According to Bellamy (2020 Sep 10. Science-Based Medicine blog), the FDA considers NAC to be an illegal dietary supplement ingredient because is a drug. For this and other reasons related to illegal claims, the FDA issued warning letters to seven companies selling hangover treatment supplements in 2020. Other points made by Bellamy were:

• "There is, in fact, some evidence that DHM is effective in reducing the ill effects of drinking alcohol."

• "According to the Mayo Clinic, there is limited research suggesting prickly pear cactus can lessen the unpleasant effects of a hangover, possibly due to an anti-inflammatory effect, but side effects can include 'mild diarrhea, nausea, increased stool volume, increased stool frequency and abdominal fullness'.”

• "While it is true...that activated charcoal is an effective treatment for poisoning, it should, according to the Mayo Clinic, only be administered for that purpose in a health care facility, where the product is mixed with a liquid and given orally as a drink or via a tube. The capsule form is not used for treating poisoning. Per our pharmacy professor, there is 'no definitive evidence showing it does anything to prevent the severity and/or duration of hangovers'."

Higenamine (norcoclaurine, demethylcoclaurine) - a stimulant found in some traditional herbal remedies.

Promoted for: weight loss, athletic performance

Presumed mechanism of action: a beta-2 adrenoreceptor agonist, causing an increase in cellular cAMP. Can increase heart contractions and speed up heart rate.

Possible adverse effects: "Higenamine is one of the main chemicals in a plant called aconite. Aconite has been shown to cause serious heart-related side effects including irregular heartbeat and even death. These side effects from aconite may, in part, be caused by higenamine" (WebMD 2021. Higenamine).

Notes: Prohibited in sports by the World Anti-Doping Agency.

Himalayan sea salt (pink Himalayan sea salt, Himalayan pink salt)

Promoted for: numerous diverse benefits

Presumed mechanism of action: allegedly contains 84 trace elements that provide nutritional benefits through their "vibrational energies."

Notes: The pink color is due to mineral impurities. Concerning the claimed benefits, Hall (2017 Jan 31. Science-Based Medicine blog) wrote, "There is no evidence for these claims. They are speculations based on findings about larger amounts of minerals that are present only in minute amounts in pink Himalayan salt...By my count, only about a quarter of the minerals in Himalayan pink salt are nutrients that the human body can or might be able to use. The other three quarters are not recognized nutrients and would be better classified as contaminants. They have no known health benefits, and many of them are known to be harmful." Claims related to "vibrational energies" are absurd.

Histidine - an essential amino acid

Promoted for: "Some people take histidine by mouth for metabolic syndrome, diarrhea caused by cholera infection, rheumatoid arthritis, allergic diseases, ulcers, and anemia caused by kidney failure or kidney dialysis" (WebMD 2021. Histidine).

Possible adverse effects: "At high intakes of histidine (>24 g/d), studies report adverse effects of histidine such as decreased serum zinc and cognitive impairment. There is limited research on the effects of histidine intake at doses between 4.5 and 24 g/d, and thus, a tolerable upper level has not been established" (Thalacker-Mercer and Gheller 2020. J Nutr. 150(Suppl 1):2588S-92S).

Review: Thalacker-Mercer and Gheller 2020. Op. cit.: "Supplementation with doses of 4.0-4.5 g histidine/d and increased dietary histidine intake are associated with decreased BMI [body mass index], adiposity, markers of glucose homeostasis..., proinflammatory cytokines, and oxidative stress. It is unclear from the limited number of studies in humans whether the improvements in glucoregulatory markers, inflammation, and oxidative stress are due to reduced BMI and adiposity, increased carnosine (a metabolic product of histidine with antioxidant effects), or both. Histidine intake also improves cognitive function (e.g., reduces appetite, anxiety, and stress responses and improves sleep) potentially through the metabolism of histidine to histamine; however, this relation is ambiguous in humans."

Notes: WebMD classifies as possibly ineffective for anemia associated with kidney failure or kidney dialysis and rheumatoid arthritis; insufficient evidence for other uses.

Homotaurine - an amino acid (but not one used in proteins) found naturally in some seaweed. It was tested as a treatment for Alzheimer's disease but did not show convincing evidence of effectiveness. Subsequently it was marketed as a dietary supplement.

Promoted for: Alzheimer's, Parkinson's disease, and age-related cognitive decline

Presumed mechanism of action: "Homotaurine works in the brain, interfering with the formation of the plaques that contribute to Alzheimer disease. It also interferes with the formation of plaques in blood vessels in the brain, that are associated with a condition called cerebral amyloid angiopathy" (WebMD 2021. Homotaurine).

Possible adverse effects: "nausea, vomiting, diarrhea, dizziness, and headache" (Ibid.).

Notes: WebMD notes insufficient evidence of effectiveness for any condition. "The Alzheimer's Association has taken a strong stand against the use of homotaurine...There is simply no clinical evidence to support the use of homotaurine as a nutraceutical for its stated indication of memory protection. It is expensive, has adverse effects, and may be harmful" (Swanoski 2009. Am J Health Syst Pharm. 66(21):1950-3).

Human growth hormone related products. Human growth hormone (HGH) is a peptide hormone produced by the pituitary gland. While it has some medical uses, it must be injected, since it would be degraded if taken orally. However, dietary supplements marketed as "HGH releasers," "HGH boosters" or "homeopathic HGH" are marketed. These allegedly increase the body's HGH levels. Products may include amino acids, vitamins, herbal compounds, and other ingredients.

Promoted for: "Many marketers would like you to believe that boosting HGH blood levels can reduce body fat; build muscle; improve sex life, sleep quality, vision and memory; restore hair growth and color; strengthen the immune system; normalize blood sugar; increase energy; and 'turn back your body’s biological clock'"(Barrett 2016. Growth hormone schemes and scams. Quackwatch).

Presumed mechanism of action: ingredients in the supplements are claimed to increase secretion of growth hormone.

Notes: These products became popular after a 1990 paper in New England Journal of Medicine showing some benefits of growth hormone administration. "FTC staff has seen no reliable evidence to support the claim that these 'wannabe' products have the same effect as prescription HGH. In fact, the New England Journal of Medicine published a follow-up editorial about 'imposter' HGH products in 2003, warning, 'If people are induced to buy a ‘human growth hormone releaser’ on the basis of research published in the Journal, they are being misled.' And for its part, the FDA says it is unaware of any reliable evidence to support anti-aging claims for over-the-counter pills and sprays that supposedly contain HGH. The agency has not approved any such products for anti-aging or any other purpose" (Federal Trade Commission 2005 June. 'HGH' pills and sprays: human growth hype?). Some amino acids (such as those included in the supplements) do cause a release of growth hormone, but this is very small, and only lasts a few minutes. The effect could be produced by protein in general, not just the combination of ingredients in the supplements.

Huperzine A - "a chemical compound that can be isolated from the plant Huperzia serrata (Chinese club moss), a traditional Chinese remedy used for contusions, strains, swelling, and schizophrenia. It can also be made in a laboratory. Huperzine A is commonly listed as “Huperzia serrata extract,” “HupA,” or “Chinese club moss” on dietary supplement product labels" (Department of Defense Dietary Supplement Resource 2020. Huperzine A: dietary supplements for brain health).

Promoted for: "brain health and cognitive performance, with claims of enhanced brain power, memory, alertness, attention, concentration, and focus" (Ibid.).

Presumed mechanism of action: anticholinesterase activity

Possible adverse effects: "the Alzheimer’s Association recommends not taking huperzine A, especially with prescription drugs, because the combination could increase the risk of serious side effects. Commonly reported adverse effects include decreased heart rate, nausea, vomiting, diarrhea, dizziness, sweating, blurred vision, and insomnia. Overall, safety data are lacking and long-term use is not well understood" (Ibid.).

Notes: "Although it is marketed in the U.S. as a dietary supplement ingredient, huperzine A is an approved drug in some other countries. For example, huperzine A is available in most hospitals in China and is used to 'treat' Alzheimer’s disease. In the U.S., however, it is unclear whether huperzine A can be legally marketed as a dietary supplement. Preliminary evidence suggests huperzine might have beneficial effects on cognitive function among Alzheimer’s disease patients, but more research is needed to establish this conclusively. Some companies have been marketing 'supplements' containing huperzine A with illegal claims that their products can 'treat' Alzheimer’s" (Ibid.). A study by Crawford et al. (2020. Clin Toxicol (Phila). 58(10):991-6) found that 73% of tested products containing huperzine A also contained ingredients not listed on their labels, and some products contained dangerous stimulants.

Hydrogen-rich water - water with dissolved hydrogen gas

Promoted for: anti-inflammatory effects (such as with arthritis), metabolic syndrome, neurodegenerative diseases, diabetes, muscle fatigue

Presumed mechanism of action: alleged to have antioxidant effects by reducing reactive oxygen species.

Notes: "So far, there is a lack of scientific consensus concerning the evidence that hydrogen has health benefits in humans. A few articles have been published on the topic, but the clinical literature is sparse and what has been published covers many conditions, but not multiple trials of any one condition" (Wikipedia 2021. Hydrogen water). Ernst (2020 Oct 21. Edzard Ernst blog) noted that in a two-year period one author "has published over a dozen experimental papers on HRW; all of them report positive findings. Whenever I see a treatment that never fails to produce positive results, regardless of the conditions it is applied to, I start asking myself, are these findings not too good to be true?"

5-Hydroxy-L-tryptophan (5HTP) - "a chemical by-product of the protein building block L-tryptophan. It is also produced commercially from the seeds of an African plant known as Griffonia simplicifolia" (MedlinePlus 2020. 5-HTP).

Promoted for: treatment of insomnia, depression, anxiety, obesity, attention deficit disorder, and many other conditions

Presumed mechanism of action: "5-HTP works in the brain and central nervous system by increasing the production of the chemical serotonin. Serotonin can affect sleep, appetite, temperature, sexual behavior, and pain sensation" (Ibid.).

Possible adverse effects: "It has been used safely in doses up to 400 mg daily for up to one year. But some people who have taken 5-HTP have developed a condition called eosinophilia-myalgia syndrome (EMS). EMS is a serious condition involving extreme muscle tenderness (myalgia) and blood abnormalities (eosinophilia). Some people think EMS might be caused by an accidental ingredient or contaminant in some 5-HTP products. But there's not enough scientific evidence to know if EMS is caused by 5-HTP, a contaminant, or some other factor. Until more is known, 5-HTP should be used cautiously. Other potential side effects of 5-HTP include heartburn, stomach pain, nausea, vomiting, diarrhea, drowsiness, sexual problems, and muscle problems. 5-HTP is POSSIBLY UNSAFE when taken by mouth in large doses. Doses from 6-10 grams daily have been linked to severe stomach problems and muscle spasms" (Ibid.). There are major interactions with some drugs for depression and possible interactions with some other drugs.

Notes: According to Natural Medicines Comprehensive Database, as cited by MedlinePlus: possibly effective for depression; possibly ineffective for Down syndrome; insufficient evidence for other conditions. According to Department of Defense Dietary Supplement Resource (2021. 5-HTP for depression and other conditions), "The latest research shows that 5-HTP can improve symptoms of depression when taken by itself. Still, many of these studies are relatively weak, and more research is needed to confirm these findings, as well as determine the optimal dose of 5-HTP for depression."     

Hydroxymethyl butyrate (HMB) - see beta-hydroxy-beta-methylbutyrate above

Inositol - part of human metabolism but not required in diet. “Inositol can be found in many forms (called isomers). The most common forms are myo-inositol and D-chiro-inositol” (WebMD 2020. Inositol).

Promoted for: metabolic syndrome, polycystic ovary syndrome, prevention of baldness, reduce cholesterol, weight loss

Presumed mechanism of action: “Inositol might balance certain chemicals in the body to possibly help with mental conditions such as panic disorder, depression, and obsessive-compulsive disorder. It might also help insulin work better. This might help with conditions such as polycystic ovary syndrome or diabetes during pregnancy” (Ibid.).

Possible adverse effects: “Inositol is POSSIBLY SAFE for most adults when taken by mouth. It may cause nausea, stomach pain, tiredness, headache, and dizziness in some people” (Ibid.).

Notes: According to WebMD (Op. cit.), it is possibly effective for metabolic syndrome, polycystic ovary syndrome, and preterm birth; possibly ineffective for acute respiratory distress syndrome, depression, anxiety, diabetic neuropathy, and retinopathy of prematurity; insufficient evidence to judge effectiveness for other conditions.

Juicing - consumption of juices from raw fruits and vegetables

Promoted for: general nutritional benefits

Presumed mechanism of action: allegedly provides superior source of nutrients and active enzymes; antioxidant effects

Notes: dried juice products are also sold. See also Noni below. Mangosteen (an Asian fruit) is another currently popular juice, supposedly providing immune and anti-aging benefits. Hall (2019 Jun 11. Science-Based Medicine blog), in a critique of Juice Plus+, wrote: "They list more than 20 journals that have published studies on Juice Plus+, but those studies don’t amount to much. They are mainly pilot studies or small studies that show changes in some laboratory value but don’t show clinically meaningful changes in actual health outcomes. They compare Juice Plus+ to inert placebo pills rather than to a more meaningful control like other nutritional supplements or a diet with more fruits and vegetables...The fiber in fruits and vegetables has protective effects; the fiber has been removed from Juice Plus+. It is not a complete nutritional supplement; it lacks the vitamin B12 and mineral content that are present in most multivitamin supplements...The company claims that the 'natural food enzymes' in Juice Plus+ provide additional benefit, but they are digested once eaten and don’t act as enzymes in the body."

Ketones - a group of organic chemical compounds. In connection with human metabolism, "ketones" refers to acetoacetate and beta-hydroxybutyrate, which are formed by the liver to be used as an alternative energy source when glucose supplies are low (also included is acetone, which is formed by the spontaneous loss of the carboxyl group from acetoacetate). "Ketones found in dietary supplements are made in a laboratory...Ketone supplements usually contain beta-hydroxybutyrate (BHB; a ketone), medium-chain triglycerides (MCTs, which your liver can make into BHB), or both, along with other ingredients. BHB is often combined with minerals such as sodium, potassium, calcium, or magnesium to form 'ketone salts.' Other ketone supplements can be in liquid form and are usually referred to as 'ketone esters'" (Department of Defense Dietary Supplement Resource 2020. Ketone supplements for performance).

Promoted for: "Ketone supplements (also known as 'exogenous ketones') are marketed to enhance physical performance, weight loss, mental performance, and energy by raising ketone levels in the blood. Recently, ketone supplements have emerged as a potential alternative (or addition) to following a strict ketogenic diet in order to start or maintain nutritional ketosis (restricting carbohydrate intake to increase ketone production)" (Ibid.). Part of rationale is to get the presumed benefits of ketones for performance while avoiding adverse effects of carbohydrate restriction.

Presumed mechanism of action: provide ketones for energy in peripheral tissue while sparing muscle glycogen needed for endurance exercise. "In addition, ketone bodies would represent a more efficient energy substrate than glucose or fatty acids because the activation of the former into an oxidizable form...does not require ATP, thereby enabling generation of more muscle work for a given energy cost" (Valenzuela et al. 2021. Adv Nutr. 12(2):305-15).

Possible adverse effects: "Possible side effects of ketone supplements include gastrointestinal upset, vomiting, diarrhea, and indigestion. BHB as a ketone salt might cause mild dehydration. Frequent or long-term consumption of ketone salts might have negative effects on blood pressure, but this has not yet been confirmed" (Ibid.).

Reviews:

• • • Sansone et al. 2018. Curr Sports Med Rep. 17(12):444-53: "While there are some encouraging results showing an increase in endurance performance, contrasting evidence regarding the efficacy of exogenous ketones for endurance performance is present and further studies should be performed to make a definitive statement." 

    • Margolis and O'Fallon 2020. Adv Nutr. 11(2):412-9: "Of the 16 performance outcomes identified by the systematic review, 3 reported positive, 10 reported null, and 3 reported negative effects of ketone supplementation on physical performance compared with controls...Heterogeneity across studies makes it difficult to conclude any benefit or detriment to consuming ketone supplements on physical performance."

    • Valenzuela et al. 2021. Op. cit.: "...evidence to date does not support a benefit of acute ketone supplementation on sports performance, cognition, or muscle recovery [although further research with long-duration exercise (i.e., >60 min), is needed], and the evidence for chronic supplementation is sparse."

Notes: "Very little scientific evidence exists to support the safety and effectiveness of ketone supplements...Ketone supplements must be taken at regular intervals to maintain increased blood ketone levels. This can be challenging because most ketone supplements don’t taste very good. In general, very few reliable scientific studies have explored the effects of ketone supplements. A few clinical trials have used ketone supplements to increase blood ketone levels over the short term (less than one week). However, the evidence is mixed regarding the safety and effectiveness when used for physical performance. Most data come only from highly-trained endurance athletes..." (Department of Defense 2020. Op. cit.).

Kombucha "mushroom" tea - "Kombucha is produced by fermenting sugared tea using a symbiotic culture of bacteria and yeast (SCOBY) commonly called a 'mother' or 'mushroom.' The microbial populations in a SCOBY vary. The yeast component generally includes Saccharomyces cerevisiae, along with other species; the bacterial component almost always includes Gluconacetobacter xylinus to oxidize yeast-produced alcohols to acetic acid (and other acids). Although the SCOBY is commonly called 'tea fungus' or 'mushroom,' it is actually 'a symbiotic growth of acetic acid bacteria and osmophilic yeast species in a zoogleal mat [biofilm].' The living bacteria are said to be probiotic, one of the reasons for the popularity of the drink" (Wikipedia 2021. Kombucha).

Promoted for: "a veritable panacea, allegedly curing asthma, cataracts, diabetes, diarrhoea, gout, herpes, insomnia and rheumatism and purported to shrink the prostate and expand the libido, reverse grey hair, remove wrinkles, relieve haemorrhoids, lower hypertension, prevent cancer, and promote general well-being. Kambucha [sic] is believed to stimulate the immune system, and help with HIV infection. And - sure enough - it is ideal for detox!!! One author goes even further and lists no less than 17 indications..." (Ernst 2018 May 13. Edzard Ernst blog).

Presumed mechanism of action: probiotic to provide healthy intestinal bacteria; allows better absorption of minerals and other nutrients; contains glucuronic acid, which is involved in detoxification; contains vitamins; antioxidant effects; antimicrobial activity

Possible adverse effects: Cases of lactic acidosis and hepatotoxicity have been reported (see review below). "But how can a simple tea like Kombucha cause such serious problems? The answer lies in the method of preparation which carries the risk of contamination: the Kombucha material is incubated at room temperature in a sugar-containing liquid for 7-12 days. It is hardly surprising that, under such conditions, human pathogens may grow. It follows that, depending on the method of preparation and standards of hygiene, some Kombucha teas may be entirely innocent whilst others carry the risk of contamination and infection" (Ibid.).

Review: Ernst 2003. Forsch Komplementarmed Klass Naturheilkd. 10(2):85-7: "No clinical studies were found relating to the efficacy of this remedy. Several case reports and case series raise doubts about the safety of kombucha. They include suspected liver damage, metabolic acidosis and cutaneous anthrax infections. One fatality is on record. Conclusions: On the basis of these data it was concluded that the largely undetermined benefits do not outweigh the documented risks of kombucha. It can therefore not be recommended for therapeutic use."

Notes: Ernst (2018. Op. cit.) wrote that "none of these claims are based on anything that even vaguely resembles evidence." Since his 2003 review (see above) there were no published clinical trials, "but more information on the risks of Kombucha has emerged."

Lecithin (phosphatidylcholine) - part of normal human metabolism, not required in diet

Promoted for: to lower cholesterol, improve memory, treat arthritis; weight loss.

Lipoic acid - part of normal human metabolism but not required in the diet

Promoted for: antioxidant, and for treatment of diabetic neuropathy, cataracts, glaucoma, other conditons

Lutein - "a type of vitamin called a carotenoid. It is related to beta-carotene and vitamin A. Foods rich in lutein include egg yolks, broccoli, spinach, kale, corn, orange pepper, kiwi fruit, grapes, orange juice, zucchini, and squash...Many multivitamins contain lutein. They usually provide a relatively small amount, such as 0.25 mg per tablet" (MedlinePlus 2021. Lutein).

Promoted for: prevention of eye diseases such as age-related macular degeneration and cataracts

Presumed mechanism of action: "Lutein is one of two major carotenoids found as a color pigment in the human eye (macula and retina). It is thought to function as a light filter, protecting the eye tissues from sunlight damage" (Ibid.). It has also been proposed to have antioxidant and anti-inflammatory properties.

Review: Buscemi et al. 2018. Nutrients. 10(9):1321: "A large body of evidence shows that lutein has several beneficial effects, especially on eye health. In particular, lutein is known to improve or even prevent age-related macular disease which is the leading cause of blindness and vision impairment. Furthermore, many studies have reported that lutein may also have positive effects in different clinical conditions, thus ameliorating cognitive function, decreasing the risk of cancer, and improving measures of cardiovascular health...In general, sustained lutein consumption, either through diet or supplementation, may contribute to reducing the burden of several chronic diseases. However, there are also conflicting data concerning lutein efficacy in inducing favorable effects on human health and there are no univocal data concerning the most appropriate dosage for daily lutein supplementation."

Notes: According to Natural Medicines Comprehensive Database, as cited by MedlinePlus, lutein is likely effective for preventing lutein deficiency; possibly effective for age-related macular degeneration, cataracts, and prevention of non-Hodgkin lymphoma; possibly ineffective, or insufficient evidence to rate effectiveness, for numerous other conditions. Some researchers feel that there should be a "DRI-like guideline" for lutein intake.

Lycopene - a carotenoid that gives fruits and vegetables a red color; most dietary intake comes from tomatoes.

Promoted for: hypertension, high cholesterol, prevention of cancer and heart disease, other

Presumed mechanism of action: antioxidant effects. However, Erdman et al. (2009. Arch Biochem Biophys. 483(2):229-35) wrote, " In our review of human and animal trials with lycopene, or lycopene-containing extracts, there is limited support for the in vivo antioxidant function for lycopene. Moreover, tissue levels of lycopene appear to be too low to play a meaningful antioxidant role. We conclude that there is an overall shortage of supportive evidence for the  'antioxidant hypothesis' as lycopene's major in vivo mechanism of action. Our laboratory has postulated that metabolic products of lycopene, the lycopenoids, may be responsible for some of lycopene's reported bioactivity...Dietary intake of lycopene, or blood or tissue lycopene, may simply serve as a marker of tomato intake."

Possible adverse effects: high levels may be unsafe in pregnancy and lactation

Reviews and major trials:

• Kavanaugh et al. 2007.  J Natl Cancer Inst. 99(14):1074-85: "The FDA found no credible evidence to support an association between lycopene intake and a reduced risk of prostate, lung, colorectal, gastric, breast, ovarian, endometrial, or pancreatic cancer. The FDA also found no credible evidence for an association between tomato consumption and a reduced risk of lung, colorectal, breast, cervical, or endometrial cancer. The FDA found very limited evidence to support an association between tomato consumption and reduced risks of prostate, ovarian, gastric, and pancreatic cancers."

• Peters et al. 2007. Cancer Epidemiol Biomarkers Prev. 16(5):962-8 [Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial]: "Lycopene and other carotenoids were unrelated to prostate cancer. Consistent with other recent publications, these results suggest that lycopene or tomato-based regimens will not be effective for prostate cancer prevention."

• Burton-Freeman and Sesso 2014. Adv Nutr. 5(5):457-85: "The available clinical research supports consuming tomato-based foods as a first-line approach to cardiovascular health. With the exception of blood pressure management where lycopene supplementation was favored, tomato intake provided more favorable results on cardiovascular risk endpoints than did lycopene supplementation."

Notes: Natural Medicines Comprehensive Database, as cited in MedlinePlus (2021. Lycopene), rates as possibly ineffective for bladder cancer, diabetes, and Parkinson disease, and insufficient evidence to rate effectiveness for other conditions. In 2005 the FDA allowed limited health claims related to risk of cancer and tomato products, but rejected claims for lycopene supplements.

Lysine - an essential amino acid

Promoted for: treatment of genital herpes and cold sores, athletic performance, diabetes

Presumed mechanism of action: “Lysine is an essential amino acid building block for making proteins in the body. It may also prevent the herpes virus from growing” (WebMD 2020. Lysine).

Possible adverse effects: “Lysine is POSSIBLY SAFE for most people at recommended doses for up to one year. It can cause side effects such as stomach pain and diarrhea” (Ibid.).

Notes: According to WebMD (2020. Lysine), it is possibly effective for cold sores, with insufficient evidence to judge effectiveness for other conditions.

Magnesium - see macrominerals (SUPPLEMENTS PART 1)

Promoted for: hypertension, heart disease, diabetes, osteoporosis, migraine, other

Presumed mechanism of action: magnesium is an essential cofactor for numerous enzymes, so a deficiency would impact many physiological processes

Possible adverse effects: "high doses of magnesium from dietary supplements or medications often result in diarrhea that can be accompanied by nausea and abdominal cramping...Symptoms of magnesium toxicity, which usually develop after serum concentrations exceed 1.74–2.61 mmol/L, can include hypotension, nausea, vomiting, facial flushing, retention of urine, ileus, depression, and lethargy before progressing to muscle weakness, difficulty breathing, extreme hypotension, irregular heartbeat, and cardiac arrest. The risk of magnesium toxicity increases with impaired renal function or kidney failure because the ability to remove excess magnesium is reduced or lost" (NIH Office of Dietary Supplements 2020. Magnesium).

Reviews and major trials:

• Dickinson et al. 2006. Cochrane Database Syst Rev. CD004640: " In view of the poor quality of included trials and the heterogeneity between trials, the evidence in favour of a causal association between magnesium supplementation and blood pressure reduction is weak and is probably due to bias."

• Larsson and Wolk 2007. J Intern Med. 262(2):208-14: "Magnesium intake was inversely associated with incidence of type 2 diabetes. This finding suggests that increased consumption of magnesium-rich foods such as whole grains, beans, nuts, and green leafy vegetables may reduce the risk of type 2 diabetes."

• Schulze et al. 2007. Arch Intern Med. 167(9):956-65: "Higher cereal fiber and magnesium intakes may decrease diabetes risk."

• Peacock et al. 2010. Am Heart J. 160(3):464-70 [Atherosclerosis Risk in Communities Study]: "This study suggests that low levels of serum Mg may be an important predictor of SCD [sudden cardiac death]. Further research into the effectiveness of Mg supplementation for those considered to be at high risk for SCD is warranted.”

• Chiuve et al. 2011. Am J Clin Nutr. 93(2):253-60 [Nurses' Health Study]: " In this prospective cohort of women, higher plasma concentrations and dietary magnesium intakes were associated with lower risks of SCD. If the observed association is causal, interventions directed at increasing dietary or plasma magnesium might lower the risk of SCD."

• Dong et al. 2011. Diabetes Care. 34(9):2116-22: "This meta-analysis provides further evidence supporting that magnesium intake is significantly inversely associated with risk of type 2 diabetes in a dose-response manner."

• Kass et al. 2012. Eur J Clin Nutr. 66(4):411-8: "To conclude, magnesium supplementation appears to achieve a small but clinically significant reduction in BP [blood pressure], an effect worthy of future prospective large randomised trials using solid methodology."

• Holland et al. 2012. Neurology. 78(17):1346-53: "Fenoprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, MIG-99 (feverfew), magnesium, riboflavin, and subcutaneous histamine are probably effective for migraine prevention (Level B)."

• Joosten et al. 2013. Am J Clin Nutr. 97(6):1299-306 [Prevention of Renal and Vascular End-Stage Disease (PREVEND) study]: "Low urinary magnesium excretion was independently associated with a higher risk of IHD incidence. An increased dietary intake of magnesium, particularly in those with the lowest urinary magnesium, could reduce the risk of IHD [ischemic heart disease]."

• Del Gobbo et al. 2013. Am J Clin Nutr. 98(1):160-73: "Circulating and dietary magnesium are inversely associated with CVD [cardiovascular disease] risk, which supports the need for clinical trials to evaluate the potential role of magnesium in the prevention of CVD and IHD."

• Derom et al. 2013. Nutr Neurosci. 16(5):191-206: "Magnesium seems to be effective in the treatment of depression but data are scarce and incongruous. Disturbance in magnesium metabolism might be related to depression. Oral magnesium supplementation may prevent depression and might be used as an adjunctive therapy."

• Qu et al. 2013. PLoS One. 8(3):e57720: "There is a statistically significant nonlinear inverse association between dietary magnesium intake and total CVD events risk. Serum magnesium concentrations are linearly and inversely associated with the risk of total CVD events."

• Zhao et al. 2020. Diabetes Metab Res Rev. 36(3):e3243: "magnesium intake has an inverse dose-response association with T2D [type 2 diabetes] incidence, and supplementation appears to be advisable in terms of glucose parameters in T2D/high-risk individuals."

• Mah and Pitre 2021. BMC Complement Med Ther. 21(1):125: "This review confirms that the quality of literature is substandard for physicians to make well-informed recommendations on usage of oral magnesium for older adults with insomnia. However, given that oral magnesium is very cheap and widely available, RCT evidence may support oral magnesium supplements (less than 1 g quantities given up to three times a day) for insomnia symptoms."

Notes: "Although magnesium is a vital component of a healthy human diet, its deficiency is relatively common, with only 32% of Americans (U.S.) meeting the daily requirements as recommended by RDA-DRI" (Das 2014. Arch Med Res. 45(7):604-6).

Manganese - see trace minerals (SUPPLEMENTS PART 1)

Possible adverse effects: not known for high dietary intakes; toxicity is known from occupational exposure or drinking water with extremely high levels. "Manganese toxicity mainly affects the central nervous system and can cause tremors, muscle spasms, tinnitus, hearing loss, and the feeling of being unsteady on one’s feet. Additional symptoms include mania, insomnia, depression, delusions, anorexia, headaches, irritability, lower extremity weakness, changes in mood and short-term memory, altered reaction times, and reduced hand-eye coordination" (NIH Office of Dietary Supplements 2020. Manganese).

Notes: "No clinical trials have evaluated the effects of manganese supplementation alone on bone health...Research in animals suggests that manganese supplementation might improve glucose tolerance, reduce oxidative stress, and improve endothelial dysfunction in diabetes, but clinical trials in humans are lacking" (Ibid.).

Mannatech - see "glyconutrients"

Mannose - "D-mannose is a simple sugar found in many fruits...It also occurs naturally in some cells in the human body" (WebMD 2020. D-Mannose).

Promoted for: urinary tract infections, prebiotic

Presumed mechanism of action: when excreted in the urine, it "acts by inhibiting bacterial adhesion to the urothelium...In details, D-mannose binds and blocks FimH adhesins located on the tip of type 1 bacterial fimbriae, playing a competitive inhibitor role against bacterial adhesion to the receptors of urothelial cells" (De Nunzio et al. 2021. Antibiotics (Basel). 10(4):373).

Possible adverse effects: Gastrointestinal effects. "D-mannose supplements should be used with caution if you have diabetes. It may make it harder to control your blood sugar. High doses of D-mannose may cause kidney damage" (WebMD 2020. D-Mannose).

Review: De Nunzio et al. 2021. Op. cit.: "D-mannose alone or in combination with several dietary supplements or Lactobacillus has a potential role in the non antimicrobial prophylaxis or recurrent UTI [urinary tract infections] in women."

Melatonin - "a hormone that your brain produces in response to darkness. It helps with the timing of your circadian rhythms (24-hour internal clock) and with sleep. Being exposed to light at night can block melatonin production. Research suggests that melatonin plays other important roles in the body beyond sleep. However, these effects are not fully understood. Melatonin dietary supplements can be made from animals or microorganisms, but most often they’re made synthetically" (NCCIH 2021. Melatonin: what you need to know).

Promoted for: "Melatonin supplements may help with certain conditions, such as jet lag, delayed sleep-wake phase disorder, some sleep disorders in children, and anxiety before and after surgery" (Ibid.).  "A handful of companies market melatonin directly for children’s use, offering flavored, low-dose versions of the supplement" (Wallace 2013 Jun 28. Wall Street Journal). There have been some preliminary trials for melatonin as a cancer treatment and for use in gynecological problems. It is suggested to have a role in preventing chronic diseases related to inflammatory processes.

Presumed mechanism of action: in addition to its normal hormonal roles (see above), it has been proposed to act as an antioxidant and have neuroprotective abilities.

Possible adverse effects: "Short-term use of melatonin supplements appears to be safe for most people, but information on the long-term safety of supplementing with melatonin is lacking" (NCCIH 2021. Op. cit.). Reported side effects during studies include headache, dizziness, nausea, and sleepiness. Hall (2020 Dec 15. Science-Based Medicine blog) noted that "Agitation and bedwetting have been reported in children. There is concern that it might delay puberty in children, but the research is inconclusive. There has not been enough research to evaluate its long-term safety or its use during pregnancy and breast-feeding. A number of drug interactions and interactions with medical conditions have been reported." Products may be contaminated with serotonin (see below), which could cause serious adverse effects.

Reviews:

• Buscemi et al. 2005. J Gen Intern Med. 20(12):1151-8: " There is evidence to suggest that melatonin is not effective in treating most primary sleep disorders with short-term use (4 weeks or less); however, additional large-scale RCTs [randomized controlled trials] are needed before firm conclusions can be drawn. There is some evidence to suggest that melatonin is effective in treating delayed sleep phase syndrome with short-term use."

• Buscemi et al. 2006.  BMJ. 332(7538):385-93: "There is no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder." However, an editorial by Herxheimer (2006. BMJ. 332(7538):373-4) said that "To lump jet lag and shiftwork disorder together in a meta-analysis thus makes no sense...The systematic review takes no account of what melatonin does and how it works."

• "Costello et al. 2014. Nutr J. 13:106: "Based on the literature to date, no recommendations for use in shift workers or to improve hormonal phase shift changes in healthy people can be made at this time."

• Liira et al. 2014. Cochrane Database Syst Rev. CD009776: "There is low quality evidence that melatonin improves sleep length after a night shift but not other sleep quality parameters."

• Hansen et al. 2015. Cochrane Database Syst Rev. CD009861: "When compared to placebo, melatonin given as premedication...can reduce preoperative anxiety in adults...Melatonin may be equally as effective as standard treatment with midazolam in reducing preoperative anxiety in adults...The effect of melatonin on postoperative anxiety...in adults is mixed but suggests an overall attenuation of the effect compared to preoperatively."

• Auld et al. 2017. Sleep Med Rev. 34:10-22: "Results from the meta-analyses showed the most convincing evidence for exogenous melatonin use was in reducing sleep onset latency in primary insomnia..., delayed sleep phase syndrome..., and regulating the sleep-wake patterns in blind patients compared with placebo."

• Esposito et al. 2019. J Transl Med. 17(1):77: "Melatonin can be safe and effective in treating both primary sleep disorders and the sleep disorders associated with various neurological conditions. However, there is a need for further studies aimed at identifying the sleep disordered infants and children who will benefit most from melatonin treatment, and determining appropriate doses based on the severity and type of disorder."

• McDonagh et al. 2019. J Child Neurol. 34(5):237-47: "These findings show that melatonin was useful in improving some sleep outcomes in the short term, particularly those with comorbid ASD [autism spectrum disorders] and neurodevelopmental disorders."

• Genario et al. 2019. Pharmacol Res. 147:104337: "Short term supplementation studies, of up to six months, suggest that a daily posology of 2-18 mg of melatonin may have the potential to improve fertility rate, oocyte quality, maturation and number of embryos. However, the evidence available so far on the effects of melatonin supplementation covering gestational age and gestational outcomes is very scarce."

• Abramova et al. 2020. J Pharm Pract. 33(4):533-9 [pediatric sleep disorders]: "At this time, we believe that the benefit of exogenous melatonin supplementation outweighs the risks of adverse events and therefore would recommend its use in aiding patients in improving their sleep."

• Zarezadeh et al. 2020. Eur J Nutr. 59(5):1803-13: " The results of the present meta-analysis support that melatonin supplementation could be effective on ameliorating of inflammatory mediators."

• Cho et al. 2021. Brain Behav Immun. 93:245-53: "Exogenous melatonin reduced levels of inflammatory markers and may be useful for prevention and adjuvant treatment of inflammatory disorders."

• Jafari-Koulaee and Bagheri-Nesami 2021. Sleep Med. 82:96-103: "The present review study showed that melatonin may be effective in improving sleep quality and insomnia in patients with cancer."

Notes: According to NCCIH (2021. Op. cit.):

• "Research suggests that melatonin supplements may help with jet lag."

• "Melatonin supplements appear to help with sleep in people with DSWPD [delayed sleep-wake phase disorder], but it’s uncertain whether the benefits outweigh the possible harms."

• "Because there aren’t many studies on children and melatonin supplements, there is a lot we don’t know about the use of melatonin in children."

• "Melatonin supplements appear to be helpful in reducing anxiety before surgery, but it’s unclear if it helps to lower anxiety after surgery."

• "Studies of the effect of melatonin supplements on cancer symptoms or treatment-related side effects have been small and have had mixed results."

• "According to practice guidelines from the American Academy of Sleep Medicine (2017) and the American College of Physicians (2016), there’s not enough strong evidence on the effectiveness or safety of melatonin supplementation for chronic insomnia to recommend its use."

• "According to two 2014 research reviews, studies on whether melatonin supplements help shift workers were generally small or inconclusive."

Gavura (2017 Mar 9. Science-Based Medicine blog) noted that "Melatonin is the fourth most popular natural product taken in the United States (after fish oils, glucosamine/chondroitin, and probiotics). In children, it’s second only to fish oil in terms of popularity...Disappointingly and despite the fact that it is considered a drug product in some countries, the clinical evidence to support the use of melatonin is really not all that impressive...Studies tend to be small, of short duration, and poorly designed. Overall the data is inconsistent and relies on subjective data. When looking at all of the trials, the evidence suggests that melatonin may:

• “Promote falling asleep faster by 4-11.7 minutes sooner (23 minutes faster in those with ‘sleep onset disorder’)

• “Increase total sleep time by 8.2-18.2 minutes (four of six meta-analyses showed statistically significant increases)

• “Modestly improve perceived sleep quality and efficiency (time asleep while in bed)

• “In those with jet lag and shift workers, melatonin improved sleep time by 18.2 minutes but didn’t improve sleep onset or quality.”

Hall (2020. Op. cit.) wrote: "Caution is advisable, since quality control is a documented problem. 71% of products did not contain within 10% of the labelled amount of melatonin, with variations ranging from -83% to +478%, lot-to-lot variability was as high as 465%...To make matters worse, 8 out of 31 products were contaminated with the neurotransmitter serotonin...The evidence is mixed and weak. There is some positive evidence for melatonin, and side effects are mild. I wouldn’t discourage anyone who wants to give it a try, but I think good sleep hygiene measures would be a better first step for treating insomnia."

Methylsulfonylmethane (MSM) - "also known as dimethyl sulfone and methyl sulfone, is an organic compound containing sulfur that occurs naturally in the body, as well as in a variety of fruits, vegetables, grains, and animals" (Hewlings and Kalman 2018. JMIR Res Protoc. 7(11):e11139).

Promoted for: osteoarthritis, pain, swelling, aging skin, allergic rhinitis, exercise-induced muscle damage, hemorrhoids, rosacea, cancer prevention

Presumed mechanism of action: provide sulfur to the body, improving cartilage formation; antioxidant effects. "Due to its enhanced ability to penetrate membranes and permeate throughout the body, the full mechanistic function of MSM may involve a collection of cell types and is therefore difficult to elucidate. Results from in vitro and in vivo studies suggest that MSM operates at the crosstalk of inflammation and oxidative stress at the transcriptional and subcellular level" (Butawan et al. 2017. Nutrients. 9(3):290). "Although MSM, when ingested, has an antioxidative effect in vivo, the molecule itself does not directly quench oxidant activity. Instead, MSM reduces the body’s production of RONS [reactive oxygen and nitrogen species]" (Withee et al. 2017. J Int Soc Sports Nutr. 14:24).

Reviews:

• Ameye and Chee 2006. Arthritis Res Ther. 8(4):R127: "According to the best-evidence synthesis...MSM provides moderate evidence of efficacy for knee OA [osteoarthritis]."

• Brien et al. 2008.Osteoarthritis Cartilage. 16(11):1277-88: "The data from the more rigorous MSM trials provide positive but not definitive evidence that MSM is superior to placebo in the treatment of mild to moderate OA [osteoarthritis] of the knee."

Notes: In the 1950s through 1970s, dimethyl sulfoxide (DMSO) was being explored for its biological effects. It was then proposed that effects of DMSO might arise from  MSM, one of its breakdown products. "MSM became popular because of a book called 'The Miracle of MSM: The Natural Solution for Pain.' But there is little published scientific research to support its use. Some literature that promotes MSM states that MSM can treat sulfur deficiency. But there is no Recommended Dietary Allowance (RDA) for MSM or sulfur, and sulfur deficiency has not been described in the medical literature" (MedlinePlus 2021. Methylsulfonylmethane (MSM)). The article cites Natural Medicines Comprehensive Database as rating possibly effective for osteoarthritis,  possibly ineffective for athletic performance and chronic venous insufficiency, and insufficient evidence of effectiveness for other conditions.

Microhydrin® - a product containing silicate particles in a form that allegedly releases negative hydrogen ions (hydride ions)

Promoted for: cellular energy, antioxidant. Regulate body pH, improve oxygen delivery, eliminate toxins, increase cellular hydration

Notes: claims are scientifically preposterous. Hydride ions cannot be used by the body to make energy. Hydride is extremely unstable in water, so none would survive the digestive tract to reach other parts of the body.

Miracle Mineral Solution (MMS) - "MMS is bleach. Specifically, it is a 28% sodium chlorite in distilled water that generates chlorine dioxide when diluted with citric acid-containing or other acid-containing foods, as instructed" (Gorski 2016 Oct 31. Respectful Insolence blog).

Promoted for: cancer, autism, AIDS, malaria, hepatitis, common colds, other

Possible adverse effects: Extremely dangerous. "The FDA recently received new reports of people experiencing severe vomiting, severe diarrhea, life-threatening low blood pressure caused by dehydration and acute liver failure after drinking these products" (FDA 2019. FDA warns consumers about the dangerous and potentially life threatening side effects of Miracle Mineral Solution).

Notes: "There is no currently known valid medical reason to administer this chemical to anyone to treat anything, much less cancer, autism, AIDS, or other medical conditions" (Gorski 2016. Op. cit.).

Mitochondrial disorders  - the following is from NIH Office of Dietary Supplements 2020. Dietary supplements for primary mitochondrial disorders: "Primary mitochondrial disorders (PMDs) are a heterogeneous group of disorders characterized by impaired mitochondrial structure or function due to mutations in nuclear or mitochondrial DNA. PMDs are the most common inborn errors of metabolism...Certain dietary supplements may be of value in treating PMDs because, as nutrients and metabolic cofactors, they help increase mitochondrial ATP production, bypass a cellular defect (e.g., a deficiency in the activity of complexes I, II, or III in the ETC [electron transport chain]), or remove toxic metabolites. However, few randomized controlled trials (RCTs) have assessed the effects of dietary supplements in PMDs, and studies have investigated the effects of only a few ingredients in dietary supplements singly or in combination in patients with PMDs. Furthermore, much of the published positive evidence for dietary supplements to manage PMDs comes from studies with designs that do not demonstrate that the intervention studied was responsible for the observed health effects (e.g., case reports as well as retrospective and open- label studies) or from underpowered small clinical trials." Results with 13 different supplement ingredients, as well as with various combinations, are described in the article.

Morinda - see noni

Mushrooms - "Many different types of mushrooms are found on dietary supplement labels, but the most common are reishi, shiitake, Cordyceps sinensis, maitake, Cordyceps militaris, lion’s mane, chaga, and turkey tail...When mushrooms are used in dietary supplements, they are often in the form of a powder or extract. The 'fruiting body' often mentioned on labels is the part usually visible above ground - the part you would typically eat as a food. The mycelium, also sometimes mentioned on labels, is the 'root' of the mushroom; it can be grown more quickly and easily than the fruiting body" (Department of Defense Dietary Supplement Resource 2020. Mushrooms in dietary supplements). Some are referred to as medicinal mushrooms.

Promoted for: "Regardless of what type they contain, mushroom supplements are marketed for numerous health benefits. Some claims are general, such as promoting vitality and immune health. Others are more specific, such as promoting healthy cellular function, enhancing cognitive performance, controlling blood sugar levels, aiding digestion, and supporting a healthy inflammatory response by the liver" (Ibid.). "Reishi mushroom is used for cancer, boosting the immune system to prevent or treat infections, and for many other conditions" (MedlinePlus 2021. Reishi mushroom).

Presumed mechanism of action: polysaccharides are alleged to have "antitumor, immunomodulatory, antioxidant, anti-inflammatory, antimicrobial, and antidiabetic activity...The best known and most abundant are α- and β-glucans. Heteroglycans, peptidoglycans, and polysaccharide–protein complexes also contribute to biological activity. They are primarily responsible for immunomodulatory effects due to their ability to bind to specific cell wall receptors and stimulate specific immune responses. Medicinal mushrooms are usually used in cancer treatments as biological response modifiers (BRMs), useful for treating cancer, reducing the side effects of therapies, and improving the quality of the patient’s life" (Venturella et al. 2021. Int J Mol Sci. 22(2):634). Terpenes "modulate the immune system by stimulating the expression of genes coding for proteins involved in the immune response, but also have anti-inflammatory, antioxidant, and antitumor properties...Mushrooms are rich in proteins, which have cytotoxic and anticancer properties. Some of them are known for their characteristic and marked immunomodulatory effect...Other fungal metabolites with bioactivity are phenolic compounds, antioxidants with different mechanisms of action (oxygen scavenging, metal inactivation, free radical inhibition, peroxidase decomposition), laccases (copper-containing oxidases), and fatty acids" (Ibid.).

Possible adverse effects: "Generally, mushrooms as a food are safe to consume, but some types can be poisonous (toxic). Consuming toxic mushrooms can result in severe side effects such as nausea, diarrhea, vomitting, liver failure, and in some cases, death. Dietary supplement products shouldn’t contain poisonous mushrooms, but without laboratory testing, it is difficult to know for sure. Currently there isn’t enough reliable information available to support the safety, effectiveness, or appropriate use of dietary supplements that contain non-toxic mushrooms. Some dietary supplement labels with mushroom ingredients carry warning statements such as, 'Avoid using if you’re pregnant, breastfeeding, or anticipate surgery.' Side effects reported from using such products include such as nausea, vomitting, diarrhea, dizziness, skin sensitivity, headache, gastrointestinal (GI) discomfort, and allergic reactions" (Department of Defense 2020. Op. cit.). "Reishi mushroom extract is POSSIBLY SAFE when taken appropriately for up to one year. Powdered whole reishi mushroom is POSSIBLY SAFE when taken appropriately for up to 16 weeks. Reishi mushroom can cause dizziness, dry mouth, itching, nausea, stomach upset, and rash" (MedlinePlus). Reishi mushrooms have possible interactions with some drugs.

Review: Klupp et al. 2015. Cochrane Database Syst Rev. CD007259: "Evidence from a small number of randomised controlled trials does not support the use of G lucidum for treatment of cardiovascular risk factors in people with type 2 diabetes mellitus." [Ganoderma lucidum is also known as lingzhi or reishi.]

Notes: "...there isn’t enough scientific evidence to support their safety or use for any specific purpose, except as a food" (Department of Defense 2020. Op. cit.). According to Natural Medicines Comprehensive Database, as cited by MedlinePlus, reishi mushrooms are possibly ineffective for elevated cholesterol and other lipids, and insufficient evidence to rate effectiveness for all other conditions. Venturella et al. (2021. Op. cit.) noted "although a great deal of research has been carried out to highlight their various beneficial properties and thus their potential use in therapeutics, many mushrooms have only been tested in vitro or in vivo in animal models, mainly mice and rats, with little or no scientific support in vivo in humans. Thus, although supplement companies often specify research to support their product claims, these are preclinical or even in vitro studies. Another aspect to take into account is undoubtedly the fact that there are innumerable mushroom supplements on the market today, but for the same species, doses, preparations, manufacturing practices, and claims vary considerably between manufacturers...Furthermore, even under the same conditions, the medicinal properties of a given mushroom can vary enormously depending on the strain, the geographical area, the growing conditions and substrate used, the part of the mushroom used, and the growing stage at the moment of processing. All these parameters change the composition of the mushroom and, consequently, its bioactive capacity." Ernst (2016 Nov 26. Edzard Ernst blog), discussing the use of mushrooms for diabetes, noted "On the basis of all this evidence, it seems fair to conclude that mushrooms have little or no effect on diabetes." Since "Diabetes is a serious condition that can be well-controlled with diet, exercise and drugs," promotion of mushrooms for its treatment is "irresponsible, unethical and outright dangerous."

N-Acetyl cysteine (NAC) - a derivative of the amino acid cysteine

Promoted for: "N-acetyl cysteine is most commonly used by mouth for cough and other lung conditions. It is also used for flu, dry eye, and many other conditions...Healthcare providers give N-acetyl cysteine by IV for conditions such as acetaminophen (Tylenol) overdose" (WebMD 2021. N-Acetyl cysteine (Nac)). Also promoted for prevention of cancer.

Presumed mechanism of action: antioxidant. "N-acetyl cysteine treats acetaminophen (Tylenol) poisoning by binding the poisonous forms of acetaminophen that are formed in the liver" (Ibid.).

Possible adverse effects: "N-acetyl cysteine is LIKELY SAFE for most adults. It can cause nausea, vomiting, and diarrhea or constipation. Rarely, it can cause rashes, fever, headache, drowsiness, low blood pressure, and liver problems" (Ibid.).

Notes: According to WebMD, it is effective for: acetaminophen poisoning, collapsed lungs, preparing for lung tests, tracheostomy care; possibly effective for: angina, irritability in autism, bronchitis, chronic obstructive pulmonary disease, kidney damage caused by contrast dyes, complications in end-stage renal disease, epilepsy disorder, hyperhomocysteinemia, high cholesterol, flu symptoms, damage during heart attacks. For all other conditions, classified as possibly ineffective, likely ineffective, or insufficient evidence to rate effectiveness.

Niacin - see section on water-soluble vitamins (SUPPLEMENTS PART 1). "Niacin is the generic name for nicotinic acid (pyridine-3-carboxylic acid), nicotinamide (niacinamide or pyridine-3-carboxamide), and related derivatives, such as nicotinamide riboside" (NIH Office of Dietary Supplements 2021. Niacin). Nicotinamide mononucleotide (NMN) is also being explored as a supplement. The main use of niacin (beyond supplying required levels) involves very high levels under medical supervision for treatment of cholesterol.

Possible adverse effects: "high intakes of both nicotinic acid and nicotinamide taken as a dietary supplement or medication can cause adverse effects, although their toxicity profiles are not the same. Thirty to 50 mg nicotinic acid or more typically causes flushing; the skin on the patient’s face, arms, and chest turns a reddish color because of vasodilation of small subcutaneous blood vessels. The flushing is accompanied by burning, tingling, and itching sensations...the flushing can be accompanied by more serious signs and symptoms, such as headache, rash, dizziness, and/or a decrease in blood pressure...Nicotinamide does not cause skin flushing and has fewer adverse effects than nicotinic acid, and these effects typically begin with much higher doses" (Ibid.) At pharmacologic doses (1000-3000 mg/day), serious adverse effects are possible with nicotinic acid.

Notes: High doses of nicotinic acid improve blood lipid profiles but do not decrease the risk of heart disease. Because of the availability of statin therapy, it is generally considered not worth the risk of using nicotinic acid for this purpose.

Nitrate and nitric oxide supplements - see also arginine, beetroot, and citrulline. "Nitric oxide (NO), a gas produced naturally in the body, relaxes blood vessels and increases blood flow. Many pre-workout supplements are marketed as 'NO' or 'nitric oxide' boosters, with claims they can improve strength, performance, and endurance. Importantly, dietary supplements do not actually contain NO, because it’s a gas. Instead, NO supplements contain amino acids - primarily L-arginine and L-citrulline - or nitrates, all of which the body uses to make NO...Foods with nitrates also are promoted to release 'NO.' Dietary sources of nitrates (NO3) include beets and green, leafy vegetables; watermelon is a good source of L-citrulline" (Department of Defense Dietary Supplement Resource 2019. Nitric oxide supplements).

Promoted for: "Supplements intended to increase your body’s production of NO purportedly enhance blood flow and the transport of oxygen and nutrients to the muscles. The intended end result is improved performance" (Ibid.).

Possible adverse effects: "Because the ingredients in NO supplements can vary greatly, it isn’t possible to make a statement about their overall safety. Some dietary supplements marketed as NO boosters contain stimulants or other potentially problematic ingredients (unrelated to the NO effect) that can increase the risk of adverse reactions" (Ibid.).

Reviews:

• MacMahon et al. 2017. Sports Med. 47(4):735-56: "Dietary NO3- supplementation is likely to elicit a positive outcome when testing endurance exercise capacity, whereas dietary NO3- supplementation is less likely to be effective for time-trial performance."

• San Juan et al. 2020. Nutrients. 12(8):2227: "Although these preliminary observations are encouraging, further research is required for the ergogenic potential of NO3- supplementation on weightlifting exercise performance to be determined."     

Notes: "Some research results suggest NO-producing supplements might improve times during distance events, delay fatigue, or both, for some people" (Department of Defense 2019. Op. cit.).

Noni (Tahitian Noni) (fruit of Morinda citrifolia)

Promoted for: "Historically, noni has been used for thousands of years in Polynesia as a food source and for medicinal uses (usually applied to the skin). Today, noni is promoted as a dietary supplement to prevent cancer, prevent infections, treat high blood pressure, and help with other conditions" (NCCIH 2021. Noni).

Presumed mechanism of action: contains proxeronine, precursor of xeronine, which allegedly enhances nutrient uptake and cell function. Several other classes of chemicals are present that potentially have diverse beneficial effects. Claimed to enhance immune system.

Possible adverse effects: "Noni might be safe when used orally or on the skin in appropriate doses. Few side effects have been reported in studies of noni. However, several cases of liver toxicity have been reported in people who had consumed noni. It is unclear whether noni caused the liver problems...Noni contains a substantial amount of potassium. People who need to restrict their intake of potassium should consult a health care provider before using noni. Noni should not be used during pregnancy. Little is known about whether it’s safe to use noni while breastfeeding" (Ibid.).

Notes: "In laboratory research, noni has shown antioxidant, immune-stimulating, and tumor-fighting properties. These results suggest that noni may warrant further study for various diseases. However, noni has not been shown to have beneficial effects on any health condition in studies of people" (Ibid.).

Nootropics - see also huperzine A, piracetam, and Prevagen. "Nootropics - also referred to as 'cognitive enhancers,' 'smart drugs,' 'memory enhancers,' or 'brain boosters' - are substances intended to improve mental performance. The term 'nootropic' originally referred to a chemical that met very specific criteria: enhances memory, helps brain function, protects the brain, and is relatively safe. No evidence exists to show that any dietary supplement product can satisfy all (or any) of these criteria. Today, however, the term is used more loosely and often refers to any naturally-occurring or synthetic (that is, created in a lab) substance that might act as a 'cognitive enhancer'...Nootropic products fall into two general categories: dietary supplements and drugs (prescription and over-the-counter). They contain substances (foods, herb, botanicals, dietary ingredients, pharmaceuticals) marketed to improve mental performance or functions - including memory, focus, motivation, concentration, and attention - and for overall brain health. The problem with nootropic dietary supplements is that they might contain drugs (approved, unapproved, or both) or potential 'new dietary ingredients'...Dietary supplements for brain health marketed as 'natural' or 'herbal' nootropics might include ingredients such as ashwagandha, Bacopa monnieri, Ginkgo biloba, ginseng, huperzine A, omega-3 fatty acids, rhodiola, and valerian. Even some vitamins and minerals are marketed as nootropics, such as the B-complex vitamins and magnesium" (Department of Defense Dietary Supplement Resource 2021. Nootropics: drugs vs. dietary supplements for brain health). Other ingredients include phenylalanine, cysteine, choline, and taurine. Nootropics "are part of a broader category of drugs known as performance and image enhancing drugs (PIED) which are used for enhancement of memory and cognition, sexual performance, athletic performance or musculature (also called 'lifestyle' drugs)" (Novella 2015 May 20. Science-Based Medicine blog).

Promoted for: enhanced mental performance

Presumed mechanism of action: "The concept behind nootropics is to target some metabolic or nutritional aspect of brain function, especially a function involved with memory or attention, and then to provide a nutritional precursor to that metabolic pathway, or a drug that enhances the activity of a neurotransmitter, enzyme, or other metabolic factor" (Ibid.).

Possible adverse effects: irritability or insomnia from phenylalanine; gastroenteritis and pancreatitis from choline; cysteine could harm fetus

Notes: "Some ingredients found in nootropic supplements - higenamine, sulbutiamine, and hordenine - are on FDA’s Dietary Supplement Ingredient Advisory List based on a preliminary evaluation that the ingredient 'does not appear to be lawfully included in products marketed as dietary supplements.' Some nootropic dietary supplement products contain multiple or mixtures of ingredients, with no evidence of how these ingredients might interact. Many contain proprietary blends that leave the consumer unaware of how much of each individual ingredient is in a product...Ingredients on the OPSS [Operation Supplement Safety] list of DoD [Department of Defense]-prohibited ingredients: DMHA (octodrine)*; DMAA*; phenibut; racetam drugs: piracetam, aniracetam, oxiracetam, omberacetam (Noopept), phenylpiracetam* (Phenotropil), pramiracetam (Nootropil), etc.; vinpocetine. Other questionable ingredients ('natural' and 'herbal' ingredients, prescription drugs, and unapproved drugs): adrafinil* (Olmifon, Noofon), B-PEA (b-phenylethylamine or beta-phenethylamine)*, halostachine (N-methyl phenylethanolamine), higenamine*, hordenine, huperzine A, methylphenidate* (Ritalin, Concerta), modafinil* (Provigil), sulbutiamine. *On the World Anti-Doping Agency Prohibited List" (Department of Defense 2021. Op. cit.).

Novella (2015. Op. cit.) wrote: "The primary plausibility problem with the PIED category of drugs is that they are further extrapolating from data in disease states to the enhancement of otherwise healthy function. Just because a drug may enhance memory function in someone with Alzheimer’s disease, that does not mean it will enhance memory function to supernormal in a healthy individual...Current non-stimulant nootropics are likely useless in healthy individuals...Nootropics are an interesting and potentially very useful class of drugs which deserve further research. Their greatest potential is likely in various states of neurological disease or injury. Their use as smart pills, however, is dubious from a plausibility standpoint and lacks sufficient evidence. Many 'smart pill' products on the market cheat by including a regular stimulant, like caffeine." A 2019 report by the Global Council on Brain Health "concludes there is no convincing evidence to recommend dietary supplements for 'brain health' in adults 50 and over who do not have identified nutrient deficiencies" (Bellamy 2020 Jan 2. Science-Based Medicine Blog). In addition to apoaequorin (found in Prevagen), "Other ingredients promoted for brain health garnering negative reviews include coenzyme Q10 (CoQ10), curcumin/turmeric, ginkgo biloba, coconut oil, and fish oil." An AARP survey found that 26% of Americans "regularly took supplements for their brain health" (Ibid.).

Olive oil

Promoted for: heart disease, high cholesterol, high blood pressure

Presumed mechanism of action: "Fatty acids in olive oil seem to decrease cholesterol levels and have anti-inflammatory effects. Olive leaf and olive oil might lower blood pressure" (MedlinePlus 2020. Olive).

Possible adverse effects: possible interactions with drugs for blood sugar, blood pressure, and blood clotting

Notes: Natural Medicines Comprehensive Database, as cited by MedlinePlus, rates as possibly effective for prevention of breast cancer, heart disease, and diabetes; for lowering blood pressure and cholesterol; and for constipation. Insufficient evidence of effectiveness for other conditions.

Oregano

Promoted for: "Oregano is taken by mouth [for] respiratory tract disorders such as coughs, asthma, allergies, croup, and bronchitis. It is also taken by mouth for stomach disorders such as heartburn, bloating, and parasites. Oregano is also taken by mouth for painful menstrual cramps, rheumatoid arthritis, urinary tract disorders including urinary tract infections (UTIs), headaches, diabetes, bleeding after having a tooth pulled, heart conditions, and high cholesterol" (RxList 2021. Oregano).

Presumed mechanism of action: "Oregano contains chemicals that might help reduce cough and spasms. Oregano also might help digestion by increasing bile flow and fighting against some bacteria, viruses, fungi, intestinal worms, and other parasites" (Ibid.).

Possible adverse effects: "Mild side effects include stomach upset. Oregano might also cause an allergic reaction in people who have an allergy to plants in the Lamiaceae family" (Ibid.). Possible interactions with drugs for diabetes and with anticoagulants.

Notes: Natural Medicines Comprehensive Database, as cited by MedlinePlus, rates evidence insufficient to determine effectiveness for all conditions.

"Organic" food - "food produced by methods complying with the standards of organic farming. Standards vary worldwide, but organic farming features practices that cycle resources, promote ecological balance, and conserve biodiversity. Organizations regulating organic products may restrict the use of certain pesticides and fertilizers in the farming methods used to produce such products. Organic foods typically are not processed using irradiation, industrial solvents, or synthetic food additives” (Wikipedia 2021. Organic food).

Promoted for: general nutrition

Presumed mechanism of action: thought to have higher concentrations of nutrients and antioxidants, and less pesticide residue and toxic metals

Reviews:

• Dangour et al. 2009.  Am J Clin Nutr. 90(3):680-5: "On the basis of a systematic review of studies of satisfactory quality, there is no evidence of a difference in nutrient quality between organically and conventionally produced foodstuffs. The small differences in nutrient content detected are biologically plausible and mostly relate to differences in production methods."

• Dangour et al. 2010. Am J Clin Nutr. 92(1):203-10: "From a systematic review of the currently available published literature, evidence is lacking for nutrition-related health effects that result from the consumption of organically produced foodstuffs."

• Smith-Spangler et al. 2012. Ann Intern Med. 157(5):348-66: "The published literature lacks strong evidence that organic foods are significantly more nutritious than conventional foods. Consumption of organic foods may reduce exposure to pesticide residues and antibiotic-resistant bacteria."

• Barański et al. 2014. Br J Nutr. 112(5):794-811: "In conclusion, organic crops, on average, have higher concentrations of antioxidants, lower concentrations of Cd and a lower incidence of pesticide residues than the non-organic comparators across regions and production seasons."

Notes: "Scientists have hypothesized that organic plants produce more antioxidants and natural toxins to defend themselves against insects and other environmental threats. It's not entirely clear to scientists whether the human body can absorb the extra antioxidants in organic foods and put them to use" (Morin 2014 Jul 14. Los Angeles Times).

Papaya

Promoted for: "Papaya is taken by mouth for cancer, diabetes, a viral infection called human papilloma virus (HPV), dengue fever, and other conditions" (WebMD 2020. Papaya).

Presumed mechanism of action: "Papaya contains a chemical called papain. Papain breaks down proteins, carbohydrates, and fats. That's why it works as a meat tenderizer. However, papain is changed by digestive juices, so there is some question about whether it could be effective as a medicine when taken by mouth. Papaya also contains a chemical called carpain. Carpain seems to be able to kill certain parasites, and it might affect the central nervous system. Papaya also seems to have antibacterial, antifungal, anti-viral, anti-inflammatory, antioxidant, and immune-stimulating effects" (Ibid.).

Possible adverse effects: possible allergic reactions if allergic to latex or papain. Fermented papaya can lower blood sugar. Possible interactions with some medications. "The unripe fruit is POSSIBLY UNSAFE when taken by mouth. Unripe papaya fruit contains papaya latex, which contains an enzyme called papain. Taking large amounts of papain by mouth may damage the esophagus...Unripe papaya fruit is POSSIBLY UNSAFE when taken by mouth during pregnancy. There is some evidence that unprocessed papain, one of the chemicals found in unripe papaya fruit, might poison the fetus or cause birth defects" (Ibid.).

Notes: According to WebMD, "there is little scientific evidence" in support of claimed benefits. Natural Medicine Comprehensive Database considers there to be insufficient evidence to rate effectiveness for all conditions.

Para-aminobenzoic acid (PABA) - part of normal human metabolism but not required in the diet

Promoted for: “PABA is taken for a disease that causes curved, painful erections (Peyronie disease), a rare autoimmune disorder that causes skinblisters (pemphigus), hardening of skin and connective tissue (scleroderma), and many other conditions” (WebMD 2020. Para-Aminobenzoic Acid (Paba)).

Possible adverse effects: “PABA is POSSIBLY SAFE when taken appropriately...It might cause nausea, vomiting, upset stomach, diarrhea, and loss of appetite. It is POSSIBLY UNSAFE to take PABA in high doses. Taking more than 12 grams per day can cause serious side effects such as liver, kidney, and blood problems” (Ibid.).

Notes: According to WebMD, possibly effective for Peyronie disease (“PABA is FDA-approved for use in this condition”); possibly ineffective for scleroderma; insufficient evidence to judge effectiveness for other conditions.

Phenibut - see also nootropics. "Phenibut is a designer drug which was synthesized by a group of Russian scientists in the 1960s...Phenibut is structurally similar to the neurotransmitter GABA (gamma amino butyric acid). GABA occurs naturally in the human nervous system and has a calming effect on the brain" (Campbell 2016 Nov 25. Science-Based Medicine blog). Phenibut is a pharmaceutical drug in Russia and some Eastern European countries; is marketed as a dietary supplement in the U.S.; and is a controlled substance in several countries.

Promoted for: In Russia, it "is used for a variety of conditions including anxiety, insomnia, post- traumatic stress disorders, depression, stuttering, tics, attention deficit disorders, and vestibular disorders. Unlike most other anxiolytic drugs, phenibut is also promoted as a nootropic drug, which implies that it can improve motivation, attention, and concentration" (Ibid.). Other proposed uses are for sleep, body building, and sexual performance.

Presumed mechanism of action: Agonist of the GABAB receptor; at high levels a possible agonist of the GABAA receptor.

Possible adverse effects: "Possible side effects may include sedation, somnolence, nausea, irritability, agitation, anxiety, dizziness, headache, and allergic reactions such as skin rash and itching. At high doses, motor incoordination, loss of balance, and hangovers may occur. Tolerance develops to phenibut with repeated use. Withdrawal symptoms may occur upon discontinuation, and, in recreational users taking high doses, have been reported to include severe rebound anxiety, insomnia, anger, irritability, agitation, visual and auditory hallucinations, and acute psychosis. Due to its central nervous system depressant effects, people taking phenibut should refrain from potentially dangerous activities such as operating heavy machinery. With prolonged use of phenibut, particularly at high doses, the liver and blood should be monitored, due to risk of fatty liver disease and eosinophilia" (Wikipedia 2021. Phenibut).

Notes: "There are over 300 published papers on phenibut. This is actually relatively little information on a drug that has been around for over fifty years. Many of these publications are in the Russian language and/or are based on studies in cats, rats or mice...Phenibut is a cleverly-designed drug with an even cleverer marketing campaign. There is no legitimate evidence to support the fact that it works for any of the stated purposes, but there are worrying reports of significant toxicity" (Campbell 2016. Op. cit.).

Phenylalanine - “There are three forms of phenylalanine: D-phenylalanine, L-phenylalanine, and the mix made in the laboratory called DL-phenylalanine. D-phenylalanine is not an essential amino acid. Its role in the body is not currently understood. L-phenylalanine is an essential amino acid. It is the only form of phenylalanine found in proteins” (WebMD 2020. Phenylalanine).

Promoted for: “Phenylalanine is most commonly used for a skin disorder that causes white patches to develop on the skin (vitiligo). It is also used for aging skin, pain, obesity, and many other conditions” (Ibid.).

Possible adverse effects: “L-phenylalanine is LIKELY SAFE for most people when taken in amounts commonly found in foods. L-phenylalanine is POSSIBLY SAFE when taken as medicine, short-term. D-phenylalanine is POSSIBLY SAFE when used as a single dose of up to 10 grams. There isn't enough reliable information to know if D-phenylalanine is safe when used as more than a single dose” (Ibid.).

Notes: According to WebMD, “Taking L-phenylalanine by mouth in combination with UVA exposure or applying L-phenylalanine to the skin in combination with UVA exposure seems to be effective for treating vitiligo in adults and in children.” Possibly ineffective for attention deficit-hyperactivity disorder and chronic pain; insufficient evidence to judge effectiveness for other conditions.

Phosphatidylserine - a phospholipid found naturally in the body

Promoted for: cognitive performance, multiple sclerosis, muscle soreness

Possible adverse effects: “Many people can take the soy-derived supplement without any side effects. Research is still preliminary but it is likely safe up to 600 milligrams a day for no more than 10 days. Side effects are more common at doses of 300 milligrams and above” (WebMD 2021. Phosphatidylserine). These may include gas, stomach upset, and trouble sleeping. Drug interactions are possible.

Notes: insufficient evidence of effectiveness for any condition

Phytochemicals - see section on phytochemicals (SUPPLEMENTS PART 1), as well as individual items in this section

Phytoestrogens - see also soy products. Plant compounds that produce estrogen-like effects. "Phytoestrogens mainly belong to a large group of substituted natural phenolic compounds: the coumestans, prenylflavonoids and isoflavones are three of the most active in estrogenic effects in this class. The best-researched are isoflavones, which are commonly found in soy and red clover" (Wikipedia 2021. Phytoestrogen). Among the isoflavones are genistein, daidzein, formononetin, and biochanin A. Lignans have also been considered as phytoestrogens.

Promoted for: menopausal symptoms, reducing risk of breast cancer, bone health, cardiovascular benefits, cognitive function

Presumed mechanism of action: mimic the effect of estrogen, reducing the effects of decline in estrogen. "During the reproductive period of life, the isoflavones may reduce the risk of breast cancer, since they inhibit the binding of the more potent estrogen 17α-estradiol to the estrogen receptor, thus exerting an effect that has been compared with that of pharmacological selective estrogen receptor modulators (SERMs)" (Comhaire and Depypere 2015. Climacteric. 18(3):364-71).

Possible adverse effects: Discussing side effects in clinical trials, Baber (2010. Maturitas 66(4):344-9) wrote, "Phytoestrogen supplements had a safe side effect profile with moderately elevated rates of gastrointestinal side effects such as abdominal pain as well as myalgia and sleepiness. No trials found any increase in breast or endometrial cancer."

Reviews:

• Baber 2010. Op. cit.: "Despite many trials there remains little evidence that phytoestrogens, whether dietary or supplemented, significantly relieve menopausal vasomotor symptoms or cognition. Several potential mechanisms for a positive effect on bone and cardiovascular health have been demonstrated however no fracture prevention data or cardiovascular end point benefit has yet been demonstrated."

• Lethaby et al. 2013. Cochrane Database Syst Rev. CD001395: "No conclusive evidence shows that phytoestrogen supplements effectively reduce the frequency or severity of hot flushes and night sweats in perimenopausal or postmenopausal women, although benefits derived from concentrates of genistein should be further investigated."

• Fritz et al. 2013. PLoS One. 8(11):e81968: "Soy consumption may be associated with reduced risk of breast cancer incidence, recurrence, and mortality. Soy does not have estrogenic effects in humans. Soy intake consistent with a traditional Japanese diet appears safe for breast cancer survivors. While there is no clear evidence of harm, better evidence confirming safety is required before use of high dose (≥100 mg) isoflavones can be recommended for breast cancer patients... Evidence on red clover is limited, however existing studies suggest that it may not possess breast cancer-promoting effects."

• Franco et al. 2016. JAMA. 315(23):2554-63: "This meta-analysis of clinical trials suggests that composite and specific phytoestrogen supplementations were associated with modest reductions in the frequency of hot flashes and vaginal dryness but no significant reduction in night sweats."

• Su et al. 2018. J Altern Complement Med. 24(8):850-1: "In conclusion, this meta-analysis of clinical trials suggests that phytoestrogen consumption is associated with significant reduction in depressive symptoms in climacteric women without increasing the adverse effects. However, because of the general suboptimal quality of the current evidence, additional larger, well-designed studies are warranted to further elucidate this association."

Piracetam - a drug marketed as a nootropic supplement. According to Cohen et al. (2020. JAMA. 180(3):458-9), "In many European countries, piracetam is prescribed for cognitive impairment, dementia, and other disorders. A Cochrane review, however, found that despite widespread use of piracetam for dementia and cognitive impairment, the evidence for its efficacy is poor in quality and quantity. In the United States, piracetam has no FDA-approved use and the only drug in its class approved for use by the FDA is levetiracetam, an antiepileptic. The FDA has determined that piracetam is not permitted to be sold as a dietary supplement, but enforcement is limited, and piracetam supplements remain available for sale...Adverse effects of piracetam at pharmaceutical dosages include anxiety, insomnia, agitation, depression, drowsiness, and weight gain. The risks of piracetam in over-the-counter supplements at supratherapeutic dosages, particularly in elderly consumers with renal insufficiency, are unknown." The authors examined five brands of supplements and found "individual doses of piracetam exceeding 1500 mg, and daily doses greater than 11 000 mg," compared to prescription doses of 800 or 1200 mg and daily doses of 2400 to 4800 mg.

Plant sterols and stanols - plant sterols (or phytosterols) are plant compounds resembling cholesterol; stanols are similar compounds lacking a double bond.

Promoted for: lowering cholesterol

Presumed mechanism of action: blocks cholesterol absorption in the intestine. "Some plant sterols might also reduce how much cholesterol is made in the body" (WebMD 2021. Plant sterols).

Possible adverse effects: "Plant sterols are LIKELY SAFE for most people. They can cause some side effects such as diarrhea or fat in the stool" (Ibid.).

Notes: WebMD considers as likely effective for lowering cholesterol; possibly effective for prevention of heart disease; insufficient evidence for prevention of cancer, metabolic syndrome, and other conditions. Pett (2016 Dec 27. Science-Based Medicine), in a review of Benecol, a plant stanol margarine, noted that phytosterols do lower cholesterol but only by about 10%; they can be effective when used with statin therapy but cannot replace statins. They need to be taken with food at least twice a day, and may be expensive.

Policosanol - "Policosanol is the generic term for a mixture of long chain alcohols extracted from plant waxes...Policosanol was originally derived from sugar cane but the chemicals can also be isolated from beeswax, cereal grains, grasses, leaves, fruits, nuts, and seeds of many foods" (Wikipedia 2021. Policosanol).

Promoted for: lowering cholesterol; reducing blood pressure

Presumed mechanism of action: "Policosanol inhibits glycation and oxidation which are associated with atrial stiffness resulting in hypertension. Furthermore, policosanol could be helpful in reducing hypertension by promoting normal arterial endothelial cell function, whilst inhibiting platelet aggregation and thrombosis" (Askarpour et al. 2019. Complement Ther Med. 45:89-97).

Review: Askarpour et al. 2019. Op. cit.: "Policosanol could lower SBP [systolic blood pressure] and DBP [diastolic blood pressure] significantly; future long term studies are required to confirm these findings in the general population."

Notes: "The first policosanol supplements were produced by Dalmer Laboratories in Cuba; studies conducted and published by that group have found that policosanol is safe and effective as a lipid-lowering agent. However these studies were small, and efforts by groups outside of Cuba have failed to replicate these results" (Wikipedia).

Pomegranate

Promoted for: "Preparations from pomegranate including the juice or extract have been promoted for prevention or treatment of many conditions including heart disease, high blood pressure, high blood cholesterol levels, cancer, and diabetes" (NCCIH 2020. Pomegranate).

Presumed mechanism of action: antioxidant and anti-inflammatory effects, with higher antioxidant levels than some other types of fruit juice. "The pomegranate plant contains alkaloids, mannite, ellagic acid, and gallic acid, and the bark and rind contain various tannins. The polyphenols in pomegranate are believed to provide the anti-oxidant activity and protect low-density lipoprotein (LDL) against cell-mediated oxidation directly by interaction with the lipoprotein and indirectly by accumulation in arterial macrophages...In addition, pomegranate juice may cause antihypertensive effects by decreasing angiotensin-converting enzyme (ACE) activity" (Haber et al. 2011. Am J Health Syst Pharm. 15;68(14):1302-5). It was also proposed to increase production of nitric oxide.

Possible adverse effects: "Pomegranate juice is believed to be safe. Pomegranate extract may also be safe. Pomegranate root, stem, and peel may not be safe when consumed in large amounts because they contain substances that can have harmful effects. Pomegranate usually doesn’t have side effects, but digestive tract symptoms, especially diarrhea, may occur in a small number of people. Allergic reactions to pomegranate have been reported. Little is known about whether it’s safe to use pomegranate extract during pregnancy or while breastfeeding" (NCCIH).

Reviews:

• Aziz et al. 2020. Complement Ther Med. 48:102236: "Current evidence does not show pomegranate has significant effects on serum lipid levels. The quality of evidence is poor to support the increasing use of pomegranate for hyperlipidaemia."

• Jandari et al. 2020. Complement Ther Med. 52:102478: "There were no significant favorable effects of pomegranate supplementation on metabolic parameters in patients with T2DM [type 2 diabetes mellitus]. Future well-designed, large scale RCTs, with longer duration are needed in this field."

Notes: "We don’t have a lot of strong scientific evidence on the effects of pomegranate on people’s health...the limited research that’s been completed so far has not shown benefits of pomegranate in preventing or treating heart disease, high blood pressure, high cholesterol levels, cancer, diabetes, or other conditions" (NCCIH). In 2010 the FDA charged the marketers of POM Wonderful, a pomegranate juice product, with deceptive advertising in making claims related to prostate cancer, heart disease, and erectile dysfunction.

Potassium - see also macrominerals

Promoted for: blood pressure, bone health, blood glucose control

Presumed mechanism of action: "Higher potassium intakes...may help decrease blood pressure, in part by increasing vasodilation and urinary sodium excretion, which in turn reduces plasma volume; this effect may be most pronounced in salt-sensitive individuals" (NIH Office of Dietary Supplements 2021. Potassium).

Possible adverse effects: "Potassium supplements can cause minor gastrointestinal side effects. Chronic ingestion of doses of potassium supplements (e.g., up to 15,600 mg for 5 days) in healthy people can increase plasma levels of potassium, but not beyond the normal range. However, very high amounts of potassium supplements or salt substitutes that contain potassium could exceed the kidney’s capacity to excrete potassium, causing acute hyperkalemia even in healthy individuals" (Ibid.).

Reviews:

• Binia et al. 2015. J Hypertens. 33(8):1509-20: "Potassium supplementation is associated with reduction of blood pressure in patients who are not on antihypertensive medication, and the effect is significant in hypertensive patients."

• Filippini et al. 2017. Int J Cardiol. 230:127-35: "Potassium supplementation in hypertensives was generally associated with decreased blood pressure, particularly in high sodium consumers, subjects not on hypertensive drug treatment, and those in the lowest category of potassium intake."

Notes: According to NIH Office of Dietary Supplements:

• "Results from most clinical trials suggest that potassium supplementation reduces blood pressure."

• "Additional research is needed to fully understand the potential link between dietary and supplemental potassium and the risk of kidney stones."

• "Observational studies suggest that increased consumption of potassium from fruits and vegetables is associated with increased bone mineral density. This evidence, combined with evidence from metabolic studies and a few clinical trials, suggests that dietary potassium may improve bone health."

• "The findings from studies conducted to date [on blood glucose] are promising. But more research, including randomized controlled trials, is needed before potassium’s link with blood glucose control and type 2 diabetes can be confirmed."

Prevagen - "Apoaequorin is a protein that comes from a specific type of jellyfish that glows. When apoaequorin is exposed to calcium, the protein and calcium bind and a blue light is produced. For more than 40 years, apoaequorin has been used in a laboratory setting to study how calcium works inside cells. Recently apoaequorin has been manufactured on a larger scale for use in the dietary supplement Prevagen" (WebMD 2021. Apoaequorin). Prevagen uses a synthetic version of apoaequorin.

Promoted for: memory loss, cognitive decline

Presumed mechanism of action: "Problems with calcium regulation in the human brain are thought to play a role in age-related mental decline. Because apoaequorin has a similar structure to human calcium-binding proteins, some researchers believe it might help regulate calcium in the brain..." (Ibid.).

Possible adverse effects: According to Eisner (2020 Oct. 21. Wired), "thousands of Americans have reported experiencing 'adverse events' while taking Prevagen, including seizures, strokes, heart arrhythmias, chest pain, and dizziness. While the existence of adverse event reports alone don’t prove a product is the cause, the nature and pattern of complaints about Prevagen worried FDA officials, according to agency records. One internal report from 2015 stated that the 'numerous adverse events reported' indicated 'a serious safety hazard'.”

Notes: "'The marketing for Prevagen is a clear-cut fraud, from the label on the bottle to the ads airing across the country,' according to [New York Attorney General Eric] Schneiderman...Published in an obscure journal, the clinical trial touted by the marketers as proving the efficacy of Prevagen actually found no overall benefit compared to a placebo for its primary endpoints involving memory and cognition. That should have been that. But the researchers, all employed by the maker of Prevagen, then did a series of subgroup analyses, a few of which found slight improvements in smaller groups of participants, mostly those who had little or no cognitive difficulty at baseline. Such secondary analyses are unreliable and - at the very least - represent cherry-picking the data for something positive to report [this is also known as 'P-hacking']. There were other methodological problems with the study as well...[The rationale for Prevagen] is scientifically implausible. Even if this hypothesis were true, as the FTC points out, the company’s own 'safety studies show that apoaequorin is rapidly digested in the stomach and broken down into amino acids and small peptides like any other dietary protein.' And even if the orally consumed protein somehow got into the bloodstream, there’s no evidence that it can cross the human blood-brain barrier to affect neurons. The company boasts that the scientist who 'discovered' apoaequorin and his colleagues won the Nobel prize in chemistry. That’s true, but that was for basic research on how jellyfish glow in the dark - it had nothing to do with human brain health" (Swartzberg 2019 Apr 17. Berkeley Wellness). A lawsuit by the FTC and New York State was still in progress as of 2019, and other class action lawsuits have been filed.

Probiotics, prebiotics, and synbiotics - "The International Scientific Association for Probiotics and Prebiotics defines 'probiotics' as 'live microorganisms that, when administered in adequate amounts, confer a health benefit on the host'. These microorganisms, which consist mainly of bacteria but also include yeasts, are naturally present in fermented foods, may be added to other food products, and are available as dietary supplements...Probiotics should not be confused with prebiotics, which are typically complex carbohydrates (such as inulin and other fructo-oligosaccharides) that microorganisms in the gastrointestinal tract use as metabolic fuel. Commercial products containing both prebiotic sugars and probiotic organisms are often called 'synbiotics.' In addition, products containing dead microorganisms and those made by microorganisms (such as proteins, polysaccharides, nucleotides, and peptides) are, by definition, not probiotics...Probiotics are also available as dietary supplements (in capsules, powders, liquids, and other forms) containing a wide variety of strains and doses. These products often contain mixed cultures of live microorganisms rather than single strains" (NIH Office of Dietary Supplements 2020. Probiotics). The International Association also proposed two categories of synbiotics: "A complementary synbiotic is composed of a probiotic and a prebiotic that together confer one or more health benefits but do not require co-dependent function; the components must be used at doses that have been shown to be effective for the component alone. A synergistic synbiotic contains a substrate that is selectively utilized by the co-administered liver microorganism(s)" (Swanson et al. 2020. Nat Rev Gastroenterol Hepatol. 17(11):687-701).

Promoted for: Considerable research has concerned use for "atopic dermatitis, pediatric acute infectious diarrhea, antibiotic-associated diarrhea, irritable bowel syndrome, hypercholesterolemia, and obesity" (NIH).  "Lactobacillus is most commonly used for diarrhea, including infectious diarrhea and diarrhea in people taking antibiotics (antibiotic-associated diarrhea). Some people also used lactobacillus for general digestion problems, a long-term disorder of the large intestines that causes stomach pain (irritable bowel syndrome or IBS), excessive crying in infants (colic), long-term swelling (inflammation) in the digestive tract (inflammatory bowel disease or IBD), inflammation of the colon, and many other conditions" (MedlinePlus 2021. Lactobacillus). "Saccharomyces boulardii is most commonly used for treating and preventing diarrhea, including infectious types such as rotaviral diarrhea in children. It has some evidence of use for other types of diarrhea, acne, and a digestive tract infection that can lead to ulcers" (MedlinePlus 2020. Saccharomyces Boulardii). Probiotics have been proposed as a possible treatment for diabetes, depression, and many other conditions.

Presumed mechanism of action: "The human gastrointestinal tract is colonized by many microorganisms, including bacteria, archaea, viruses, fungi, and protozoa. The activity and composition of these microorganisms (collectively known as the gut microbiota, microbiome, or intestinal microflora) can affect human health and disease. Probiotics exert their effects usually in the gastrointestinal tract, where they may influence the intestinal microbiota. Probiotics can transiently colonize the human gut mucosa in highly individualized patterns, depending on the baseline microbiota, probiotic strain, and gastrointestinal tract region. Probiotics also exert health effects by nonspecific, species-specific, and strain-specific mechanisms. The nonspecific mechanisms vary widely among strains, species, or even genera of commonly used probiotic supplements. These mechanisms include inhibition of the growth of pathogenic microorganisms in the gastrointestinal tract (by fostering colonization resistance, improving intestinal transit, or helping normalize a perturbed microbiota), production of bioactive metabolites (e.g., short-chain fatty acids), and reduction of luminal pH in the colon. Species-specific mechanisms can include vitamin synthesis, gut barrier reinforcement, bile salt metabolism, enzymatic activity, and toxin neutralization. Strain-specific mechanisms, which are rare and are used by only a few strains of a given species, include cytokine production, immunomodulation, and effects on the endocrine and nervous systems. Through all of these mechanisms, probiotics might have wide-ranging impacts on human health and disease" (NIH). "'Friendly' bacteria such as Lactobacillus can help us break down food, absorb nutrients, and fight off 'unfriendly' organisms that might cause diseases such as diarrhea" (MedlinePlus 2021. Lactobacillus).

Possible adverse effects: "Many probiotic strains derive from species with a long history of safe use in foods or from microorganisms that colonize healthy gastrointestinal tracts. For these reasons, the common probiotic species - such as Lactobacillus species (acidophilus, casei, fermentum, gasseri, johnsonii, paracasei, plantarum, rhamnosus, and salivarius) and Bifidobacterium species (adolescentis, animalis, bifidum, breve, and longum) - are unlikely to cause harm...Side effects of probiotics are usually minor and consist of self-limited gastrointestinal symptoms, such as gas. In a few cases, mainly involving individuals who were severely ill or immunocompromised, the use of probiotics has been linked to bacteremia, fungemia (fungi in the blood), or infections that result in severe illness" (NIH). Costa et al. (2018. BMC Complement Altern Med. 18(1):329) reported 93 cases of infectious complications, and concluded that "The use of probiotics cannot be considered risk-free and should be carefully evaluated for some patient groups."

Reviews (2016-2021 only unless subject not covered in a later review):

• Szajewska and Chmielewska 2013. BMC Pediatr. 13:185: "Supplementation of infant formula with B lactis results in growth similar to what is found in infants fed unsupplemented formula. Limited data do not allow one to reach a conclusion regarding the effect of LGG [Lactobacillus rhamnosus GG] supplementation on infant growth."

• Bernaola Aponte et al. 2013. Cochrane Database Syst Rev. CD007401: "There is limited evidence suggesting probiotics may be effective in treating persistent diarrhoea in children."

• Sung et al. 2013. JAMA Pediatr. 167(12):1150-7: "Although L reuteri may be effective as treatment for crying in exclusively breastfed infants with colic, there is still insufficient evidence to support probiotic use to manage colic, especially in formula-fed infants, or to prevent infant crying."

• King et al. 2014. Br J Nutr. 112(1):41-54 [acute respiratory infectious conditions]: "This systematic review provides evidence from a number of good-quality RCT [randomized controlled trials] that probiotics reduce the duration of illness in otherwise healthy children and adults."

• Cabana 2014. Evid Based Med. 19(4):144: "At this time, there is insufficient evidence to recommend the use of probiotic supplements for the prevention of asthma and wheezing for the general population, or for specific subgroups of patients."

• Ford et al. 2014. Am J Gastroenterol. 109(10):1547-61: " Probiotics are effective treatments for IBS [irritable bowel syndrome], although which individual species and strains are the most beneficial remains unclear. Further evidence is required before the role of prebiotics or synbiotics in IBS is known. The efficacy of all three therapies in CIC [chronic idiopathic constipation] is also uncertain.

• Chisholm 2015. Urol Nurs. 35(1):18-21, 29 [recurrent urinary tract infections in women]: "Although more research is needed, probiotics should be considered a useful and safe alternative to antibiotics."

• Ozen et al. 2015. Expert Opin Biol Ther. 15(1):9-20 [pediatric upper respiratory tract infections]: "At least one beneficial effect of prophylactic probiotic was observed in the majority of RCTs. Even a minimal reduction of 5 - 10% in the incidence of URTIs would have an important clinical and economic mpact [sic] on societies."

• Cuello-Garcia et al. 2015. J Allergy Clin Immunol. 136(4):952-61: "Probiotics used by pregnant women or breast-feeding mothers and/or given to infants reduced the risk of eczema in infants; however, the certainty in the evidence is low. No effect was observed for the prevention of other allergic conditions."

• Huang et al. 2016. Nutrients. 8(8):483: "We found that probiotics were associated with a significant reduction in depression, underscoring the need for additional research on this potential preventive strategy for depression."

• Blattner et al. 2016. Pediatr Allergy Immunol. 27(4):425-8: "In conclusion, probiotic supplementation may provide a significant reduction in the development of pediatric AD [atopic dermatitis]."

• Dermyshi et al. 2017. Neonatology. 112(1):9-23: "This meta-analysis of RCT and observational studies found that the use of probiotics was beneficial for the prevention of severe NEC [necrotizing enterocolitis], late-onset sepsis, and all-cause mortality in VLBW [very low birth weight] infants. "

• Wang et al. 2017.  J Pediatr Endocrinol Metab. 30(6):611-22: "Probiotics may have beneficial effects on the reduction of glucose, insulin and HbA1c for diabetes, especially for T2DM mellitus patients."

• Derwa et al. 2017. Aliment Pharmacol Ther. 46(4):389-400: "VSL#3 may be effective in inducing remission in active UC [ulcerative colitis]. Probiotics may be as effective as 5-ASAs [5-aminosalicylates] in preventing relapse of quiescent UC. The efficacy of probiotics in CD [Crohn's disease] remains uncertain, and more evidence from RCTs is required before their utility is known.

• Wilkins and Sequoia 2017. Am Fam Physician. 96(3):170-8: "There is high-quality evidence that probiotics are effective for acute infectious diarrhea, antibiotic-associated diarrhea, Clostridium difficile- associated diarrhea, hepatic encephalopathy, ulcerative colitis, irritable bowel syndrome, functional gastrointestinal disorders, and necrotizing enterocolitis. Conversely, there is evidence that probiotics are not effective for acute pancreatitis and Crohn disease."

• Mohammed et al. 2017. Clin Rheumatol. 36(12):2697-707: "Probiotics lowered pro-inflammatory cytokines IL-6 in RA [rheumatoid arthritis]; however, its clinical effect is still unclear. "

• Abraham and Quigley 2017. Gastroenterol Clin North Am. 46(4):769-82: "Well-designed studies of probiotics in IBD [inflammatory bowel disease] in humans remain scanty. Available evidence supports a role for probiotics in pouchitis and mild/moderate ulcerative colitis but not in Crohn disease."

• Mo et al. 2019. Med Clin (Barc). 152(12):473-81: "This meta-analysis revealed that the use of probiotics can significantly lower TC [total cholesterol] and LDL-C [low-density lipoprotein cholesterol] levels in hypercholesterolaemic adults, which brings hope for reducing the risk factors for developing cardiovascular disease."

• Buggio et al. 2019. BMC Womens Health. 19(1):25: "Despite increasing marketing of probiotics for the treatment of vulvovaginal candidiasis and prevention of preterm birth robust evidence demonstrating a beneficial effect is scarce. Moreover, there was considerable heterogeneity among the different studies in terms of route of administration, strain/s of probiotic adopted, and length of probiotic use. Before recommending the systematic use of probiotics to treat bacterial vaginosis and VVC and prevent preterm birth, high-quality research is needed."

• Scott et al. 2019. Cochrane Database Syst Rev. CD012941: "Probiotics may prevent AOM [acute otitis media] in children not prone to AOM, but the inconsistency of the subgroup analyses suggests caution in interpreting these results."

• Liu et al. 2019. Neurosci Biobehav Rev. 102:13-23: "There is general support for antidepressant and anxiolytic effects of probiotics, but the pooled effects were reduced by the paucity of trials with clinical samples."

• Tiderencel et al. 2020. Diabetes Metab Res Rev. 36(1):e3213: "Based on the evidence reviewed, multistrain probiotics that contain seven million to 100 billion colony forming units of Lactobacillus acidophilus, Streptococcus thermophilus, Lactobacillus bulgaricus, and/or Bifidobacterium lactis administered for 6 to 12 weeks may be efficacious for improving glycaemic control in adults with T2DM [type 2 diabetes mellitus]."       

• Akram et al. 2020. Aust Dent J. 65(1):12-20: "The outcomes of this review show weak evidence to support the use of probiotics in reducing inflammatory periodontal parameters in gingivitis. Significant heterogeneity and limited available data may reduce the impact of these conclusions."

• Tenorio-Jiménez et al. 2020. Nutrients. 12(1):124: "Despite the diversity of the published studies, the intake of probiotics for patients with MetS [metabolic syndrome] may offer a discrete improvement in some of the clinical characteristics of the MetS and a decrease in inflammatory biomarkers. Nevertheless, these beneficial effects seem to be marginal compared to drug therapy and a healthy lifestyle and clinically non-relevant."

• Kocsis et al. 2020. Sci Rep. 10(1):11787: "Our data clearly suggest that probiotics could be a supplementary therapeutic approach in type 2 diabetes mellitus patients to improve dyslipidemia and to promote better metabolic control."

• Qi et al. 2020. Lipids Health Dis. 19(1):79: "This meta-analysis found a moderate and statistically significant reduction for either SBP [systolic blood pressure] or DBP [diastolic blood pressure] with probiotics supplement compared with controls. Thus, probiotics is a potential for the dietary treatment of hypertension."

• Iheozor-Ejiofor et al. 2020. Cochrane Database Syst Rev. CD007443: "The effectiveness of probiotics for the maintenance of remission in ulcerative colitis remains unclear. This is due to low- to very low-certainty evidence from poorly conducted studies, which contribute limited amounts of data from a small number of participants."

• Masulli et al. 2020. Diabetes Res Clin Pract. 162:108111: "Probiotics during pregnancy do not reduce the incidence of GDM [gestational diabetes], with a very little (statistically but not clinically significant) reduction of fasting plasma glucose."

• Mohr et al. 2020. J Acad Nutr Diet. 120(4):548-64: "probiotic supplementation was concluded to have a limited effect on immune and inflammatory markers in healthy adults. Overall, the evidence was heterogenous, precluding a meta-analysis, and difficult to aggregate and conclude on effect size."

• Morgan et al. 2020. Gastroenterology. 159(2):467-80: " In a systematic review and network meta-analysis of studies to determine the effects of single-strain and multistrain probiotic formulations on outcomes of preterm, low-birth-weight neonates, we found moderate to high evidence for the superiority of combinations of 1 or more Lactobacillus spp and 1 or more Bifidobacterium spp vs single- and other multiple-strain probiotic treatments."

• Pecora et al. 2020. Front Immunol. 11:957: "A possible role was documented for probiotics in improving CD [celiac disease]-related symptoms, modulating the peripheral immune response and altering the fecal microbiota, although the results were not consistent in all of the studies. No evidence was found that probiotic administration might prevent CD onset."

• Seiler et al. 2020. Am J Gastroenterol. 115(10):1584-95: " Probiotics may improve GI symptoms in patients with CD [celiac disease]."

• Liu et al. 2020. Complement Ther Med. 54:102547: "Our present study suggests that Lactobacillus consumption in capsule form when the daily dose is above 5 × 109 CFU [colony forming unit] for more than 8 weeks can decrease SBP [systolic blood pressure] or DBP [diastolic blood pressure] in T2DM patients, borderline hypertension participants or Asian individuals."

• Fu et al. 2020. Biomed Res Int. 2020:7947342: "In summary, the evidence for the efficacy of probiotics, prebiotics, and synbiotics in improving HIV-infected patients' CD4 counts as presented in currently published RCTs is insufficient."

• Yu et al. 2021. BMJ Open. 11(3):e041393 [postmenopausal women]: "We conclude cautiously that supplementation with probiotics could increase lumbar BMD [bone mineral density]. More RCTs are recommended to validate or update these results."

• Liang et al. 2021. Crit Rev Food Sci Nutr. 61(10):1670-88 [type 2 diabetes]: "Our analysis revealed that glycemic, lipids, blood pressure and inflammation indicators are significantly improved by probiotic supplementation, particularly the subjects who ages = 55, baseline BMI< 30 kg/m2, duration of intervention more than 8 weeks, and received multiple species probiotic."

• Chi et al. 2021. Pediatrics. 147(1):e20200706: "The efficacy of single probiotic supplements is limited, compared to combined use of probiotics. To achieve optimal effect on premature infant health, combined use of prebiotic and probiotic, especially Lactobacillus or Bifidobacterium, is recommended."

• Meirlaen et al. 2021. Nutrients. 13(3):934: "While there is substantial evidence from animal studies in well controlled conditions that selected probiotic strains may offer benefits in the prevention of wheezing and asthma, outcomes from clinical studies in infants (including as well pre- and postnatal administration) are disappointing...There is little evidence to recommend administration of pro, pre- or synbiotics in the prevention of asthma and allergic rhinitis in children."

• Trivic et al. 2021. Eur J Pediatr. 180(2):339-51: "This systematic review showed that the use of Lactobacillus reuteri DSM 17938 modestly reduces the pain intensity in children with functional abdominal pain."

• Wang et al. 2021. Front Public Health. 9:645035: "In the current studies using probiotics, pre-biotics or synbiotics for the treatment of pre-diabetes, the benefits of modulating the abundance of gut microbiota were partially demonstrated. However, there is insufficient evidence to show significant benefits on glucose metabolism, lipid metabolism and body composition."

• Liao et al. 2021.  J Clin Gastroenterol. 55(6):469-80: "This updated meta-analysis suggested that using probiotics as early as possible during antibiotic therapy has a positive and safe effect on preventing AAD [antibiotic-associated diarrhea] in adults."

Notes: NIH Office of Dietary Supplements (2020. Probiotics) summarizes research findings as follows:

• "Overall, the available evidence suggests that the use of probiotics might reduce the risk of developing atopic dermatitis and lead to significant reductions in atopic dermatitis SCORAD scores, but these products might provide only limited relief from the condition."

• "...the cost-effectiveness of the use of probiotic supplements to manage acute viral diarrhea lacks consensus."

• "Overall, the available evidence suggests that starting probiotic treatment with Lactobacillus rhamnosus GG or Saccharomyces boulardii in 2 days of the first antibiotic dose helps reduce the risk of AAD [antibiotic-associated diarrhea] in children and adults aged 18 to 64, but not in elderly adults."

• "Overall, the available evidence indicates that probiotics might reduce some symptoms of IBS [irritable bowel syndrome]. However additional high-quality clinical trials are needed to confirm the specific strain, dose, and duration of treatment required as well as the type of IBS (such as with predominant diarrhea or constipation) that can be treated effectively with probiotics."

• "Overall, research suggests that the use of multiple probiotic strains in combination as well as of probiotics containing Lactobacillus acidophilus, a mixture of Lactobacillus acidophilus and Bifidobacterium lactis, or Lactobacillus plantarum might reduce total and LDL [low-density lipoprotein] cholesterol levels. However, more research is needed to confirm these findings."

• "Taken together, these results indicate that the effects of probiotics on body weight and obesity might depend on several factors, including the probiotic strain, dose, and duration, as well as certain characteristics of the user, including age, sex, and baseline body weight. Additional research is needed to understand the potential effects of probiotics on body fat, body weight, and obesity in humans."

MedlinePlus (2021. Lactobacillus) cites Natural Medicines Comprehensive Database as rating lactobacillus possibly effective for hay fever, some types of diarrhea, eczema, allergies, overgrowth of bacteria in the vagina, colic, constipation, diabetes, H. pylori infection, high cholesterol, oral mucositis, pouchitis, infection of the airways, rheumatoid arthritis, and ulcerative colitis. Many products contain bacteria that do not survive the digestive process.

Cohen (2018. JAMA Intern Med. 178(12):1577-8) wrote:

• • • "Although preliminary evidence supports the use of specific strains of probiotics in certain clinical settings, such as preventing C difficile and antibiotic-associated diarrhea, widespread use, particularly among people who are healthy, has greatly outpaced the science."

    • "Despite the advertised indications, there are no large, long-term clinical trials proving that probiotics offer clinical benefits for people who are already healthy."

    • "...studies have found commercial probiotics that contain live microorganisms not listed on their labels."

    • "The FDA’s requirements do not address the unique risks that probiotics may pose, such as the potential to introduce new genes into consumers’ microbiomes. Of particular concern are genes that may confer antibiotic resistance. Bacteria sold as probiotics, like all bacteria, may have intrinsic as well as acquired resistance to antibiotics."

    • "Until more data are available regarding the transfer of probiotic genes in humans, modern manufacturing techniques should be used to ensure that mobile resistance genes are not contained in the probiotics consumed by millions of people in the United States. Standards designed to decrease exposure to mobile resistance genes have been implemented in Canada and several European countries. The FDA, however, does not require these safeguards in the United States."

Athalye-Jape et al. (2019. Microb Biotechnol. 12(2):249-53) wrote: "Over 25 systematic reviews and meta-analyses of RCTs (~12 000 participants) have reported that probiotics significantly reduce the risk of all-cause mortality, NEC [necrotizing enterocolitis] = Stage II, LOS [late onset sepsis] and feeding intolerance in preterm infants."

Among the points made by Abid and Koh (2019. Infection. 47(6):911-7):

• "most strains originated from the food industry: based on a role in food fermentation, easy cultivability, and wide availability and almost none are human-derived (apart from Bifidobacterium infantum in infant formula). Except for the latter, none have been ‘rationally derived’ from animal or human models, for preventing or treating a specific disease."

• "There is no 'standard' gut microbial composition as it varies not just across communities, but also among individuals within a community and within individuals over time and the lifespan..."

• "Probiotics may potentially be harmful to critically ill and immunocompromised hosts, and are best avoided in immuno-oncology patients, particularly during treatment."

Novella (2020 Jan 15. Science-Based Medicine blog), summarizing a paper Neunez et al. (2020. Front Med (Lausanne). 6:296), states that the authors "assessed the accuracy, completeness, and reliability of the information found online about probiotics. Only 23% of the claims made for probiotics on the 150 websites reviewed were backed by scientific evidence. Another 20% had essentially no supportive evidence, while the rest had some evidence but not enough to justify the claims."

Gavura (2020 Jul 9. Science-Based Medicine blog) wrote, "Direct-to-consumer advertising is common, and the evidence behind efficacy claims is often unclear. Over time, the usage of probiotics has grown significantly, but that growth has not been accompanied by a solid evidence base to demonstrate that these products are beneficial." He summarized new clinical practice guidelines from the American Gastroenterological Association (Su et al. 2020. Gastroenterology. 159(2):697-705). For pouchitis, prevention of C. difficile infections, and for preterm and low-birth-weight infants, specific strains were recommended. For treatment of C. difficile infections, Crohn's disease, ulcerative colitis, and irritable bowel syndrome, probiotics were only recommended in the context of a clinical trial. Probiotics were not recommended for acute infectious gastroenteritis in children. Gavura also noted, "Given the variety of species, strains, and manufacturing methods, it’s not possible to extrapolate across different products to assume that one will provide the same benefits as another. While manufacturers and marketers continue to make vague and often unproven claims of effectiveness, the evidence for probiotics is far less impressive than the hype."

In a commentary accompanying the above guidelines, Khoruts et al. (2020. Gastroenterology. 159(2):409-13) made the following points:

• "Many health care providers routinely encourage taking probiotics for various digestive diseases as well as some systemic illnesses. Recommendations to take probiotics are often included in hospital discharge orders under the presumption that they can mitigate potential harms of antibiotics."

• "By 2023, the industry’s yearly global sales are projected to reach approximately US$70 billion."

• "One critical fact that has muddled the field is the lack of recognition that many functions of bacteria are specific to the strain, not the species."

• "A common notion that probiotics 'balance' the intestinal microbial composition is almost certainly wrong. The intestinal microbiota is made up of assemblages of highly specialized microbes that are well adapted to the host environment and interconnected with each other through complex functional networks. Although these communities are dynamic, they are also intrinsically stable and resilient to invasion."

• "Notably, most of the probiotic strains available on the market today are not adapted to the environment of the human intestine. Most probiotic strains were derived from fermented foods, and even microbes of intestinal origin, such as EcN, have long adjusted to the conditions of their in vitro cultivation. This is one of the reasons why probiotics are generally considered to be safe. Companies may also prefer strains that do not colonize the intestine to strengthen the rationale for daily administration."

• "Perhaps most alarmingly, given that a common rationale for recommending probiotics to patients is to reverse antibiotic injury to gut microbes, treatment with this preparation of probiotics actually delayed recovery of normal intestinal microbial community structure."

In a consensus statement (Marco et al. 2021. Nat Rev Gastroenterol Hepatol. 2021 Mar;18(3):196-208), the International Scientific Association for Probiotics and Prebiotics distinguished between probiotics and fermented foods. "Fermented foods and beverages are sometimes characterized or labelled as 'probiotic foods' or 'contains probiotics.' These declarations might reflect efforts by manufacturers to communicate to consumers that living, health-promoting microorganisms are present in the product. However...the term ‘probiotic’ should only be used when there is a demonstrated health benefit conferred by well-defined and characterized live microorganisms. The health benefit must, at least in part, be due to the live microorganisms and must extend beyond any nutritional benefit of the food matrix. For these reasons, the terms ‘fermented food’ and ‘probiotics’ cannot be used interchangeably...certain jurisdictions [Canada, Europe] recognize several common species for which the term ‘probiotic’ can be used in foods...However, in our view, even if the fermented food contains one or more of those species, the label 'contains probiotics' should only be used when the strains in the fermented food are defined to the strain level, the genome sequences are known and the strains are present at an appropriate number during product shelf-life."

Propolis ("bee glue") - "a resinous mixture that honey bees produce by mixing saliva and beeswax with exudate gathered from tree buds, sap flows, or other botanical sources" (Wikipedia 2020. Propolis). "Propolis is rarely available in its pure form. It is usually obtained from beehives and contains bee products" (MedlinePlus 2020. Propolis).

Promoted for: "diabetes, cold sores, and swelling (inflammation) and sores inside the mouth (oral mucositis). It is also used for burns, canker sores, genital herpes, and other conditions" (Ibid.).

Presumed mechanism of action: "Propolis seems to have activity against bacteria, viruses, and fungi. It might also have anti-inflammatory effects and help skin heal" (Ibid.). Antioxidant effects.

Possible adverse effects: "It can cause allergic reactions, especially in people who are allergic to bees or bee products. Lozenges containing propolis can cause irritation and mouth ulcers" (MedlinePlus). May make asthma worse and slow blood clotting. Possible interactions with some medications.

Review: Braakhuis 2019. Nutrients. 11(11):2705: "There is significant promise for propolis as an effective antioxidant and anti-inflammatory agent with particular promise in cardiometabolic health."

Notes: Natural Medicines Comprehensive Database, as cited by MedlinePlus, rates as possibly effective for diabetes, cold sores, and sores in the mouth; insufficient evidence to rate effectiveness for other conditions.

Psyllium - see HERBS article

Pycnogenol® - pine bark extract. See HERBS article (Maritime pine)

Pyridoxal phosphate - see vitamin B6 below and section on water-soluble vitamins (SUPPLEMENTS PART 1)

Pyruvate - part of normal human metabolism, not required in diet. The protonated form (conjugate acid) is pyruvic acid.

Promoted for: weight loss, improve endurance, reduce cholesterol, antioxidant

Review: Pittler and Ernst 2004. Am J Clin Nutr. 79(4):529-36: “Considering the evidence available from rigorous clinical trials, the case of pyruvate as an aid to body-composition changes and weight loss is weak.”

Notes: "Pyruvate is sold as a weight-loss supplement, though credible science has yet to back this claim. A systematic review of six trials found a statistically significant difference in body weight with pyruvate compared to placebo. However, all of the trials had methodological weaknesses and the magnitude of the effect was small. The review also identified adverse events associated with pyruvate such as diarrhea, bloating, gas, and increase in low-density lipoprotein (LDL) cholesterol. The authors concluded that there was insufficient evidence to support the use of pyruvate for weight loss" (Wikipedia 2021. Pyruvic acid).

Quercetin - "a polyphenolic flavonol that is naturally present in a variety of fruits (such as apples), vegetables (such as onions), and beverages (such as wine and, especially, tea)" (NIH Office of Dietary Supplements 2019. Dietary supplements for exercise and athletic performance).Promoted for: ergogenic aid

Presumed mechanism of action: "The mechanisms by which quercetin might enhance exercise and athletic performance when taken in much larger amounts are not known, but many have been hypothesized. For example, quercetin might increase the number of mitochondria in muscle, reduce oxidative stress, decrease inflammation, and improve endothelial function (blood flow)" (Ibid.). "Though it has antioxidant properties in vitro and is abundant in common foods, Q is poorly bioavailable and rapidly metabolized in vivo so that the antioxidant activity cannot be the only mechanism behind Q's cardiovascular protective effects. ..Q and its in vivo metabolites, 3'-O-methyl quercetin and 4'-O-methyl quercetin exerted antioxidant effects, resulting in a reduction of ROS [reactive oxygen species]. Moreover, Q, but not its two O-methylated derivatives, was able to positively modulate 2 prosurvival signaling pathways, ERK1/2 and PI3K/Akt, and to reduce caspase-3 activity and DNA fragmentation, confirming Q's potential role in counteracting CVD [cardiovascular disease]" (Malaguti et al. 2015. J Am Coll Nutr. 34 Suppl 1:22-7). Modulation of the expression of numerous genes was proposed.

Notes: "More research, including larger clinical trials, on quercetin supplementation to improve aerobic capacity in trained athletes during specific sports and competitions is needed before any recommendations can be made" (NIH 2019. Op. cit.).

Raw (unpasteurized) milk

Promoted for: allegedly more nutritious than pasteurized milk, since nutrients are not destroyed in heating; contains beneficial probiotics

Possible adverse effects: illnesses and deaths have been caused by Salmonella and other bacteria

Notes: Novella (2020 Jul 8. Science-Based Medicine blog) provided a critique of raw milk. Among his points: "For regular pasteurized milk, therefore, there is no significant nutritional difference. Any minor differences are clinically irrelevant. Ultra-pasteurized or shelf stable milk has reduced thiamine, which is only an issue if milk is your primary source of thiamine, which is likely not true for most people...raw milk microbiota has minimal lactic acid bacteria....What raw milk does contain in abundance is pathogenic bacteria, those capable of causing infection. Further, raw milk is loaded with antibiotic resistant genes (residing in those bacteria). Consuming raw milk not only risks infection, it is potentially seeding the bacteria already in your body with antibiotic resistant genes...The bottom line is that there is no health benefit to drinking raw milk vs pasteurized milk, but there is a clear increased risk from pathogenic bacteria and now possibly from increased spread of antibiotic resistant genes."

Red yeast rice - "Red yeast rice is made by culturing rice with various strains of the yeast Monascus purpureus. Some preparations of red yeast rice are used in food products in Chinese cuisine...Some red yeast rice products contain substances called monacolins, which are produced by the yeast. Monacolin K is chemically identical to the active ingredient in the cholesterol-lowering drug lovastatin, which is one of the drugs in the category known as statins" (NCCIH 2013. Red yeast rice).

Promoted for: lowering cholesterol as an alternative to statin drugs

Presumed mechanism of action: "Red yeast rice contains varying amounts of monacolins, a family of naturally occurring substances that inhibit hydroxymethylglutaryl-coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis...Approximately 90% of the total monacolin content of RYR consists of monacolin K and its hydroxy acid form, monacolin KA. Other active ingredients with the potential to lower cholesterol in commercially available RYR products include plant sterols (beta-sitosterol, campesterol, stigmasterol), isoflavones, and monounsaturated fatty acids...Little is known about the pharmacodynamics of the other monacolins contained in RYR, but it has been suggested that they may also have lipid-lowering effects or potentiate the effects of monacolin K" (Burke 2015.Curr Atheroscler Rep. 17(4):495).

Possible adverse effects: "The same types of side effects that can occur in patients taking lovastatin as a drug can also occur in patients who take red yeast rice products that contain monacolin K. Potential side effects include myopathy (muscle symptoms such as pain and weakness), rhabdomyolysis (a condition in which muscle fibers break down, releasing substances into the bloodstream that can harm the kidneys), and liver toxicity...Red yeast rice supplements should not be used while pregnant or breastfeeding. Lovastatin can interact with a variety of drugs to increase the risk of rhabdomyolysis...Red yeast rice containing monacolin K could interact with drugs in the same way. If the process of culturing red yeast rice is not carefully controlled, a substance called citrinin can form. Citrinin has been shown to cause kidney failure in experimental animals and genetic damage in human cells. In a 2011 analysis of red yeast rice products sold as dietary supplements, 4 of 11 products were found to contain this contaminant" (NCCIH). The FDA issued warnings concerning the safety of red yeast rice products in 2007 and 2013. Cohen et al. (2017. Eur J Prev Cardiol. 24(13):1431-4) analyzed 28 brands of red yeast rice supplements. " In the 26 brands that contained monacolin K, the quantity ranged more than 60-fold from 0.09 to 5.48 mg per 1200 mg of red yeast rice. Following the manufacturers' recommendations for daily servings, the quantity of monacolin K consumed per day would range more than 120-fold from 0.09 to 10.94 mg...Adverse effects of statins are dose dependent and, therefore, the risks from red yeast rice supplements are of particular concern when combined with prescription statins. However, 93% of red yeast rice supplement labels in our study did not advise consumers to avoid prescription statins when using the supplements...Red yeast rice often contains additional monacolins with potential statin-like activity and variability of other monacolins might create additional variability of these products." Gordon  et al. (2010. Arch Intern Med. 170(19):1722-7) also reported a high degree of variability of monacolin levels in commercial red yeast rice products.

Review: Yang and Mousa 2012. Complement Ther Med. 20(6):466-74: "Studies reviewed show that RYR significantly lowered LDL [low-density lipoprotein] cholesterol and total cholesterol. Effects on triglycerides and HDL cholesterol were also observed in some studies. Compared with statins, RYR was shown to have an equal efficacy to statins when combined with or without other dietary supplements."

Notes: "The composition of red yeast rice products varies depending on the yeast strains and culture conditions used to manufacture them. The strains and conditions used to produce culinary red yeast rice differ from those used to produce products that are intended to lower cholesterol. Tests performed by the FDA indicate that the red yeast rice sold as a food product contains only traces of monacolin K or none at all...In 1998, the FDA determined that a red yeast rice product that contained a substantial amount of monacolin K was an unapproved new drug, not a dietary supplement. On several occasions since then, the FDA has taken action against companies selling red yeast rice products that contain more than trace amounts of monacolin K, warning them that it is against the law to market these products as dietary supplements" (NCCIH). "The FDA reasoned that the absence of statins in traditional RYR compared with statin content in RYR supplement implied that the supplement industry was marketing a regulated drug as an unregulated 'natural' product..RYR supplement is a product produced by industrial methods under carefully controlled conditions. There exists a marked variability in the statin content in commercial RYR supplements. The literature has additionally documented that some producers may spike their products with pharmaceutical lovastatin" (Gold et al. 2018. Eur J Prev Cardiol. 25(1):73-5). Gavura (2017 Aug 24. Science-Based Medicine blog) noted that "The only red yeast rice products that are legally permitted for sale contain little, if any lovastatin, so they are in effect, ineffective for the intended purpose." He concluded: "If you want to lower your cholesterol and be confident that you’re actually reducing your risk of heart attacks and strokes, take a statin drug. If you want to spend more, prefer products with no obvious quality control, and don’t mind paying more for an active ingredient that may or may not actually be in the bottle, then take red yeast rice. Why red rice yeast extract would be preferred over a drug product is unclear, unless one puts a priority on something 'natural' over something that’s standardized, predictable, and demonstrated to be effective. If you need lovastatin, take the drug lovastatin, rather than a supplement that may-or-may-not actually contain lovastatin."

Reishi mushroom - see mushrooms.

Resveratrol - "Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants in response to injury or when the plant is under attack by pathogens, such as bacteria or fungi. Food sources of resveratrol include the skin of grapes, blueberries, raspberries, and mulberries. Interest in resveratrol began with the 'French Paradox' describing the cardiovascular health benefits of red wine, which contains high concentrations of non-flavonoid resveratrol, to explain a comparatively low incidence of cardiovascular events among the French populations despite a high dietary consumption of saturated fat" (Abu-Amero et al. 2016. Nutrients. 8(4):200). "A milestone in resveratrol research came in the early 2000s when some authors reported that resveratrol is able to mimic caloric restriction effects and increased yeast, worms, flies and rodents lifespan. This effect was ascribed to the resveratrol ability to activate sirtuin proteins, NAD+-dependent de-acetylase involved in the regulation of metabolism, apoptosis, mitochondrial biogenesis, inflammation, fatty acid metabolism, and glucose homeostasis" (Ponzo et al. 2014. J Transl Med. 12:158).

Promoted for: "Resveratrol is most commonly used for high cholesterol, cancer, heart disease, and many other conditions" (MedlinePlus 2021. Resveratrol).

Presumed mechanism of action: Antioxidative and anti-inflammatory properties. It is an activator of sirtuin 1 (see above), but has many other molecular targets. "Resveratrol might expand blood vessels and reduce the activity of cells important in blood clotting. Some research suggests that resveratrol has weak estrogen (a female hormone) effects. It may also decrease pain and swelling (inflammation). Resveratrol might reduce levels of sugar (glucose) in the blood and help the body fight against disease. It might also prevent proteins in the brain from sticking together to help prevent diseases such as Alzheimer's disease" (Ibid.). "It was postulated that resveratrol modulates signaling pathways that limit the spread of cancer cells, protects nerve cells from damage, helps to prevent diabetes, and acts as an antiaging agent that improves age-related problems" (Weiskirchen and Weiskirchen 2016. Adv Nutr. 15;7(4):706-18).

Possible adverse effects: possible interactions with medications

Reviews:

• Hausenblas et al. 2015. Mol Nutr Food Res. 59(1):147-59: "Statistically significant (p < 0.05) positive effects, indicating that resveratrol supplementation was more effective than placebo/control, were identified for systolic blood pressure, hemoglobin A1c, and creatinine, but not for fasting glucose, homeostatic model assessment of insulin resistance, diastolic blood pressure, insulin, triglycerides, LDL [low-density lipoprotein], or HDL [high-density lipoprotein] cholesterol."

• Szkudelski and Szkudelska 2015. Biochim Biophys Acta. 1852(6):1145-54: "Preliminary clinical trials show that resveratrol is also effective in type 2 diabetic patients. Resveratrol may, among others, improve glycemic control and decrease insulin resistance. These results show that resveratrol holds great potential to treat diabetes and would be useful to support conventional therapy."

• Zordoky et al. 2015. Biochim Biophys Acta. 1852(6):1155-77: "Despite the promise of resveratrol as a treatment for numerous cardiovascular diseases, the clinical studies for resveratrol are still limited. In addition, several conflicting results from trials have been reported, which demonstrates the challenges that face the translation of the exciting preclinical findings to humans."

• Jeyaraman et al. 2020. Cochrane Database Syst Rev. CD011919: "The limited available research does not provide sufficient evidence to support any effect, beneficial or adverse, of four to five weeks of 10 mg to 1000 mg of resveratrol in adults with T2DM [type 2 diabetes mellitus]."

• Koushki et al. 2020. Postgrad Med J. 96(1134):197-205 [oxidative stress]: "Collectively, our findings of available RCTs did no show any benefit of resveratrol supplementation on SOD [superoxide dismutase], CAT [catalase] and GPx [glutathione peroxidase] except for TAC [total antioxidant capacity]. Well-designed RCTs are necessary to confirm these results."

• Nyambuya et al. 2020. Molecules. 25(23):5645: "In all, resveratrol supplementation in hypoglycemic therapy improves glucose control and lowers blood pressure; however, additional evidence is necessary to confirm its effect on renal function in patients with T2D."

• Jakubczyk et al. 2020. Nutrients. 12(8):2435: "Currently available evidence is insufficient to confirm the efficacy of resveratrol in the management of NAFLD [nonalcoholic fatty liver disease]."

• Wei and Yu 2021. Complement Ther Med. 57:102635: "The overall results indicated that resveratrol supplementation did not affect liver enzymes in patients with NAFLD."

• Rafiee et al. 2021. Complement Ther Clin Pract. 42:101281: "Overall, the results of the present study show that resveratrol supplementation does not affect the management of NAFLD although it can improve some inflammatory markers."

Notes: According to Natural Medicines Comprehensive Database, as cited by MedlinePlus, resveratrol is possibly effective for obesity; possibly ineffective for heart disease, metabolic syndrome, and nonalcoholic fatty liver disease; insufficient evidence to rate effectiveness for other conditions. John Pezzuto, author of one of the key discoveries sparking widespread interest in resveratrol, looked back at 20 years of research (Pezzuto 2019. Biomol Ther (Seoul). 27(1):1-14), and noted that there have been over 20,000 research papers and over 100 human clinical trials on resveratrol. He stated that "Numerous commercial products are marketed to the general public with suggestions of life extension as well as a multitude of other health benefits. Nonetheless, at the present time, there is no consensus regarding the usage of resveratrol based on scientific evidence...most animal, human, and in vitro studies employ concentrations of resveratrol that vastly exceed even the largest quantity that could be rationally ingested by dietary means...it has been clear from the outset that resveratrol does not abide by the concept of ‘one drug, one target.' In the case of resveratrol, this dogma simply does not apply. The molecule is incredibly promiscuous, interacting with a host of targets...It is highly disconcerting to think consumers could actually believe taking resveratrol will extend their lifespan, reduce their body weight, and fulfill all of the other numerous claims of vibrancy and contentment."

Riboflavin  - see water-soluble vitamins (SUPPLEMENTS PART 1)

Promoted for: migraine, cancer prevention

Presumed mechanism of action: “Experts have theorized that riboflavin might help prevent the DNA damage caused by many carcinogens by acting as a coenzyme with several different cytochrome P450 enzymes” (NIH Office of Dietary Supplements 2021. Riboflavin).

Possible adverse effects: “Intakes of riboflavin from food that are many times the RDA have no observable toxicity, possibly because riboflavin’s solubility and capacity to be absorbed in the gastrointestinal tract are limited. Because adverse effects from high riboflavin intakes from foods or supplements (400 mg/day for at least 3 months) have not been reported, the FNB [Food and Nutrition Board] did not establish ULs for riboflavin. The limited data available on riboflavin’s adverse effects do not mean, however, that high intakes have no adverse effects, and the FNB urges people to be cautious about consuming excessive amounts of riboflavin” (Ibid.).

Notes: “Some, but not all, of the few small studies conducted to date have found evidence of a beneficial effect of riboflavin supplements on migraine headaches in adults and children...The Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society concluded that riboflavin is probably effective for preventing migraine headaches and recommended offering it for this purpose. The Canadian Headache Society recommends 400 mg/day riboflavin for migraine headache prevention, noting that although the evidence supporting this recommendation is of low quality, there is some evidence for benefit and side effects (such as discolored urine) are minimal...data on the relationship between riboflavin and cancer prevention or treatment are limited and study findings are mixed. A few large observational studies have produced conflicting results on the relationship between riboflavin intakes and lung cancer risk...Observational studies on the relationship between riboflavin intakes and colorectal cancer risk have not yielded conclusive results either” (NIH Office of Dietary Supplements 2021).

Ribose - a five-carbon sugar used for nucleotides. Part of normal human metabolism, not required in the diet.

Promoted for: ergogenic aid

Presumed mechanism of action: used for the synthesis of ATP, which provides cellular energy

Notes: "Supplemental ribose does not appear to improve aerobic or anaerobic performance" (NIH Office of Dietary Supplements 2019. Dietary supplements for exercise and athletic performance).

RNA and DNA

Promoted for: to "rejuvenate" cells, improve memory, prevent wrinkling of skin, provide nucleotides for T cells

Possible adverse effects: increased uric acid

Notes: no nutritional requirement; components of RNA and DNA can be made by the body. Ingested RNA and DNA would be digested, and even if not, would be unlikely to reach cells and provide useful functions.

Royal jelly - secretion of bees, given to future queens

Promoted for: prevention or treatment of chronic fatigue syndrome, asthma, insomnia, emotional disturbances, menopausal symptoms, premenstrual syndrome; increase stamina, enhance immune system, slow aging.

Presumed mechanism of action: “Royal jelly is a rich source of proteins, peptides, sugars, fatty acids, and other bioactive substances...Most of the health and metabolic benefits of the royal jelly are due to the glycosylated proteins...It contains in small amounts peptides such as aspimin, royalisine and jelleines (jelleines-I to jelleines-IV). From these, royalisine and jelleines exert antimicrobial effects and enhance the efficiency of the immune response to common infections...long-term dietary supplementation of leucine, isoleucine and valine extracted from royal jelly, enhances the expression of sirtuin 1, mitochondrial biogenesis and reduces the production of reactive oxygen species (ROS) in the skeletal muscles and myocardium...The most common fatty acids from royal jelly are 10-hydroxy-2-decenoic acid (10H2DA), sebacic acid (SA) and 10-hydroxydecanoic acid (10-HDA)...10-HDA was reported as a potent inhibitory agent of matrix metalloproteinases (MMPs), which contribute to tisular aging and cause several inflammatory diseases such as arthritis. SA, 10-HDA, and 10H2DA are able to mediate estrogen signaling by increasing the activity of the estrogen receptors (ER)” (Balan et al. 2020. Molecules. 25(14):3291). “HDEA [10H2DA] was found to have many pharmacological activities such as anti-tumor, antibiotic, and neuroprotective properties” (Mahboobi et al. 2019. Complement Ther Med. 44:235-41).

Possible adverse effects: anaphylaxis has caused at least one death

Reviews:

• Maleki et al. 2019. Complement Ther Med. 43:20-7: “Although royal jelly supplementation resulted in significant reductions in HOM A-I R [homeostatic model assessment- insulin resistance index] in three studies, the findings on insulin levels were controversial. In addition, royal jelly substantially improved serum levels of triglycerides, cholesterol, HDL [high-density lipoprotein], LDL [low-density lipoprotein], VLDL [ver-low-density lipoprotein] and Apo-A1 [apolipoprotein A1] in diabetes mellitus. In addition, royal jelly resulted in a decrease oxidative stress indicators and increase antioxidant enzymes levels.”

• Mahboobi et al. 2019. Op. cit.: “RJ supplementation did not beneficially affect markers of glycemia. However, due to methodology issues and potential confounders like diet as well as diverse populations, we recommend future studies well designed and well controlled for major confounders...”

Notes: Protein components are likely to be digested and not have any effect. Secreted bee hormones are unlikely to have any effect on human metabolism (if not digested first).

S-Adenosylmethionine (SAM-e, SAMe, or AdoMet) - part of normal human metabolism, not required in diet

Promoted for: depression, cognitive function, arthritis, liver disease

Presumed mechanism of action: SAMe levels are thought to be lower in patients with depression, Alzheimer’s disease, and chronic liver disease, so the aim of the supplement is to restore the levels. “The stimulatory effect of SAMe on central monoaminergic neurotransmitters [serotonin and norepinephrine] is a likely viable mechanism underlying its antidepressant effect” (Bottiglieri 2013. Psychiatr Clin North Am. 36(1):1-13).

Possible adverse effects: gastrointestinal distress, nausea. “As an activating antidepressant, it can disturb sleep if taken after 4:00 PM...patients who are sensitive to activation may feel jittery, overstimulated, anxious, or agitated...SAMe is contraindicated in patients with bipolar disorder because it can induce mania” (Ibid.).

Reviews:

• Rambaldi and Gluud 2006. Cochrane Database Syst Rev. CD002235: ”We could not find evidence supporting or refuting the use of SAMe for patients with alcoholic liver diseases.”

• Papakostas 2009. J Clin Psychiatry. 70 Suppl 5:18-22: “Controlled trials have found SAM-e to be more efficacious than placebo and equal in efficacy to the tricyclic antidepressants for treating major depressive disorder (MDD) when administered parenterally (either intravenously or intramuscularly). Less evidence supports the use of oral SAM-e, although some trials have demonstrated its efficacy as well. In addition, there is a paucity of evidence examining whether oral forms of SAM-e can be safe, well tolerated, and efficacious when used as adjunctive treatment for antidepressant nonresponders with MDD.”

• Lu and Mato 2012. Physiol Rev. 92(4):1515-42: “AdoMet is effective in cholestasis of pregnancy, and its role in other human liver diseases remains to be better defined.”

• Varteresian and Lavretsky 2014. Curr Psychiatry Rep. 16(8):456: "SAMe can be beneficial for depression, however the data is lacking for the geriatric population...The data evaluating the efficacy of SAMe in cognitive disorders is less extensive than the data in depression...there is insufficient data available to support a cognitive enhancing effect of SAMe."

Notes: A 2002 report by the Agency for Healthcare Research and Quality indicated that results appeared promising for depression, arthritis, and liver disease. SAMe is unstable, so supplements can vary widely in quality. “‘Bargain brands’ marketed on the Internet and through stores often contain inactive isomers. Tablets must be preserved in individual blister packs that should not be refrigerated” (Bottiglieri 2013. Op. cit.).

Saffron - see also crocin. A spice derived from Crocus sativus L.

Promoted for: depression, premenstrual syndrome, sexual dysfunction, Alzheimer's disease

Presumed mechanism of action: Major bioactive compounds are crocin, crocetin, picrocrocin, and safranal. Anti-inflammatory, antioxidant, antiplatelet effects. "It is suggested that saffron exerts its antidepressant effect by regulating certain chemicals in the brain, including serotonin, dopamine, and norepinephrine...The animal model showed that the use of saffron inhibited reuptake of these substances in the synapse, allowing their positive effect to stay in the brain to combat with depression" (Dai et al. 2020. J Nerv Ment Dis. 208(4):269-76).

Possible adverse effects: at very high doses, decreases in blood pressure have been observed.

Reviews:

• Rahmani et al. 2020. Complement Ther Med. 49:102298: "the present study indicates beneficial effects on WC [waist circumference] and FPG [fasting plasma glucose], following saffron supplementation."

• Dai et al. 2020. Op. cit.: "Overall results showed that saffron possessed better efficacy in the improvement of depressive symptoms when compared with placebo, whereas saffron was as effective as synthetic antidepressants...Saffron could be considered as an alternative to synthetic antidepressants in the treatment of mild to moderate depression. However, multicenter trials with larger sample size, longer treatment duration, and different ethnic groups are required to verify our results. "

• Asbaghi et al. 2021. Phytother Res. 35(1):20-32: " The overall results indicated that saffron supplementation did not affect inflammatory cytokines."

Sea salt, seawaters  See also Himalayan sea salt.

Promoted for: to supply needed minerals; prevention of cancer, heart disease, other diseases

Notes: “The main differences between sea salt and table salt are in their tastes, texture and processing. Sea salt comes from evaporated sea water and is minimally processed, so it may retain trace minerals. The minerals sea salt contains depend on the body of water from which it is evaporated. This may promote a different taste or color in the salt. When speaking in terms of health, the minerals are minor and easily consumed through daily food intake” (Mayo Clinic Health System 2015. Is sea salt healthier than table salt?).

Selenium - see also trace minerals (SUPPLEMENTS PART 1). "Selenium is available in multivitamin/multimineral supplements and as a stand-alone supplement, often in the forms of selenomethionine or of selenium-enriched yeast (grown in a high-selenium medium) or as sodium selenite or sodium selenate" (NIH Office of Dietary Supplements 2021. Selenium). "The use of inorganic selenium compounds have been rigorously forbidden owing to their high toxicity, low toxic thresholds close to the necessary nutrient level, and low utilization efficiency, with the US, Japan, and other countries having banned the addition of inorganic selenium compounds such as sodium selenite to foods. In contrast, most organic selenium compounds are good sources of selenium and may serve as a biologically active form of selenium" (Lv et al. 2021. Bull Environ Contam Toxicol. 106(5):715-26).`

Promoted for: cancer prevention, cardiovascular disease, cognitive decline, thyroid disease

Presumed mechanism of action: " Selenium, which is nutritionally essential for humans, is a constituent of more than two dozen selenoproteins that play critical roles in reproduction, thyroid hormone metabolism, DNA synthesis, and protection from oxidative damage and infection...Because of its effects on DNA repair, apoptosis, and the endocrine and immune systems as well as other mechanisms, including its antioxidant properties, selenium might play a role in the prevention of cancer...Selenoproteins help prevent the oxidative modification of lipids, reducing inflammation and preventing platelets from aggregating. For these reasons, experts have suggested that selenium supplements could reduce the risk of cardiovascular disease or deaths associated with cardiovascular disease...Serum selenium concentrations decline with age. Marginal or deficient selenium concentrations might be associated with age-related declines in brain function, possibly due to decreases in selenium’s antioxidant activity...Selenium concentration is higher in the thyroid gland than in any other organ in the body, and, like iodine, selenium has important functions in thyroid hormone synthesis and metabolism" (NIH).

Possible adverse effects: "Early indicators of excess intake are a garlic odor in the breath and a metallic taste in the mouth. The most common clinical signs of chronically high selenium intakes, or selenosis, are hair and nail loss or brittleness. Other symptoms include lesions of the skin and nervous system, nausea, diarrhea, skin rashes, mottled teeth, fatigue, irritability, and nervous system abnormalities" (NIH). There are interactions with some medications.

Reviews and major trials:

• Stranges et al. 2007. Ann Intern Med. 147(4):217-23 [Nutritional Prevention of Cancer trial]: "Selenium supplementation does not seem to prevent type 2 diabetes, and it may increase risk for the disease."

• Nicastro and Dunn 2013. Nutrients. 5(4):1122-48 [Selenium and Vitamin E Cancer Prevention Trial]: "neither selenium nor vitamin E reduced the incidence of prostate cancer after seven years...It is likely that only specific subpopulations may benefit from selenium supplementation."

• Strózyk et al. 2019. J Hum Nutr Diet. 32(5):635-64: "Currently, there is no evidence to support the effectiveness of Se supplementation in the T2DM [type 2 diabetes mellitus] population."

• Jenkins et al. 2020. Am J Clin Nutr. 112(6):1642-52: "Overall, no association of selenium alone or antioxidants was seen with CVD [cardiovascular disease] and all-cause mortality. However, a decreased risk with antioxidant mixtures was seen for CVD mortality when selenium was part of the mix...Similarly, when selenium was part of the antioxidant mixture, a decreased risk was seen for all-cause mortality...The addition of selenium should be considered for supplements containing antioxidant mixtures if they are to be associated with CVD and all-cause mortality risk reduction."

Notes: From NIH 2021. Op. cit.:

• "Selenium deficiency is very rare in the United States and Canada, and selenium deficiency in isolation rarely causes overt illness."

• "Randomized controlled trials of selenium supplementation for cancer prevention have yielded conflicting results...In 2003, the FDA allowed a qualified health claim on foods and dietary supplements containing selenium to state that while 'some scientific evidence suggests that consumption of selenium may reduce the risk of certain forms of cancer… FDA has determined that this evidence is limited and not conclusive.' More research is needed to confirm the relationship between selenium concentrations and cancer risk and to determine whether selenium supplements can help prevent any form of cancer."

• "The epidemiological data on the role of selenium in cardiovascular disease have yielded conflicting conclusions...The limited clinical-trial evidence to date does not support the use of selenium supplements for preventing heart disease, particularly in healthy people who already obtain sufficient selenium from food."

• "The results of observational studies [concerning cognitive decline] are mixed."

• "Additional research is needed to determine whether selenium supplements can help prevent or treat thyroid disease."

Sexual enhancement products - common ingredients are "yohimbine, maca, horny goat weed, and Ginkgo biloba" (Corazza et al. 2014. Biomed Res Int. 2014:841798). These are all described in the HERBS article.

Promoted for: "enhance erectile function as well as sexual arousal and desire" (Ibid.).

Possible adverse effects: “The FDA provides a long list of nearly 300 ‘sexual enhancement’ products that have been found to contain sildenafil, tadalafil, vardenafil, and other analogs. And it says the list only includes a small fraction of the potentially hazardous products with hidden ingredients. They warn consumers about undeclared ingredients, unknown contaminants, risky interactions with other medications, and uncontrolled doses” (Hall 2017 Aug 22. Science-Based Medicine blog). Adverse effects include "induction of psychological symptoms, such as mood changes, anxiety, and hallucinations as well as addictive behaviours" (Corazza et al. 2014. Op. cit.).

Shark cartilage - main use has been for cancer (see article on CANCER therapies). This section describes use as a dietary supplement for other purposes.

Promoted for: "osteoarthritis, plaque psoriasis, age-related vision loss, wound healing, damage to the retina of the eye due to diabetes, and inflammation of the intestine (enteritis)" (MedlinePlus 2019. Shark cartilage).

Presumed mechanism of action: compounds in the cartilage are alleged to inhibit the grown of new blood vessels.

Notes: Natural Medicines Comprehensive Database states that there is insufficient evidence to rate effectiveness for the above conditions (as well as being likely ineffective for cancer).

"Smart drinks," "smart drugs" - see nootropics

Sodium bicarbonate (baking soda)

Promoted for: ergogenic aid

Presumed mechanism of action: temporarily increases blood pH, making it easier to dispose of excess acidity produced by anaerobic exercise and preventing muscle fatigue

Possible adverse effects: "The main side effect of sodium bicarbonate supplementation in gram quantities is gastrointestinal distress, including nausea, stomach pain, diarrhea, and vomiting" (NIH Office of Dietary Supplements 2019. Dietary supplements for exercise and athletic performance).

Review: Grgic et al. 2020. Sports Med. 50(7):1361-75: " Overall, sodium bicarbonate supplementation acutely improves muscular endurance of small and large muscle groups, but no significant ergogenic effect on muscular strength was found."

Notes: "Many studies have assessed sodium bicarbonate as an ergogenic aid in swimmers, cyclists, rowers, boxers, tennis and rugby players, judo practitioners, and others. These studies usually included a small number of participants who underwent one or more trials in a laboratory over several days. Because the research results are conflicting, the activities and individuals most likely to benefit from sodium bicarbonate supplementation in real-world conditions is not clear" (NIH).

Soluble fibers - see fibers, soluble

Soy products - see also phytochemicals. "In addition to its food uses, soy is available in dietary supplements. Soy supplements may contain soy protein, isoflavones (compounds similar in structure to the female hormone estrogen), or other components" (NCCIH 2020. Soy). The isoflavones may have attached glucose units (these are the glucoside forms: genistin, diadzin, and glycitin), which are hydrolyzed in the intestine to give the aglycone (without sugar) forms (genistein, daidzein, and glycitein).

Promoted for: "menopausal symptoms, bone health, improving memory, high blood pressure, and high cholesterol levels" (Ibid.).

Presumed mechanism of action: isoflavones may have estrogen-like effects. One of these would be to relax vascular smooth muscle.

Possible adverse effects: "The most common side effects of soy are digestive upsets, such as constipation and diarrhea" (NCCIH). Some women are taking soy isoflavone supplements as an alternative to estrogen replacement therapy, but these present potential dangers. Doses are much larger than in Asian diets. Trade-off of estrogenic and anti-estrogenic effects could increase cancer rather than prevent it. Benefits seen in Asian diets might be from taking early in life; large amounts later in life could be harmful.

Reviews:

• Zhan and Ho 2005. Am J Clin Nutr. 81(2):397-408: "Soy protein containing isoflavones significantly reduced serum total cholesterol, LDL [low-density lipoprotein] cholesterol, and triacylglycerol and significantly increased HDL [high-density lipoprotein] cholesterol, but the changes were related to the level and duration of intake and the sex and initial serum lipid concentrations of the subjects. "

• Reynolds et al. 2006. Am J Cardiol. 98(5):633-40: "Meta-regression analyses showed a dose-response relation between soy protein and isoflavone supplementation and net changes in serum lipids. These results indicate that soy protein supplementation reduces serum lipids among adults with or without hypercholesterolemia."

• Liu et al. 2009. Bone. 44(5):948-53: "Soy isoflavone supplementation is unlikely to have significant favorable on BMD [bone mineral density] at the lumbar spine and hip in women."

• Ricci et al. 2010. J Womens Health (Larchmt). 19(9):1609-17: "Our review and meta-analysis suggest that IF [isoflavone] mixtures are not effective in decreasing bone loss in perimenopausal and postmenopausal Western women. The role of isolated genistein and individual genetic capacity to metabolize IFs is still open to evaluation."

• Taku et al. 2010. Bone. 47(2):413-23: "Soy isoflavone supplements moderately decreased the bone resorption marker DPD [deoxypyridinoline], but did not affect bone formation markers BAP [bone alkaline phosphatase] and OC [osteocalcin] in menopausal women. The effects varied between studies, and further studies are needed to address factors relating to the observed effects of soy isoflavones on DPD and to verify effects on other bone turnover markers."

• Taku et al. 2010. J Hypertens. 28(10):1971-82: " Soy isoflavone extracts significantly decreased SBP [systolic blood pressure] but not DBP [diastolic blood pressure] in adult humans, and no dose-response relationship was observed. Further studies are needed to address factors related to the observed effects of soy isoflavones on SBP and to verify the effect in hypertensive patients."

• Nanri et al. 2010. J Nutr. 140(3):580-6: "Overall, our results suggest that there are no benefits of soy product or isoflavone intake with respect to risk of type 2 diabetes in either men or women. The possible protective associations of soy and isoflavone intakes among overweight women deserves further investigation."

• Anderson and Bush 2011. J Am Coll Nutr. 30(2):79-91: "Regular consumption of 1 to 2 servings of soy protein daily (15 to 30 g) has a significant favorable impact on serum lipoprotein risk factors for CHD [coronary heart disease]."

• Taku et al. 2012. Menopause. 19(7):776-90: "Soy isoflavone supplements, derived by extraction or chemical synthesis, are significantly more effective than placebo in reducing the frequency and severity of hot flashes. Additional studies are needed to further address the complex array of factors that may affect efficacy, such as dose, isoflavone form, baseline hot flash frequency, and treatment duration."

• Zhang et al. 2013.  Nutrition. 29(1):8-14: "soy isoflavone supplementation could be beneficial for body weight reduction, glucose, and insulin control in plasma. Large and well-designed studies are recommended to confirm this conclusion."

• Lethaby et al. 2013. Cochrane Database Syst Rev. CD001395: "No conclusive evidence shows that phytoestrogen supplements effectively reduce the frequency or severity of hot flushes and night sweats in perimenopausal or postmenopausal women, although benefits derived from concentrates of genistein should be further investigated."

• Mosallanezhad et al. 2021. Complement Ther Med. 59:102692: "Our results suggest that soy intake is associated with an ameliorating effect on blood pressure in adults."

• Hariri et al. 2021. Complement Ther Med. 59:102715: " Published RCTs did not provide strong evidence regarding beneficial effect of soy isoflavones or the combination of soy isoflavones and soy protein on serum CRP [C-reactive protein] concentration among postmenopausal women."

Notes: Effects may arise from isoflavones acting as phytoestrogens (see above), but the protein may be important in itself or in allowing proper absorption. There is an FDA-allowed health claim that soy protein may help lower cholesterol and reduce the risk of heart disease. In 2017 the FDA proposed changing this to a qualified health claim because "the totality of currently available evidence calls into question the certainty of this relationship" (FDA 2017 Oct 30. Statement from Susan Mayne, Ph.D., on proposal to revoke health claim that soy protein reduces risk of heart disease).

The following points were made by NCCIH (2020. Soy):

• Consuming soy protein in place of other proteins may lower levels of total cholesterol and LDL (“bad”) cholesterol to a small extent.

• Soy isoflavone supplements or soy protein may help to reduce the frequency and severity of menopausal hot flashes, but the effect may be small.

• Observational studies indicate that among Asian women, higher dietary intakes of soy during childhood and adolescence are associated with a lower risk of breast cancer later in life. The amounts of soy in Western diets may be too low for this association to be observed. Soy products in supplement form have not been shown to reduce breast cancer risk.

• Current evidence suggests that soy isoflavone mixtures probably have a beneficial effect on bone health in postmenopausal women, but the evidence is not entirely consistent.

• Soy protein may slightly reduce blood pressure in people with hypertension (high blood pressure).

Spirulina (blue-green algae).  See also chlorophyll. "Blue-green algae" are not actually algae but are cyanobacteria. "Spirulina" is both the name of a genus of cyanobacteria (later divided into Spirulina and Arthrospira), as well as a term used to refer to the dried biomass of two species, A. platensis and A. maxima. Blue-green algae "grow in salt water and some large fresh water lakes. They have been used for food for several centuries in Mexico and some African countries. They have been sold as a supplement in the US since the late 1970s...Some blue-green algae products are grown under controlled conditions. Others are grown in a natural setting, where they are more likely to be contaminated by bacteria, liver poisons (microcystins) produced by certain bacteria, and heavy metals" (MedlinePlus 2021. Blue-green algae).

Promoted for: "Blue-green algae products are used for treating high blood pressure. They are also used as a protein supplement and for high levels of cholesterol or other fats (lipids) in the blood (hyperlipidemia), diabetes, obesity, and many other conditions" (Ibid.). They are promoted as a source of vitamins A and B12, minerals (potassium, calcium, magnesium, selenium, other), chlorophyll, neuropeptides, and DNA. Among the uses are as a mental and physical stimulant; an aid in weight loss; stimulation of the immune system; and  treatment of headache, Alzheimer's, allergies, and cancer.

Presumed mechanism of action: "Blue-green algae have a high protein, iron, and other mineral content which is absorbed when taken orally. Blue-green algae are being researched for their potential effects on the immune system, swelling (inflammation), and viral infections" (Ibid.).

Possible adverse effects: "Blue-green algae products that are free of contaminants, such as liver-damaging substances called microcystins, toxic metals, and harmful bacteria, are POSSIBLY SAFE for most people when used short-term...But blue-green algae products that are contaminated are POSSIBLY UNSAFE. Contaminated blue-green algae can cause liver damage, stomach pain, nausea, vomiting, weakness, thirst, rapid heartbeat, shock, and death. Don't use any blue-green algae product that hasn't been tested and found to be free of microcystins and other contamination...Blue-green algae are POSSIBLY UNSAFE for children. Children are more sensitive to contaminated blue-green algae products than adults" (MedlinePlus). Contamination with insect parts is possible. May slow blood clotting and affect blood glucose levels. There are interactions with some medications.

Reviews:

• • • Yousefi et al. 2019. Complement Ther Med. 2019 Feb;42:137-44: "The systematic review revealed that oral dosage range of 1-19gr/day for 0.5-6 months of Spirulina supplementation have positive effects on metabolic syndrome components."

    • Bobescu et al. 2020. Mar Drugs. 18(12):651: "Spirulina is a valuable cyanobacterium that can be used as a food supplement for the management of metabolic syndrome, and it is able to reduce the risk of cardiovascular events."

Notes: Natural Medicines Comprehensive Database rates as possibly effective for high blood pressure, while there is insufficient evidence to rate effectiveness for all other uses. Nutrients can easily be obtained from other foods. "You may have been told that blue-green algae are an excellent source of protein. But, in reality, blue-green algae are no better than meat or milk as a protein source and cost about 30 times as much per gram" (MedlinePlus). Neuropeptides would be digested; even if not, would not cross blood-brain barrier. Claims for DNA are preposterous; DNA would be digested, and even if not could not contribute useful genetic information. "Spirulina is considered to be a relevant vitamin B12 source for vegans and vegetarians...However, 83% of the existing vitamin B12 is found to be 'pseudo' B12," which is inactive in humans (Grosshagauer et al. 2020. J Agric Food Chem. 68(14):4109-15).

Superoxide dismutase (SOD), catalase - cellular enzymes that protect from damaging effects of superoxide anion and hydrogen peroxide, respectively

Promoted for: protection from oxidative damage, thus preventing aging and degenerative diseases

Notes: like other proteins, these will mostly be digested rather than being absorbed intact. Even if absorbed, they are unlikely to reach a useful site of action.

Tart or sour cherry

Promoted for: ergogenic aid

Presumed mechanism of action: "The Montmorency variety of tart or sour cherry (Prunus cerasus) contains anthocyanins and other polyphenolic phytochemicals, such as quercetin. Researchers hypothesize that these compounds have antiinflammatory and antioxidant effects that might facilitate exercise recovery by reducing pain and inflammation, strength loss and muscle damage from intense activity, and hyperventilation trauma from endurance activities"  (NIH Office of Dietary Supplements 2019. Dietary supplements for exercise and athletic performance).

Notes: "There is no expert consensus on the value of taking tart-cherry products to enhance exercise and athletic performance" (Ibid.). In 2006 the FDA took action against 29 companies for unsupported claims.

Testosterone boosters (T-boosters) - see also sexual enhancement products. A review of products available online (Balasubramianian et al. 2019. J Sex Med. 16(2):203-12) found that the most popular ingredients were tongkat ali, horny goat weed, saw palmetto, boron, and nettle. "Though marketing, sometimes disguised as consumer reviews on online product pages, would lead consumers to believe otherwise, evidence that rigorously supports a positive impact of these products on testosterone levels and hypogonadal symptoms is lacking. Our review revealed that only limited, flawed human studies have evaluated efficacy of some of the most common ingredients in these supplements, with no definitive findings." Another type of product is the "designer steroid," an anabolic-androgenic steroid "synthesized from a known parent steroid and chemically modified with the intent to circumvent controlled substances laws...Designer steroids share a common mechanism of action with testosterone, acting at the androgen receptor...Severe side effects including hepatotoxicity, cholestasis, renal failure, hypogonadism, gynecomastia, and infertility have been reported secondary to the use of these products" (Rahnema et al. 2015. Andrology. 3(2):150-5).

Gomella (2020. Can J Urol. 27(1):10067) wrote, "These natural male enhancement supplements often stress the ability to increase free testosterone subtly suggesting this is a more desirable effect than just increasing total testosterone. If this increase in free testosterone is proven to be valid, here is where we may have a problem. Although it is generally agreed that testosterone replacement in hypogonadal men does not cause prostate cancer, several recent studies have suggested that there is a relationship in free testosterone and prostate cancer...Men should be aware that we have no data concerning these OTC testosterone supplements and how they may impact prostate cancer risk."

Thiamine - see water-soluble vitamins (SUPPLEMENTS PART 1).

Notes: According to NIH Office of Dietary Supplements (2021. Thiamine), more research is needed to determine whether thiamine supplements are beneficial for heart failure, Alzheimer's disease, and diabetes. An editorial by Goel et al. (2019. Am J Clin Nutr. 110(6):1270-1) stated that "studies on thiamin supplementation have shown mixed results but as of now there is no clear evidence to support the routine use of thiamin therapy in most chronic heart failure patients."

Tianeptine - "Tianeptine, sold under the brand names Stablon and Coaxil among others, is an atypical antidepressant which is used mainly in the treatment of major depressive disorder, although it may also be used to treat anxiety, asthma, and irritable bowel syndrome" (Wikipedia 2021. Tianeptine). The drug is legal in some countries but not in the United States. Nevertheless, it is being marketed as a dietary supplement. According to Felton (2021 Feb 4. Consumer Reports), " tianeptine-related calls to poison control centers have skyrocketed. There have been at least 883 since 2015, up from 27 the decade before. At least four people have died after using the drug, and almost two dozen have reported hospitalization and other adverse effects."

Tinnitus remedies - A review by Vendra et al. (2019. Laryngoscope. 129(8):1898-1906) noted that "A wide array of unproven OTCTR [over-the-counter tinnitus remedies] exist on today's market. All make unfounded claims of relief from ear ringing. Most of the products considered in this study consist of mixtures of inexpensive and common vitamins, minerals, and/or herbs sold at a premium compared to similar preparations not expressly advertised for tinnitus....Certain brands...target otolaryngologists by advertising in specialty journals and prominently featuring supposed endorsement by 'Ear-Nose-and-Throat Doctors' in their marketing." However, "The Clinical Practice Guideline of the American Academy of Otolaryngology-Head & Neck Surgery (2014) stated that clinicians should not recommend dietary supplements for the treatment of tinnitus."

Tissue salts (cell salts) (Schuessler Salts) - similar to homeopathic remedies. Tiny doses of common mineral salts are sold as solutions or lactose pills, labeled with Latin names. See Holistic article, homeopathy section (Holistic Part 1), variants of homeopathy.

Promoted for: treatment of various disorders

Possible adverse effects: unlikely since extremely small amounts of ordinary chemicals are used

Tryptophan (L-tryptophan) - an essential amino acid

Promoted for: "severe PMS symptoms (premenstrual dysphoric disorder or PMDD), athletic performance, depression, insomnia, and many other conditions" (MedlinePlus 2020. L-Tryptophan).

Presumed mechanism of action: "L-tryptophan is considered an essential amino acid because our bodies can't make it. It is important for the development and functioning of many organs in the body. After absorbing L-tryptophan from food, our bodies convert some of it to 5-HTP (5-hydroxytryptophan), and then to serotonin. Our bodies also convert some L-tryptophan to niacin (vitamin B3). Serotonin is a hormone that transmits signals between nerve cells. It also causes blood vessels to narrow. Changes in the level of serotonin in the brain can alter mood" (Ibid.).

Possible adverse effects: "L-tryptophan can cause some side effects such as heartburn, stomach pain, belching and gas, nausea, vomiting, diarrhea, and loss of appetite. It can also cause headache, lightheadedness, drowsiness, dry mouth, visual blurring, muscle weakness, and sexual problems in some people. In 1989, L-tryptophan was linked to over 1500 reports of eosinophilia-myalgia syndrome (EMS) and 37 deaths. EMS is a neurological condition that causes many different symptoms. These symptoms tend to improve over time, but some people may still experience symptoms up to 2 years after they develop EMS. In 1990, L-tryptophan was recalled from the market due to these safety concerns. The exact cause of EMS in patients taking L-tryptophan is unknown, but some evidence suggests it is due to contamination. About 95% of all EMS cases were traced to L-tryptophan produced by a single manufacturer in Japan" (Ibid.). Should not be taken with some sedatives. Care is needed in combination with other medications, especially antidepressants.

Notes: Natural Medicines Comprehensive Database rates as possibly effective for severe PMS symptoms; possibly ineffective for teeth grinding (bruxism) and myofascial pain syndrome; and insufficient evidence to rate effectiveness for other purposes.

Valine - an essential amino acid

Promoted for: fighting stress, athletic performance, support liver and gallbladder

Vanadium (vanadyl sulfate)

Promoted for: insulin-like effects; provide extra energy during exercise

Possible adverse effects: high doses produce gastrointestinal disturbances and green tongue

Notes: vanadium compounds inhibit tyrosine phosphatases. Research supports insulin-like actions in animals; human benefits not yet documented. Nahas and Moher (2009. Can Fam Physician. 55(6):591-6) wrote: "There is insufficient evidence to support the use of vanadium in the treatment of type 2 DM [diabetes mellitus]."

Vinegar - see apple cider vinegar

Vinpocetine - "a synthetic substance derived from an alkaloid compound found in the leaves of the Vinca minor, or lesser periwinkle plant, and Voacanga seed" (Department of Defense Dietary Supplement Resource 2021. Vinpocetine in dietary supplement products).

Promoted for:  "Dietary supplements containing vinpocetine are often marketed for uses that include enhanced memory, focus, or mental acuity; increased energy; and weight loss" (FDA 2019 Jun 3. Statement on warning for women of childbearing age about possible safety risks of dietary supplements containing vinpocetine).

Presumed mechanism of action: increase blood flow to the brain. "Vinpocetine has several cellular targets, including Ca2+/calmodulin-stimulated cyclic nucleotide phosphodiesterase 1 (PDE1), voltage-dependent Na+ channel and IκB kinase (IKK)" (Zhang and Yan 2020. J Cell Immunol.  2(5):211-9). Inhibition of the Na+ channel may be neuroprotective, while inhibition of IKK may inhibit inflammation.

Possible adverse effects: "Side effects such as facial flushing, headache, sleep disturbances, nausea, and dizziness have been associated with vinpocetine use. Because vinpocetine can affect blood flow, anyone taking blood thinners should use caution...in 2019 FDA released a statement warning women of childbearing age about possible safety risks associated with dietary supplements containing vinpocetine. According to FDA, vinpocetine has been associated with adverse reproductive effects and might cause a miscarriage or harm fetal development" (Department of Defense).

Notes: "Some studies of elderly and stroke patients suffering mild or moderate symptoms of dementia have reported improvements in memory, concentration, and cognitive skills. However, vinpocetine does not appear to benefit those with more severe symptoms of mental disorders and dementia...On 6 September 2016, the Food and Drug Administration (FDA) announced its 'tentative conclusion' that 'vinpocetine (1) does not meet the definition of a dietary ingredient, and (2) is excluded from the definition of a dietary supplement.' A final ruling has not yet been made on whether or not vinpocetine can be included as an ingredient in dietary supplement products" (Ibid.). Cohen (2015. Mayo Clin Proc. 90(10):1455) wrote, "Today, more than 340 brands of supplements contain vinpocetine. The FDA may have assumed that vinpocetine was a botanical extract, but it is not...to my knowledge, vinpocetine itself has never been identified in lesser periwinkle or any other plant...The FDA has permitted an unapproved new drug with unproven efficacy and known adverse effects to be sold directly to consumers."

Vitamin A - see also sections on fat-soluble vitamins and antioxidants (SUPPLEMENTS PART 1), and beta carotene (above). "Vitamin A is available in multivitamins and as a stand-alone supplement, often in the form of retinyl acetate or retinyl palmitate. A portion of the vitamin A in some supplements is in the form of beta-carotene and the remainder is preformed vitamin A; others contain only preformed vitamin A or only beta-carotene" (NIH Office of Dietary Supplements 2021. Vitamin A).

Promoted for: cancer cure; antioxidant; prevention of heart attacks, stroke, and cancer; treatment of mouth cancer

Presumed mechanism of action: since vitamin A regulates cell growth and differentiation, supplements may affect the incidence or progression of cancer. "AMD [age-related macular degeneration]’s etiology is usually unknown, but the cumulative effect of oxidative stress is postulated to play a role. If so, supplements containing carotenoids with antioxidant functions, such as beta-carotene, lutein, and zeaxanthin, might be useful for preventing or treating this condition" (Ibid.).

Possible adverse effects: "Because vitamin A is fat soluble, the body stores excess amounts, primarily in the liver, and these levels can accumulate. Although excess preformed vitamin A can have significant toxicity (known as hypervitaminosis A), large amounts of beta-carotene and other provitamin A carotenoids are not associated with major adverse effects. The manifestations of hypervitaminosis A depend on the size and rapidity of the excess intake. The symptoms of hypervitaminosis A following sudden, massive intakes of vitamin A, as with Arctic explorers who ate polar bear liver, are acute. Chronic intakes of excess vitamin A lead to increased intracranial pressure (pseudotumor cerebri), dizziness, nausea, headaches, skin irritation, pain in joints and bones, coma, and even death. Although hypervitaminosis A can be due to excessive dietary intakes, the condition is usually a result of consuming too much preformed vitamin A from supplements or therapeutic retinoids. When people consume too much vitamin A, their tissue levels take a long time to fall after they discontinue their intake, and the resulting liver damage is not always reversible. Observational studies have suggested an association between high intakes of preformed vitamin A (more than 1,500 mcg daily - only slightly higher than the RDA), reduced bone mineral density, and increased fracture risk. However, the results of studies on this risk have been mixed, so the safe retinol intake level for this association is unknown" (Ibid.).

Notes: The following points were made by NIH-ODS (2021. Vitamin A):

• "...the relationship between serum vitamin A levels or vitamin A supplementation and cancer risk is unclear."

• "Several prospective and retrospective observational studies in current and former smokers, as well as in people who have never smoked, found that higher intakes of carotenoids, fruits and vegetables, or both are associated with a lower risk of lung cancer. However, clinical trials have not shown that supplemental beta-carotene and/or vitamin A helps prevent lung cancer."

• "The evidence on the relationship between beta-carotene and prostate cancer is mixed."

• "The ATBC and CARET study results suggest that large supplemental doses of beta-carotene with or without retinyl palmitate have detrimental effects in current or former smokers and workers exposed to asbestos. The relevance of these results to people who have never smoked or to the effects of beta-carotene or retinol from food or multivitamins (which typically have modest amounts of beta-carotene) is not known."

• Concerning the AREDS2 study (on age-related eye disease), "the study revealed that beta-carotene was not a required ingredient; the original AREDS formulation without beta-carotene provided the same protective effect against developing advanced AMD."

• "Vitamin A deficiency is a known risk factor for severe measles." Reviews and a meta-analysis show that vitamin A "significantly reduced measles mortality. The vitamin A doses used in these studies are much higher than the UL. The effectiveness of vitamin A supplementation to treat measles in countries, such as the United States, where vitamin A intakes are usually adequate is uncertain."

Vitamin B6 (pyridoxal phosphate) - see also water-soluble vitamins (SUPPLEMENTS PART 1). "Vitamin B6 is available in multivitamins, in supplements containing other B complex vitamins, and as a stand-alone supplement. The most common vitamin B6 vitamer in supplements is pyridoxine (in the form of pyridoxine hydrochloride [HCl]), although some supplements contain PLP [pyridoxal phosphate]...Absorption of vitamin B6 from supplements is similar to that from food sources and does not differ substantially among the various forms of supplements. Although the body absorbs large pharmacological doses of vitamin B6 well, it quickly eliminates most of the vitamin in the urine" (NIH Office of Dietary Supplements 2021. Vitamin B6).

Promoted for: prevention of heart disease and cancer; cognitive benefits in the elderly; premenstrual syndrome; nausea and vomiting of pregnancy

Presumed mechanism of action: "Scientists have hypothesized that certain B vitamins (folic acid, vitamin B12, and vitamin B6) might reduce cardiovascular disease risk by lowering homocysteine levels...Some research has associated low plasma vitamin B6 concentrations with an increased risk of certain kinds of cancer...Poor vitamin B6 status has been hypothesized to play a role in the cognitive decline that some older adults experience...The potential effectiveness of vitamin B6 in alleviating the mood-related symptoms of PMS [premenstrual syndrome] could be due to its role as a cofactor in neurotransmitter biosynthesis" (Ibid.).

Possible adverse effects: "High intakes of vitamin B6 from food sources have not been reported to cause adverse effects. However, chronic administration of 1–6 g oral pyridoxine per day for 12–40 months can cause severe and progressive sensory neuropathy characterized by ataxia (loss of control of bodily movements)...Other effects of excessive vitamin B6 intakes include painful, disfiguring dermatological lesions; photosensitivity; and gastrointestinal symptoms, such as nausea and heartburn" (Ibid.). Interactions with some medications are possible.

Notes: The following points were made by NIH-ODS (2021. Vitamin B6):

• "The research to date provides little evidence that supplemental amounts of vitamin B6, alone or with folic acid and vitamin B12, can help reduce the risk or severity of cardiovascular disease and stroke."

• " ...the small number of clinical trials completed to date has not shown that vitamin B6 supplementation can help prevent cancer or reduce its impact on mortality."

• "...a systematic review of 14 randomized controlled trials found insufficient evidence of an effect of vitamin B6 supplementation alone or in combination with vitamin B12 and/or folic acid on cognitive function in people with normal cognitive function, dementia, or ischemic vascular disease. According to this review, most of the studies were of low quality and limited applicability."

• "Although vitamin B6 shows promise for alleviating PMS symptoms, more research is needed before drawing firm conclusions."

• "The authors of a recent Cochrane review of studies on interventions for nausea and vomiting in pregnancy could not draw firm conclusions on the value of vitamin B6 to control the symptoms of morning sickness...The American Congress of Obstetrics and Gynecology (ACOG) recommends monotherapy with 10–25 mg of vitamin B6 three or four times a day to treat nausea and vomiting in pregnancy."

Vitamin B12 - see also water-soluble vitamins (SUPPLEMENTS PART 1). "The most common form of vitamin B12 in dietary supplements is cyanocobalamin. Other forms of vitamin B12 in supplements are adenosylcobalamin, methylcobalamin, and hydroxycobalamin. No evidence indicates that absorption rates of vitamin B12 in supplements vary by form of the vitamin. These rates are about 50% at doses (less than 1–2 mcg) that do not exceed the cobalamin-binding capacity of intrinsic factor and are substantially lower at doses well above 1–2 mcg. For example, absorption is only about 2% at doses of 500 mcg and 1.3% at doses of 1,000 mcg" (NIH Office of Dietary Supplements 2021. Vitamin B12).

Promoted for: prevention of heart disease; cognitive performance; energy and endurance

Presumed mechanism of action: "An elevated homocysteine level has been associated with an increased risk of CVD [cardiovascular disease]. Vitamin B12 and other B vitamins are involved in homocysteine metabolism, and researchers have hypothesized that supplementation with these micronutrients can reduce CVD risk by lowering homocysteine levels...Scientists hypothesize that elevated homocysteine levels might have a negative effect on the brain via numerous mechanisms, including cerebrovascular ischemia leading to neuronal cell death, activation of tau kinases leading to tangle deposition, and inhibition of methylation reactions...Because of its role in energy metabolism, vitamin B12 is often promoted as an energy enhancer and an athletic performance and endurance booster" (Ibid.).

Possible adverse effects: "Even at large doses, vitamin B12 is generally considered to be safe because the body does not store excess amounts." However, "Vitamin B12 has the potential to interact with certain medications" (Ibid.).

Notes: The following points were mad by NIH-ODS (2021. Vitamin B12):

• "The evidence for a relationship between vitamin B12 and cancer risk is mixed. Some evidence supports a link between increased cancer risk and higher intakes or blood concentrations of vitamin B12, some supports a link with lower intakes or concentrations, and some evidence indicates no link at all."

• "RCTs [randomized controlled trials] have found that vitamin B12 (and folic acid) supplements lower homocysteine levels, but not CVD [cardiovascular disease] risk...Overall, the available evidence suggests that supplementation with vitamin B12 alone or in combination with other B-vitamins does not reduce the risk of CVD or of CVD-related death."

• "...supplementation with vitamin B12 alone or with other B vitamins does not appear to decrease the risk or slow the progression of dementia or Alzheimer’s disease in older adults."

• "... vitamin B12 supplementation appears to have no beneficial effect on performance in the absence of a nutritional deficit."

Vitamin C - see also sections on water-soluble vitamins and antioxidants (SUPPLEMENTS PART 1). "Supplements typically contain vitamin C in the form of ascorbic acid, which has equivalent bioavailability to that of naturally occurring ascorbic acid in foods...Other forms of vitamin C supplements include sodium ascorbate; calcium ascorbate; other mineral ascorbates; ascorbic acid with bioflavonoids; and combination products..." (NIH Office of Dietary Supplements 2021. Vitamin C).

Promoted for: antioxidant; preventive for heart disease, cancer, and age-related macular degeneration. See Cancer article for use in cancer treatment. Prevention and treatment of the common cold.

Proposed mechanism of action: "Due to its function as an antioxidant and its role in immune function, vitamin C has been promoted as a means to help prevent and/or treat numerous health conditions...Vitamin C can limit the formation of carcinogens, such as nitrosamines, in vivo; modulate immune response; and, through its antioxidant function, possibly attenuate oxidative damage that can lead to cancer...In addition to its antioxidant properties, vitamin C has been shown to reduce monocyte adherence to the endothelium, improve endothelium-dependent nitric oxide production and vasodilation, and reduce vascular smooth-muscle-cell apoptosis, which prevents plaque instability in atherosclerosis...AMD [age-related macular degeneration] and cataracts are two of the leading causes of vision loss in older individuals. Oxidative stress might contribute to the etiology of both conditions. Thus, researchers have hypothesized that vitamin C and other antioxidants play a role in the development and/or treatment of these diseases" (Ibid.).

Possible adverse effects: "Vitamin C has low toxicity and is not believed to cause serious adverse effects at high intakes. The most common complaints are diarrhea, nausea, abdominal cramps, and other gastrointestinal disturbances due to the osmotic effect of unabsorbed vitamin C in the gastrointestinal tract...However, in individuals with hereditary hemochromatosis, chronic consumption of high doses of vitamin C could exacerbate iron overload and result in tissue damage. Under certain conditions, vitamin C can act as a pro-oxidant, potentially contributing to oxidative damage " (Ibid.). A large Swedish study found an increase in cataracts in women taking high-dose (1000 mg) vitamin C. Possible interactions with some medications.

Reviews and major trials (see also reviews of multiple antioxidant vitamins (SUPPLEMENTS PART 1)):

• Choi et al. 2009. Arch Intern Med. 169(5):502-7 [Health Professionals Followup Study]: "Higher vitamin C intake is independently associated with a lower risk of gout. Supplemental vitamin C intake may be beneficial in the prevention of gout."

• Hemilä and Chalker 2013. Cochrane Database Syst Rev. CD000980: "The failure of vitamin C supplementation to reduce the incidence of colds in the general population indicates that routine vitamin C supplementation is not justified, yet vitamin C may be useful for people exposed to brief periods of severe physical exercise. Regular supplementation trials have shown that vitamin C reduces the duration of colds, but this was not replicated in the few therapeutic trials that have been carried out. Nevertheless, given the consistent effect of vitamin C on the duration and severity of colds in the regular supplementation studies, and the low cost and safety, it may be worthwhile for common cold patients to test on an individual basis whether therapeutic vitamin C is beneficial for them."

• Al-Khudairy et al. 2017. Cochrane Database Syst Rev. CD011114: "Currently, there is no evidence to suggest that vitamin C supplementation reduces the risk of CVD [cardiovascular disease] in healthy participants and those at increased risk of CVD, but current evidence is limited to one trial of middle-aged and older male physicians from the USA. There is limited low- and very low-quality evidence currently on the effect of vitamin C supplementation and risk of CVD risk factors."

• Padhani et al. 2020. Cochrane Database Syst Rev. CD013134: "Due to the small number of included studies and very low quality of the existing evidence, we are uncertain of the effect of vitamin C supplementation for the prevention and treatment of pneumonia."

• Liu et al. 2021. Complement Ther Med. 60:102761: "The results of present meta-analysis have demonstrated that vitamin C supplementation could make a reduction of SUA [serum uric acid]."

Notes: little increase in plasma level is seen at intakes above 200 mg/day. The following points were made by NIH-ODS (2021. Vitamin C):

• "At this time, the evidence is inconsistent on whether dietary vitamin C intake affects cancer risk. Results from most clinical trials suggest that modest vitamin C supplementation alone or with other nutrients offers no benefit in the prevention of cancer."

• "Results from most clinical intervention trials have failed to show a beneficial effect of vitamin C supplementation on the primary or secondary prevention of cardiovascular disease. In the Women’s Antioxidant Cardiovascular Study, a secondary prevention trial involving 8,171 women aged 40 years or older with a history of cardiovascular disease, supplementation with 500 mg/day vitamin C for a mean of 9.4 years showed no overall effect on cardiovascular events. Similarly, vitamin C supplementation (500 mg/day) for a mean follow-up of 8 years had no effect on major cardiovascular events in male physicians enrolled in the Physicians’ Health Study II. Other clinical trials have generally examined the effects on cardiovascular disease of supplements combining vitamin C with other antioxidants, such as vitamin E and beta-carotene, making it more difficult to isolate the potential contribution of vitamin C...overall, the findings from most intervention trials do not provide convincing evidence that vitamin C supplements provide protection against cardiovascular disease or reduce its morbidity or mortality."

• "Overall, the currently available evidence does not indicate that vitamin C, taken alone or with other antioxidants, affects the risk of developing AMD, although some evidence indicates that the AREDS formulations might slow AMD progression in people at high risk of developing advanced AMD."

• "Overall, the evidence to date suggests that regular intakes of vitamin C at doses of at least 200 mg/day do not reduce the incidence of the common cold in the general population, but such intakes might be helpful in people exposed to extreme physical exercise or cold environments and those with marginal vitamin C status, such as the elderly and chronic smokers. The use of vitamin C supplements might shorten the duration of the common cold and ameliorate symptom severity in the general population, possibly due to the anti-histamine effect of high-dose vitamin C. However, taking vitamin C after the onset of cold symptoms does not appear to be beneficial."

Lykkesfeldt (2020. Redox Biol. 34:101532) wrote, " The intervention studies may serve to demonstrate that supplementation with vitamin C to already saturated individuals apparently has little or no effect on morbidity and mortality. However, it remains unknown if supplementation with vitamin C to individuals with poor vitamin C status can prevent disease development or progression."

Vitamin D - see also section on fat-soluble vitamins (SUPPLEMENTS PART 1). "In foods and dietary supplements, vitamin D has two main forms, D2 (ergocalciferol) and D3 (cholecalciferol), that differ chemically only in their side-chain structures. Both forms are well absorbed in the small intestine" (NIH Office of Dietary Supplements 2021. Vitamin D).

Promoted for: bone health, cancer prevention and treatment, cardiovascular disease, depression, multiple sclerosis, diabetes, weight loss.

Presumed mechanism of action: "Osteoporosis is most often associated with inadequate calcium intakes, but insufficient vitamin D intakes contribute to osteoporosis by reducing calcium absorption...Vitamin D is also needed for the normal development and growth of muscle fibers...Laboratory and animal studies suggest that vitamin D might inhibit carcinogenesis and slow tumor progression by, for example, promoting cell differentiation and inhibiting metastasis. Vitamin D might also have anti-inflammatory, immunomodulatory, proapoptotic, and antiangiogenic effects...Vitamin D helps regulate the renin-angiotensin-aldosterone system (and thereby blood pressure), vascular cell growth, and inflammatory and fibrotic pathways. Vitamin D deficiency is associated with vascular dysfunction, arterial stiffening, left ventricular hypertrophy, and hyperlipidemia. For these reasons, vitamin D has been linked to heart health and risk of CVD [cardiovascular disease]...Vitamin D is involved in various brain processes, and vitamin D receptors are present on neurons and glia in areas of the brain thought to be involved in the pathophysiology of depression...This uneven [geographical] distribution [of multiple sclerosis] has led to speculation that lower vitamin D levels in people who have less sunlight exposure might predispose them to the disease...Vitamin D plays a role in glucose metabolism. It stimulates insulin secretion via the vitamin D receptor on pancreatic beta cells and reduces peripheral insulin resistance through vitamin D receptors in the muscles and liver. Vitamin D might be involved in the pathophysiology of type 2 diabetes through its effects on glucose metabolism and insulin signaling as well as its ability to reduce inflammation and improve pancreatic beta-cell function" (Ibid.).

Possible adverse effects: "Excess amounts of vitamin D are toxic. Because vitamin D increases calcium absorption in the gastrointestinal tract, vitamin D toxicity results in marked hypercalcemia..., hypercalciuria, and high serum 25(OH)D levels...Hypercalcemia, in turn, can lead to nausea, vomiting, muscle weakness, neuropsychiatric disturbances, pain, loss of appetite, dehydration, polyuria, excessive thirst, and kidney stones. In extreme cases, vitamin D toxicity causes renal failure, calcification of soft tissues throughout the body (including in coronary vessels and heart valves), cardiac arrhythmias, and even death" (Ibid.). Increased risk of kidney stones. Interactions with some medications.

Reviews and major trials (2016-later only, unless not covered in a later review):

• Munger et al. 2004. Neurology. 62(1):60-5 [Nurses' Health Study]: "These results support a protective effect of vitamin D intake on risk of developing MS [multiple sclerosis]."

• Helzlsouer and VDPP Steering Committee 2010. Am J Epidemiol. 172(1):4-9: "The Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP) brought together 10 cohorts to conduct a prospective study of the association between vitamin D status, measured as serum concentrations of 25-hydroxyvitamin D (25(OH)D), and the development of 7 rarer cancer sites: endometrial, esophageal, gastric, kidney, non-Hodgkin lymphoma, ovarian, and pancreatic cancers...Across each cancer site, there was no evidence of a protective association between higher concentrations of 25-hydroxyvitamin D (>75 nmol/L) and cancer outcome. An increased risk at very high levels (> or =100 nmol/L) was noted for pancreatic cancer..."

• Beaudart et al. 2014. J Clin Endocrinol Metab. 99(11):4336-45: "Vitamin D supplementation has a small positive impact on muscle strength, but additional studies are needed to define optimal treatment modalities, including dose, mode of administration, and duration."

• Varteresian and Lavretsky 2014. Curr Psychiatry Rep. 16(8):456: "there is not convincing evidence to support supplementation in individuals with normal vitamin D levels or mild depression."

• Jiang et al. 2016. Clin Cardiol. 39(1):56-61: "Vitamin D supplementation may decrease serum levels of parathyroid hormone and inflammatory mediators in CHF [chronic heart failure] patients, whereas it has no beneficial effects on improvement of left ventricular function and exercise tolerance."

• Pilz et al. 2016. Anticancer Res. 36(3):1379-87: "it has been documented in meta-analyses of randomized controlled trials that vitamin D3 supplementation is associated with a moderate, yet statistically significant, reduction in mortality. This latter finding must be interpreted in light of some limitations such as incomplete follow-up data, but such a reduction of mortality with vitamin D3 supplementation as the finding of meta-analyses of randomized controlled trials strongly argues for the benefits and, importantly, also the safety of vitamin D."

• Wu et al. 2016. Pain Physician. 19(7):415-27: "A significantly greater mean decrease in pain score (primary outcome) was observed with vitamin D supplementation compared with placebo in people with chronic pain. These results suggest that vitamin D supplementation could have a role in the management of chronic pain."

• Gao et al. 2017. Int J Surg. 46:14-20: "Vitamin D supplementation was effective in improving the WOMAC pain and function in patients with knee OA [osteoarthritis]. However, it had no beneficial effect on the prevention of tibial cartilage loss. Therefore, there is currently a lack of evidence to support the use of vitamin D supplementation in preventing the progression of knee OA."

• Jolliffe et al. 2017. Lancet Respir Med. 5(11):881-90: "Vitamin D supplementation reduced the rate of asthma exacerbations requiring treatment with systemic corticosteroids overall."

• Yong et al. 2017. Clin Rheumatol. 36(12):2825-33 [chronic widespread pain]: "In this meta-analysis, we conclude that vitamin D supplementation is able to decrease pain scores and improve pain despite no significant change in VAS [visual analog scale] after increasing serum vitamin D level."

• Autier et al. 2017. Lancet Diabetes Endocrinol. 5(12):986-1004: "Although vitamin D doses were greater than those assessed in the past, we found no new evidence that supplementation could have an effect on most non-skeletal conditions, including cardiovascular disease, adiposity, glucose metabolism, mood disorders, muscular function, tuberculosis, and colorectal adenomas, or on maternal and perinatal conditions...The main new finding highlighted by this systematic review is that vitamin D supplementation might help to prevent common upper respiratory tract infections and asthma exacerbations. There remains little evidence to suggest that vitamin D supplementation has an effect on most conditions, including chronic inflammation, despite use of increased doses of vitamin D, strengthening the hypothesis that low vitamin D status is a consequence of ill health, rather than its cause."

• Goulão et al. 2018. Am J Clin Nutr. 107(4):652-63: "We did not find evidence to suggest that vitamin D supplementation alone reduces the incidence of cancer or cancer mortality, even after including long-term follow-up results."

• Bolland et al. 2018. Lancet Diabetes Endocrinol. 6(11):847-58: "Our findings suggest that vitamin D supplementation does not prevent fractures or falls, or have clinically meaningful effects on bone mineral density. There were no differences between the effects of higher and lower doses of vitamin D. There is little justification to use vitamin D supplements to maintain or improve musculoskeletal health."

• Vellekkatt and Menon 2019. J Postgrad Med. 65(2):74-80: "Vitamin D supplementation favorably impacted depression ratings in major depression with a moderate effect size. These findings must be considered tentative owing to the limited number of trials available and inherent methodological bias noted in few of them."

• Manson et al. 2019. N Engl J Med. 380(1):33-44: "Supplementation with vitamin D did not result in a lower incidence of invasive cancer or cardiovascular events than placebo."

• Jolliffe et al. 2019. Thorax. 74(4):337-45: "Vitamin D supplementation safely and substantially reduced the rate of moderate/severe COPD [chronic obstructive pulmonary disease] exacerbations in patients with baseline 25-hydroxyvitamin D levels <25 nmol/L but not in those with higher levels."

• Barbarawi et al. 2019. JAMA Cardiol. 4(8):765-76: "In this updated meta-analysis, vitamin D supplementation was not associated with reduced major adverse cardiovascular events, individual CVD end points (myocardial infarction, stroke, CVD mortality), or all-cause mortality. The findings suggest that vitamin D supplementation does not confer cardiovascular protection and is not indicated for this purpose."

• Palacios et al. 2019. Cochrane Database Syst Rev. CD008873: "Supplementing pregnant women with vitamin D alone probably reduces the risk of pre-eclampsia, gestational diabetes, low birthweight and may reduce the risk of severe postpartum haemorrhage. It may make little or no difference in the risk of having a preterm birth < 37 weeks' gestation."

• Pittas et al. 2019. N Engl J Med. 381(6):520-30 [trial with 2423 participants]: "Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo."

• Zittermann and Pilz 2019. Anticancer Res. 39(9):4627-35: "Based on a conservative benefit-risk management approach, vitamin D doses beyond the nutritionally recommended amounts of 600 to 800 IE daily currently cannot be advised for the prevention of CVD events."

• Farapti et al. 2020. F1000Res. 9:633: "Vitamin D supplementation significantly increases 25(OH)D concentrations and seems beneficial in lowering BP [blood pressure], specifically in the elderly with elevated BP and vitamin D deficiency."

• Zhang et al. 2020. Diabetes Care. 43(7):1650-8: "In persons with prediabetes, vitamin D supplementation reduces the risk of T2DM [type 2 diabetes mellitus] and increases the reversion rate of prediabetes to normoglycemia. The benefit of the prevention of T2DM could be limited to nonobese subjects."

• Okereke et al. 2020. JAMA. 324(5):471-80 [Vitamin D and Omega-3 Trial-Depression Endpoint Prevention (VITAL-DEP)]: "Among adults aged 50 years or older without clinically relevant depressive symptoms at baseline, treatment with vitamin D3 compared with placebo did not result in a statistically significant difference in the incidence and recurrence of depression or clinically relevant depressive symptoms or for change in mood scores over a median follow-up of 5.3 years. These findings do not support the use of vitamin D3 in adults to prevent depression."

• Lan et al. 2020. Sci Rep. 10(1):14261: "In conclusion, this meta-analysis suggested that the administration of vitamin D did not provide additional advantages over placebo for critically ill patients."

• Guo et al. 2020. Food Funct. 11(9):7389-99: "The present study provides substantial evidence that supplemental vitamin D has favorable effects on glycemic control and insulin sensitivity in NAFLD [non-alcoholic fatty liver disease] patients. Vitamin D could be as an adjuvant pharmacotherapy of NAFLD."

• AlAnouti et al. 2020. Nutrients. 12(11):3352: "VDS [vitamin D supplementation] seems not to affect blood lipids in adults with MetS [metabolic syndrome]."

• Christen et al. 2020. JAMA Ophthalmol. 138(12):1280-9 [Vitamin D and Omega-3 Trial (VITAL)]: "Neither vitamin D3 nor marine ω-3 fatty acid supplementation had a significant overall effect on AMD [age-related macular degeneration] incidence or progression."

• Peng et al. 2020. PLoS One. 15(12):e0243768: "Vitamin D supplement was not associated with reduced all-cause mortality in critically ill patients."

• Theodoridis et al. 2021. Nutrition. 82:111024: "A favorable effect of oral vitamin D supplementation in patients with psoriasis could not be verified."

• Abshirini et al. 2020.  J Hum Nutr Diet. 33(2):207-21: "The present review demonstrates that vitamin D supplementation resulted in small but nonsignificant improvements in muscle strength compared to control in postmenopausal women. No significant effect was observed in mobility after vitamin D administration."

• Zittermann et al. 2021. Int J Mol Sci. 22(6):2896: "In conclusion, there is no strong evidence for beneficial vitamin D effects on CVD risk, either in the general population or in high-risk groups."

• Jolliffe et al. 2021. Lancet Diabetes Endocrinol. 9(5):276-92: "Despite evidence of significant heterogeneity across trials, vitamin D supplementation was safe and overall reduced the risk of ARI [acute respiratory infections] compared with placebo, although the risk reduction was small."

• Michos et al. 2021. J Am Coll Cardiol. 77(4):437-49: "Multiple observational studies have linked low serum 25-hydroxyvitamin D concentrations with increased cardiovascular risk. However, subsequent randomized controlled trials (RCTs) failed to demonstrate cardiovascular benefit with vitamin D supplementation. Although vitamin D supplements do not appear to be harmful for cardiovascular health, the lack of benefit in RCTs should discourage their use for this purpose, favoring optimizing vitamin D status through healthy lifestyles such as specific foods and modest sunlight exposure."

Notes: The following points were made by NIH-ODS (2021. Vitamin D):

• • • "The FNB [Food and Nutrition Board] committee that established DRIs for vitamin D found that the evidence was inadequate or too contradictory to conclude that the vitamin had any effect on a long list of potential health outcomes (e.g., on resistance to chronic diseases or functional measures), except for measures related to bone health. Similarly, in a review of data from nearly 250 studies published between 2009 and 2013, the Agency for Healthcare Research and Quality concluded that no relationship could be firmly established between vitamin D and health outcomes other than bone health."

    • "Most of the studies described in this section measured serum 25(OH)D levels using various methods that were not standardized by comparing them to the best methods. Use of unstandardized 25(OH)D measures can raise questions about the accuracy of the results and about the validity of conclusions drawn from studies that use such measures and, especially, from meta-analyses that pool data from many studies that use different unstandardized measures."

    • Concerning bone health: "All adults should consume recommended amounts of vitamin D and calcium from foods and supplements if needed. Older women and men should consult their healthcare providers about their needs for both nutrients as part of an overall plan to maintain bone health and to prevent or treat osteoporosis."

    • "The USPSTF [United States Preventive Services Task Force] stated that, due to insufficient evidence, it was unable to assess the balance of benefits and harms of supplemental vitamin D to prevent cancer. Taken together, studies to date do not indicate that vitamin D with or without calcium supplementation reduces the incidence of cancer, but adequate or higher 25(OH)D levels might reduce cancer mortality rates."

    • "Overall, clinical trials show that vitamin D supplementation does not reduce CVD risk, even for people with low 25(OH)D status..."

    • "Overall, clinical trials did not find that vitamin D supplements helped prevent or treat depressive symptoms or mild depression, especially in middle-aged to older adults who were not taking prescription antidepressants."

    • "Experts have reached no firm consensus on whether vitamin D can help prevent MS given the lack of clinical trial evidence. In addition, studies have not consistently shown that vitamin D supplementation tempers the signs and symptoms of active MS or reduces rates of relapse."

    • "Clinical trials to date provide little evidence that vitamin D supplementation helps maintain glucose homeostasis, reduces the risk of progression from prediabetes to type 2 diabetes, or helps manage the disease, particularly in vitamin D-replete individuals."

Gavura (2020 Aug 6. Science-Based Medicine blog) wrote, "The repeated failure of vitamin D in prospective trials raises the question as to whether or not these large trials can be justified financially with public dollars. On one hand, the compelling results could help patients and physicians make better treatment decisions about vitamin D, if those decisions are influenced by evidence. There is also continued public interest in vitamin D consumption, driven in large part by the supplement industry. Given the limited research dollars available and the number of public health issues that would benefit from research, it would seem that industry should be funding this research. But in the absence of requiring supplement manufacturers to provide persuasive evidence to justify marketing their products, it falls on governments and other researchers to do these types of studies."

Reijven et al. (2020. Clin Nutr. 39(9):2663-74) wrote, "Studies addressing the association between vitamin D status and cancer, cardiovascular diseases, auto-immune diseases, inflammation and severe illness are reviewed. A search for RCTs with positive effects of Vit D supplementation on different diseases yielded only a few studies. The vast majority of RCTs showed no significant positive effects. The presumed high prevalence of Vit D deficiency is questioned based on these results and on altered concentrations of Vit D binding protein, leading to low Vit D levels in plasma but not to low active Vit D levels during disease related inflammation In these conditions, plasma levels of Vit D are therefore not a valid reflection of Vit D status...It is concluded that further widespread fortification of foods and stimulation of supplement use should be reconsidered."

Vitamin E - see also sections on fat-soluble vitamins and antioxidants (SUPPLEMENTS PART 1). “Supplements of vitamin E typically provide only alpha-tocopherol, although ‘mixed’ products containing other tocopherols and even tocotrienols are available. Naturally occurring alpha-tocopherol exists in one stereoisomeric form. In contrast, synthetically produced alpha-tocopherol contains equal amounts of its eight possible stereoisomers; serum and tissues maintain only four of these stereoisomers. A given amount of synthetic alpha-tocopherol (all rac-alpha-tocopherol; commonly labeled as ‘DL’ or ‘dl’) is therefore only half as active as the same amount (by weight in mg) of the natural form (RRR-alpha-tocopherol; commonly labeled as ‘D’ or ‘d’). Most vitamin-E-only supplements provide ≥67 mg (100 IU of natural vitamin E) of the nutrient. These amounts are substantially higher than the RDAs. Alpha-tocopherol in dietary supplements and fortified foods is often esterified to prolong its shelf life while protecting its antioxidant properties. The body hydrolyzes and absorbs these esters (alpha-tocopheryl acetate and succinate) as efficiently as alpha-tocopherol” (NIH Office of Dietary Supplements 2021. Vitamin E).

Promoted for: prevention and/or treatment of coronary artery disease, cancer, eye disorders, cognitive decline

Presumed mechanism of action: “The mechanisms by which vitamin E might provide this protection include its function as an antioxidant and its roles in anti-inflammatory processes, inhibition of platelet aggregation, and immune enhancement...In vitro studies have found that the nutrient inhibits oxidation of low-density lipoprotein (LDL) cholesterol, thought to be a crucial initiating step for atherosclerosis. Vitamin E might also help prevent the formation of blood clots that could lead to a heart attack or venous thromboembolism....Antioxidant nutrients like vitamin E protect cell constituents from the damaging effects of free radicals that, if unchecked, might contribute to cancer development. Vitamin E might also block the formation of carcinogenic nitrosamines formed in the stomach from nitrites in foods and protect against cancer by enhancing immune function...the cumulative effects of oxidative stress have been postulated to play a role [in eye disease such as age-related macular degeneration and cataracts]. If so, nutrients with antioxidant functions, such as vitamin E, could be used to prevent or treat these conditions...Researchers hypothesize that if cumulative free-radical damage to neurons over time contributes to cognitive decline and neurodegenerative diseases, such as Alzheimer’s disease, then ingestion of sufficient or supplemental antioxidants (such as vitamin E) might provide some protection" (Ibid.).

Possible adverse effects: “...high doses of alpha-tocopherol supplements can cause hemorrhage and interrupt blood coagulation in animals, and in vitro data suggest that high doses inhibit platelet aggregation” (Ibid.). Possible increase in prostate cancer. Interactions with some medications.

Reviews and major trials:

• Christen et al. 2008. Ophthalmology. 115(5):822-829.e1 [Women’s Health Study]: “These data from a large trial of apparently healthy female health professionals with 9.7 years of treatment and follow-up indicate that 600 IU natural-source vitamin E taken every other day provides no benefit for age-related cataract or subtypes.”

• Devore et al. 2010. Arch Neurol. 2010 Jul;67(7):819-25 [Rotterdam Study]: “Higher intake of foods rich in vitamin E may modestly reduce long-term risk of dementia and AD [Alzheimer’s disease].”

• Schürks et al. 2010. BMJ. 341:c5702: “In this meta-analysis, vitamin E increased the risk for haemorrhagic stroke by 22% and reduced the risk of ischaemic stroke by 10%. This differential risk pattern is obscured when looking at total stroke. Given the relatively small risk reduction of ischaemic stroke and the generally more severe outcome of haemorrhagic stroke, indiscriminate widespread use of vitamin E should be cautioned against.”

• Klein et al. 2011. JAMA. 306(14):1549-56 [Selenium and Vitamin E Cancer Prevention Trial (SELECT)]: “Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men.”

• Xu et al. 2014. PLoS One. 9(4):e95008: “In conclusion, there is currently insufficient evidence to support a potential beneficial effect of vitamin E supplementation on improvements of HbA1c [hemoglobin A1c] and fasting glucose and insulin concentrations in subjects with T2DM [type 2 diabetes mellitus].”.

• Jiang et al. 2014. J Nutr Sci Vitaminol (Tokyo). 60(3):194-205: “Neither vitamin E intake alone nor combined with other agents is associated with a reduction in all-cause mortality. But a low dose (<400 IU/d) of vitamin E combined with other agents is correlated with a reduction in all-cause mortality, and vitamin E intake combined with other agents is correlated with a reduction in the mortality rate among individuals without probable or confirmed diseases.”

• Curtis et al. 2014. Cardiovasc Drugs Ther. 28(6):563-73: “The evidence from pooled analysis of 18 randomised controlled trials undertaken in apparently healthy people shows no effect of vitamin E supplementation at a dose of 23-800 IU/day on all-cause mortality.”

• Saboori et al. 2015. Eur J Clin Nutr. 69(8):867-73: “The results of this meta-analysis suggest that supplementation with vitamin E in the form of either α-tocopherol or γ-tocopherol would reduce serum CRP [C-reactive protein, a measure of chronic inflammation] levels.”

• Emami et al. 2019. J Hum Hypertens. 33(7):499-507: “This meta-analysis suggested that vitamin E supplements decreased only SBP [systolic blood pressure] and had no favorable effect on DBP [diastolic blood pressure] and MAP [mean arterial pressure].”

Notes: The following points were made by NIH-ODS (2021. Vitamin D):

• “In general, clinical trials have not provided evidence that routine use of vitamin E supplements prevents cardiovascular disease or reduces its morbidity and mortality. However, participants in these studies have been largely middle-aged or elderly individuals with demonstrated heart disease or risk factors for heart disease. Some researchers have suggested that understanding the potential utility of vitamin E in preventing CHD [coronary heart disease] might require longer studies in younger participants taking higher doses of the supplement. Further research is needed to determine whether supplemental vitamin E has any protective value for younger, healthier people at no obvious risk of CHD.”

• “Evidence to date is insufficient to support taking vitamin E to prevent cancer. In fact, daily use of large-dose vitamin E supplements (400 IU of synthetic vitamin E [180 mg]) may increase the risk of prostate cancer.”

• “Overall, the available evidence is inconsistent with respect to whether vitamin E supplements, taken alone or in combination with other antioxidants, can reduce the risk of developing AMD [age-related macular degeneration] or cataracts. However, the formulations of vitamin E, other antioxidants, zinc, and copper used in AREDS [Age-Related Eye Disease Study] hold promise for slowing the progression of AMD in people at high risk of developing advanced AMD.”

• “In summary, most research results do not support the use of vitamin E supplements by healthy or mildly impaired individuals to maintain cognitive performance or slow its decline with normal aging [51]. More research is needed to identify the role of vitamin E, if any, in the management of cognitive impairment.”

Vitamin K - see also section fat-soluble vitamins (SUPPLEMENTS PART 1). “'Vitamin K,' the generic name for a family of compounds with a common chemical structure of 2-methyl-1,4-naphthoquinone, is a fat-soluble vitamin that is naturally present in some foods and is available as a dietary supplement. These compounds include phylloquinone (vitamin K1) and a series of menaquinones (vitamin K2). Menaquinones have unsaturated isoprenyl side chains and are designated as MK-4 through MK-13, based on the length of their side chain. MK-4, MK-7, and MK-9 are the most well-studied menaquinones...Several forms of vitamin K are used in dietary supplements, including vitamin K1 as phylloquinone or phytonadione (a synthetic form of vitamin K1) and vitamin K2 as MK-4 or MK-7. Few data are available on the relative bioavailability of the various forms of vitamin K supplements. One study found that both phytonadione and MK-7 supplements are well absorbed, but MK-7 has a longer half-life” (NIH Office of Dietary Supplements 2021. Vitamin K).

Promoted for: osteoporosis, coronary heart disease

Presumed mechanism of action: “Vitamin K is a cofactor for the gamma-carboxylation of many proteins, including osteocalcin, one of the main proteins in bone...Matrix Gla-protein (MGP) is a vitamin K-dependent protein that may play a role in the prevention of vascular calcification. Although the full biological function of MGP is unclear, a hypothesis based on animal data suggests that inadequate vitamin K status leads to undercarboxylated MGP, which could increase vascular calcification and the risk of coronary heart disease.”

Possible adverse effects: “The FNB [Food and Nutrition Board] did not establish ULs for vitamin K because of its low potential for toxicity. In its report, the FNB stated that ‘no adverse effects associated with vitamin K consumption from food or supplements have been reported in humans or animals’” (Ibid.). There are interactions with some medications. “Vitamin K can have a serious and potentially dangerous interaction with anticoagulants such as warfarin (Coumadin®)” (Ibid.).

Review: Vlasschaert et al. 2020. Nutrients. 12(10):2909: “The findings indicate that vitamin K does not consistently prevent progression of calcification, atherosclerosis or arterial stiffness. There may be some benefit in people with calcification at study entry.”

Notes: According to NIH-ODS (2021. Vitamin K), “Although vitamin K is involved in the carboxylation of osteocalcin, it is unclear whether supplementation with any form of vitamin K reduces the risk of osteoporosis...In Japan and other parts of Asia, a pharmacological dose of MK-4 (45 mg) is used as a treatment for osteoporosis. The European Food Safety Authority has approved a health claim for vitamin K, noting that ‘a cause and effect relationship has been established between the dietary intake of vitamin K and the maintenance of normal bone.’ The FDA has not authorized a health claim for vitamin K in the United States...At this time, the role of the different forms of vitamin K on arterial calcification and the risk of coronary heart disease is unclear, but it continues to be an active area of research in the general population and in patients with chronic kidney disease.”

Wheat germ oil - rich in octacosanol and vitamin E

Promoted for: increased vigor and endurance

Wheatgrass - “the freshly sprouted first leaves of the common wheat plant (Triticum aestivum), used as a food, drink, or dietary supplement...Wheatgrass juice is often available at juice bars, and some people grow and juice their own in their homes. It is available fresh as produce, in tablets, frozen juice, and powder” (Wikipedia 2021. Wheatgrass). “The alleged salubrious effects of wheatgrass were promoted in the 1940s by a Lithuanian immigrant to Boston named Ann Wigmore, a holistic health practitioner who was inspired by the biblical story of King Nebuchadnezzar” (who gained strength by eating grass) (Shermer 2008. Wheatgrass juice and folk medicine. Scientific American. 299(2):42). “Wigmore also noted that dogs and cats eat grass when they are ill and feel better after regurgitation” (Ibid.).

Promoted for: source of amino acids, minerals, vitamins, enzymes, and chlorophyll. Allegedly provides “bio-electricity.”

Presumed mechanism of action: provision of nutrients, detoxification by chlorophyll, beneficial effects of enzymes

Notes: Shermer (2008. Op. cit.) quoted William Jarvis: “Orally ingested enzymes are digested in the stomach and have no activity in the eater...chlorophyll cannot ‘detoxify the body’ because it is not absorbed.”

Whey protein - “the protein contained in whey, the watery portion of milk that separates from the curds when making cheese” (MedlinePlus 2020. Whey protein).

Promoted for: “Whey protein is commonly used for improving athletic performance and increasing strength...Whey protein is also used to reverse weight loss in people with HIV and to help prevent allergic conditions in infants” (Ibid.).

Presumed mechanism of action: source of protein, possible effects on immune system. Includes all essential amino acids.

Possible adverse effects: “High doses can cause some side effects such as increased bowel movements, nausea, thirst, bloating, cramps, reduced appetite, tiredness (fatigue), and headache” (Ibid.). Should be avoided by those allergic to cow’s milk. Interferes with the absorption of some medications, especially levodopa.

Notes: According to Natural Medicines Comprehensive Database, whey protein is possibly effective for athletic performance, prevention of eczema and other allergies, weight loss in people with HIV, and psoriasis; possibly ineffective for chronic obstructive pulmonary disease and bone loss in people taking steroids. There is insufficient evidence of effectiveness for other uses.

Yam - “Wild yam is a plant. It contains a chemical called diosgenin. This chemical can be converted in the laboratory into various steroids, such as estrogen and dehydroepiandrosterone (DHEA). The root and the bulb of the plant are used as a source of diosgenin, which is prepared as an ‘extract,’ a liquid that contains concentrated diosgenin. However, while wild yam does seem to have some estrogen-like activity, it is not actually converted into estrogen in the body. It takes a laboratory to do that. Sometimes wild yam and diosgenin are promoted as a ‘natural DHEA.’ This is because in the laboratory DHEA is made from diosgenin. But this chemical reaction is not believed to occur in the human body. So, taking wild yam extract will not increase DHEA levels in people” (MedlinePlus 2020. Wild yam).

Promoted for: “Wild yam is most commonly used as a 'natural alterative' to estrogen therapy for symptoms of menopause, infertility, menstrual problems, and other conditions” (Ibid.).

Presumed mechanism of action: estrogen-like effects

Possible adverse effects: “Large amounts may cause vomiting, upset stomach, and headache...Taking wild yam along with estrogen pills might decrease the effects of estrogen pills.”

Notes: According to MedlinePlus, “there is no good scientific evidence” to support the uses noted above. Natural Medicines Comprehensive Database rates it as possibly ineffective for symptoms of menopause, insufficient evidence to rate effectiveness for other conditions.

Zinc - see also section on trace minerals (SUPPLEMENTS PART 1). "Supplements contain several forms of zinc, including zinc gluconate, zinc sulfate, and zinc acetate...In addition to standard tablets and capsules, some zinc-containing cold lozenges are labeled as dietary supplements" (NCCIH Office of Dietary Supplements 2021. Zinc).

Promoted for: treatment of colds, enhance sex drive, restore taste, help swollen prostate, delaying progression of age-related macular degeneration

Presumed mechanism of action: "Researchers have hypothesized that zinc could reduce the severity and duration of cold symptoms by directly inhibiting rhinovirus binding and replication in the nasal mucosa and suppressing inflammation" (Ibid.). Note that use for colds is thus a topical application rather than a dietary supplement. "Researchers have suggested that both zinc and antioxidants delay the progression of age-related macular degeneration (AMD) and vision loss, possibly by preventing cellular damage in the retina" (Ibid.).

Possible adverse effects: "Zinc toxicity can occur in both acute and chronic forms. Acute adverse effects of high zinc intake include nausea, vomiting, loss of appetite, abdominal cramps, diarrhea, and headaches...Intakes of 150–450 mg of zinc per day have been associated with such chronic effects as low copper status, altered iron function, reduced immune function, and reduced levels of high-density lipoproteins...the safety of intranasal zinc has been called into question because of numerous reports of anosmia (loss of smell), in some cases long-lasting or permanent, from the use of zinc-containing nasal gels or sprays" (Ibid.). Interactions with some medications.

Reviews:

• Loef et al. 2012. Nutr Neurosci. 15(5):2-12: "The current state of evidence does not allow conclusions to be drawn on whether supplementation of Zn is beneficial for the prevention or treatment of AD [Alzheimer's disease], although a subclinical deficiency appears common in the elderly and subjects with AD."

• Singh and Das 2013. Cochrane Database Syst Rev. CD001364: "Zinc administered within 24 hours of onset of symptoms reduces the duration of common cold symptoms in healthy people but some caution is needed due to the heterogeneity of the data. As the zinc lozenges formulation has been widely studied and there is a significant reduction in the duration of cold at a dose of ≥ 75 mg/day, for those considering using zinc it would be best to use it at this dose throughout the cold. Regarding prophylactic zinc supplementation, currently no firm recommendation can be made because of insufficient data."

• Khazdouz et al. 2020. Biol Trace Elem Res. 195(2):373-98: "Meta-analysis showed that zinc supplementation significantly decreased plasma levels of triglyceride..., very-low-density lipoprotein..., and total cholesterol...Similarly, zinc supplementation significantly decreased fasting blood glucose...and HbA1c [hemoglobin A1c]. The effects of zinc supplementation on blood pressure and anthropometric indices were not statistically significant..."

• Mousavi et al. 2020. Eur J Nutr. 59(5):1815-27: "We found a significant reduction in SBP [systolic blood pressure] following zinc supplementation. However, zinc supplementation had no significant effect on DBP [diastolic blood pressure]."

• Li and Zhao 2021. J Matern Fetal Neonatal Med. 34(13):2140-5: "Zinc supplementation is effective to decrease FPG [fasting plasma glucose], insulin, HOMA-IR [Homeostatic Model Assessment for Insulin Resistance] and improve QUICKI [quantitative insulin-sensitivity check index] in gestational diabetes, but has no significant impact on LDL [low-density lipoprotein]-cholesterol and total cholesterol."

Notes: "...the authors of a systematic review and meta-analysis published in 2007 concluded that zinc is not effective for the primary prevention of early AMD, although zinc might reduce the risk of progression to advanced AMD" (Ibid.). In 2006, manufacturers of Zicam Cold Remedy agreed to settle 340 lawsuits for $12 million; the suits claimed damage to the sense of smell of users.

REFERENCES