VITAMINS AND MINERALS
Definitions:
Dietary supplement - regulatory term. Includes vitamins, minerals, herbs, botanicals, fatty acids, and amino acids as long as they are prescribed in dosage forms, such as capsules, tablets, liquids, gels or powders.
Nutraceutical - includes dietary supplements and foods with therapeutic value
Medical food - includes macronutrients (carbohydrate, fat, protein) as well as micronutrients and is prepared in powder form.
Vitamins - complex organic substances (i.e. carbon containing compounds) not made in the body, essential in small quantities for normal functioning of the body.
Term “vitamine” was coined in 1911/1912 by Polish scientist Casimir Funk to designate a group of compounds discovered to be vital for life
Vitamin D is an exception; it is made in the body from cholesterol if there is sun exposure.
Niacin is an exception too; it is synthesized in small amounts in the body from tryptophan.
Minerals - non-organic (i.e. no carbon atoms), homogenous substances found in the earth's crust.
Popularity:
Sales of all dietary supplements, including vitamins, minerals, herbs, and a variety of other compounds defined in the U.S. as dietary supplements was estimated at $8.8 billion in 1994, $15.7 billion in 2000, $17.8 billion in 2001, $23 billion in 2006.
According to NHANES 1999-2000, 35% of adults reported using multivitamins (Am J Epidemiol. 2004. 160. 339-349).
According to NHANES III, at least 30% of U.S. population takes vitamin supplements regularly (Arch Fam Med. 2000. 9. 258-262). Spending estimated at $1.5 billion yearly.
History:
The word vitamine was coined in 1911/1912 by Polish biochemist Casimir Funk, meant to capture the notion of important factors in the diet, or vital amines.
When chemical names were originally given to vitamins, it was not appreciated that vitamins may exist in a number of different molecular forms (i.e. retinoic acid, retinol, retinal).
Large scale fortification in the U.S. began in 1924 with the addition of iodine to table salt, continued with the addition of vitamin D to milk in 1933, then the addition of thiamin, riboflavin, niacin, and iron to flour in 1941.
In the 1940’s the first multivitamin was introduced.
Paradigm shift:
Old Paradigm: Vitamins and minerals at RDA to prevent deficiency diseases with a short latency (i.e. rickets, scurvy, beri beri, pellagra).
New Paradigm:
Vitamins and minerals in pharmacologic doses to prevent or treat diseases with multifactorial causation. Historically, this paradigm originated in 1954 with the discovery that niacin in high doses lowered cholesterol levels.
Vitamins in doses to achieve optimal levels and prevent insufficiency, as distinct from deficiency (i.e. vitamin B12 in a dose to prevent a rise in homocysteine or methylmalonic acid, vitamin D in a dose to prevent a rise in PTH).
Nutrigenetics – taking into account the effect of genetic variation on metabolic requirements and dosing vitamins in doses which are individualized based in part on knowledge of the effect of single nucleotide polymorphisms (SNP’s) upon vitamin metabolism (i.e. higher doses of folate or oral 5-methyltetrahydrofolate supplementation for individuals with high homocysteine who do not respond to 0.4 mg supplemental folate, as data suggests that 10% of the population is homozygous for “sluggish” enzyme in the folate/homocysteine cycle).
Nutrigenomics – the effect of bioactive food components on gene expression.
Orthomolecular Medicine:
This term describes the practice of using the most appropriate nutrients in the most therapeutic amounts, according to a particular individual's biochemical requirements, with the goal of establishing optimum health.
Roger Williams coined the term ‘biochemical individuality’ in the 1950’s to describe the above practice.
This treatment provides the body and the brain with the best possible biochemical environment.
Historically, this term was first used by Linus Pauling in a published article in Science in 1968.
Orthomolecular medicine is referred to by some as megavitamin therapy, but this term is really an oversimplification.
Proven benefits of vitamins and minerals in pharmacologic doses:
Vitamin B3 (niacin) in high doses (3-6 grams/day) has been conventional treatment for hypercholesterolemia for years (Archives of Biochemistry and Biophysics. 1955. 54. 558-559).
Folate 0.8 mg/day, started before pregnancy, markedly decreases the risk of first occurrence of neural tube defects (New Engl J Med. 1992. 327. 1832-1835), and recurrent defects in women with a previously affected pregnancy (Lancet. 1991. 338. 131-137; JAMA. 1993. 269. 1257-1261).
Folate 10 mg/day in a RCT with 18 healthy men was shown to prevent tolerance to transdermal nitroglycerine administered continuously for 7 days, despite a lack of change in homocysteine levels (Circulation. 2001. 104. 1119-1123).
Vitamin B2 (riboflavin) 400 mg/day decreases the attack frequency of headache days in migrainers from 4/month to 2/month, decreases the number of headache days per month from 5 1/2 to 2 1/2, and decreases the severity in a randomized, double-blind, placebo-controlled trial including 55 patients with 2-7 attacks/month and at least a one year history of migraines. Frequency declined after one month of treatment (Neurology. 1998. 50. 466-470).
Vitamin C 2000 mg one half hour pre-exercise lessens the severity of exercise-induced asthma, based on a placebo-controlled study in 20 subjects (Arch of Ped and Adolescent Med. 1997. 151. 367-370).
Vitamin C 500 mg daily for one month decreased blood pressure by 9% compared to a 3% decline in those taking placebo (Lancet. 1999. 354. 2048-2049).
Vitamin C 500 mg daily for 50 days after a wrist fracture reduced the incidence of reflex sympathetic dystrophy from 22% in controls to 7% in those taking Vitamin C (Lancet. 1999. 354. 2025-2028).
Vitamin E beneficial in the treatment of symptomatic PVD
A 3 month RCT in 33 patients with severe intermittent claudication showed that vitamin E 400 IU/day increased walking distance statistically significantly more than placebo (Angiology. 1963. 14. 198-208).
Another 3 month RCT showed that vitamin E 400 mg 4 times a day is effective at increasing walking distance in individuals with intermittent claudication based on a RCT in 33 patients with a definite history of intermittent claudication, radiographic evidence of arterial disease, and a minimum of 3 months on the therapy (CMAJ. 1962. 87. 538-541).
Another previous 3 month RCT in 34 patients with intermittent claudication symptoms for at least 5 years also showed significant improvement in walking distance with 600 mg of Vitamin E daily. In this study, the investigators noted a considerable delay before any response was noted (Lancet. 1958. 2. 602-604).
NOTE a 12 week RCT in 41 patients showed no benefit, but the dose of Vitamin E was only two 75 mg capsules 3 times a day, or 450 mg per day (Lancet. 1953. 1. 367-370).
Chromium picolinate 200 mcg/day shown to lower fasting blood glucose, total cholesterol level, triglyceride level and insulin level in Type II Diabetes. Increase in HDL cholesterol also noted (Am J Clin Nutr. 1983. 38. 404-410).
Chromium picolinate 1000 mcg/day lowers fasting blood glucose and 2 hour postprandial glucose by about 35%, lowers insulin levels, lowers glycosylated hemoglobin by 2%, and lowers cholesterol by 6% in a 4 month double-blind, placebo-controlled study of180 patients, conducted in China. Toxicity of this dose is unknown (Diabetes. 1997. 46. 1786-1791).
Magnesium sulfate 2 grams iv as an adjunct to standard therapy improves pulmonary function in patients with severe asthma presenting to the emergency department, based on a RCT involving 248 individuals with a a FEV1 of <30% predicted (Chest. 2002. 122. 489-497).
Magnesium (trimagnesium dicitrate) 600 mg/day effective in reducing the frequency and severity of migraines, based on a 12 week RCT with 81 patients. At month 2, treatment patients had 2 migraines per month compared to 3 per month in the placebo group, and treatment patients experienced 2.4 headache days per month compared to 4.7 headache days in the treatment group (Cephalagia. 1996. 16. 257-263).
Zinc as a lozenge or nasal gel is associated with a significant reduction in the duration and severity of symptoms of the common cold, based on a systematic review of 15 clinical trials [n=966] (Cochrane Database Syst Rev. 2011:CD001364).
Zinc gluconate lozenges 13.3 mg started within 24 hours of the onset of cold symptoms and continued every 2 hours until symptoms were gone reduced the median time to resolution of all cold symptoms from 7.6 days to 4.4 days (p < 0.001) in a study of 100 employees of the Cleveland Clinic (Ann Intern Med. 1996. 125. 81-88).
Zinc acetate lozenges containing 12.8 mg of zinc and started within 24 hours of onset of cold symptoms and continued every 2-3 hours while awake until cold symptoms resolved reduced the average duration of cold symptoms from 8.1 days in the placebo group to 4.5 days in the treatment group, in a RCT with 48 subjects (Arch Intern Med. 2000. 133. 245-252).
Zinc oxide/glycine cream is an effective treatment for facial and circumoral herpes infections with predictable adverse effects that are completely reversible, based on a randomized controlled trial with 46 subjects who applied cream every 2 hours until the cold sore resolve or until 21 days elapsed. Subjects who began treatment within 24 hours of onset of signs and symptoms experienced a mean duration of cold sores of 5 days compared with 6.5 days in the placebo cream group (p=.018) [Alternative Therapies. 2001. 7. 49-56].
Antioxidant vitamins (beta-carotene, C, E) and minerals (Zinc, Copper, Manganese and Selenium)
There is a strong theoretic rationale for taking anti-oxidant vitamin and mineral supplements.
Normal metabolism (i.e. oxidative respiration) produces free radicals (i.e. chemical compounds which are short one electron) such as superoxide anion radical, hydroxyl radical and peroxyl radical as byproducts.
Sun exposure, cigarette smoke, and environmental radiation all increase free radical production in the body.
While these free radicals are necessary for life in small amounts (i.e. for phagocytosis of bacteria), they are chemically unstable and can also damage cell membranes, proteins and DNA, and are part of the pathogenesis of cancer, cataracts, and coronary artery disease. Damage caused by free radicals is named ‘oxidative stress.’
The theory is that the concentration of free radicals in our bodies is higher than is optimal, and that antioxidant supplements can offset damage from free radicals, and thus facilitate healthy aging. (There is emerging data that antioxidants also modulate intracellular redox potential by affecting cell signaling and transcription).
Epidemiological data correlates beta-carotene intake with reduced risk of lung cancer, cervical cancer and stomach cancer; vitamin E intake with reduced risk of cataracts; selenium intake with reduced risk of colon cancer.
Animal data suggests a protective role of beta-carotene with regards to lung cancer.
Observational studies in patients with no established CAD support the protective role of Vitamin E (see below in this outline for details of the studies).
There is some data from primary prevention trials to support the use of anti-oxidant supplements
An intervention trial in Linxian, China, a rural area whose population suffers from dietary deficiencies of multiple vitamins and whose gastric and esophageal cancer mortality rates are among the highest in the world. 29,584 adults were randomized to receive daily 30 mg Vitamin E plus 15 mg beta carotene plus 50 micrograms of selenium versus placebo. After a mean 5.2 years of follow up, those receiving the supplements had a 21% reduction in mortality from stomach cancer, a 4% reduction in mortality from esophageal cancer, and a 20% reduction in mortality from all other cancers combined. There were however no significant reductions in cardiovascular events (J NCI. 1993. 85. 1483-1492).
An intervention study of 1312 men and women aged 18-80 with a history of basal or squamous cell skin cancer, with half given a 200 microgram selenium supplement and half given placebo, with a mean treatment period of 4.5 years, and mean follow up of 6.4 years. Selenium supplementation had no effect on skin cancer rates but was associated with significant reductions in lung, colorectal, and prostate cancer rates (JAMA. 1996. 276. 1957-1963).
A RCT in 13,017 French adults (SU.VI.MAX Study) showed that a daily low dose antioxidant supplement with 120 mg of ascorbic acid, 30 mg vitamin E, 6 mg beta carotene, 100 mcg selenium, and 20 mg of zinc lowered total cancer incidence and all-cause mortality in men but not women (Arch Intern Med. 2004. 164. 2335-2342).
However, the data from randomized controlled trials (RCTs) fails to show benefit of anti-oxidant supplements and in several trials there is evidence of harm.
A Cochrane analysis of 67 RCTs (n=232,550) examining either vitamin A, vitamin C, vitamin E, beta-carotene, selenium or combinations of these antioxidants found that antioxidants do NOT reduce all-cause mortality in primary or secondary prevention. In this analysis, 21 of the RCTs (n=164,439) included healthy patients, and the other 46 RCTs (n=68,111) included patients with various diseases. 47 of these RCTs were judged to have a low risk for bias (Cochrane Database Syst Rev. 2008. 2. CD007176).
An updated Cochrane analysis of 78 RCTs (n=296,707) examining either vitamin A, vitamin C, vitamin E, beta-carotene, selenium or combinations of these antioxidants found that antioxidants do NOT reduce all-cause mortality in primary or secondary prevention. In this updated analysis, 26 of the RCTs (n=215,900) included healthy patients, and the other 52 RCTs (n=80,807) included patients with various diseases. 56 of these RCTs, covering 82% of the participants, were judged to have a low risk for bias. The mean duration of supplementation was 3 years.(Cochrane Database Syst Rev. 2012. 3[3]. CD007176).
A meta-analysis of 7 RCTs of vitamin E at doses of 50 – 800 IU/day found that vitamin E did not reduce all-cause mortality, the risk of cardiovascular death or the risk of CVA. In this same paper, a meta-analysis of 8 RCTs of beta carotene at doses of 15-50 mg/day found a small but significant increase in all-cause mortality. All individual studies in this meta-analysis had at least 1000 subjects, and follow-up of at least 1.4 years (Lancet. 2003. 361. 2017-2023).
A RCT in 20,536 adults age 40 to 80 with CHD, other arterial disease, or diabetes in which participants received either an antioxidant with 600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene or placebo determined that there were no differences in all-cause mortality, vascular events, incident cancer, hospitalization rates, tests of pulmonary function, and cognitive function at 5 years of follow up, despite higher plasma concentrations (Lancet. 2002. 360. 23-33).
Seven large randomized clinical trials with a combined total of over 100,000 patients have failed to show a significant benefit of Vitamin E in the prevention of CAD events (see vitamin E below in this outline for the specifics).
Trials showing evidence of harm from high dose antioxidant supplements include (1) the ATBCCPS study of beta carotene - see beta carotene below, (2) the CARET study of beta carotene - see beta carotene below, (3) a four arm study published in 2001 in the NEJM examining antioxidants and niacin in conjunction with prescription Zocor - see vitamin E below, (4) the WAVE trial – see vitamin E below, and (5) the 2005 meta-analysis of vitamin E studies published in the Annals of Internal Medicine - see vitamin E below.
Cochrane review negative – the authors conclude based on a meta-analysis of results of 67 RCTs (n=232,500) that there is “no evidence to support antioxidant supplements to prevent mortality in healthy people, or patients with various diseases” (Cochrane Database Syst Rev. 2008).
Antioxidant vitamins and endurance exercise (Alt Med Alert. 2007. 10. 66-69) – despite a strong theoretical rationale (i.e. exercise increases oxidative stress), the evidence to date fails to show benefit from administration of antioxidant vitamins.
The literature indicates that neither long term nor short term supplementation has an impact on exercise performance, aerobic performance, or muscle strength (Am J Clin Nutr. 2000. 72. 647S-652S).
An exception to the data on lack of benefit is that subgroup analysis of a meta-analysis of vitamin C for common cold prevention shows that vitamin C ‘pretreatment’ reduces the incidence of colds in endurance athletes (Cochrane Database Syst Rev. 2004).
The discrepancy between the epidemiologic data and the randomized, controlled trial data may a function of the use of isolated synthetic anti-oxidants in the controlled studies whereas whole foods are consumed as the basis of the epidemiologic studies.
In a very old study, vitamin E deficient laboratory animals fed tocopherols died sooner than control animals (American Journal of Digestive Diseases. 1945. 12. 20-21).
Synthetic antioxidants in moderate to high doses cause fatigue and muscle weakness in some individuals.
There are thousands and probably tens of thousands of anti-oxidant compounds present in whole foods (i.e. hundreds of carotenoids and flavonoids), and giving a single compound or even a cocktail of several anti-oxidants, such as beta carotene + vitamin C + alpha tocopherol (i.e. vitamin E) in pharmacological doses may upset the balance that exists in nature.
Nutritional Supplementation - indications (Pizzorno, Joseph. IMCJ. 2022. 21[1]. 8-11)
“Multivitamin and mineral at modest dosages to ensure that all bases are covered”
“For special circumstances e.g., living in a polluted city.”
“To address genetic susceptibilities, e.g., VDR receptor deficit”
For specific clinical purposes, e.g., promoting immune function during an infection”
Vitamins and Minerals – reasons why supplementation (therapeutic nutrition) is clinically useful
(Pizzorno, Joseph. IMCJ. 3(6). 6-8; Gaby, Alan. 2007 Gaby/Wright conference presentation)
Compensation for a deficient diet.
Recent changes in dietary choices to foods with lower nutrient density.
Many Americans do not obtain the RDA of a variety of micronutrients from their diet, using the RDIs as a standard, based on NHANES data.
Magnesium - according to USDA surveys, 62% of Americans fail to consume the RDA (Consumer Reports on Health. 6/05); NHANES III data shows that 75% of Americans don’t obtain the RDA of magnesium (Adv Data; 1994. 258: 1-28).
Zinc - according to USDA surveys, 73% of Americans fail to consume the RDA (Consumer Reports on Health. 6/05); according to NHANES III, 91% of U.S. children, 49% of 51-70 year olds, and 57% of elderly obtain less than the RDA of zinc from their diet (J Nutr. 2000. 130. 1367S-1375S).
In one study in which the subjects were research center employees of the USDA in Beltsville, MD found that fewer than 5% consumed the RDA of all vitamins and minerals (Am J Clin Nutr. 1984. 40 [suppl]. 1323-1403).
The USDA estimates that 75% of Americans eat less than 2/3 of the RDI for one or more nutrient.
NHANES data indicates that approximately 100% of Americans don’t consume the RDI of potassium, 80-90% dont consume the RDI of vitamin D, vitamin E, and choline, 60% don’t consume the RDI of vitamin K, and 50% don’t consume the RDI of magnesium.
Many fruits and vegetables have a lower vitamin and mineral content than they did 50 years ago. Furthermore, Weston A. Price, DDS, author of Nutrition and Physical Degeneration, analyzed diets consumed at the time of his cross cultural research in the 1930’s and found that primitive diets contained at least four times the concentration of minerals and water-soluble vitamins of the average American diet (in the 1930’s) and at least 10 times the amount of fat soluble vitamins of the average American diet (Prologue to Nutrition and Physical Degeneration. 1939).
A study which compared the USDA nutrient content data for 43 garden crops between 1950 and in 1999 found noticeable decreases in six of 13 nutrients examined (protein, calcium,, phosphorus, iron, riboflavin, and ascorbic acid), with percentage reductions ranging from 6% for protein to 38% of riboflavin. The authors suggest that any real declines are generally most easily explained by changes in cultivated varieties between 1950 and 1999 (Davis D, Epp M, Riordan H. Changes in the USDA food composition data for 43 garden crops, 1950-1999. J Am Coll Nutr. 2004. 23. 669-82).
A study of mineral content of fruits, vegetables, meat and dairy from 1940-1991 reports decreases in potassium, magnesium, calcium, iron, copper and zinc (of 20-77%) and increases sodium and phosphorous content (Nutr Health. 2003. 17. 85-115).
A study which compared the mineral content of 20 fruits and 20 vegetables grown in the UK in the 1930s versus the 1980s, using the Government Composition of Food Tables, showed significant reductions in calcium, copper, magnesium, and sodium in vegetables, and significant reductions in copper, iron, magnesium, and potassium in fruit. Data is reported for 7 minerals in this paper, and the only mineral that showed no significant differences over the time period was phosphorous. For reasons not apparent, the abstract of the paper in the second sentence states that zinc is the eighth mineral usually measured for Composition of Food Tables, but no data at all is provided on zinc in the paper itself. Also for reasons not apparent, the abstract in the third sentence refers to foods grown in the 1930s and 1980s, but the methods section indicates that the Composition of Food Tables used for this paper were the 1960 version and the 1991 version (Mayer AM. Historical changes in the mineral content of fruits and vegetables. Br Food Journal. 1997. 99. 207-211).
Possible explanations for lower density of micronutrients in food.
Deforestation and overgrazing of land by cattle has led to loss of soil as dust, so that soil depth is often much less than a century ago.
Lack of crop rotation depletes the soil of valuable nutrients.
Selection of plant strains with higher yield per acre through sophisticated plant breeding, which may sacrifice nutritional content.
Most chemical fertilizers replace only the 3 minerals essential to increase crop yield (nitrogen, potassium, and phosphorus), not all 16 nutrients which plants need to be healthy. This changes the ecology of the soil (PLoS One. 29019. 14. e0217018).
The microbiome of the root system is altered - the fungi which have a symbiotic relationship with plant roots with regard to exchange of sugars and minerals are reduced by high levels of phosphate and nitrogen in the soil as well as acidification of the soil.
In addition there may be an increase in toxic metals in the soil in association with use of chemical fertilizers.
Modern agriculture uses heavy farm equipment, which might change the ecology of the soil.
Large tractors cause severe compaction of the soil
Subsequent plowing may break down the surface characteristics of the soil, leaving it susceptible to erosion.
Foods are picked before they are ripe, so they do not acquire their full complement of vitamins and minerals.
Transportation and storage of foods allows time for loss of some nutrients.
Better analytic methods which allow for a more accurate measurement now than 50 years ago – this explanation is discounted by the researchers who publish the actual Tables.
Many types of food processing and cooking damage or remove nutrients.
Additives may interfere with absorption of nutrients.
Refining of flour depletes vitamins and minerals – estimates of the loss of minerals are as follows:
Calcium 60%
Chromium 40%
Copper 68%
Iron 76%
Magnesium 85%
Manganese 86%
Potassium 77%
Selenium 16%
Zinc 78%
Vitamin B1/Thiamine 77%
Vitamin B2/Riboflavin 80%
Vitamin B3/Niacin 81%
Vitamin B9/Pantothenate 50%
Vitamin B6 72%
Vitamin B9/Folic acid 67%
Vitamin E 86%
Betaine 23%
Choline 30%
Refining of sugar depletes minerals – estimates of the loss of minerals are as follows:
Chromium 80%
Copper 43%
Magnesium 99%
Manganese 93%
Molybdenum 100%
Zinc 60%
Increased requirements resulting from disease, medications, stress, environmental factors (i.e. toxins), and biochemical individuality (absorption defects, transport defects, renal wasting, enzyme defects).
Poor digestive function results in an inability to strip nutrients from food complexes.
Common genomic variations result in substantial differences amongst individuals in actual nutrient needs.
Beta-carotene absorption varied more than 40-fold among “healthy” people. (Am J Clin Nutr. 1991. 53. 1443-1439).
Hereditary isolated absorption defects have been described for the following nutrients:
Folic acid (J Pediatr. 1973. 82. 450)
Biotin (N Engl J Med. 1983. 308. 639)
Zinc (Nutr Rev. 1975. 33. 327)
Magnesium (Lancet. 1983. 1. 701)
Genetic polymorphisms of the vitamin D receptor have been identified – higher doses of vitamin D can overcome this interference with receptor binding.
Those with the AA allele of manganese superoxide dismutase show reduced activity of this antioxidant enzyme
In the Physicians’ Health Study, men with the AA variant who had high plasma antioxidant levels had a 10-fold lower risk of prostate cancer than those men with low plasma antioxidant levels (Cancer Res. 2005. 65. 2498-2504).
In the Western New York Breast Cancer Study, those women with the AA variant with lower fruit and vegetable intake had a 4-fold increased risk of breast cancer compared with women with a higher intake of fruits and vegetables (Cancer Res. 1999. 59. 602-606).
Defectively formed, under-active enzymes can be induced by high concentrations of nutrient co-factors.
Health problems associated with defectively formed enzymes can sometimes be overcome with high doses of substrate to drive the chemical reaction.
Direct pharmacologic activity is expressed by some nutrients at high doses.
Vitamin C: antiviral, antibacterial, antihistamine
Vitamin B12: nonenzymatic degradation of sulfites
Mg: increases solubility of calcium oxalate
Enzyme induction
Pyridoxine 100 mg/day induces erythrocyte aspartate aminotransferase (increase coincides with improvement in carpal tunnel syndrome) [Proc Natl Acad Sci. 1982. 79. 7494-8].
Riboflavin 5 mg/day induces erythrocyte glutathione reductase (J Clin Invest. 1969. 48. 1957-1966).
Thiamine 200 mg/day incudes transketolase in patients with liver disease (Scand J Gastroenterol. 1978. 13. 133-8).
Vitamins and Minerals – general principles
The body generally does not use vitamins as they occur in food; they must be transformed into biologically active forms (i.e. thiamin to thiamin pyrophosphate, riboflavin to flavinmononucleotide [FMN], niacin to nicotinamide adenine dinucleotide [NADH], pantothenic acid to Coenzyme A, pyridoxine to pyridoxal 5’ phosphate, cobalamin to methylcobolamin, folate to 5-methyl-tetrahydropteroylglutamate).
There can be tissue-specific deficiencies whereby the blood level of a given nutrient is normal, but tissue levels are low. Examples include low tissue folate levels in gingivitis and cervical dysplasia, low tissue magnesium levels in heart disease.
A large body of research has documented the association between low levels of specific nutrients and a wide range of specific diseases (i.e. asthma and low antioxidant levels)
A challenge test is a more sensitive indicator of vitamin insufficiency than a serum level. The challenge test may be an empiric trial of a supplement or may be in the form of a magnesium load test in which urine excretion is measure or a methionine load test in which homocysteine is measured.
Vitamins and Minerals - controversies
Form - tablet versus capsule versus liquid versus gummies
Benefits of tablets – most stable formulation and thus maintain potency for a longer period of time
Drawbacks of tablets - if the ingredients of tablets are packed under too much pressure, they will not be absorbed; tablets more likely to contain flowing agents such as magnesium stearate, which allow tableting machines to run faster, but might interfere with absorption.
Benefits of capsules (gel caps) – the outer layer of gelatin is easily digestible, and thus the ingredients are highly bioavailable.
Drawbacks of capsules (gel caps) – contain fewer nutrients than liquids or powders, some gelatins are not vegetarian
Benefits of powders and liquids – easier to swallow, more immediately bioavailable, may contain higher amounts of nutrients per dosage
Drawbacks of powders and liquids – taste may be unpalatable, may contain artificial sweeteners (natural sugar alcohols such as xylitol or sorbitol are considered best), may contain chemical preservatives to prolong shelf life, may oxidize rapidly
Benefits of gummies – they taste good and are easy to digest
Drawbacks of gummies – quantity of various vitamin and mineral ingredients is usually much less than in other formulations; quantity of active ingredients tends to vary significantly from batch to batch and often the quantity in the gummy is different from the quantity specified on the labels (because, as per personal correspondence with Scott Berliner, RPh, “all gummies are made in molds using heat so there are changes from the heat and from the base itself“); usually contain sugar or artificial sweeteners (xylitol or natural berry flavoring is considered the best, if one chooses to consume gummies)
Additives - silicon dioxide, titanium dioxide, and magnesium citrate are considered preferable to magnesium stearate and dicalcium phosphate (Natural Solutions. March 2009. 56-60).
Natural versus synthetic – the research is limited
Synthetic nutrients are usually less expensive than natural (whole food) supplements, may be more easily absorbed, especially in those with digestive problems (i.e. B12), can be provided in activated form, and are often available in higher doses.
However synthetic nutrients may be a different chemical from the natural form, may have a different optical form than the natural form, and may have contaminants introduced as part of the manufacturing process.
The rationale for whole food supplements is that vitamins occur in nature in complexes which include enzymes, coenzymes, antioxidants, trace elements, and other unknown factors that allow the vitamin to be transformed into its biologically active form – whole food supplements preserve this complex natural relationship whereas synthetic vitamins provide only the vitamin (i.e. organic substance) in isolation.
If the individual taking the synthetic vitamin does not have an adequate supply of all of the other elements complexed with the vitamin in its natural form, then the individual may not be able to effectively utilize the synthetic vitamin.
There are poorly documented reports that synthetic vitamin C does not cure scurvy and that synthetic thiamine does not cure beri-beri.
There are anecdotes of individuals who experience a ‘rush’ when they take synthetic vitamins.
By regulation, vitamins can be labeled natural if they are 10% natural. Natural vitamins, like synthetic vitamins, are isolated organic substances rather than the whole complex which occurs in nature.
Excipients
Inert substances which act as binders, fillers, and coatings in vitamins. Excipients are used as flow agents, for uniform consistency, to facilitate disintegration, stabilize, and/or provide volume.
Examples of excipients include cellulose starch, corn starch, dicalcium phosphate, magnesium stearate, maltodextrin, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polysorbate 80, polyvinylpyrrolidone, propylparaben, silicon dioxide, sodium acetate, sodium benzoate, sorbitol, stearic acid, and talc.
Magnesium stearate, a flowing agent, might impair immune system function.
Propylparaben might irritate the GI tract and might cause CNS depression
Capsules generally have fewer excipients than tablets, but many capsules are made of gelatin, which is a beef byproduct.
May be best to avoid excipients derived from dairy, wheat, corn, and yeast, because these can be allergenic.
Excipients can alter the absorption of the active ingredients. Tablets using poor quality excipients can be compressed so tightly that they can pass through the GI tract undigested.
Multivitamins
According to NHANES III, from 1988-1994, at least 30% of the U.S. population takes multivitamin supplements regularly (Arch Fam Med. 2000. 9. 258-262).
From 2003-2006, it is estimated that 39% of the U.S. population takes multivitamin supplements regularly (NCHS Data Brief. 2011. 1-8). Spending is estimated at $1.5 billion a year.
NHANES data between 1999-2012 (n=37,958 adults, 74% response rate) shows that use of a multivitamin within the preceding 30 days decreased from 37% in 1999-2000 to 31% 2011-2012 (p for the trend <0.001) [JAMA. 2016. 316. 1464-1474].
According to NHANES 1999-2000, 35% of U.S. adults reported using multivitamins (Am J Epidemiol. 2004. 160. 339-349).
Data from 2003-2006 indicate that 39% of U.S. adults reported using multivitamins (NCHS Data Brief. 2011. 61. 1-8).
The USPSTF in 2003 concluded that there is no definitive proof that taking a multivitamin daily is helpful to a healthy adult.
In a 2013 update, USPSTF “found no evidence of an effect of nutritional doses of vitamins or minerals on CVD, cancer, or mortality in healthy individuals… In most cases, data are insufficient to draw any conclusion…” The authors identified 3 RCTs of multivitamins and 24 RCTs of single or paired vitamins. In the abstract, the authors’ state “High quality studies (k = 24, n = 324 653) of single and paired nutrients … were scant and heterogeneous…” They state further in the concluding paragraph of the paper, “We identified 2 multivitamin trials (n = 27 658) that both found lower overall cancer incidence in men. Both trials were methodologically sound, but the lack of an effect for women (albeit in 1 trial), the borderline significance in men in both trials, and the lack of effect on CVD in either study makes it difficult to conclude that multivitamin supplementation is beneficial” (Ann Intern Med. 2013. 159. 824-834). In a separate article, “The USPSTF concludes that current evidence is insufficient to assess the benefits and harms of single- or paired-nutrient supplements (except beta-carotene and vitamin E) for the prevention of cardiovascular disease or cancer (I statement). The USPSTF recommends against beta-carotene and vitamin E supplements for for the prevention of cardiovascular disease and cancer (D statement) [Ann Intern Med. 2014. 160. 558-564].
In a 2022 update, USPSTF conclusion was similar to those in past USPSTF reports (JAMA. 2022. 327. 2326-2333)
This conclusion was based on review of 9 RCTs, 3 of which were large, good-quality trials that examined specifically death, cardiovascular disease, and cancer.
For a critique by Alan Gaby, MD of the negative trials, scroll down to the section just below entitled “Alan Gaby, MD critique of negative trials which form the basis of the USFSTF 2022 guidelines“
Some experts suggest a multivitamin daily for all adults.
"We recommend that all adults take one multivitamin daily" (Fletcher RH and Fairfield KM. Vitamins for Chronic Disease Prevention in Adults: Clinical Applications. JAMA. 2002. 287. 3127-3129).
"At about a nickel a day, a multivitamin is a cheap and genuine ‘life insurance' policy. It won't make up for the sins of an unhealthy diet, but it can fill in the nutritional holes that can plague even the most conscientious eaters" (Willett, Walter. Eat, Drink, and Be Healthy. 2001. 24-25).
The Lewin Group concluded in 2003 based on a systematic review of the literature on health effects of multivitamin use among adults over age 65 and an analysis of Medicare claims data that daily multivitamin use by seniors could result in $1.6 billion savings to Medicare in the next 5 years, based on improved immune system functioning and also a reduction in the relative risk for coronary artery disease. The cost of the vitamins would be $2.3 billion, with an estimated reduction of $3.9 in Medicare claims over 5 years.
Theoretical rationale - a study of mineral content of fruits, vegetables, meat and dairy from 1940-1991 reports decreases in potassium, magnesium, calcium, iron, copper and zinc, and increases sodium and phosphorous content (Nutr Health. 2003. 17. 85-115).
Epidemiologic data is supportive of benefits of consumption of a daily multivitamin
Multivitamin use in the Nurses’ Health Study (N=88,756) associated with a reduced risk of colon cancer at 18 years of follow up (Giovannucci et al. Ann Intern Med. 1998)
Multivitamin supplementation for one year associated with a 21% reduced risk of heart attack in men and a 34% reduced risk of heart attack in women, in the SHEEP trial (J Nutr. 2003. 133. 2650-2654).
The clinical trial data is mixed: The USPSTF (United States Preventive Services Task Force) in 2022, based upon a review of 84 studies “concludes that the evidence is insufficient to determine the balance of benefits versus harms of supplementation with multivitamins for the prevention of cardiovascular disease or cancer” (JAMA. 2022. 327. 2326-2333 and editorial 2294-2295).
A one year RCT of 96 healthy people over age 65 showed a 50% reduction in infection related illness from a mean of 48 days per year to a mean of 23 days per year (p = 0.002), improvements in several laboratory measures of immune system function, and correction of measurable but subclinical nutritional deficiencies in the treatment group (Lancet. 1992. 340. 1124-1127).
In a one year RCT of 130 community-dwelling adults over age 45, there was a statistically significant reduction in self-reported infectious illness from 73% in the placebo arm to 43% in the treatment arm, which consisted of a multivitamin and mineral supplement daily (p<0.001). Infection-related absenteeism was 57% in the placebo group compared with 21% in the treatment group (p <0.001). In subgroup analyses, those under age 65 had benefits similar in magnitude to those over age 65, but the subgroup of diabetics had far greater benefit than the subgroup of nondiabetics (Ann Intern Med. 2003. 138. 365-371).
An 8 month RCT in 60 children found an average rise of 10 points in non-verbal IQ in those taking the supplement, with no change in the IQ of the control children (Lancet. 1988. 1. 140-143). A 3 month RCT in 615 children found an average rise of 4.5 points in those taking the supplement (Person Individ Diff. 1991. 12. 351-352). According to Patrick Holford, Ph.D., author of Optimum Nutrition for the Mind, 15 other trials have found similar results. Benefit is seen only in those who are sub optimally nourished at baseline, and in most trials is more dramatic in women. One trial found that the basis of the increase in non-verbal IQ was that children on the supplement were able to work faster and answer more questions on the test in the allotted time (Person Individ Diff. 1997. 22. 131-134).
A placebo controlled study in prison inmates found that those given vitamins, minerals, and essential fats demonstrated a 35% decrease in aggressive acts (Brit J Psychiatry. 2002. 181. 22-28).
A 28 component multi was ineffective in the TACT trial of 1708 participants (see negative trials just below), but in prespecified subgroup analysis of the 27% of participants who were not taking a statin at baseline, the incidence of the primary endpoint was 22.76% in the statin group versus 36.44% in the placebo group (p=0.002) [Am H Journal. 2018. 195. 70-77].
HOWEVER, there are also negative trials
In a 441 day RCT in 652 noninstitutionalized individuals over age 60, severity of infections was not influenced by multivitamin-multimineral preparations (JAMA. 2002. 288. 715-721).
SU.VI.MAX study - RCT of 13,017 French men and women, with a median follow up of 7.5 years. The ingredients in the supplement were beta carotene, vitamins C and E, selenium and zinc. The incidence of cancer and all-cause mortality was non-significantly lower in the supplement group; incidence ischemic heart disease was the same in both groups. Of note, when the data for men and women were analyzed separately, while the differences in women between treatment group and placebo group were not significant, in men the incidence of cancer was significantly lower by 31% and all-cause mortality was significantly lower by 37% (Arch Intern Med. 2004. 164. 2335-2342). See critique of this study by Alan Gaby, MD, just below.
A RCT in 748 nursing home residents found no differences in infection rate between the groups. A post-hoc analysis though did show a lower infection rate in the subgroup without dementia, and univariate analysis did show fewer antibiotic days in the treatment group (J Am Geriatr Soc. 2007. 55. 35-42).
A RCT of 1708 patients (one arm of the TACT trial of chelation therapy) showed that at a mean follow up of 55 months, “High-dose multivitamins and multi-minerals did not statistically significantly reduce cardiovascular events in patients after MI who received standard medications (Ann Intern Med. 2013. 159. 797-804). A possible explanation of the negative results is a combination of a high non-adherence rate (46%) in the treatment arm, combined with 42-45% of the subjects in the control arm were taking “ordinary dose” multivitamins (Guilliams TG. IMCJ. 2014. 13[1]. 18-20). HOWEVER, positive results in pre-specified subgroup analysis of the 27% of participants who were not taking a statin at baseline (see details just above).
Physicians’ Heath Study II - RCT of 14,641 male physicians treated with a multi-vitamin (Centrum Silver) or placebo for a mean of 11.2 years. Total mortality was non-significantly lower in the treatment group and the incidence of cardiovascular events was non-significantly higher (JAMA. 2012. 308. 1751-1760). Note a sub-study of 5947 male physicians over age 65 showed that at an average duration of follow up of 8.5 years, there was no difference in the mean cognitive change between the treatment and placebo groups (Ann Intern Med. 2013. 159. 806-814).
See critique of this study by Alan Gaby, MD, just below.
A potential explanation for the negative results of the sub-study include that cognitive function was assessed via telephone interview, the first cognitive assessment was conducted on average 2.5 years after randomization to the multivitamin, and that control subjects might have been taking supplements with a beneficial effect on cognitive function, unknown to the researchers (Guilliams TG. IMCJ. 2014. 13[1]. 18-20).
COSMOS - RCT of 21,442 US adults treated with a multi-vitamin (Centrum Silver) or placebo for a mean of 3.6 years. The incidence of cancer, schemic heart disease and all-cause mortality were non-significantly lower in the supplement group (Am J Clin Nutr. 2022. 115. 1501-1510).
Alan Gaby, MD critique of negative trials which form the basis of the USFSTF 2022 guidelines (Townsend Letter. August/September 2022. 86-87)
SU.VI.MAX study (Arch Intern Med. 2004. 164. 2335-2342). Negative results might have been due to the supplement containing a modest daily dose of zinc (20 mg/day) but not containing copper.
Physicians’ Heath Study II (JAMA. 2012. 308. 1751-1760). Centrum Silver was the multivitamin used in this study, and for approximately 70% of the 11 year study, copper in Centrum Silver was in the form of cupric oxide, which is poorly absorbed in humans. Thus, one possible explanation for the negative results is that the 20 mg of zinc per day in the supplement induced copper insufficiency. In addition, several aluminum-based coloring agents are present in Centrum Silver, and these chemicals have the potential to adversely affect outcomes.
COSMOS study (Am J Clin Nutr. 2022. 115. 1501-1510). Negative results might have been a function of the wide range of potentially toxic chemicals in Centrum Silver.
A systematic review and meta-analysis of 8 RCTs concluded that the evidence that a routine multivitamin plus multimineral in the elderly reduces infections is inconclusive (BMJ. 2005. 330. 871-874).
Prospective observational data gathered for a median of 8 years in 161,808 participants in the Women’s Health Initiative clinical trials (n=68,132) an observational study (n=93,676) did NOT show a lower risk of cancer or cardiovascular disease in those taking a daily multivitamin. Total mortality was the same in those taking multivitamins (41.5% of the participants) and those not taking multivitamins (Arch Intern Med. 2009. 169. 294-304).
Prospective observational data in 38,772 older women in the Iowa Women’s Health Study showed that use of multivitamins was associated with a 2.4% absolute increase in adjusted mortality rate. In this same study, supplemental use of folate, vitamin B6, copper, iron, magnesium, and zinc were also associated with an increase in adjusted mortality. The association of iron with total mortality was strong (RR 1.10) and dose-dependent. However, after adjustment for multiplicity, only multivitamins and copper retained the significant association with all cause mortality. Calcium and vitamin D supplementation were associated with a lower total mortality, before and after adjustment for multiplicity (RR 1.06, 95% CI 1.02-1.10). A potential limitation of this study is confounding by indication [i.e. those sicker at baseline in ways not addressed in the study, such as with asthma or migraines self-selected to take vitamins] (Arch Intern Med. 2011. 171. 1625-1633). Dr Alan Gaby, author of Nutritional Medicine is critical of this report, stating in an interview published on line on PR Web, “The authors of the study have reached an incorrect conclusion, based on the data that were collected. They did not report the actual death rates, only the statistically-adjusted death rates of supplement users compared to non-users. The problem is, for every category in which they made this adjustment—caloric intake, cigarette smoking, body mass index, blood pressure, diabetes, physical activity, and intake of fruits and vegetables—the supplement users were in the healthier category. Because they were healthier, they were probably less likely to die. So the researchers must have adjusted the supplement users' death rates upward, which may have skewed the results by over-adjusting their data. When the data were adjusted only for age and caloric intake, there was no statistically significant difference in death rate between the two groups. Unfortunately, the media picked up on this story without understanding the potential problems in the study’s statistical methods."
Data in 14,641 male US physicians initially aged 50 years or older who participated in the Physicians' Health Study II showed that those randomized to a multivitamin (Centrum Silver) daily had an 8% lower incidence of total cancer (HR 0.92, p=0.04) at a mean follow up of 11.2 years. The multivitamin however did not reduce mortality from all cancers, or total mortality. Furthermore, there was no evidence of an association between adherence and a protective effect (JAMA. 2012. 308. 1871-1880 and editorial 1916-1917). In a separate published report, “taking a multivitamin did not reduce major cardiovascular events, MI, stroke, [or] CVD mortality…” (JAMA. 2012. 308. 1751-1760 and editorial 1802-1803).
A meta-analysis of 21 RCTs (primary and secondary prevention, n=91,074, mean age, 62, mean duration of supplementation, 43 months) showed a non-significant 2% decrease in all-cause mortality in all trials, and a trend toward a significant reduction in all-cause mortality in the primary prevention trials (RR=0.94, 95% CI 0.89-1.00) [Am J Clin Nutr. 2013. 97. 437-444].
Choosing a multivitamin with mineral (if you choose to take one)
Read the label and be aware that many multivitamin with mineral products also contain extracts of foods such as soy and herbs such as ginkgo or ginseng.
Be aware that the information on many multivitamin labels with regard to the percentage of daily value in the product may be based on outdated standards (Consumer Reports on Health. 10/04).
Choose a product with a maximum of 3000 IU/day (900 mcg RAE/day) of vitamin A for men, a maximum of 2100 IU/day (700 mcg RAE/day) for women. Additional vitamin A (in a multivitamin) in the form of beta carotene is acceptable, as long as the beta carotene dose does not exceed 5000 IU/day (3 mg/day)
Choose a product with either mixed tocopherols (vitamin E) or no more than 60 IU per day of vitamin E in the form of alpha tocopherol. NOTE
1 IU vitamin E = 0.67 mg for d-alpha-tocopherol (natural), , and effective in 2020, 1 mg vitamin E (as alpha-tocopherol) label claim = 1 mg of natural α-tocopherol
1 IU vitamin E = 0.9 mg for dl-alpha-tocopherol (synthetic), and effective in 2020, 1 mg vitamin E (as alpha-tocopherol) label claim = 2 mg of synthetic α-tocopherol
Choose a product with little or no iron unless you are a menstruating woman. Excess iron may increase the risk of hemochromatosis, cancer and heart disease.
Look for labels marked “USP” or preferably “USP-Verified.”
Vitamin A
Refers to a family of fat soluble compounds called retinoids. Preformed Vitamin A is found only in animal products, but approximately 50 of more than 600 carotenoids can be converted into Vitamin A.
Discovered in 1913.
Important for bone development, cellular differentiation, epithelial tissue maintenance, night vision and proper functioning of the immune system.
Classic toxicity does not occur acutely unless the dose exceeds 50,000 IU per day.
Units of measure and regulatory change
In May 2016, the U.S. Food and Drug Administration (FDA) announced regulations that require amendments to the existing supplement facts label, which uses units and conversions based on the 1968 Recommended Daily Allowances (RDA). The new regulations became mandatory in 2019-2020.
For vitamin A,
Historic conversion: 1 IU = 0.3 mcg retinol
2020 conversion: 1 mcg RAE = 1 mcg retinol
There is emerging data on dangers of excess Vitamin A
The National Academy of Sciences in 2001 reduced the RDA by about 10% to 900 mcg RAE / 3000 IU for men and 700 mcg RAE / 2100 IU for women.
The upper limit for safe consumption was set in 2001 at 3000 mcg RAE / 10,000 IU for adults, 1680 mcg RAE / 5600 IU daily for children ages 9-13, 900 mcg RAE / 3000 IU for children ages 4-8, and 600 mcg RAE / 2000 IU for children under the age of 3.
It is especially important for women in the first trimester of pregnancy to not exceed 10,000 IU per day, secondary to an increased risk of birth defects associated with high dosages of vitamin A.
A Cochrane Review of “Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases” found that vitamin A supplements increased total mortality rate by 16% (Cochrane Database Syst Rev. 2008 Apr 16;(2):CD007176).
16 prominent nutrition experts, including Walter Willett, MD, DrPH wrote an editorial warning about the dangers of consumption of high doses of vitamin A, including a warning about consumption of cod liver oil (Cannell JJ et al. Cod Liver Oil, Vitamin A Toxicity, Frequent Respiratory Infections, and the Vitamin D Deficiency Epidemic. Annals of Otology, Rhinology & Laryngology 2008; 117(11):864-870).
Excess dietary intake of Vitamin A is associated with decreased bone mineral density and an increased risk of hip fractures in some but not all studies. The presumed mechanism is that high intake of vitamin A antagonizes vitamin D - these vitamins likely compete for absorption, and there is evidence that vitamin A inhibits vitamin D activated gene expression. For abstracts of specific scientific publications on vitamin A supplementation and bone density/fracture risk, navigate to the Osteoporosis page of this web site.
NHANES III showed that low serum retinol levels were rare in children and adults, but suboptimal levels were an issue in African American and Mexican American children (Am J Clin Nutr. 1994. 60. 176-182), so one must conclude that the therapeutic window for vitamin A is low.
According to 1996 USDA data, 56.2% of Americans obtain less than the RDA of vitamin A from their diet. According to the Weston Price Foundation, traditional diets contained ten times more vitamin A than the typical modern diet.
Uses
May be useful in the treatment of acne and psoriasis.
Infections - high doses (50,000 – 100,000 IU per day for one or two days) are sometimes used to treat infections in non-pregnant women.
Rationale is (1) most infections provoke an acute phase response that reduces synthesis of retinol-binding protein in the liver, thus decreasing circulating vitamin A levels, (2) vitamin A excretion increases during infections, especially those associated with fever and (3) vitamin A has been shown to inactivate a number of viruses in vitro.
In a RCT of 93 children with chicken pox, a single dose of 200,000 IU of vitamin A, crusting of the lesions occurred in mean of 5.34 days versus 6.37 days in the placebo group (p < 0.01) and there were zero complications in the placebo group versus 5 complications in the treatment group (J Pediatr. 1994. 125. 1017-1018).
Beta carotene - see Dietary Supplements outline on this website
B complex vitamins
Important in energy metabolism, hematopoiesis, and other metabolic actions, including neurotransmitter synthesis.
Need is increased by stress, drug or alcohol use, smoking, chronic illness, high sugar intake.
Thiamine (Vitamin B1)
Discovered in 1910.
100 mg daily may be useful in treatment of alcoholism, ataxia, confusion, dementia, depression, fatigue, functional dysautonomia (autonomic nervous system imbalance), memory loss, neuropathy, and pain.
Parkinson's disease - 100 mg intramuscular twice a week for 3 months to 2.3 years associated with significant improvement in both motor and nonmotor symptoms in an open label trial of 50 patients (J Altern Complement Med. 2015. 21. 740-747).
Often deficient in those with alcohol abuse - give 100 mg a day.
The herb horsetail may deplete thiamine.
Drugs which may deplete thiamine include antibiotics, diuretics, and oral contraceptives.
May be deficient if diet is high in fats and sugars.
Thiamine is destroyed by sulfites, a common food additive, and also by excessive cooking.
Some Candida organisms synthesize thiaminase, which can destroy thiamine in the gut and thus lead to thiamine deficiency.
Blueberries, Brussels sprouts, red beet root and tea antagonize thiamine.
RDA is 1.1 - 1.4 mg for adults based on sex and pregnancy/lactation status of females.
According to 1996 USDA data, 30.2% of Americans obtain less than the RDA of vitamin B1 from their diet.
No evidence of toxicity from oral use.
Riboflavin (Vitamin B2)
Discovered in 1920.
May help in prevention of migraines (see above in this outline).
May be useful in treatment of acne, alcoholism, angular stomatitis, arthritis, athlete’s foot, baldness, cataracts, cheilosis, depression, diabetes, diarrhea, hysteria, indigestion, light sensitivity, neuropathy, seborrheic dermatitis, and stress.
Inactivated by light, both visible and ultraviolet.
May be chelated by caffeine, copper, saccharin, theophylline, tryptophan, vitamin B3, vitamin C, and zinc.
The herb psyllium may deplete riboflavin.
Drugs which may deplete riboflavin include anticholinergics, Phenobarbital, and tricyclic antidepressants.
This vitamin causes the urine to turn bright yellow.
RDA is 1.1-1.6 mg for adults based on sex and pregnancy/lactation status of females.
According to 1996 USDA data, 30.0% of Americans obtain less than the RDA of vitamin B2 from their diet.
No evidence of toxicity from oral use.
Niacin (Vitamin B3)
Discovered in 1936.
In the US, flour, rice, and grains have been fortified with vitamin B3 since the 1940s, to prevent deficiency disease (pellagra).
Not truly a vitamin since small amounts are synthesized in the body from tryptophan, with iron, riboflavin, and pyridoxine as co-factors.
Approximately 60 mg of tryptophan is required to synthesize 1 mg of niacin (i.e. 1.5% conversion rate) – some have hypothesized that humans from an evolutionary perspective are slowly losing the ability to synthesize niacin.
Exists in 2 forms – nicotinic acid (also known as niacin) and niacinamide (also known as nicotinamide).
Nicotinic acid: (niacin):
Lowers cholesterol, raises HDL, but raises homocysteine (J Clin Lipidol. 2018. 12. 810-821), and in those at high risk of cardiovascular disease and on high dose statins, addition of high dose niacin is NOT associated with improved cardiovascular outcomes in those at high risk of CAD (N Engl J Med. 2011. 365. 2255-2267; N Engl J Med. 2014. 371. 203-212).
Therapeutic dose for lowering cholesterol is 3-6 grams/day.
May be useful in treatment of migraines - start with a dose of 500 mg, increase to the dose which produces a full body flush. Observational data indicates that in those with migraines who benefit from niacin, a full body flush is a necessary prerequisite to pain relief.
May be useful in anorexia nervosa, dyspepsia, nicotine addiction, Meniere's, Raynaud’s, and schizophrenia
Contraindicated in gout and peptic ulcer disease.
Used to be considered contraindicated in diabetes, but recent data shows that if the diabetes is controlled, effect of even high dose niacin on blood sugar values is minimal.
Associated with an increased risk of high blood pressure at supplemental doses as low as 14.3 mg (many multivitamins contain a higher dose), based on data i12,243 participants in the China Health and Nutrition Survey (Zhang Z et al. JAMA Netw Open. 2021. 4. e2031669).
Immediate release niacin produces a niacin flush, sometimes with as little as 25 mg, due to dilation of blood vessels in the skin. This is a wave of heat and redness that starts about 10 minutes after taking the pill and spreads down from the head to the feet, affecting the whole body.
Long-acting preparations cause less flushing but are more likely to cause liver toxicity at doses greater than 2-3 grams/day. Advisable to monitor liver enzymes if high doses are consumed.
Lecithin 1200 mg twice a day may decrease the risk of elevated liver enzymes associated in some people with consumption of high doses of niacin.
Inositol hexaniacinate, a derivative of nicotinic acid, 500 mg three times a day may be effective for cholesterol lowering, but without the side effect of flushing. However the is currently no human data to prove a lipid lowering effect.
Niacinamide (nicotinamide):
The form of niacin customarily included in vitamin supplements.
Converted to NAD, which is important in the electron transport chain (cellular energy production).
Does not produce same side effects as niacin.
Usual dose is 500 mg twice a day - beware doses above 3000 mg per day might cause liver damage
Possible side effect of nausea - if so, decrease the dose
Uses
Acne - niacinamide 4% topical cream from a compounding pharmacist, twice a day as beneficial as clindamycin 1% in two RCTs (Int J Dermatol. 1995. 34. 434-437; Int J Dermatol. 2013. 52. 999-1004).
Anxiety - frequent anecdotes of benefit at 500-1000 mg three times a day; studies in mice have found that niacinamide has benzodiazepine-like actions.
Glaucoma - 2.5 grams daily may be beneficial, based on mechanistic data and mouse data, but there is no human data (N Engl J Med. 2017. 376. 2079-2081).
Osteoarthritis - frequent anecdotes of benefit at 500-1000 mg three times a day; beneficial in a pilot double-blind trial, at a dose of 500 mg 6 times a day (Inflamm Res. 1996. 45. 330-334).
Schizophrenia - Abram Hoffer, MD treated more than 5000 schizophrenics over 50 years and reported benefits with both niacin and niacinamide.
Skin cancer prevention - presumed mechanism of action is prevention of UV radiation-induced immunosuppression.
500 mg once or twice daily reduced the incidence of squamous and basal cell cancer in those with at least 4 actinic keratoses (J Invest Dermatol. 2012. 132. 1497-1500).
In the ONRAC trial, a 12 month RCT of 386 patients with a history of at least two non-melanoma skin cancers, the rate of new non-melanoma skin cancer diagnosis was 23% lower in the group receiving niacinamide 500 mg twice a day (N Engl J Med. 2015. 373. 1618-1626).
RDA is 14-18 mg in adults based on sex and pregnancy/lactation status.
According to 1996 USDA data, 26.0% of Americans obtain less than the RDA of vitamin B3 from their diet.
Drugs which may deplete niacin include antibiotics and oral contraceptives.
Pantothenic Acid (Vitamin B5)
Discovered in 1931.
500-1000 mg/day may be beneficial in the treatment of adrenal dysfunction, allergies, Alzheimer’s, environmental toxicity, fatigue, nausea from formaldehyde, Parkinson’s, recurrent infections, rheumatoid arthritis, and ulcerative colitis.
Important cofactor in the synthesis of the neurotransmitter acetylcholine.
Pantothine is the active form of this vitamin, and pantothine is available in supplement form.
No evidence of toxicity from oral use.
There is no RDA, but adequate intake is estimated at 5 mg in adults.
May be useful in treatment of hypercholesterolemia
Presumed mechanism is inhibition of HMG Co A reductase.
In an 8 week RCT of 32 patients, those who received pantethine 300 mg twice a day for 8 weeks, and then 300 mg three times a day for 8 weeks showed a mean decrease in LDL of 11%, as compared with 3% in the placebo group (p=0.01) [Vasc Health Risk Manag. 2014. 10. 89-100].
In a 16 week RCT in a North American population, those randomized to pantethine 200 mg three times a day showed a 6 mg/dl drop in total cholesterol, and a 4 mg/dl drop in LDL cholesterol, as compared with a placebo group which followed a therapeutic lifestyle diet (Nutrition Research. 2011. 31. 608-615).
Widely used in Japan; evaluated in 28 controlled clinical trials involving Asian patients at high risk for cardiac events.
Vitamin B6 (Gaby AR. The Doctor’s Guide to Vitamin B6. Rodale Press. 1984).
Discovered in 1934.
Often referred to as pyridoxine, but really a group of six related compounds, of which pyridoxine is the most biochemically stable.
The three primary forms are pyridoxine, pyridoxal, and pyridoxamine.
Pyridoxine is the most common form seen in supplements; PLP and PMP are the phosphorylated active coenzymes also available in some supplements.
Pyridoxamine 5’ phosphate (PMP) prevents the formation of AGEs
Conversion into an active form in the body requires zinc, ATP, and FMN
Involved in roughly 100 enzymatic reactions, including methylation.
Cigarette smoking is associated with vitamin B6 deficiency – maleic hydrazide is a pesticide commonly sprayed on tobacco plants, and small amounts of hydrazine are found naturally in tobacco plants.
Actual or suspected (environmental) vitamin B6 antagonists (these, if present, competitively inhibit vitamin B6 dependent enzymes, increasing the requirement for vitamin B6).
Hydrazine used in rocket fuel – individuals who live near military bases or launching pads, as well as individuals involved in the production of rocket fuel may have significant exposure to hydrazine.
Maleic hydrazide, an herbicide sprayed on onions, potatoes (present in potato chips), and tobacco.
Succinic acid 2,2-dimethylhydrazide, a chemical ripening agent.
Tartrazine, a coloring agent added to food and medications.
Polychlorinated biphenyls (PCBs) – further use banned in the US in 1976 based on cancer-causing effects, but residues persist in the environment.
Drugs which may deplete vitamin B6 include antibiotics, hydralazine, isoniazide, levodopa, oral contraceptives, penicillamine, phenobarbital, phenytoin, theophylline.
Food processing (refining of grains and sugar) depletes these food sources of vitamin B6; oxidized vegetable oils (oxidation is due to excessive heating of the oil, and this is especially an issue in commercial preparation of french fries) may deplete vitamin B6.
Tryptophan load test is frequently used to detect vitamin B6 deficiency.
Prevention of colorectal cancer – a meta-analysis of 9 prospective studies on vitamin B6 intake and 4 prospective studies on blood pyridoxal 5'- phosphate (PLP) levels showed that vitamin B6 intake and blood PLP levels were inversely associated with the risk of colorectal cancer. There was heterogeneity among the studies of vitamin B6 intake (onelarge cohort study contributed substantially to this heterogeneity, and thus was excluded from the analysis) but there was not heterogeneity among the studies of blood PLP levels. The risk of colorectal cancer decreased by 49% for every 100 pmol/ml increase in blood PLP levels (JAMA. 2010. 303. 1077-1083).
50-100 mg twice daily may be useful in the treatment of arthritis (inflammatory), asthma, attention deficit disorder, autism, bladder cancer (to prevent recurrence), carpal tunnel syndrome, depression (especially if associated with oral contraceptive use), eczema, kidney stones (calcium oxalate), morning sickness, PMS, osteoporosis, and tardive dyskinesia.
The data on Vitamin B6 and carpal tunnel syndrome is mixed. There are case reports of improvement in clinical signs and EMG with supplementation for 2-3 months (Am J ClinNutr. 1979. 32. 2040-2046), but some authorities feel that the benefits are actually derived from treatment of peripheral neuropathy instead of carpal tunnel syndrome (Arch PhysMed Rehabil. 1984. 65. 712-716), and there are two negative RCT's - one a 10 week trial in 15 patients using a treatment dose of 200 mg of Vitamin B6 (South Med J. 1989. 82. 841-842) and the other a 12 week trial in 32 patients using a treatment dose of 200 mg of Vitamin B6 (Can Fam Physician. 1993. 39. 2122-2127). Negative trials might have been due to a failure to administer supplemental magnesium with vitamin B6.
The data on Vitamin B6 as a treatment for PMS in women is mixed. A systematic review found that of 9 RCT's only one was of high methodologic quality and that study had too few subjects to achieve statistical power. Nonetheless, the results from these studies suggested that Vitamin B6 is more effective than placebo (BMJ. 1999. 318. 1375-1381).
Supplements decrease homocysteine levels, thus MAY decrease heart disease risk.
Doses of 500 mg/day for prolonged periods can result in sensory nerve damage, so as a precaution, best not to consume more than 200 mg per day.
Magnesium supplementation with vitamin B6 is advisable as per Alan Gaby, MD, and this may reduce the likelihood of vitamin B6 toxicity.
Zinc supplementation is advisable with long term vitamin B6 supplementation, as high dose vitamin B6 can occasionally trigger zinc deficiency.
Doses above 150 mg daily may suppress lactation.
RDA ranges from 1.2-1.7 mg in adults, based on age and sex.
According to 1996 USDA data, 53.6% of Americans obtain less than the RDA of vitamin B6 from their diet.
NHANES data - plasma pyridoxal 5'- phosphate (PLP) levels were measured in 7822 blood samples collected in 2003-2004. Vitamin B6 inadequacy was defined as a plasma PLP concentration less than 20 nmol/L. Eleven percent of supplement users and nearly a quarter of non-users demonstrated plasma PLP levels of less than 20 nmol/L. Nearly all users of oral contraceptive had PLP plasma levels of less than 20 nmol/L (Am J Clin Nutr. 2008. 87. 1446-1454).
Biotin (Vitamin B7)
Discovered in 1936.
Eight isomers exist, but only one is biologically active.
Biotin is widely available in foods, but its bioavailability is widely variable.
Raw egg whites can interfere with absorption of biotin. Lipoic acid might interfere with biotin-dependent enzymes.
Drugs which may deplete biotin include carbamazepine, phenytoin, Phenobarbital, and primidone.
5 mg daily may be beneficial in terms of hair, skin and nail health.
10 - 16 mg a day may be helpful in the treatment of diabetes.
100 mg three times a day reported as beneficial in several trials of progressive multiple sclerosis.
Biotin supplementation should be accompanied by carnitine supplementation, as per Robert Crayhon, M.S.
Important factor in development of healthy hair and nails.
No evidence of toxicity from oral use.
Beware of interactions of high doses with multiple laboratory assays (discontinue high dose supplements ( > 2 mg/day) at least 72 hours in advance of routine lab work)
False negative troponin values in patients experiencing a MI (Cardiovasc Res. 2019. 115. 1950-1951).
High doses can interfere with laboratory tests for TSH, testosterone, estrogen, progesterone, DHEA-S, PTH, LH, FSH, 25-OH vitamin D, vitamin B12, and PSA.
There is no RDA, but adequate intake is estimated at 30 mcg in adults.
Folate (Vitamin B9)
Discovered in 1941.
This is the name given to a naturally occurring family of compounds (8 forms) which share a common molecular architecture called pteroylglutamate.
Most folate in food exists in the form of polyglutamates which must be hydrolyzed to monoglutamates in order to be absorbed.
Thus folate in food is about half as bioavailable as folic acid in fortified foods and synthetic supplements.
HOWEVER, the folate in many supplements and fortified foods is pteroylmonoglutamate (PGA), an oxidized form that is rarely found in nature. At doses below 0.2-0.4 mg daily, all PGA is converted into biologically active forms of folate via absorption by intestinal activation and transport. At higher doses, a nonsaturable transport mechanism involving passive diffusion begins to allow unmetabolized synthetic PGA into the blood and the long term ramifications of this are unknown (BMJ. 2004. 328. 211-214).
Folate naturally present in food (as opposed to an additive, such as in grain) is in the activated (methylfolate) form, as per Joseph Pizzorno, ND
Unstable molecule that can be destroyed by heat or light. Ultraviolet light exposure to the skin has a destructive effect on folate.
Excess alcohol can cause depletion.
Medications which may deplete folate include antibiotics, carbamazepine, chemotherapy medications, cholestyramine, colestipol, corticosteroids, diuretics, H2 blockers, metformin, methotrexate, NSAIDs, oral contraceptives, phenytoin, potassium sparing diuretics, primidone, salicylic acid.
NOTE a high serum folate concentration in the absence of high doses of folic acid supplementation is a marker for small-intestinal bacterial overgrowth (SIBO), because some organisms that colonize the small intestine are capable of synthesizing folates (Gastroenterology. 1996. 110. 991-998.)
Metabolism of folate in the body – converted to folinic acid (also known as leucovorin or 5-formyltetrahydrofolate), which is then converted to 5-methyltetrahydrofolate, the active form.
Supplement forms of folate
Folic acid - this is a synthetic, oxidized monoglutamyl form of folate that is more stable and thus is the form of folate in many supplements and fortified foods. To be utilized by the human body, though, this form must be reduced to 5-MTHF via a multistep enzymatic conversion
Folinic acid – this form of supplement is used primarily in combination with certain anticancer drugs.
Methylfolate, also known as L-methylfolate, 5-MTHF, and 5-methyltetrahydrofolate) - became available as a dietary supplement in approximately 2005.
Somewhat more bioavailable than folic acid, as it raises plasma and erythrocyte folate levels to a greater extent than folic acid (Am J Clin Nutr. 2006. 84. 156-161); Br J Pharmacol. 2009. 158. 2014-2021).
Does not lower homocysteine more effectively than folic acid (Circulation. 2000. 101. 2829-2832; Am J Clin Nutr. 2003. 77. 658-662; Am J Clin Nutr. 2004. 79. 473-478).
Less stable molecule than folic acid, and this might be significant when methylfolate is incorporated into a multivitamin, as it may react with other active ingredients in the multivitamin.
Potential benefits of folate supplementation
Autism spectrum disorders prevention
Findings from a large case-control study, Childhood Autism Risks from Genetics and Environment (CHARGE) suggested that maternal folate status during the periconceptual period was associated with a reduced risk of autism spectrum disorders (Am J Clin Nutr. 2012. 96. 80-89).
In a study sample of 85,176 children in the population-based, prospective Norwegian Mother and Child Cohort Study (MoBa), “use of prenatal folic acid supplements around the time of conception was associated with a lower risk of autistic disorder,” with an odds ratio in children of folic acid users of 0.61 (0.41-0.90). Secondary analyses showed did not show an association between autism and (1) fish oil supplements before and during pregnancy and (2) folic acid use at 22 weeks’ gestation, thus suggesting that the association of prenatal folic acid use with a lower risk of autism is NOT due to unmeasured confounding in this observational study (JAMA. 2013. 309. 570-577 and editorial 611-613).
CAD – improves blood flow by increasing nitric oxide production in vascular epithelial cells.
Cervical dysplasia – role of folate 10 mg/day is unclear, with one placebo-controlled study in women taking oral contraceptives showing significant improvement in Pap smears initially showing mild-moderate dysplasia (Am J Clin Nutr. 1982. 35. 73-82), but another 6 month placebo-controlled study (published in Italian) in 154 individuals with grade 1 or 2 cervical intraepithelial dysplasia showing no benefit (Minerva Ginecol. 1996. 48. 397-400).
Cleft lip prevention – a retrospective case control analysis showed that folate fortification of 400 mcg or more per day in early pregnancy was associated with a 40% reduced risk of isolated cleft lip (BMJ. 2007. 334. 464).
Congenital heart defect prevention – the average prevalence of severe congenital heart defects at birth was 1.64 per 1000 births during the 9 years before mandatory food fortification with folate in Canada; the rate fell by 6.2% annually during the 7 years after mandatory food fortification (BMJ. 2009. 338. b1673).
Deafness - 0.8 mg/day slowed the decline in ability to hear frequencies associated with everyday speech (0.5 – 2 kHz) in a 3 year RCT in 728 older men and women in The Netherlands. Note that the entry criteria in this country which does not mandate folate supplementation of grains was a homocysteine level > 13 umol/L and a B12 level > 200 pmol/l, so it is uncertain whether the beneficial effect observed would apply to individuals with a higher baseline folate level (Ann Intern Med. 2007. 146. 1-9). An accompanying editorial raises the issue that the improvement seen might be a function of improved cognitive function rather than a direct effect of folate on the inner ear (Ann Intern Med. 2007. 146. 63-64).
Depression, as an adjunct to prescription antidepressants
15 mg methylfolate daily is beneficial, but 7.5 mg is not beneficial (Am J Psychiatry. 2012. 169. 1267-1274).
0.5 mg of folic acid is beneficial in women, but not in men (J Affect Disord. 2000. 60. 121-130).
Gingivitis - 5 mg per 5 ml of mouthwash may be useful in treatment of gingivitis, based on a study in which subjects rinsed twice a day for one minute for a total of 4 weeks (J Clin Periodontol. 1984. 11. 619-628).
Hyperhomocysteinemia - supplemental doses will decrease homocysteine levels.
Neural tube defect prevention in infants - 0.4 mg/day (OTC) proven useful in prevention (see very beginning of this outline).
NOTE higher doses of folate are advised in pregnant smokers based on the following data - 345 cigarette-smoking women who were less than 21 weeks of gestation were randomized to folate 0.8 mg/day versus 4 mg/day. The incidence of fetal growth restriction was significantly lower by 35% in those randomized to the lower dose of folate, and the incidence of small for gestational age was 31% lower, of borderline statistical significance (JAMA Pediatr. 2019. 212. 124-130).
Nitrate tolerance – beneficial in prevention of development of nitrate tolerance (see very beginning of this outline).
Stroke prevention – in a meta-analysis of 15 RCTs that examined the effect of folate supplementation on stroke risk, there was an overall 8% reduction in risk of stroke (p<0.04). In the 10 trials conducted in countries in which there was no or minimal folic acid supplementation of food, supplementation reduced the risk by 11% (p=0.01), whereas in the remaining 5 trials conducted in populations in which folic acid supplementation is widespread, supplementation had no significant effect on stroke risk. A daily dose of 0.4 – 0.8 mg folate appeared as protective as higher doses (Int J Clin Pract. 2012. 66. 544-551).
Potential risk of folic acid supplementation
Supplements can mask the anemia associated with Vitamin B12 deficiency (probably rare), may increase the risk of seizures in people with seizure disorders and might interfere with the action of prescription drugs like methotrexate, trimethoprim and sulfasalazine.
No evidence of toxicity from oral use, but hypersensitivity reactions (insomnia, irritability, GI problems) have been noted in some individuals on high doses, and high doses (15 mg/day) might interfere with effectiveness of phenytoin (Dilantin) and might interfere with absorption of zinc.
May predispose one to zinc deficiency.
May increase the risk of prostate cancer, based on secondary analysis of a RCT of aspirin and folic acid 1 mg daily for chemoprevention in those with colorectal adenomas (Urology. 2013. 82. 1197-1203).
RDA is 400 mcg for adults, 600 mcg for pregnant women.
Fortification of food with folic acid (i.e. grains) was initiated in the U.S. in 1996 and became mandatory in January, 1998.
Even with fortification of grain, and a subsequent increase in average folate consumption of 100 mcg/day, only 23-33% of women of reproductive age are consuming >400 mcg/day of dietary folate (Am J Public Health. 2006. 96. 2040-2047).
NHANES 2011 - 2016 data which examined rbc folate levels and defined folate insufficiency as < 748 nmol/L found that folate insufficiency was found in 18.6% of women (Am J Clin Nutr. 2019. 110. 1088-1097).
NOTE though that 20-30% of the population carries at least one copy of a SNP called MTHFR C-T and it appears that these individuals need more than the RDA of folate.
Cobalamin (Vitamin B12)
Discovered in 1948
This is a group of cobalt-containing compounds named cobolamins – the biologically active forms are (1) methylcobalamin and (2) 5-deoxyadenosylcobalamin, commonly known as adenosylcobalamin.
Deficiency seen in those on vegetarian diets, in some individuals over age 50, in individuals taking medication to reduce stomach acid (H2 blockers, PPIs), in individuals taking prescription metformin for diabetes, in individuals with Crohn’s disease affecting the terminal ileum, and in individuals status post gastric bypass surgery for obesity.
Inadequate intake is an issue for vegans, but even some vegans who do not take supplemental vitamin B12 might not become deficient because some vitamin B12 is synthesized by the “good” bacteria that reside in the gut.
According to 1996 USDA data, 17.2% of Americans obtain less than the RDA of vitamin B12 from their diet.
Prevalence of vitamin B12 deficiency is 5% at age 65 and 20% at age 80 (Age Ageing. 2004. 33. 34-41).
Inadequate absorption is common in older individuals and those on acid blockers, because stomach acid and the digestive enzyme pepsin are required to uncouple the vitamin B12 from the protein it is bound to in food. The National Academy of Sciences estimates that up to 30% of adults over age 50 have impaired absorption of protein-bound vitamin B12 in food. Seniors may require as much as 500 mcg daily of vitamin B12 in supplement form.
Inadequate absorption is infrequently due to pernicious anemia, an autoimmune condition in which there are antibodies to “intrinsic factor,” a protein needed for efficient absorption of vitamin B12.
Even though water soluble, vitamin B12 stores in the liver may last up to 5 years, so it can take years for deficiency to develop.
Vitamin B12 in dietary supplements and fortified foods is in crystalline form rather than protein-bound form; the crystalline form is absorbed efficiently even in the absence of stomach acid and the digestive enzyme pepsin.
Vitamin B12 insufficiency can be defined biochemically as a normal vitamin B12 level, associated with a high methylmalonic acid (MMA) level. Elevated MMA is a sensitive and specific indicator of inadequate B12 despite a normal level. Renal disease and hypovolemia can also cause elevated MMA levels.
As many as 10% of individuals with low normal B12 levels (i.e. 200-400 pg/mL) may develop neuropsychiatric symptoms of B12 deficiency in the absence of megaloblasticanemia.
Neurologic dysfunction is seen in the elderly with B12 levels below 460 pg/ml (cited on pgs 751-767, chapter on diabetic neuropathy, in book Principles & Practice of Geriatric Medicine published in 2010).
CONTRARY to conventional wisdom, even in individuals with pernicious anemia (i.e. deficient intrinsic factor), 1% to 2% of vitamin B12 is absorbed passively, so oral vitamin B12 in doses of 1 mg to 2 mg per day is an alternative to parenteral vitamin B12 for treatment of vitamin B12 deficiency (Blood. 1998. 92. 1191-1198).
May be beneficial in treatment of AIDS, asthma, ataxia, chronic fatigue syndrome, dementia, depression, epilepsy, fibromyalgia, infertility, irritability, multiple sclerosis, neuropathy, sulfite sensitivity (pharmacologically facilitates nonenzymatic degradation of sulfites) and tinnitus.
Drugs which may deplete vitamin B12 include antibiotics, colchicine, colestipol, H2 blockers, metformin, oral contraceptives, phenobarbital, phenytoin, proton pump inhibitors, salicylic acid.
False positive elevated B12 levels - in as many as 20% of individuals with significantly elevated levels, macro forms of vitamin B12 are evident (detected with use of a PEG precipitation procedure) and these macro forms consist of immunoglobulin-vitamin B12 complexes which are considered biologically inactive, but will interfere with laboratory measurement of vitamin B12 (Clin Chem Lab Med. 2020. 58. 408-415).
NOTE an elevated vitamin B12 level in the absence of supplementation suggests the possibility of underlying liver disease, (Clin Chem Lab Med. 2013. 51. 489-496.)
Vitamin B12 is a more important determinant of elevated homocysteine concentrations in older people than is folate (Age Ageing. 2004. 33. 34-41).
No known toxicity for oral or parenteral use.
Use preservative free preparations parenterally if chemical sensitivity is suspected.
Routes of administration
Intravenous – may be less effective than intramuscular, because transient high serum level may cause more to be lost in the urine.
Subcutaneous – not widely used in clinical trials, but may produce less burning and may produce levels similar to intramuscular
Intramuscular – produces a supraphysiological level, and this may be the basis of benefit in a wide range of conditions, via mechanism unknown.
Inhalation - long term safety not documented, and possible that it could damage the lungs
Intranasal – long term safety not documented, and possible that it could damage the nasal mucosa.
Sublingual – does not appear to be absorbed more efficiently than oral (Br J Clin Pharmacol. 2003. 56. 635-638).
Oral – generally effective
Three supplement forms:
Cyanocobalamin is the most common, least expensive, and commercially available, but it is not natural in the body. Leads to the release of small amounts of cyanide, which can cause problems in those who are unable to excrete cyanide efficiently.
Hydroxocobalamin is a form that naturally occurs in the human body, found primarily in cytoplasm where it is converted into its active coenzyme forms (methylcobalamin and adenosylcobalamin) – as compared with cyanocobolamin, produces higher and more sustained serum vitamin B12 levels (Blood. 1961. 18. 511-521; Blood. 1966. 27. 234-241).
Methylcobalamin – this is one of the active coenzyme forms – a potential disadvantage is that it apparently cannot be converted to adenosylcobalamin (Eur J Clin Nutr. 2015. 69. 1-2).
RDA is 2.4 mcg in adults.
Vitamin C (ascorbate) [JAMA. 1999. 281. 1415-1423]
Discovered in 1920.
Exists in 3 primary forms – ascorbic acid, semidehydroascorbate, and dehydroascorbate.
Vitamin C content in foods decreased rapidly once they have been picked or sliced.
Vitamin C is present in nature in association with bioflavonoids, and some authorities recommend that if supplemental vitamin C is taken, it should be a product with bioflavonoids.
Vitamin C supplements are popular - NHANES 1999-2000 data shows that 12.4% of US adults were taking vitamin C supplements (Am J Epidemiol. 2004. 160. 339-349).
In addition to its anti-oxidant (i.e. free radical quenching) activity, vitamin C has been shown in vitro and in vivo to inhibit NF-KB, thereby decreasing inflammation (Mol Cell Biol. 2004. 24. 6645-6652).
Pharmacologic effects of vitamin C – antihistamine, antiviral.
Most animals synthesize vitamin C – exceptions are guinea pigs, monkeys, and humans.
Humans lack one enzyme in the 6 enzyme process of synthesizing vitamin C from glucose.
Some have estimated that primates lost the ability to synthesize vitamin C 20 million years ago.
Linus Pauling asserted in the 1970’s that extrapolation of the daily quantity of vitamin C synthesized by animals would suggest that the optimal intake for humans is 10-30 grams per day (100 times the RDA).
Experimental data shows that when animals are under physical stress or ill, production of vitamin C increases markedly. In humans vitamin C levels have been documented to drop precipitously at the onset of an infection.
Vitamin C and all-cause mortality - there is provocative data to suggest that high intake of vitamin C/high serum levels of vitamin C is associated with an increase in all-cause mortality
Data from NHANES 2003-2004 and 2005-2006 shows that at median follow-up of 10.6 years, there is a statistically significant U-shaped relationship between serum vitamin C levels, all-cause, and cardiovascular-associated mortality (Tian T et al. Nutrition. 2022. 101. 111696).
A systematic review and dose-response meta-analysis of prospective observational studies shows a U-shaped relationship between vitamin C intake and mortality, with data suggesting that the optimal daily dose from food plus supplements is 125 mg/day (Jayedi A et al. Adv Nutr. 2018. 9. 701-716).
Vitamin C and heart disease
Many beneficial actions – protects endothelial cells from homocysteine-induced damage, neutralizes Lp (a), reduces oxidation of LDL, slows progression of atherosclerosis (Sinatra ST and Roberts JC. Reverse Heart Disease Now. 2007).
In a pooled analysis of 9 cohorts, vitamin C supplement use exceeding 700 mg/day was associated with a statistically significant 25% reduction in coronary heart disease risk (Am J Clin Nutr. 2004. 80. 1508-1520).
HPS Study – RCT in 20,536 individuals with coronary artery disease, occlusive arterial disease, or diabetes who received vitamin E 600 mg daily + vitamin C 250 mg daily + beta carotene 20 mg daily or placebo. 83% in each group completed the 5 year follow up. Despite a significant increase in blood levels of the vitamins, there were no differences between the treatment and placebo groups with regard to all-cause mortality, nonfatal MI, or heart disease death (Lancet. 2002. 360. 23-33).
Women’s Antioxidant Cardiovascular Study - RCT in 8171 female health care professionals at increased risk of cardiovascular disease (a previous event or 3 or more risk factors). A 2 x 2 x 2 design found no overall effects from vitamin E (d alpha tocopherol acetate 600 IU every other day), vitamin C 500 mg/day or beta carotene 50 mg every other day, alone or in combinations (Arch Intern Med. 2007. 167. 1610-1618).
Physicians’ Health Study II - RCT in 14,641 US male physicians who were age 50 or older at entry; only 5.1% of the cohort had prevalent cardiovascular disease at entry. The treatment group received 400 IU of vitamin E (synthetic alpha tocopherol) every other day along with 500 mg of vitamin C daily. At 8 years of follow up, neither vitamin E nor vitamin C reduced the risk of major cardiovascular events. In this trial, there was a 74% increase in the risk of hemorrhagic stroke associated with vitamin E supplementation, but no increase in the incidence of CHF (JAMA. 2008. 300. 2123-2133).
Uses:
Allergies – vitamin C is an antihistamine
Asthma (exercise-induced) prevention – see above in this outline for reference
Attention - in a 4-week RCT of 214 healthy young Korean adults, 500 mg of vitamin C twice a day significantly eat increased attention (p = 0.030, engagement in work (p = 0.03) and cognitive function (p =0.04) [Eur J Nutr. 2022. 61. 447-459].
Autoimmune disease – anecdotes
Cancer – may have anti-cancer effects when given at high doses intravenously – cytotoxic effects and biological response modifier
Depression
Strong theoretical rationale for those with depression associated with excess histamine production, based on anti-histamine effects.
A controlled trial shows that vitamin C supplementation enhances recovery from depression (Brit J Psychiat. 1963. 109. 294-299).
In a 6 month RCT of patients with pediatric major depressive disorder and taking fluoxetine (Prozac) 10-20 mg daily, 1 gram of vitamin C daily was associated with associated with a significant decrease in depressive symptoms (Nutr J. 2013. 3. 12-31).
Gallbladder disease prevention - based on NHANES III data (Arch Intern Med. 2000. 160. 931-936).
Gout prevention
During 20 years of follow up in 46,994 male participants in the Health Professionals Follow Up Study, as compared to men with a vitamin C intake of less than 250 mg/day, those with intake of 500-999 mg/day had a RR of 0.83, those with intake of 1000-1499 mg/day had a RR of 0.66, and those with intake of >1500 mg/day had a RR of 0.55 (Arch Intern Med. 2009. 169. 502-507).
Vitamin C supplementation lowers uric acid levels via a uricosuric effect, based on data from a meta-analysis of RCTs (Arthritis Care Res. 2011. 63. 1295-1306).
Heavy metal exposure – effective in removing arsenic, cadmium, and lead from the blood based on test tube data.
Hypercholesterolemia - in a 30 day trial, 500 mg daily of vitamin C was associated with significant reductions in total cholesterol and LDL, with no effect on HDL or triglycerides (J Sci Res. 2012. 4. 775-781).
Hypertension – see above in this outline for reference.
Infections – increases interferon production and may have antiviral effects when given at high doses intravenously.
Narcotic withdrawal - partially alleviates symptoms
Osteoarthritis - Framingham data shows that higher intake is associated with slower progression of osteoarthritis symptoms.
Osteoporosis – important in the synthesis of bone matrix.
Prostate cancer prevention - ineffective in the Physicians’ Health Study II (JAMA. 2009. 301. 52-62 and editorial 102-103).
Reflex sympathetic dystrophy prevention after fracture – see above in this outline for reference.
Schizophrenia – benefit likely based on anti-histamine properties. Vitamin C is also an anti-stress vitamin and may counter too much adrenalin.
Sepsis - preponderance of clinical trial data is negative
Strong theoretical rationale - vitamin C deficiency is common in those with sepsis, plasma concentrations of vitamin C in septic shock are inversely correlated with measures of multiorgan dysfunction, and vitamin C attenuates the cytokine surge seen in sepsis (Editorial. JAMA. 2019. 322. 1257-1258).
Benefit reported in a single-center observational study of vitamin C with thiamine and hydrocortisone - 47 patients treated with the combination of vitamin C with thiamine and hydrocortisone were compared with 47 historical controls, and hospital mortality was 8.5% in the treatment group versus 40.7% in the control group (Chest. 2017. 151. 1229-1238).
“Negative study” - CITRIS-ALI RCT of 167 patients with sepsis and ARDS treated with iv vitamin C 50 mg/kg every 6 hours for 96 hours. None of the 3 primary outcomes showed benefit of vitamin C; a secondary outcome of reduced 28 day all-cause mortality was significantly lower in the sepsis group (HR 0.55) but this might be due to chance because there were so many secondary outcomes. It is possible that this study was negative because vitamin C was given too late in the course, as inclusion criteria required sepsis and ARDS (JAMA. 2019. 322. 1261-1270 and editorial 1257-1258).
Negative multicenter study - VITAMINS RCT of 216 septic shock patients. No difference in outcomes between the group which received vitamin C, thiamine and hydrocortisone, as compared with the group which received hydrocortisone alone. The low dose of vitamin C (1.5 grams) and the timing of administration of vitamin C (12.1 hours from time of determination of study eligibility) might explain the negative findings (JAMA. 2020. 323. 423-431).
Negative multicenter study - ACTS RCT of 205 randomized patients in septic shock, which compared ascorbic acid (1500 mg), hydrocortisone (50 mg) and thiamine (100 mg) every 6 hours for 4 days to placebo (JAMA. 2020. 324. 642-650).
Negative multicenter study - VICTAS RCT of 501 adults at 43 sites. Unfortunately, enrollment was terminated early due to withdrawal of funding so the study was underpowered (JAMA. 2021. 325. 742-752 and editorial 730-731).
ASTER RCT in progress in 2021 - randomization of 900 septic patients to placebo, iv acetaminophen, or iv vitamin C 50 mg/kg every 6 hours.
A systematic review and component network meta-analysis failed to show benefit of vitamins B1, C and glucocorticoids (Intesntive Care Med. 2022. 48 16-24), as did a second systematic review and meta-analysis (Crit Care Med. 2022. 50. e458-e467).
Negative (borderline negative) multicenter study - 28-day all-cause mortality was nonsignificantly lower (p = 0.10) in a RCT of 126 adults in which the treatment group received a bolus of 10 grams vitamin C over 30 minutes, followed by an infusion of 250 mg/hour for 96 hours. Post-hoc analysis showed a borderline significant benefit (p = 0.05) in those in those receiving positive pressure ventilation (Crit Care Med. 2022. 50. e304-e312).
Negative international multi-center study - LOIVIT RCT of 872 patients at 35 sites, all receiving vasopressor support in the ICU, randomized to vitamin C 50 mg/kg infusion every 6 hours for up to 96 hours or a matched placebo. Primary outcome was a composite of death or persistent organ dysfunction, and at 28 days of follow up, the primary outcome occurred in 44.5% of patients in the vitamin C treatment group and 38.5% of patients in the placebo group (CI 1.04-1.40, p=0.01) [N Engl J Med. 2022. 386. 2387-2398].
Smoking and pregnancy - in a RCT of 179 pregnant smokers, in those randomized to vitamin C 500 mg daily, there were better PFT results and less wheezing at age 1 year in infants (JAMA. 2014. 311. 2074-2082).
Surgery
Vitamin C 2 grams by mouth 1 hour prior to induction of anesthesia was associated with less post-operative self-administration of morphine (via PCA pump) in the first 24 hours after surgery, in a randomized trial in 80 patients undergoing laparoscopic cholysystectomy [p=0.02] (Can J Anesth. 2012. 59. 538-543).
Vitamin C 500 mg twice a day for 6 weeks was associated with reduced pain and better functional outcomes in a RCT of 60 patients who had undergone surgery for a closed ankle fracture (Foot Ankle Surg. 2019. 25. 542-545).
Upper respiratory infection (URI) prevention and treatment – theoretic rationale is antiviral properties; systematic review found that evidence for prevention was weak, but there was a consistent and significant reduction in duration and severity of colds when vitamin C was used for treatment (Cochrane Database Syst Rev. 2004. 18. CD000980).
NOTE there is data that leukocyte vitamin C concentrations fall precipitously (to levels seen in scurvy) within 24 hours of onset of an URI (Scott Med J. 1973. 18. 3-7).
NOTE in one negative study (Med J Aust. 2001. 175. 359-362), limitations include group differences at baseline, loss of 46% of patients to follow-up, a delay of up to 13 hours from symptom onset until initiation of the intervention tablets, and lack of statistical power to detect a reduction in symptomatic days of less than 40%.
Prevention – in an 8 week RCT, conducted in young men with adequate-to-low vitamin C status, those randomized to vitamin C 1 gram daily had a lower incidence of cold symptoms (FASEB J. 2014. 28. 1).
Prevention and Treatment - a RCT of 818 volunteers reported that [Can Med Assoc J. 1972. 107. 503-508]
Vitamin C 250 mg four times a day for a mean of 103 days during the winter was associated with 26% of the treatment subjects free of URI during the trial as compared with 18% of the placebo subjects (p < 0.05) but the mean number of illnesses in the treatment group during the trial was nonsignificantly 7% lower.
Vitamin C 1 gram four times a day at the first sign of any illness was associated with a mean of 30.4% less days confined to the home due to symptoms of illness (p < 0.001).
Risks:
No known toxicity
Calcium oxalate kidney stones
May increase risk of oxalate kidney stones in people genetically predisposed and known as "stone formers."
NOTE vitamin B6 intake and magnesium intake may protect against formation of calcium oxalate kidney stones
Conflicting data in prospective cohort studies
In a 6 year prospective study of 51,529 male health professionals the risk of developing kidney stones was 22% lower in men consuming 1500 mg per day or more of vitamin C, as compared with men consuming 250 mg per day or less (J Urol. 1996. 155. 1847-1851).
In a 14 year prospective study of 85,557 female nurses, higher intake of vitamin C (> 1500 mg/day) was not associated with an increased risk of kidney stones (J Am Soc Nephrol. 1999. 10. 840-845).
In a prospective cohort of 48,850 Swedish men, vitamin C supplementation was associated with an increased risk of kidney stones (JAMA Intern Med. 2013. 173. 386-388).
A prospective cohort of 40,536 male health professionals did show a trend toward a higher incidence of kidney stones in association with vitamin C intake, but a prospective study of 156,735 female nurses did not show an association (Am J Kidney Dis. 2016. 67. 400-407).
High doses can interfere with certain diagnostic lab tests such as tests for occult blood in the urine or stool.
Many supplements are derived from corn-based material, which might thus cause symptoms in those with a food sensitivity to corn.
Enhances the absorption of non-heme iron; relatively contra-indicated in those with hereditary hemochromatosis.
Doses in excess of 1 gram per day can decrease the blood levels of indinavir, a drug used to treat AIDS, so individuals on this prescription drug need to avoid high doses of vitamin C.
High doses may cause self-limited diarrhea or bloating.
Doses above 100 mg might be dangerous in those with chronic renal failure and in those on hemodialysis.
In one study 500 mg daily shown to have a pro-oxidant effect on the DNA base adenine (Nature. 1998. 392. 559).
May cause hemolysis if given intravenously to somebody with a glucose-6-phosphate dehydrogenase deficiency (BMJ. 1993. 306. 841-842).
There is controversy regarding whether vitamin C high dose intravenous is contra-indicated in those with G6PD deficiency (Crit Care. 2019. 23. doi 10.1186/s13054-019-2397-6).
Screen for G6PD deficiency prior to administering iv doses.
Dosage and impact upon plasma level
In a study in 17 healthy volunteers, it was shown that intravenous administration produces high plasma levels in a dose dependent manner, but oral administration even at high doses impacts negligibly upon plasma levels (Ann Intern Med. 2004. 140. 533-537).
Requirements:
RDA was 60 mg in adults, is now 90 mg in men and 75 mg in women, based on a stepped repletion study in 7 young healthy men initially fed a vitamin C deficient diet (Proc Natl AcadSci. 1996. 93. 3704-3709).
According to 1996 USDA data, 37.5% of Americans obtain less than the RDA of vitamin C from their diet.
NHANES 2003-2004 data in 7277 individuals show that 7.1% are vitamin C deficient by serological testing. Deficiency prevalence highest in smokers and those with low income (Am J Clin Nutr. 2009. 90. 1252-1263).
Estimated average requirement (EAR) is calculated at 100 mg with a calculated RDA of 120 mg based on either (1) saturation of neutrophils or (2) threshold of urine excretion (JAMA. 1999. 281. 1415-1423). Note though that vitamin C accumulation in activated neutrophils is increased as much as 10-fold the mM concentrations present in normal neutrophils (J BiolChem. 1993. 268. 15531-15535). This data would suggest that vitamin C requirements may be much higher than the RDA in inflammatory states. Also note that there is data that schizophrenic patients can metabolize ten times more vitamin C than normal people (Int J Neuropsychiatry. 7/22/65; Biol Psychiatry. 1990. 28. 959-966). Those with exposure to heavy metals and those with excess histamine production may benefit from higher doses of vitamin C (see ‘Uses’ just above).
The USDA recommended 5 servings per day of fruits and vegetables provides an average of 200 mg of vitamin C, but the amount of vitamin C in food decreases markedly with as food ages on the shelf of the supermarket, and also decreases markedly with cooking of food.
Upper limit (UL) of vitamin C in adults is considered 2 grams.
Prehistoric intake estimated at 440-604 mg/day.
Vitamin D (Mayo Clin Proc. 2003. 78. 1457-1459; IMCJ. 2004. 3. 44-54; BMJ. 2005. 330. 524-526; Mayo Clin Proc. 2006. 81. 353-373; N Engl J Med. 2007. 357. 266-281; Alt Med Alert. 2009. 12. 37-43)
Dosage: 50 mcg = 2000 IU, 125 mcg = 5000 IU
Discovered in 1920.
Not truly a vitamin by strict definition because we can synthesize it from cholesterol in the skin with UV-B light exposure; also a pro-hormone.
As a pro-hormone, essential for efficient utilization of dietary calcium.
Converted in the liver to 25-hydroxyvitamin D and then in the kidney to 1, 25 dihydroxyvitamin D (calcitriol).
Calcitriol increases calcium and phosphorous absorption in the intestine, induces osteoclast maturation and bone remodeling, promotes calcium deposition in bone, and suppresses PTH (parathyroid hormone). With vitamin D insufficiency, inadequate absorption of calcium leads to a rise in PTH levels, and PTH induces phosphaturia and hypophosphatemia
Deficiency causes muscle weakness and muscle aches and pains.
In its autocrine metabolism, circulating 25-hydroxyvitamin D is taken up by a wide variety of cells in the body, and targets more than 200 human genes.
Many cells, including pancreatic islet cells, monocytes, transformed B lymphocytes, activated T lymphocytes, neurons, prostate cells, ovarian cells, and aortic endothelial cells have nuclear, cytosolic, or membrane-bound vitamin D receptors (Br J Nutr. 2003. 89. 552-572).
Many cells and tissues, including breast, lung, skin, lymph nodes, colon, pancreas, adrenal medulla, and brain contain the 1-alpaha-hydroxylase enzyme and can thus synthesize their own calcitriol intracellularly as long as exposed to an adequate concentration of 25-OH vitamin D (J Clin Endocrinol Metab. 2001. 86. 888-894). BEWARE this is a rationale for supplementing renal failure patients with vitamin D3 along with calcitriol.
Vitamin D is known to bind to the VDR, a type 1 nuclear receptor, and to modulate gene expression. One report indicated that over 200 genes have vitamin D response elements (Recent Results Cancer Res. 2003. 164. 29-42). A more recent report has identified 27,091 genes that might be transcribed or repressed by the VDR (Molecular Endocrinol. 2005. 19. 2685-2695).
Vitamin D appears to modulate neurotransmitter function.
Vitamin D is immunoregulatory; upregulates production of cathelicidin, a naturally occurring broad spectrum antimicrobial substance (Altern Med Rev. 2008. 13. 6-20).
Vitamin D reduces inflammation.
Vitamin D may also have paracrine (around the cell) effects.
Exists in two major forms (see ‘vitamin D supplementation’ just below for more details on vitamin D2 versus vitamin D3)
Ergocalciferol (Vitamin D2) is a synthetic product first produced in the 1920s, used to fortify foods such as milk, and available by prescription – source is either irradiation of yeast or plant ergosterol.
Cholecalciferol (Vitamin D3) is present naturally in certain animal foods, is synthesized in the skin after exposure to ultraviolet B (i.e. sun), and is available OTC in supplement form, with supplemental vitamin D3 manufactured by irradiation of 7-dehydrocholesterol from lanolin.
Sources of vitamin D – Note, according to NHANES III, 90% of U.S. adults 51 - 70 years old and 98% of U.S. elderly obtain less than the RDA of vitamin D from their diet (J Am Diet Assoc. 2004. 104. 980-983); it is estimated that 90% of our required vitamin D comes from exposure to sunlight (J Cell Biochem. 2003. 88. 296-307).
Food - vitamin D is found in relatively few foods. Vitamin D3 is found only in animal foods; reported in 2013 that mushrooms exposed to UV light synthesize vitamin D3.
Natural food sources of vitamin D are high fat fish such as wild salmon and sardines, and also egg yolks.
According to the Weston Price Foundation, traditional diets contained ten times more vitamin D than the typical modern diet.
Fortified foods – fortified with vitamin D2
Historically in the US, starting in the 1930's, Vitamin D2 was added to animal feed and many foods, including flour, milk, margarine, and breakfast cereals. It was estimated that the average American was consuming as much as 2400 IU/day (Am J Clin Nutr. 1979. 32. 58-83), and there were several cases of accidental Vitamin D overdose due to over-supplementation of food. This led to the elimination of vitamin D fortification of most foods.
Milk in the US is fortified with 400 IU per quart vitamin D2 (based on public policy and information on the label). HOWEVER a study in which the vitamin D content of milk was actually measured found that only 29% of samples actually contained 320-480 IU per quart. Skim milk had undetectable levels of vitamin D (N Engl J Med. 1993. 329. 1507).
Fortified foods in the US at this time include milk, cereal, orange juice, and yogurt.
UV-B sunlight (290-315 nm)
Full-body exposure to sunlight can produce the equivalent of 10,000 – 25,000 IU of vitamin D3 per day (Am J Clin Nutr. 1999. 69. 842-856).
If a person in a bathing suit is exposed to sun long enough to produce slight pinkness of the skin (1 minimal erythema dose), this is equivalent to ingesting 20,000 IU of vitamin D (J Cell Biochem. 2003. 88. 296-307).
Older individuals are much less efficient at synthesizing vitamin D from sunlight exposure – there is a 75% reduction in ability to make vitamin D in a 70 year old, compared with a 20 year old.
Application of SPF 8 sunscreen reduces the capacity of the skin to make vitamin D by 95% (J Cell Biochem. 2003. 88. 296-307).
Surprisingly, vitamin D levels do not necessarily correlate with sun exposure, based on studies in Honolulu, Miami, and Tucson (J Clin Endocrinol Metab. 2005. 90. 1557-1562; J Clin Endocrinol Metab. 2007. 92. 2130-2135; Am J Clin Nutr. 2008. 87. 608-613). See ‘Controversies’ just below.
Melanin pigmentation (dark skin), high latitudes, and staying indoors reduce cutaneous production of vitamin D from sunlight.
At latitudes beyond 35 degrees from the equator, vitamin D cannot be synthesized from UV-B sunlight from approximately October – April, because the rays of the sun are passing through the ozone in the upper atmosphere at such an oblique angle that no UV-B makes it through the ozone.
Note that glass blocks ultraviolet B and thus prevents synthesis of vitamin D3 from sunlight, but does not block ultraviolet A, and thus glass does not prevent sunburn.
Note sun exposure, and sunburn in particular, do increase the risk of skin cancer - for more information click Here
Supplements
Requirements for vitamin D – Note that gastrointestinal absorption of dietary vitamin D at an advanced age may not be as efficient, and the capacity of the skin to synthesize 25-hydroxy vitamin D in the skin decreases with age.
The Institute of Medicine 1997 – adequate dietary intake is 200 IU/day for children and adults to age 50, 400 IU/day for adults age 51-70, and 600 IU/day for those over age 70. Note 100 IU = 2.5 micrograms.
The Institute of Medicine 2010 – recommended dietary allowance is 600 IU/day for children and adults to age 50, 600 IU/day for adults age 51-70, and 800 IU/day for those over age 70. Note 100 IU = 2.5 micrograms.
Upper limit of intake as per 1997 IOM report is 2000 IU/day, as per 2010 IOM report is 4000 IU/day, but there is data to indicate that intakes as high as 10,000 IU/day are safe (Vieth R. J Steroid Biochem Mol Biol. 2004. 89-90. 575-579).
Some vitamin D experts state that the body requires at least 3000 - 5000 IU/day for normal metabolism (Am J Clin Nutr. 1999. 69. 842-856; Am J Clin Nutr. 2003. 78. 1047).
Obesity increases the requirements for vitamin D, in part because vitamin D is sequestered in fat cells and in part because obesity apparently interferes with the ability to synthesize vitamin D from sunlight exposure (Am J Clin Nutr. 2000. 72. 690-693).
Vitamin D requirements may be higher in those taking anticonvulsants, cholestyramine, corticosteroids, and rifampin.
Monitoring of vitamin D status - this is done primarily by monitoring 25-hydroxy vitamin D levels and serum calcium.
1, 25 dihydroxy vitamin D levels can also be measured, but are not considered a reliable measure of vitamin D sufficiency
Anecdotally, measurement of 1, 25 dihydroxy vitamin D levels may be valuable in cancer patients on chemotherapy and in patients with multiple chemical sensitivities.
Quest lab offers a vitamin D panel which measures 25 hydroxy and 1, 25 dihydroxy vitamin D levels.
25-hydroxy vitamin D levels
The serum level necessary to protect against rickets and osteomalacia is 11 ng/ml.
The Institute of Medicine currently considers a level of 15 ng/ml to be the minimum for sufficiency.
There is a general consensus that a 25-hydroxy vitamin D level of at least 20 ng/ml (50 nmol/L) is necessary (Am J Clin Nutr. 2002. 76. 187-192).
Dr. Alan Gaby states that the evidence is weak to support 30 ng/ml as the lower limit of normal as opposed to 20 ng/ml.
Some experts, including Drs. Heaney and Holick, render an opinion that levels should always be greater than 30 ng/ml (75 nmol/L), and that levels of 60-80 are optimal.
A level of 60 ng/ml (150 nmol/L) as optimal is based on theoretical data, and the assumption that levels achieved by supplementation are analogous to levels associated with sun exposure (and Dr. Alan Gaby challenges this assumption).
It is likely that levels of 50 ng/ml or higher were present throughout most of human evolution (Am J Clin Nutr. 1999. 69. 842-856).
Vitamin D kinetics are similar to the kinetics of other steroid hormones (i.e. negative feedback inhibition with regard to the effect of high intake on the serum level) only when the serum level of 25 hydroxy vitamin D rises to 50-60 ng/ml. At lower levels of 25 hydroxy vitamin D, the kinetics are labeled first order, mass action kinetics (Hollis BW, et al. Circulating vitamin D3 and 25-hydroxyvitamin D in humans: An important tool to define adequate nutritional vitamin D status. J Steroid Biochem Mol Biol. 2007; 103(3-5):631-634).
Levels up to 80 - 100 ng/ml (200-250 nmol/L) appear to be safe, as these levels are regularly observed in equatorial populations with regular sun exposure, and in lifeguards.
Limitations of relying upon 25-hydroxy vitamin D level as an assessment of vitamin D status
25-hydroxy vitamin D is only 1 of more than 50 vitamin D metabolites identified, and thus levels may not totally reflect the vitamin D status of the individual, especially at high intakes of supplemental vitamin D, as the 25 hydroxylases might become saturated at high intakes, possibly leading to storage of large amounts of unmetabolized vitamin D (Gaby AR 2011 presentation “Controversies in Nutrition”).
Commercially available lab tests cannot distinguish true 25-hydroxy vitamin D from an endogenous 25-hydroxy vitamin D isomer or from other compounds that have the same molecular weight as 25-hydroxy vitamin D (such as a specific bile acid precursor), as per Dr. Alan Gaby (Commentary in January 2020 Townsend Letter. Page 30).
25-hydroxy vitamin D levels may vary significantly as a function of the time of day of the blood draw, based on a case study in a healthy woman taking 5000 IU daily who had levels measured 3 times a day for 4 days. The mid-day level was 20% higher than the morning level and 13% higher than the evening level (J Med Case Rep. 2019. 13. 29).
Probiotic supplementation might affect 25 hydroxy vitamin D levels – a secondary analysis of a 13 week RCT of 127 patients administered a Lactobacillus reuteri NCIMB 30242 probiotic found that via an unknown mechanism, those administered probiotic had an average increase of 6 ng/ml (25%) in 25 hydroxy vitamin D levels (p=0.003) [Jones ML et al. J Endocrinol Metab. Epub 4/22/13].
25 OH vitamin D levels tend to be lower in African Americans, but this is not necessarily problematic
Lower 25 OH vitamin D levels may be attributable to lower levels of vitamin D-binding protein (as a function of genetic polymorphisms), such that bioavailable 25 OH vitamin D is similar between Caucasians and African Americans (N Engl J Med. 2013. 369. 1991-2000 and editorial 2047-2048).
Cross sectional data in 1773 adult participants in the Multi-Ethnic Study of Atherosclerosis showed that 25 OH vitamin D levels were highest in Caucasians and lowest in African Americans, but bone mineral density was highest in African-Americans (Bone. 2015. 78. 186-193).
25 hydroxy vitamin D levels drop in response to inflammation, as vitamin D is an acute phase reactant (Am J Med Sci. 2021. 36.333-335).
Dr. Alan Gaby asserts that 25 hydroxy vitamin D levels are an unreliable indicator of vitamin D nutritional status UNLESS the individual has outright vitamin D deficiency (level < 20 ng/ml) or toxicity (level > 100 ng/ml).
Vitamin D safety
Vitamin D (whether from sunlight or supplements) increases CYP3A4, and this may affect levels of many prescription drugs, including immunosuppressants and antidepressants (Lindh JH. Drug Metab Dispos. Epub 2/24/11).
Vitamin D supplementation might increase calcification in plaque - in a cross sectional study of 340 African Americans with type 2 diabetes, serum 25 OH vitamin D levels were positively associated with increased calcified atherosclerotic plaque in the aorta and carotid arteries, but not in the coronary arteries (J Clin Endocrinol Metab. 2010. 95. 1076-1083).
Vitamin D safety cannot be inferred from data regarding safety of sun exposure, and evidence supporting long term safety of vitamin D at dosages > 2000 IU/day is weak (Gaby AR. Townsend Letter. February/March 2019. 95-96).
Vitamin D toxicity
High oral intakes of Vitamin D (50,000 – 100,000 IU/day in adults) are associated with significant toxicity.
Toxicity is unlikely unless supplemental doses exceed 10,000 – 20,000 IU daily. Doses of 10,000 IU/day for up to 5 months have not been associated with toxicity (Vieth R. J Steroid Biochem Mol Biol. 2004. 89-90. 575-579).
Vitamin D toxicity is associated with 25-hydroxy vitamin D levels >150 ng/ml.
Hypercalcemia appears to be the mechanism of vitamin D toxicity.
Symptoms of vitamin D toxicity (information based on historical literature) include nausea, fatigue, unintentional weight loss and urinary frequency as initial symptoms, weakness and increased thirst as secondary symptoms, and diarrhea, emesis, and abdominal pain as symptoms of progressive and severe vitamin D toxicity. There are published reports of death due to vitamin D toxicity (1940’s).
Overexposure to sun does not cause Vitamin D toxicity in healthy people because of physiologic regulation of production of Vitamin D3.
Vitamin D hypersensitivity syndrome is much more common than direct vitamin D toxicity.
This occurs when aberrant tissue uncontrollably produces calcitriol.
Primary hyperparathyroidism, sarcoidosis, tuberculosis, Crohn’s disease, and cancer may cause this syndrome.
Consider weekly measurement of serum calcium for one month, then monthly measurement in individuals taking high dose vitamin D supplementation to monitor for vitamin D hypersensitivity syndrome.
Vitamin D deficiency – global issue
A study of 290 patients on a general medical ward showed that 57% were deficient in vitamin D, based on measurements of serum 25 hydroxy vitamin D. In this study, 46% of those inpatients who said that they took a multivitamin daily were still vitamin D deficient! (New Engl J Med. 1998. 338. 777-783).
A study of postmenopausal women admitted with hip fractures showed that 50% were deficient (JAMA. 1999. 281. 1505-1511).
In a Minnesota-based study of 150 patients aged 10 to 65 who presented with nonspecific musculoskeletal pain syndromes refractory to standard therapies, 93% had deficient levels of vitamin D (<20 ng/ml) [Mayo Clin Proc. 2003. 78. 1463-1470].
At least 62% of morbidly obese are vitamin D deficient (Obes Surg. 1993. 3. 421-424).
Deficiency is common even in healthy youth, based on data gathered in a sample 382 youth aged 6-21, which showed that 55% had inadequate vitamin D levels (Am J Clin Nutr. 2007. 86. 150-158).
Prevalence of low 25-OH vitamin D levels (<20 ng/mL) is 36% in otherwise healthy young adults (Am J Med. 2002. 112. 659-662), 42% in black women aged 15-49 based on NHANES III data (Am J Clin Nutr. 2002. 76. 187-192), and 41% in outpatients aged 49-83 (Lancet. 1998. 351. 805-806).
NHANES III data on 7186 male and 7902 female adults showed a mean 25-OH vitamin D level of 30 ng/ml (Arch Intern Med. 2007. 167. 1159-1165).
In a large international study of postmenopausal women, 4% were vitamin D deficient and another 24% had inadequate vitamin D status, based on elevated levels of PTH (J ClinEndocrinol Metab. 2001. 86. 1212-1221).
African Americans and homebound elderly are at higher risk for deficiency.
Those with diseases associated with fat malabsorption (sprue, cystic fibrosis, Crohn’s) are at especially high risk for vitamin D deficiency.
Vitamin D supplements
Popularity
Sales estimated at $425 million in 2009, compared with $40 million in 2000 (Nutrition Business Journal)
NHANES data between 1999-2012 (n=37,958 adults, 74% response rate) shows that use of vitamin D within the preceding 30 days increased from 5.1% in 1999-2000 to 19% 2011-2012 (p for the trend <0.001) [JAMA. 2016. 316. 1464-1474].
Forms of supplements
Vitamin D2 (ergocalciferol) is produced by exposing ergosterol from yeast to UVB radiation.
Vitamin D3 (cholecalciferol) is bio-identical to that produced in the human body, but supplemental vitamin D3 is derived from animal sources so vegans may want to avoid this supplement.
Does of supplements (50 mcg = 2000 IU, 125 mcg = 5000 IU)
Based on the most recent data on vitamin D requirements and vitamin D toxicity, supplementation for therapeutic purposes (see below) should be in the range of 4000-10,000 IU/day of vitamin D3. Serum 25-hydroxyvitamin D levels do not plateau until after 3-4 months of supplementation.
A graded oral dosing study in men determined that 1000 IU/day of supplemental vitamin D3 raises 25-OH-vitamin D levels at 8 weeks by an average of 11.6 ng/ml, and 10,000 IU/day of supplemental vitamin D3 raises 25-OH-vitamin D levels at 8 weeks by an average of 58.5 ng/ml. Furthermore, BMI accounts for 90% of the variance in dose-response relationship (Osteoporosis Int. 1998. 8. 222-230).
Most individuals require 2000-4000 IU/day in the winter and 1000-2000 IU/day in the summer to achieve a level of 50 ng/ml.
Some experts recommend administering 4000 IU per day to all pregnant women (Am J Clin Nutr. 2004. 79. 717-726).
There is data that supplemental doses of 1000-2000 IU in infants and children is safe, and is associated with a reduced incidence of Type I diabetes (Lancet. 2001. 358. 1500-1503).
The current conventional medicine recommendation is to treat vitamin D deficiency with 50,000 IU vitamin D once/week for 8 weeks, to increase the 25-hydroxyvitamin D level to greater than 20 ng/ml (Am J Clin Nutr. 2004. 79. 362-371).
Those with renal or liver failure will not efficiently convert vitamin D to its active 1, 25 dihydroxy vitamin D form and are best supplemented with calcitriol.
Vitamin D Controversies
The observational data showing correlation between vitamin D status and disease might be due to confounding factors rather than a causal relationship (Gaby 2011 presentation “Controversies in Nutrition”).
High vitamin D levels in populations may be more a function of sun exposure than vitamin D supplementation, and people with greater sun exposure may differ from those who do not spend time in the sun.
Human testes can hydroxylate vitamin D, and thus higher levels may be a marker in males for optimal testicular function, which is likely to be correlated with higher levels of testosterone in these individuals (Lancet. 2010. 376. 1301).
High 25 hydroxy vitamin D levels might be primarily a function of more efficient 25 hydroxylase enzymes, and these enzymes are also responsible for detoxification of xenobiotics as well as synthesis of DHEA and estriol.
If sun exposure is beneficial, the benefit might not be entirely due to increased synthesis of vitamin D. Sunlight also produces photodegradation products, stimulates production of CRH in the hypothalamus, and may directly influence hypothalamic and pituitary function via the retina.
Some data can be interpreted to suggest that low vitamin D levels are a consequence of disease, rather than the cause of disease. Theoretically, supplementation to achieve ‘optimal levels’ may cause undesired immunosuppression and might contribute to obesity (BioEssays. 2008. 30. 173-182).
Vitamin D supplementation might increase calcification in plaque - in a cross sectional study of 340 African Americans with type 2 diabetes, serum 25 OH vitamin D levels were positively associated with increased calcified atherosclerotic plaque in the aorta and carotid arteries, but not in the coronary arteries (J Clin Endocrinol Metab. 2010. 95. 1076-1083).
A study of 93 adults in Honolulu, Hawaii with a mean self-reported sun exposure of 11.1 hours per week of total body exposure with no sunscreen found that the mean 25-OH vitamin D level was 31 ng/ml. The maximum level in this sample of 62 ng/ml. This study indicates a variable responsiveness amongst individuals to UV-B radiation, and suggests that a level of 30 ng/ml may be optimal (Binklye N et al. J Clin Endocrinol Metab. 2007. 92. 2130-2135).
The optimal vitamin D level for bone health may vary by race – in whites a 25 OH level > 30 ng/ml is required to normalize serum PTH levels whereas in blacks a level of 20 ng/ml is sufficient to normalize PTH.
Vitamin D3 supplements versus vitamin D2 supplements
Based on studies in the 1930’s, the WHO in 1949 made no distinction between vitamin D2 and D3, but data became available in the 1950s showing preparations of Vitamin D3 approximately 4 times more potent in humans than vitamin D2 (Houghton LA et al. The case against ergocalciferol (vitamin D2) as a vitamin supplement. Am J Clin Nutr. 2006. 84. 694-697).
A Cochrane analysis (see just below) concluded that vitamin D3 supplementation reduces all cause mortality whereas vitamin D2 supplementation does not.
A study in 30 healthy human males administered a single 50,000 IU dose of either vitamin D2 or vitamin D3 concluded that the potency of vitamin D2 is at most 29.4% that of vitamin D3, and may be as low as 10.6% that of vitamin D3, based on levels of 25-OH vitamin D measured 14 days after a single dose (J Clin Endocrinol Metab. 2004. 89. 5387-5391). HOWEVER, an 11 week RCT in 68 healthy adults, 60% of whom were vitamin D deficient at the onset of the study, found 1000 IU of vitamin D2 and 1000 IU of vitamin D3 equipotent with regard to raising 25-OH vitamin D levels at 3 months (J Clin Endocrinol Metab. 2008. 93. 677-681).
Vitamin D and disease – BEWARE much of the data is epidemiological data, which does not imply cause and effect
Low levels associated with increased all-cause mortality – data on 13,331 adults in NHANES III shows that the lowest quartile of 25 hydroxy vitamin D level is independently associated with all-cause mortality (Arch Intern Med. 2008. 168. 1629-1637). HOWEVER, there is also data showing a U-shaped curve, with higher 25-OH vitamin D levels epidemiologically associated with higher mortality. In a prospective cohort of 1194 elderly men (mean age 71), during a median follow up of 12.7 years, an approximately 50% higher mortality was observed in those men with levels in the lowest 10% (< 46 nmol/L = < 18.4 ng/ml) and in those men with levels in the highest 5% (> 98 nmol/L = 39.2 ng/ml) [Am J ClinNutr. 2010. 92. 841-848].
High levels also associated with increased all-cause mortality – in the CopD Study, a J-shaped relationship was observed between 25 hydroxy vitamin D levels and all-cause mortality. This study followed nearly 250,000 individuals in Denmark for a median of 3 years, and found that serum levels of 20-24 ng/ml were associated with the lowest risk of dying. Those with a level of 56 ng/ml had a 42% higher risk of dying during the study than those with a level of 20 ng/ml (Durup et al. J Clin Endocrinol Metab. Epub 2012).
Supplementation and total mortality - the data is mixed
Data from 18 independent RCTs (n=57,311) in which daily vitamin D supplements of 300 IU to 2000IU were administered (mean supplemental dose 528 IU) shows that the relative risk for all-cause mortality in the vitamin D group is 0.93 (95% CI 0.87 – 0.99). There was no indication of heterogeneity amongst individual studies, nor evidence of publication bias. Mean follow-up, adjusted for study size, was 5.7 years. Compliance ranged from 47.7% to 95%. This reduced total mortality risk was independent of whether or not calcium supplementation with vitamin D was part of the intervention. All-cause mortality was not a primary endpoint in any of the individual trials, and the difference in all-cause mortality between the treatment and placebo groups in each of the individual trials was not statistically significant (Arch Intern Med. 2007. 167. 1730-1737 and editorial 1709-1710).
A meta-analysis of 22 RCTs (n=30,716) showed that overall vitamin D supplementation did not reduce mortality, compared with placebo. However, analysis of the 14 RCTs of vitamin D3 (n=13,637) did show a statistically significant 11% reduction in mortality 95% CI 1% - 20%), with a NNT of 53 (BMJ. 2014. 348. G1903).
A patient level pooled analysis of 70,528 patients from eight major vitamin D trials in which vitamin D was given alone or with calcium – statistically significant 9% decrease in all-cause mortality in those supplemented with both vitamin D and calcium, non-significant 4% decrease in all-cause mortality in those supplemented with vitamin D alone (J Clin Endocrinol Metab. 2012. 97. 2670-2681).
Data from 32 trials including nearly 75,000 patients shows that vitamin D3 supplementation was associated with a RR of death of 0.94 (NNT of 161) at a median follow up of 2 years. Most of these trials were conducted in women. Subgroup analysis showed that those with low baseline 25 hydroxy vitamin D levels benefited the most. There was no benefit associated with vitamin D2 supplementation (Cochrane Database Syst Rev. 2011. CD007470).
HOWEVER, in a more current Cochrane review of 29 trials (n=71,032) of vitamin D or vitamin D plus calcium supplementation, mortality was not statistically affected by supplementation.
Negative meta-analysis: A meta-analysis of 21 RCTs (n=83,291) that examined the long term effects (> 1 year) of vitamin D supplementation found no effect of supplementation on major cardiovascular events, MI, stroke, CVD mortality or all-cause mortality (Barbarawi M et al. JAMA Cardiology. Epub 6/19/19).
Supplementation and a composite of nonskeletal health outcomes - a systematic review of 172 RCTs of the effect of vitamin D supplementation on nonskeletal health outcomes found little or no evidence that vitamin D supplementation was beneficial (Lancet Diabetes Endocrinol. 2014. 2. 76-89).
Ankylosing spondylitis – theoretical rational based on data that deficiency is common (Wien Klin Wochenschr. 2001. 113. 328-332).
Asthma
In a RCT of 334 school children in which the treatment group received 1200 IU/day vitamin D3 in supplement form, in the prespecified subgroup with a prior diagnosis of asthma, exacerbations were less common in the treatment group (2 children in the treatment group, 12 children in the placebo group, p=0.006) [Urashima M. Am J Clin Nutr. 2010. 91. 1255-60].
Negative RCT – in a 28 week RCT of 408 patients with persistent asthma and vitamin D insufficiency, vitamin D3 100,000 IU once, followed by 4000 IU daily did not reduce the rate of first treatment failure or exacerbation (JAMA. 2014. 311. 2083-2091).
Negative RCT – in the VDAART trial, a RCT of prevention in which pregnant women were randomized to 4400 IU vitamin D3 versus 400 IU vitamin D3 (control group) starting at 10-18 weeks of pregnancy, there was a suggestion of decreased asthma at 3 years of age (JAMA. 2016. 315. 362-370), but at 6 years of age there was no difference in incidence of asthma or recurrent wheeze. Entry criteria for this trial were that both mother and father had to have a diagnosis of asthma, allergic rhinitis or eczema, and thus all children in this trial were at high risk for developing asthma (N Engl J Med. 2020. 382. 525-533 and editorial 575-575).
Negative RCT – in a RCT of 192 high risk children with asthma, aged 6 -16 and taking low dose inhaled corticosteroid, and with a 25-OH vitamin D level < 30 ng/ml, vitamin D 4000 IU daily as compared with placebo did not significantly improve the time to a severe asthma exacerbation (JAMA. 2020. 324. 752-760).
Athletic performance – theoretical rational based on published data from the U.S. and Germany and Russia that ultraviolet irradiation improves athletic performance. Most of the published articles are in Russian and German, but one is in English (Arch Phys Med. 1945. 10. 641-44).
Atopic dermatitis – see ‘eczema’
Atrial fibrillation prevention - NEGATIVE STUDY - in the 2 x 2 VITAL Rhythm study of vitamin D 2000 IU daily (and also EPA 460 mg/day plus 380 mg/day) in 25,119 participants aged 50 and older, at a median follow up of 5.3 years, atrial fibrillation occurred in 3.7% of the vitamin D group versus 3.4% of the placebo group (P = 0.19) [JAMA. 2021. 325. 1061-1073].
Autoimmune disease risk - beneficial for prevention in the VITAL trial, a RCT of 25,871 older participants (median age 67 years), with a two-by-two factorial design of vitamin D3 2000 IU daily and fish oil 1 gram daily, containing 460 mg EPA + 380 mg DHA. Median follow up 5.3 years, and median 25 OH vitamin D level at baseline was 30.8 ng/ml. There was a 22% lower risk of autoimmune disease in those who were randomized to vitamin D (p=0.05). Vitamin D had the greatest magnitude of benefit in those with lower BMI - hazard ration for autoimmune disease with vitamin D versus placebo was 0.47 for those with a BMI of 18, 0.69 for those with a BMI of 25, and 0.90 for those with a BMI of 30 (Hahn J, et al. BMJ. 2022. 376. e066452).
Autism - beneficial in a 4 month RCT of 109 children ages 3-10, at a dose of 300 IU per kg/maximum dose of 5000 IU daily (Saad, K. et al. Randomized controlled trial of vitamin D supplementation in children with autism spectrum disorder. Journal of Child Psychology and Psychiatry. Epub 11/21/16).
CAD (coronary artery disease)
Cross sectional data show that MI incidence increases as distance from the equator increases (QJM. 1996. 89. 579-589), that 25-hydroxy vitamin D levels are lower in heart attack sufferers compared with controls (Int J Epidemiol. 1990. 19. 559-563), and show that heart attacks are 53% more common in winter months than summer months in the U.S. (J Am Coll Cardiol. 1998. 31. 1226-1233).
However, there is a U shaped curve in regard to vitamin D levels and death following MI, based on data in 477 men followed for 57 months. Men with levels less than 10 ng/ml or greater than 30 ng/ml had a higher risk of mortality (Int J Cardiol. 2016. 223. 962-966).
Negative RCT: After 5 years of follow up in 2686 men and women 65 years or older randomized to receive 100,000 IU vitamin D3 every 4 months, the hazard ratio for ischemic heart disease in the vitamin D group was 0.94 (0.77 – 1.15). Of note, this study did show significant reduction in bone fractures, with a hazard ratio of 0.78. The daily supplemental dose can be calculated at 100,000 IU divided by 122 days = 820 IU/day (BMJ. 2003. 326. 469-472).
Negative RCT: In the Women’s Health Initiative, after 7 years of follow up in 36,282 postmenopausal women randomized to receive calcium carbonate 1 gram per day + vitamin D 400 IU per day, the hazard ratio for coronary heart disease in the calcium + vitamin D group was 1.04 (0.92-1.18). This was not a predetermined endpoint in the study though, and fewer than 60 % of participants had adequate adherence to study medications at the end of this trial (Circulation. 2007. 115. 846-854).
A prospective cohort study of 3258 male and female patients scheduled for coronary angiography at a single tertiary care center (angiography indicated based on symptoms or abnormal noninvasive test results) found that those patients in the lowest quartile of 25-OH vitamin D levels had significantly higher cardiovascular and all-cause mortality than those in the highest quartile, at 7.7 years of follow up (Arch Intern Med. 2008. 168. 1340-1349).
A prospective nested case control study in 18,225 men in the Health Professionals Follow-Up Study showed that low levels of 25-OH vitamin D are associated with a higher risk of MI in a graded manner, even after controlling for potential confounding variables (Arch Intern Med. 2008. 168. 1174-1180).
In the Framingham Offspring Study, a prospective observational study in 1739 middle aged whites, the hazard ratio for cardiovascular events was 1.8 for those with a 25 hydroxyvitamin D level < 10 ng/ml (Circulation. 2008. 117. 503-511).
In NHANES 2001-2004, low vitamin D levels found in 74% of 8351 adults with cardiovascular diseases (Am J Cardiol. 2008. 102. 1540-1544).
A systematic review of 7 prospective observational studies in 5 cohorts found that there was an increased risk for clinical cardiovascular outcomes in those with low vitamin D intake or low serum vitamin D levels in 5 of the 7 analyses; the methods of the original studies were too heterogeneous to consider pooling across studies. Four trials found no effect of supplementation on cardiovascular outcomes (Ann Intern Med. 2010. 152. 307-314).
Prospective analysis of 41,504 patient records in a large electronic medical record database with at least one measured 25 OH vitamin D level showed a prevalence of deficiency (<30 ng/ml) of 63.6% and “an association between vitamin D levels and prevalent and incident CV risk factors and outcomes” (Am J Cardiol. 2010. 106. 963-968).
Critique of the data by IOM committee members (Commentary. JAMA. 2011. 305. 2565-2566).
A retrospective cohort study of 10,899 patients followed by a cardiovascular practice at a large academic medical center showed that “Vitamin D supplementation was significantly associated with better survival, specifically in patients with documented deficiency” (Am J Cardiol. 2012. 109. 359-363).
Negative meta-analysis - a meta-analysis of 9 trials (n = 48,647) failed to show benefit of vitamin D supplementation on MI or ischemic heart disease (Lancet Diabetes Endocrinol. 2014. 2. 307-320).
Negative RCT - VIDA trial, a 3-year RCT of 5110 persons in New Zealand. 100,000 IU vitamin D monthly had no effect on the incidence of major cardiovascular events (JAMA Cardiol. 2017. 2. 608-616).
Negative RCT - VITAL trial, a RCT of 25,871 older participants (median age 67 years), with a two-by-two factorial design of vitamin D3 2000 IU daily and fish oil 1 gram daily, containing 460 mg EPA + 380 mg DHA. Median follow up 5.3 years, and median 25 OH vitamin D level at baseline was 30.8 ng/ml. “Supplementation with vitamin D did not result in a lower incidence of invasive … cardiovascular events than placebo” (N Engl J Med. 2019. 380. 33-44 and editorial 91-93).
Cancer
Mechanism of action of vitamin D in terms of possible cancer prevention includes inhibition of cell proliferation and DNA synthesis, modulation of signal transduction pathways, and induction of apoptosis, programmed cell death. Presumed mechanism involves intracellular production of calcitriol in breast, colon, prostate and other cells from 25-OH vitamin D.
Epidemiologic data which shows an increased cancer mortality in many cancers (i.e. bladder, breast, colon, esophagus, kidney, lung, non-Hodgkin’s lymphoma, ovary, pancreas, prostate, stomach, uterus) in those who live at higher latitudes (i.e. north of Florida in North America) [Cancer. 2002. 94. 1867-1875].
Dozens of references regarding vitamin D and cancer prevention are listed on pg 364 of Mayo Clin Proc. 2006. 81. 353-373.
Summary of data on vitamin D and colon cancer prevention (Alt Med Alert. 2006. 9. 49-55; Alt Med Alert. 2008. 11. 102-104) – the data is mixed.
A review of 63 observational studies, 30 of which examined colon cancer, 26 of which examined prostate cancer, 13 of which examined breast cancer, and 7 of which examined ovarian cancer, concludes that the evidence is consistent, showing a protective effect of vitamin D status against cancer (Am J Pub Health. 2006. 96. 252-261).
A 3-arm, 4 year RCT in 1180 postmenopausal women living in the Midwest showed a 60% reduction in the relative risk of cancer in those who received 1000 IU vitamin D3 plus 1500 mg calcium daily. There was no difference in cancer incidence between the placebo arm and the calcium monotherapy supplementation arm of the study (Am J Clin Nutr. 2007. 85. 1586-1591).
Prospective data in 512 women with breast cancer diagnosed between 1989 and 1996 shows that those with vitamin D deficiency (25 OH vitamin D < 20 ng/ml) at the time of diagnosis had an increased risk of distant recurrence (RR 1.94) and death (RR 1.73), as compared with sufficient levels (25 OH vitamin D > 30 ng/ml) [J Clin Oncology. 2009. 27. 3757-3763]. RCT negative – WHI Trial in which supplemental calcium and vitamin D were administered, and follow up was 8 years (J Natl Cancer Inst. 2008. 100. 1581-1591).
Prospective data in 44 men with low risk prostate cancer (Gleason score of 6 or less, PSA of 10 or less, clinical stage T1c or T2a) who elected active surveillance were administered 4000 IU per day vitamin D3 for one year. As compared with 19 historical controls, the proportion of patients who showed progression was lower in the vitamin D supplementation group (34% vs. 63%, p=0.025). Men in the vitamin D supplementation group with a baseline 25 OH vitamin D level of < 20 ng/ml seemed to benefit less from supplementation than those with a higher baseline vitamin D level (J Clin Endocrinol Metab. 2012. 97. 2315-2324). However, there is data showing a U shaped relationship between vitamin D levels and prostate cancer risk such that risk is lowest in those with levels of 18-28 ng/ml (Cancer Epidemiol Biomarkers Prev. 2014. 23. 1494-1504).
A meta-analysis of four randomized controlled trials on vitamin D supplementation and total cancer incidence, and three randomized controlled trials on vitamin D supplementation and total cancer mortality found that (1) vitamin D supplementation had no significant effect on total cancer incidence, and (2) vitamin D supplementation significantly reduced total cancer mortality by 12%. Individual trails were typically 2-7 years and typically used does of 400-1100 IU/day vitamin D (Keum N, Giovannucci E. Br J Cancer. Epub 6/10/2014).
Negative meta-analysis - a meta-analysis of 7 trials (n = 48,167) failed to show benefit of vitamin D supplementation on cancer mortality (Lancet Diabetes Endocrinol. 2014. 2. 307-320).
Negative meta-analysis - a second meta-analysis of 4 trials (n = 45,151) failed to show benefit of vitamin D supplementation on cancer mortality (Br J Cancer. 2014. 976-980).
Negative Cochrane review - data from 18 RCTs (n = 50,623) showed no benefit of vitamin D supplementation (Cochrane Database Syst Rev. 2014. CD007469).
Negative RCT - in a 4 year RCT of 2303 healthy postmenopausal women with an average baseline 25 OH vitamin D level of 32.8 ng/ml, 2000 IU/day vitamin D3 and 1500 mg/day calcium did not significantly reduce the risk of total cancer (HR 0.70, 95% CI 0.47-1.02) [JAMA. 2017. 317.1234-1243 and editorial 1217-1218].
Negative RCT - VITAL trial, a RCT of 25,871 older participants (median age 67 years), with a two-by-two factorial design of vitamin D3 2000 IU daily and fish oil 1 gram daily, containing 460 mg EPA + 380 mg DHA. Median follow up 5.3 years, and median 25 OH vitamin D level at baseline was 30.8 ng/ml. “Supplementation with vitamin D did not result in a lower incidence of invasive cancer … than placebo” (N Engl J Med. 2019. 380. 33-44 and editorial 91-93).
Cardiovascular disease - see ‘CAD just above
CHF
In NHANES 2001-2004, low vitamin D levels were present in 89% of adults with a combination of CAD and CHF (Am J Cardiol. 2008. 102. 1540-1544).
In a controlled study in 123 patients using 2000 IU/day of vitamin D, the treatment group showed a 43% increase in levels of IL-10, an anti-inflammatory cytokine, compared with controls. Additionally, there was no increase in TNF-alpha in the treatment group over the course of the study, whereas controls showed a 12% increase. The clinical relevance of this is uncertain, as ejection fraction did not increase in the treatment group (Am J Clin Nutr. 2005. 83. 754-759).
In a 3 month RCT of 80 infants with idiopathic cardiomyopathy, those randomized to 1000 IU daily of vitamin D3 showed an increase in vitamin D levels from 13 ng/ml to 33 ng/ml, and the average ejection fraction increased from 36% to 52%, clinically and statistically significant compared to the increase from 37% to 43% with placebo plus standard treatment (Shedeed SA. Pediatr Cardiol. Epub 2/18/12).
In the RECORD trial of 5292 subjects, those randomized to vitamin D 800 IU daily showed a 25% decreased risk of developing heart failure at 3 year follow up. This was a four arm trial, with subjects randomized to vitamin D 800 IU daily, calcium 1000 mg daily, vitamin D 800 IU daily + calcium 1000 mg daily, or placebo (Am J Clin Nutr. 2014. 100. 746-755).
MIXED RESULTS: In the VINDICATE study, a 1-year RCT of 229 patients (mean age, 69 years) with heart failure (New York Heart Association class II or III), a left ventricular ejection fraction (LVEF) of 45% or lower (mean, 26.1%), and a serum 25-hydroxyvitamin D level below 20 ng/ml (mean, 14.9 ng/ml), those randomized to 4,000 IU per day of vitamin D3 or placebo, those randomized to vitamin D supplementation showed a trend toward worse aerobic capacity but a significant improvement in physiological parameters (LVEF and left ventricular structure) [J Am Coll Cardiol. 2016. 67. 2593-2603].
NEGATIVE STUDY: In the EVITA trial, a 3 year study of 400 patients with NYHA Class II or III heart failure and a serum 25 OH vitamin D level below 30 ng/ml, the mortality rate was non-significantly higher in those randomized to vitamin D 4000 IU daily (19.6% vs. 17.9%, p=0.73), and the proportion of patients who needed a mechanical circulatory support implant (a secondary endpoint) was significantly higher in the vitamin D group (15.4% vs. 9.0%, p=0.03) [Eur Heart J. 2017. 38. 2279-2286].
Cognitive decline in the elderly
Low levels of vitamin D were associated with substantial cognitive decline in a prospective study of 858 adults age 65 or older at baseline, followed for 6 years (Arch Intern Med. 2010. 170. 1135-1141).
HOWEVER, in a RCT of 2157 adults aged 70 years or older, vitamin D3 2000 IU per day did not modify cognitive function, as measured by the Montréal Cognitive Assessment, at 3 years of follow-up (JAMA. 2020. 324. 1855-1868).
COPD
Negative small RCT. A one year RCT in 182 patients in which vitamin D3 was dosed at 100,000 IU once a month failed to show an effect on exacerbation rates (except in post-hoc analysis of the subgroup with 25 OH vitamin D levels < 10 ng/ml at baseline) even though the mean 25 OH vitamin D level in the treatment group rose to 52 ng/ml (Ann Intern Med. 2012. 156. 105-114 and editorial 156-157).
Negative systematic review and meta-analysis of individual patient data in 3 RCTs (N = 469) - found that vitamin D supplementation did not affect exacerbation rates except in the prespecified subgroup analysis of those with baseline levels < 10 ng/ml. Of note, in the two large studies in this meta-analysis (third study was small) the vitamin D was administered infrequently as at a high dose (Thorax. 2019. 74. 337-345).
Crohn’s disease
A RCT in 108 patients in remission showed that the relapse rate was 55% lower in the group treated with vitamin D 1200 IU/day (13% relapse rate in treatment group compared with 29% relapse rate in placebo group). Statistical significance only borderline though (p=0.06) [Aliment Pharmacol Ther. 2010. 32. 377-383].
In a 24 week uncontrolled study of 18 patients with mild to moderate Crohn’s disease, those who received 1000 IU per day initially, and then escalating doses every 2 weeks until serum 25-OH vitamin D level reached 40 ng/ml or the dose was 5000 IU per day, the mean CDAI score improved from 230 at baseline to 118 (p<0.0001) and quality of life scores improved significantly (p=0.0004). Mean 25 OH vitamin D level increased from 16 ng/ml at baseline to 45 ng/ml (Clin Trans Gastroenterol. 2013. 4. E33).
NEGATIVE TRIAL - in the EVITA trial, a 3 year RCT of 400 patients with NYHA class II or III heart failure and a serum level of 25 OH vitamin D below 30 ng/ml, the mortality rate was nonsignificantly 9.5% higher (19.6% vs. 17.9%, p=0.73) in those randomized to vitamin D 4000 IU daily, and the patients who needed mechanical circulatory support, a secondary endpoint was significantly higher in the vitamin D group (15.4% vs. 9.0%, p=0.03) [Eur Heart J. 2017. 38. 2279-2286].
Depression prevention
Ineffective at 2000 IU daily for a median treatment duration of 5.3 years in the VITAL-DEP ancillary study of 18,353 middle aged and older adults without depression at baseline (JAMA. 2020. 324. 471-480).
Depression treatment (also see ‘seasonal affective disorder’ below)
Benefit likely, based on epidemiologic data, theoretical rationale, and anecdotes, with limited controlled trial data, except for SAD (see below).
In a one year RCT in obese and overweight subjects, those randomized to 20,000 – 40,000 IU/week supplementation with Vitamin D showed significant improvement in BDI scores (J Intern Med. 2008. 264. 599-609).
In a large population-based cohort study involving 1,282 older adults between the ages of 65 and 95 years, vitamin D status was found to be compromised in patients with minor or major depressive disorder, based on measurement of 25-OH vitamin D levels and PTH levels (Arch Gen Psychiatry. 2008; 65(5): 508-12).
Negative RCT – 6 month RCT of 231 participants randomized to 40,000 IU vitamin D3 vs. placebo (even though the vitamin D group’s vitamin D levels rose from 19 ng/ml to a mean level of 59 ng/ml) [Kjærgaard M et al. Br J Psychiatry. Epub 7/12/12].
Augmentation of Prozac – an 8 week RCT of 42 patients with major depression found that those randomized to 1500 IU of Vitamin D along with Prozac 20 mg showed significantly greater improvement in depression symptoms at 4, 6 and 8 weeks (p<0.01). Mean serum 25 OH vitamin D level at baseline was 23 ng/ml (Khoraminya N, et al. Therapeutic effects of vitamin D as adjunctive therapy to fluoxetine in patients with major depressive disorder. Aust N Z J Psychiatry. 2013. 47. 271-275).
Detoxification – vitamin D is important in brain detoxification pathways.
Diabetes Type I prevention
In the North Finland Birth Cohort Study, children supplemented with 2000 IU per day vitamin D in the first year of life had an 80% lower risk of type I diabetes by age 31 (Lancet. 2001. 358. 1500-1503).
A meta-analysis of 5 observational studies of vitamin D supplementation reported a 29% reduction in relative risk of type I diabetes in children who ever received vitamin D supplementation (Arch Dis Child. 2008. 93. 512-517).
In an 18 month trial of 38 Brazilian patients with new onset type I diabetes, 2000 IU daily of vitamin D3 slowed the progression. At the end of the trial, fasting C-peptide levels were undetectable in 18.7% of vitamin D patients versus 62.5% of placebo patients (p=0.01) and stimulated C-peptide levels were undetectable in 6.2% of vitamin D patients versus 37.5% of placebo patients (p<0.05) [Arch Pediatr Adolesc Med. 2012. 166. 601-607].
Diabetes Type II prevention - vitamin D supplementation is beneficial
In the Nurses’ Health Study, analysis of data in 83,779 women showed that those taking supplemental vitamin D and calcium had a lower risk of developing diabetes, with greatest reduction in risk (33% reduction) seen with >1200 mg supplemental calcium in conjunction with>800 IU supplemental vitamin D (Diabetes Care. 2006. 29. 650-656).
A systematic review and meta-analysis of data from 8 trials (N = 4896) report a statistically significant relative risk reduction of 11% - 12% for new onset diabetes with vitamin D supplementation. Of the individual trials, 3 had a low risk of bias and the rest had either unclear or high risk of bias (Diabetes Care. 2020. 43. 1650-1658).
A meta-analysis of 9 trials (N = 43,559) also reported a statistically significant relative risk reduction of 11% - 12% for new onset diabetes with vitamin D supplementation. Of note, this meta-analysis included 2 trials (N = 38,780) that were conducted for non-diabetes outcomes (fracture reduction) and the data on new onset diabetes was derived from postdoc analyses (Barbarawi M et al. J Clin Endocrinol Metab. 2020. 105).
A systematic review and meta-analysis of the individual participant data from 3 randomized trials, with all 3 trials at low risk for bias, reported that vitamin D supplementation reduced the risk for diabetes by 15%, with a 3-year absolute risk reduction of 3.3% (Ann Intern Med. 2023. 176. 355-363 and ACP Journal Club. 2023. 176. JC55).
Dosages of vitamin D in these 3 trials were 20,000 IU vitamin D3 weekly (Tromso study of 511 participants), 4000 IU vitamin D3 daily (D2d study of 2423 participants), and 0.75 mcg eldecalcitol daily (DPVD study of 1526 participants).
Of note, in this meta-analysis there is no evidence of difference in the rate ratios for adverse events of kidney stones, hypercalcemia, hypercalciuria, or death (but vitamin D at these doses has been associated with hypercalcemia and falls vitamin D at these doses has been associated with hypercalcemia and falls in other clinical trials).
Diabetes Type II treatment
Higher 25-hydroxyvitamin D levels are correlated with improved insulin sensitivity in observational studies (Am J Clin Nutr. 2004. 79. 820-825; Int J Clin Pract. 2003. 57. 258-261; J Clin Biochem Nutr. 1992. 13. 45-51).
A 3 year intervention study in 92 people with impaired fasting glucose at baseline showed that those randomized to take vitamin D 700 IU daily with calcium citrate 500 mg daily showed a slower rise in blood glucose levels, and a smaller increase in HOMA-IR scores, a measure of insulin resistance (Diabetes Care. 2007. 30. 980-986).
Negative Trial: A 4 month RCT in 24 patients with relatively controlled diabetes failed to show any impact of 400 IU per day or 1200 IU per day of vitamin D3 upon fasting glucose, HbA1c, or insulin sensitivity. Mean 25 hydroxy vitamin D level increased in the low dose group from 17.6 ng/ml to 25.5 ng/ml and in the high dose group from 15.6 ng/ml to 27.4 ng/ml (J Diabetes. 2010. 2. 36-40).
In a 12 week RCT in 44 subjects, those randomized to receive 2000 IU/day of vitamin D showed improvements in a prespecified index of pancreatic function, in association with a rise in 25 hydroxy vitamin D level from 24 to 30 ng/ml (Am J Clin Nutr. 2011. 94. 486-494).
Eczema
4000 IU daily beneficial in a 21 day RCT (J Allergy Clin Immunol. 2008. 122. 829-31).
Beneficial in those with a low baseline vitamin D level of 7.4 ng/ml (J Am Acad Dermatol. 2013. 69. 238-244).
4000 IU daily INEFFECTIVE in a 3 week RCT of those with a baseline vitamin D level of 28.4 ng/ml ((J Eur Acad Dermatol Venereol. 2014. 28. 781-789).
1000 IU daily beneficial in a 1 month trial of 107 Mongolian children (presumably with vitamin D deficiency), with improvement in 31% of treatment group compared with 16% of placebo group (p=0.04) [J Allergy Clin Immunol. 2014. 134. 831-835].
Epilepsy – several anticonvulsant drugs interfere with the formation of calcitriol in the kidney. Supplementation with 4000-16,000 IU vitamin D2 shown to reduce seizure frequency (Br Med J. 1974. 2. 258-259).
Fall risk
Clinical data is mixed with the preponderance of data showing no benefit of vitamin D supplementation
See multiple additional citations on the Osteoporosis outline on this site, section on Vitamin D.
Fibromyalgia
Deficiency present in 50% in one study (J Rheumatol. 2001. 28. 2535-2539).
In a 24 week RCT of 32 women with fibromyalgia and a 25 OH vitamin D level of < 32 ng/ml, vitamin D supplementation (2400 IU daily for levels < 24, otherwise 1200 IU daily) raised vitamin D levels and significantly decrease pain severity (p = 0.03), but did not improve overall health or overall fibromyalgia severity (Pain. 2014. 155. 261-268).
Fracture healing - potential harm from high dose bolus. In a RCT of 32 postmenopausal women with a fracture of the distal radius, those who received a single dose of 75,000 IU vitamin D at the time of the fracture and a repeat dose of 75,000 IU 6 weeks later showed impaired fracture healing (J Bone MIner Res. 2021. 36. 1492-1501).
Grave’s disease – deficiency present in 58% in one study (Endocrinol J. 2001. 48. 63-69).
Hypertension
An 8 week RCT in 148 women, mean age 74, all with 25-OH vitamin D levels less than 20 ng/ml, showed a greater reduction in systolic blood pressure in those administered 800 IU vitamin D + 1200 mg calcium daily, as compared with those administered only the 1200 mg calcium (J Clin Endocrinol Metabol. 2001. 86. 1633-1637).
Data on 12,644 persons in NHANES III showed an inverse relationship between 25-hydroxy vitamin D levels and blood pressure. About ½ of the increased incidence of HTN in blacks as compared with whites could be attributed to ethnic differences in serum levels (Am J Hypertens. 2007. 20. 713-719).
A systematic review identified 3 cohorts that reported data on 25 OH vitamin D levels and HTN, found no significant heterogeneity amongst these studies; there was a 76% higher incidence for the odds of HTN in those with low versus high 25 OH vitamin D levels. This same review reported that 10 trials found that vitamin D supplementation did not significantly reduce systolic BP (mean difference -1.9 mm Hg) and did not affect diastolic BP (Ann Intern Med. 2010. 152. 307-314).
An 8 week RCT of 42 individuals with HTN and vitamin D deficiency showed that 50,000 IU weekly vitamin D3 significantly lowered systolic, diastolic, and mean arterial BP (Mozaffari-Khosravi H et al. Blood Press Monit. Epub 10/27/14).
However, in the DAYLIGHT trial, a 6-month trial RCT of 534 individuals with prehypertension or stage I hypertension and a serum 25 OH vitamin D level < 25 ng/ml, 4000 IU daily of vitamin D3 did not lower the mean 24-hour systolic BP, as compared with 400 IU vitamin D3 daily (Circulation. 2015. 131. 254-262).
However, in a RCT of 2157 adults aged 70 years or older, vitamin D3 2000 IU per day did not affect systolic or diastolic blood pressure at 3 years of follow-up (JAMA. 2020. 324. 1855-1868).
Infections - Negative trial: in a RCT of 2157 adults aged 70 years or older, vitamin D3 2000 IU per day did not affect the incidence of infections at 3 years of follow-up (JAMA. 2020. 324. 1855-1868).
Influenza (information derived from Vitamin D Council Newsletter 5/16/09, written by John Cannell, MD)
Virologists are concerned with three aspects of any influenza virus: (1) novelty, (2) transmissibility, (3) lethality.
In the macrophage, the presence of vitamin D also appears to suppress the pro-inflammatory cytokines. Thus, vitamin D appears to … dampen certain destructive arms of the immune response, especially those responsible for the signs and symptoms of acute inflammation, such as the cytokine storms operative when influenza kills quickly.
Recent evidence indicates seasonal impairments of the antimicrobial peptide (AMPs) are caused by seasonal fluctuations in 25-hydroxy-vitamin D levels. Antimicrobial peptides are a key component of the innate immune system – they protect mucosal epithelial surfaces by creating a hostile antimicrobial barricade. The epithelia secrete them constitutively into the thin layer of fluid that lies above the apical surface of the epithelium but below the viscous mucous layer.
RCT of supplementation showed mixed results – in a RCT in 334 school children conducted from Dec 2008 to March 2009, those who received 1200 IU/day vitamin D3 in supplement form had a significantly lower incidence of influenza A (p=0.04), diagnosed via influenza antigen testing with a nasopharyngeal swab specimen. However, there was a trend toward an increased incidence of influenza B (p=0.13), and overall, there was no significant change in total flu incidence between the supplemented and placebo group (Urashima M. Am J Clin Nutr. 2010. 91. 1255-1260).
Another RCT showed mixed results – in a 2 month RCT of 247 Japanese high school students randomized to receive 2000 IU daily of vitamin D3 or placebo during the 2009 pandemic of H1N1 influenza A, the incidence of influenza diagnosed by rapid diagnostic test was nonsignificantly higher by 11% in the treatment group, but post hoc analysis showed that the incidence was significantly lower in the vitamin D3 group in the first month of treatment (p<0.01), but higher in the vitamin D3 group in the second month. The findings of this study and the 2010 study, cited just above, raise the possibility that progressive accumulation of vitamin D leads to subtle toxicity which impairs immune system function (Food Funct. 2014. 5. 558-562).
Irritable bowel syndrome - Vitamin D3 50,000 IU every other week for 6 months beneficial in a RCT of 74 adults. The Vitamin D group experienced significant improvements in the mean IBS QoL scores in dysphoria, health worries, food avoidance, social reaction, relationships and sex life in comparison to the placebo group (P < 0.001) [Abbasnezhad A, et al. Effect of vitamin D on gastrointestinal symptoms and health-related quality of life in irritable bowel syndrome patients: a randomized double-blind clinical. Neurogastroenterology & Motility. 2016].
Kidney disease - In the VITAL-DKD study, a prespecified ancillary study to the VITAL study, with a 2 x 2 design of 1312 adults with type 2 diabetes, neither vitamin D3 2000 IU daily nor fish oil at a dose of EPA + DHA 1 gram per day for 5 years resulted in significant difference in change in estimated GFR at five years as compared with placebo (JAMA. 2019. 322. 1899-1909 and editorial 1866-1868).
Low back pain – deficiency present in 83% of 360 patients in one study (Spine. 2003. 28. 177-179).
Lupus - monitor for hypercalcemia
NOTE, Plaquenil interferes with conversion of vitamin D to calcitriol.
Deficiency present in 50% in one study (J Rheumatol. 2001. 28. 2535-2539). However, data on 186,389 nurses followed for 22 years in the Nurses Health Study did not show a relationship between vitamin D intake and risk of developing the disease (Costenbader FH et al. Ann Rheum Dis. Epub 7/31/07), suggesting the possibility that a low vitamin D level is a consequence of the disease and not a cause (BioEssays. 2008. 30. 173-182).
In a 1 year RCT of 267 patients with lupus, those randomized to receive 2000 IU daily vitamin D3 experienced a significant decrease in SLE-related antibodies (p=0.05) and a lower probability of a flare up (10% vs. 24%, p<0.05). The 25 hydroxy vitamin D levels in the treatment group increased from a mean of 19.8 ng/ml to 37.8 ng/ml (J Rheumatol. 2013. 40. 265-272).
In a 24 week RCT of 45 adolescents and young adults with juvenile-onset SLE, vitamin D3 50,000 IU weekly was associated with significant improvement in SLE Disease Activity Index (p=0.01) [Arthritis Care Res. 2016. 68. 91-98].
Macular degeneration (AMD) – protective effect, based on data from NHANES III (Arch Ophthamol. 2007. 125. 661-667).
Memory loss – see ‘Cognitive Decline’ just above
Migraine
In a 10 week RCT of 65 Iranians with migraine, randomized to either 50,000 IU Vitamin D weekly or placebo, (1) there was no significant difference in severity or duration of migraine between the two groups, but (2) there was a trend (p=0.06) toward a lower frequency of migraines in the treatment group. At baseline, 15.4% of patients were vitamin D deficient (< 12 ng/ml), and 66.1% were insufficient (12-30 ng/ml) [Mottaghi T et al. Effect of Vitamin D supplementation on symptoms and C-reactive protein in migraine patients. Journal of Research in Medical Sciences. 2015].
In a 24 week RCT of 57 adults with episodic migraine, those randomized to simvastatin 20 mg twice daily plus vitamin D 1000 IU twice daily showed a 30% fewer migraine days (p<0.001) [Buettner C., et al. Simvastatin and Vitamin D for Migraine Prevention. Ann Neurol. 2015].
Multiple sclerosis
Deficiency is present in 48% in one study (J Neuroimmunol. 2003. 134. 128-132).
In an interventional study in which the response of each patient was compared with his/her own case history as control, the number of exacerbations observed during 1-2 years of supplementation with 5000 IU per day vitamin D with 1000 mg calcium and 600 mg magnesium daily was less than one half the number expected from case histories (Med Hypotheses. 1986. 21. 193-200).
In the Nurses’ Health Study and Nurses’ Health Study II, a cohort of over 95,000 women, those who took vitamin D 400 IU daily had a 40% lower risk of developing multiple sclerosis (Neurology. 2004. 62. 60-65).
In a prospective nested case control study, higher serum vitamin D levels were associated with a lower risk for developing MS in Caucasians (JAMA. 2006. 296. 2832-2838).
In an interventional study in 12 patients with active MS who received progressively higher doses of vitamin D3, from 28,000 IU once a week to 280,000 IU once a week for 6 weeks, along with calcium 1200 mg/day, disease activity and disease progression did not change, but the number of gadolinium-enhancing lesions decreased significantly (p=0.03). No adverse effects were seen (Am J Clin Nutr. 2007. 86. 645-651).
An open-label randomized prospective controlled 52-week trial of 49 patients in which treatment patients received escalating vitamin D doses up to 40,000 IU/day over 28 weeks to raise serum 25-hydroxyvitamin D rapidly and assess tolerability, followed by 10,000 IU/day (12 weeks), and further down-titrated to 0 IU/day (along with Calcium 1,200 mg/day) concluded that high dose vitamin D is safe, with immunomodulatory effects. There was a trend toward fewer relapses in the treatment group (p=0.09). No adverse effects were seen (Neurology. 2010. 74. 1852-1859).
NEGATIVE TRIAL: In a 6 month RCT in 23 patients with relapsing-remitting MS, in which the treatment group was administered approximately 13,000 IU per day vitamin D2 dose adjusted to maintain a serum level of 25 OH vitamin D of 52-70 ng/ml), and the control group was administered 1000 IU per day vitamin D2, the median Expanded Disability Scale was significantly worse in the high dose group (p=0.04) and the relapse rate was significantly worse in the high dose group (p=0.04) [Neurology. 2011. 77. 1611-1618].
In a one year RCT of 30 patients with clinically isolated syndrome (optic neuritis), all of those randomized to vitamin D3 50,000 IU weekly delayed onset of multiple sclerosis, whereas 5 of the 11 control patients were diagnosed with multiple sclerosis (Derakhshandi H et al. Acta Neurol Belg. E pub 12/19/12).
In a one year RCT of 66 patients, in which the treatment group received 20,000 IU of vitamin D3 once a week as an add-on therapy with interferon beta 1b, those in the treatment group showed significantly fewer lesions on brain MRI and strong trends toward lower lesion burden, reduced disability scales, and improved ability to walk, compared to controls. 25(OH) D levels went from 22 ng/ml to 44 ng/ml in one year (J Neurol Neurosurg Psychiatry. 2012. 83. 565-71).
Muscle strength
6 months of vitamin D supplementation led to significant improvements in isometric knee extensor strength (Aging. 2000. 12. 455-460). Note that low 25-OH-vitamin D levels are correlated with sarcopenia (J Clin Endocrinol Metab. 2003. 88. 5766-5772).
See multiple additional citations on the Osteoporosis outline on this site, section on Vitamin D.
Musculoskeletal pain - in a Minnesota-based study of 150 patients aged 10 to 65 who presented with nonspecific musculoskeletal pain syndromes refractory to standard therapies, 93% had deficient levels of vitamin D (<20 ng/ml) [Mayo Clin Proc. 2003. 78. 1463-1470].
Osteoarthritis
Framingham data showed slower progression of knee osteoarthritis symptoms in those with higher 25-hydroxyvitamin D levels (Ann Intern Med. 1996. 125. 353-359). However, other epidemiologic studies have failed to link vitamin D intake or levels to the incidence or prevalence of osteoarthritis (Alt Med Alert. 2008. 11. 85-90).
Positive RCT – in a 1 year RCT of 103 patients, conducted in India, and with all patients with a baseline 25 OH level below 20 ng/ml, there was a greater decrease in WOMAC scores in the treatment group (p <0.001), and greater improvements in physical function in the treatment group (p <0.001). The treatment group received 60,000 IU of vitamin D for 10 days and then 60,000 IU once a month for a year (Sanghi D et al. Does Vitamin D Improve Osteoarthritis of the Knee: A Randomized Controlled Pilot Trial. Clin OrthopRelat Res. 2013).
Negative RCT - in a 2 year RCT of 146 participants with symptomatic knee OA, vitamin D3 2000 IU per day, with dose escalation to achieve a serum 25 hydroxy vitamin D level of > 36 ng/ml, was not associated with reduction in knee pain or cartilage volume loss (JAMA. 2013. 309. 155-162).
Osteoporosis
Dose of vitamin D for prevention of bone loss
RCTs show that vitamin D 800 IU is more effective than vitamin D 400 IU at stabilizing bone density (measured by DEXA scan).
High dose vitamin D increases bone loss based on a RCT of 333 adults in Calgary with a baseline 25 hydroxy vitamin D level in the normal range, randomized to 400 IU, 4,000 IU or 10,000 IU daily. Treatment with 4,000 IU daily and 10,000 IU daily significantly decreased BMD of the lower radius, as compared with 400 IU daily, and 10,000 ID daily significantly decreased BMD of the tibia, as compared with 400 IU daily (JAMA. 2019. 322. 736-745).
For the data on vitamin D and (1) fracture risk, (2) fall prevention, and (3) muscle strength go to the Osteoporosis outline on this site.
Otitis media prevention - a prospective controlled trial of vitamin D supplementation in children with a history of recurrent otitis media showed a significantly reduced incidence of acute otitis media in the subgroup of children with low baseline vitamin D levels (Pediatr Infect Dis J. 2013. 32. 1055–1060).
Pain – in an uncontrolled 12 week trial in Iran of 62 adult patients with chronic pain and treated with 50,000 IU/week of vitamin D3 and 1,000 mg of calcium/day, the researchers found that 53 of the 62 patients (85.5%) responded to treatment, with pain scores diminishing more than 60%. In 47 (75.8%) patients, the pain subsided completely. At baseline, 95% of the patients had levels less than 20 ng/ml (Abbasi M et al. Global J Health Sci. 2013. 5).
Parkinson’s disease – in a 12 month RCT of 112 patients randomized to 1200 IU vitamin D3 or placebo, vitamin D3 prevented progression. There was no worsening of scores in the treatment group on the HY scale, whereas the disease progressed in the placebo group (p=0.005). In addition, there was no worsening of scores in the treatment group on the UPDRS part II, whereas the disease progressed in the placebo group (p=0.004). 25 OH vitamin D levels rose from 22.5 ng/ml to 41.7 ng/ml in the treatment group (Am J Clin Nutr. 2013. 97. 1004-1013).
Peripheral arterial disease – data in 4839 participants in NHANES 2001-2004 shows that low 25-OH vitamin D levels are associated with a higher prevalence of peripheral arterial disease (Arterioscler Thromb Vasc Biol. 2008. 28. 1179-1185).
Polycystic ovary syndrome - supplementation with 1500 mg calcium daily and 50,000 IU vitamin D2 weekly shown beneficial in a small study (Steroids. 1999. 64. 430-435).
Pregnancy
Vitamin D supplementation in pregnancy is associated with a decreased risk of a multitude of chronic diseases.
In 2007, the Canadian Pediatric Society recommended that pregnant women take 2,000 IU of vitamin D3 per day. Some experts recommend even higher doses than 2000 IU/day vitamin D3 in pregnancy and for breastfeeding (Hollis BW, Wagner CL. Vitamin D deficiency during pregnancy: an ongoing epidemic. Am J Clin Nutr. 2006 Aug; 84:273; Wagner CL, et al. High-dose vitamin D3 supplementation in a cohort of breastfeeding mothers and their infants: a 6-month follow-up pilot study. Breastfeed Med. 2006 Summer; 1:59-70).
Psoriasis – calcitriol inhibits proliferation of human keratinocytes, and vitamin D analogues are available by prescription to treat this condition.
Respiratory infection prevention
A meta-analysis of 5 RCTs found that the combined relative risk for a respiratory infection was 0.58 for those taking vitamin D. The dose of vitamin D in the five trials ranged from 400 IU/day to 2,000 IU/day, with one using a single dose of 100,000 IU. The length of the trials ranged from 3 months to three years (J Pharmacol Pharmacother. 2012; 3:300-303).
A meta-analysis of 11 RCTs, conducted by the Karolinska Institute in Stockholm found a protective effect, with an odds ratio (OR) of 0.64 for taking a vitamin D supplement rather than a placebo. The protective effect was larger in studies using once-daily dosing compared to bolus doses (OR = 0.51 vs. OR = 0.86, p = 0.01).The doses of vitamin D in the studies was variable, and the studies were heterogeneous. The authors conclude “Aggregated evidence from 11 randomized controlled trials indicates that supplementation with vitamin D could be an effective means of preventing respiratory tract infection.” (Bergman P et al. PLOS One. 2013).
In a RCT of 107 long term care residents over age 60, high dose vitamin D, 100,000 IU once a month was associated with a significantly lower risk of respiratory infection (RR = 0.67), BUT falls were twice as common in the group supplemented with vitamin D (Ginde AA et al. J Am Geriatr Soc. ePub 11/16/16).
In a systematic review and meta-analysis of individual patient data from 25 high-quality RCTs (N = 11,321), vitamin D3 supplementation reduces the risk for acute respiratory tract infection. The effects were greatest in those with the lowest baseline 25 OH vitamin D levels. Adverse event rates were similar to those with placebo (BMJ. 2017. 356. i6583, as cited in ACP Journal Club. 2017. 166. JC51).
A systematic review and meta-analysis of data from RCTs shows that supplementation of 400 - 1000 IU daily reduces the risk of upper respiratory infections (Lancet Diabetes Endocrinol. 2021. 9. 276-292).
Rheumatoid arthritis
Deficiency is common (Proc Soc Exp Biol Med. 2000. 223. 230-233). Data on 1160 patients with rheumatoid arthritis, mean age 64, at the Washington D.C. VA showed that deficiency was present in 45%, insufficiency in 85%, with a mean vitamin D level of 22 ng/ml (presentation 2009 meeting American College Rheumatology).
However, data on 186,389 nurses followed for 22 years in the Nurses' Health Study did not show a relationship between vitamin D intake and risk of developing the disease (Costenbader FH et al. Ann Rheum Dis. Epub 7/31/07), suggesting the possibility that a low vitamin D level is a consequence of the disease and not a cause (BioEssays. 2008. 30. 173-182).
In the Iowa Women’s Health Study, vitamin D intake correlated inversely with disease prevalence (Arthritis Rheum. 2004. 50. 72-77).
High dose vitamin D supplementation may be harmful – in a one year RCT of 22 patients, all with baseline 25 OH vitamin D levels < 25 ng/ml, vitamin D treatment was associated with a significant worsening of the Patient Assessment of Global Health (p=0.02) and Patient Global Assessment of RA (p=0.01). Treatment group received vitamin D2 50,000 IU 3 times per week for 4 weeks, then 50,000 IU twice a month, with dose increased to 50,000 IU weekly if 25 OH vitamin D level at 2 or 5 months was < 25 ng/ml (J Clin Rheum. 2014. 20. 112-114).
Positive intervention trial – in an open-label trial of 73 patients with active rheumatoid arthritis and a 25 OH vitamin D level < 20 ng/ml, those randomized to 60,000 IU weekly of vitamin D weekly for 6 weeks, followed by 60,000 IU monthly for a total trial duration of 12 weeks showed less disease activity and improved vitamin D levels at 12 weeks (Chandrashekara S et al. Int J Rheum Dis. Epub 10/20/15).
Seasonal affective depression – supplementation with 400-800 IU vitamin D3 improved mood in a study of 44 patients (Psychopharmacology. 1998. 135. 319-323).
Statin induced muscle pain – a small trial showed that those with this condition and vitamin D deficiency diagnosed by blood test experience resolution of symptoms within 3 months of initiation of vitamin D, and most do not have recurrence of symptoms upon re-challenging with the statin (Clin Endocrinol. 2009. 71. 154-156).
Strength – see section just above ‘Muscle Strength’
Stroke
Negative RCT: After 5 years of follow up in 2686 men and women 65 years or older randomized to receive 100,000 IU vitamin D3 every 4 months, the hazard ratio for stroke in the vitamin D group was 1.02 (0.77 – 1.36). Of note, this study did show significant reduction in bone fractures, with a hazard ratio of 0.78, but did not show benefit in reduction of incidence of ischemic heart disease (see ‘CAD’ just above). The daily supplemental dose can be calculated at 100,000 IU divided by 122 days = 820 IU/day (BMJ. 2003. 326. 469-472).
Negative RCT: In the Women’s Health Initiative, after 7 years of follow up in 36,282 postmenopausal women randomized to receive calcium carbonate 1 gram per day + vitamin D 400 IU per day, the hazard ratio for stroke in the calcium + vitamin D group was 0.95 (0.82-1.10). This was not a predetermined endpoint in the study though, and fewer than 60 % of participants had adequate adherence to study medications at the end of this trial (Circulation. 2007. 115. 846-854).
Negative meta-analysis - a meta-analysis of 8 trials (n = 46,43`) failed to show benefit of vitamin D supplementation in stroke or cerebrovascular disease (Lancet Diabetes Endocrinol. 2014. 2. 307-320).
Traumatic brain injury – a 3 month, 3-arm RCT of 60 patients in Iran showed benefit in the group randomized to receive one mg/kg of progesterone intramuscularly every 12 hours for 5 days and also 200 IU/kg of vitamin D once-a-day for 5 days. At 3 months, 35% of patients in the progesterone + vitamin D group made “Good Recovery,” as assessed by the Glasgow Outcome Scale, while only 25% met this assessment in the progesterone group and only 15% in the placebo group (p=.03). Ten-percent died in the progesterone + vitamin D group, compared to 20% in the progesterone group and 40% in the placebo group (p=.03) [Aminmansour B et al. Adv Biomed Res. 2012].
Tuberculosis – low levels of vitamin D are common (Thorax. 1985. 40. 187-190), and the time taken to convert to sputum negativity can be predicted by the VDR genotype (Tuberculosis. 2007. 87. 295-302).
Upper respiratory infections (also see ‘respiratory infections’ just above)
Observational studies have reported an inverse association between serum 25 hydroxy vitamin D levels and incidence of upper respiratory infections
Negative RCT: An 18 month RCT of 322 healthy adults with a mean baseline serum 25 hydroxy vitamin D level of 29 ng/ml showed that monthly administration of 100,000 IU of vitamin D3 did not reduce the incidence or severity of URI’s in healthy adults, even though the serum level was increased to 48 ng/ml in the treatment group (JAMA. 2012. 308. 1333-1339 and editorial 1375-1376).
Negative RCT in young healthy children: A RCT of 349 participants aged 1-5 randomized to receive either 400 IU daily vitamin D or 2000 IU daily vitamin D for a minimum of 4 months between September and May showed no difference in the frequency of wintertime upper respiratory infections (JAMA. 2017. 318. 245-254).
Vitamin E (Mayo Clin Proc. 2001. 76. 1131-1136; Alt Med Alert. 2007. 10 37-42)
Consists of a group of 8 molecules, 4 tocopherols and 4 tocotrienols, each named alpha, beta, gamma, and delta, which function as lipid-soluble antioxidants.
The tocopherols and tocotrienols (i.e. alpha, beta, gamma, delta) differ from each other with regard to the chemical structure of the head of the molecule (i.e. location and number of methyl groups).
The tocopherols differ from the tocotrienols with regard to the chemical structure of the tail of the molecule (i.e. the number of double bonds).
Alpha tocopherol is the most abundant member of the vitamin E family in human blood and tissues, but it is estimated that 70% of vitamin E in our diet is in the form of gamma tocopherol. The explanation for this discrepancy between dietary intake and plasma levels is a preferential uptake of alpha tocopherol by the hepatic alpha tocopherol transfer protein.
Supplementation with just alpha tocopherol can decrease plasma gamma tocopherol levels by 30-50% in humans (J Nutr. 1985. 115. 807-813; J Nutr. 2003. 133. 3137-3140).
History
Named in 1924 as a missing factor in the diet that was making male rats sterile.
Based on this, main function of vitamin E was thought to be support of reproductive capacity.
Alpha tocopherol was isolated in 1936, beta and gamma tocopherols in 1937, delta tocopherol at a later date, the tocotrienols not until the 1950s.
Potency
Based on the mistaken notion that the primary function of vitamin E is to support reproductive capacity, the potencies of the different tocopherols were determined with a fetal resorption rat bioassay (i.e. the dose needed to prevent fetal resorption in vitamin E deficient rats).
Based on the rat bioassay, alpha tocopherol was determined to be the most potent form of vitamin E. Based on this assay, beta tocopherol is 50% as potent as alpha tocopherol, gamma tocopherol is 10% as potent as alpha tocopherol, alpha tocotrienol is 30% as potent as alpha tocopherol, the potency of the other 4 members of the family of 8 compounds is too low to be a factor.
As scientists learn of the multiple functions of the various tocopherols and tocotrienols in the body, potency becomes somewhat irrelevant, as potency is useful only for comparing compounds with the same function. Tocotrienols may be 40-60 times morpotent than tocopherols in their antioxidant capacity, and up to 70 fold more bioavailable
Activity of vitamin E as expressed in IU is based on the fetal resorption rat bioassay, and thus IU is not a useful measure for the purpose of measuring the relative amounts of the different tocopherols and tocotrienols in a supplement.
Nomenclature
RRR-alpha tocopherol is the new name for d-alpha tocopherol, which is the natural form (i.e. the form found in nature).
All-rac-alpha tocopherol is the new name for dl-alpha tocopherol, which is the synthetic form.
Units of measure and regulatory change
1 IU vitamin E = 0.67 mg for d-alpha-tocopherol (natural), , and effective in 2020, 1 mg vitamin E (as alpha-tocopherol) label claim = 1 mg of natural α-tocopherol
1 IU vitamin E = 0.9 mg for dl-alpha-tocopherol (synthetic), and effective in 2020, 1 mg vitamin E (as alpha-tocopherol) label claim = 2 mg of synthetic α-tocopherol
Dosage equivalents for vitamin E (Papas A. The Vitamin E Factor. 1999. Appendix C).
d alpha tocopherol 1.49 IU/mg
d alpha tocopheryl acetate 1.36 IU/mg
d alpha tocopheryl succinate 1.21 IU/mg
dl alpha tocopherol 1.10 IU/mg
dl alpha tocopheryl acetate 1.0 IU/mg
dl alpha tocopheryl succinate 0.89 IU/mg
Common food sources include oils of vegetables, nuts, and seeds.
Palm fruit oil (not to be confused with palm kernel oil) is the only common and complete source of all 4 tocotrienols.
Cooking or processing foods can substantially lower vitamin E amounts.
Gamma tocopherol is the predominant form of vitamin E in food.
Supplement forms of vitamin E (The Vitamin E Factor (1999) by Andreas Papas, PhD. Ch 3-4)
Synthetic vitamin E, dl-alpha tocopherol is a mixture of 8 different stereoisomers; there is no evidence that it is harmful to humans, but there is good evidence in humans (deuterium tagged studies, tissue biopsies) that synthetic vitamin E is 50% as bioavailable as natural vitamin E (and 1/3 as bioavailable as synthetic vitamin E to the fetus). Synthetic vitamin E is manufactured in large chemical plants, usually from the chemicals isophytol and trimethyl hydroquinone.
“Natural” vitamin E, d-alpha tocopherol, is bioidentical to the vitamin E found in food sources. It is a single stereoisomer. Natural vitamin E may be synthesized from beta, gamma, and delta tocopherols via a chemical process called methylation, and thus is called “natural-source” – the raw material for production of natural vitamin E is vegetable oil deodorizer distillate, a by-product of vegetable oil processing.
Alpha tocopherol, both natural and synthetic, may be esterified (i.e. alpha-tocopherol acetate or alpha-tocopherol succinate) by chemically combining alpha-tocopherol (an alcohol) with an acid – the purpose creation of the ester is to protect the tocopherol (alcohol) from oxidation in the vitamin tablet or capsule; esterases in the gut remove the acid, making the free tocopherol available for absorption. This is thus not problematic for humans.
TPGS (d-alpha tocopherol polyethylene glycol 1000 succinate) is a special ester form which dissolves in water and may be a superior chemical form for people with diseases which affect the gut (AIDS, cystic fibrosis, IBD) and rare diseases characterized by inability to produce bile acids.
Mixed tocopherols – beware these may contain filler oil as 33-50% of the product, and the filler oil may be subject to rancidity.
Mixed tocopherols and tocotrienols.
Functions of vitamin E in the body – maintenance of cell membrane integrity through free radical quenching potential. In addition to its anti-oxidant (i.e. free radical quenching) activity, vitamin E can also “modulate cellular behavior by specific interactions with enzymes, structural proteins, lipids, and transcription factors (Zingg JM, Azzi A. Non-antioxidant activities of vitamin E. Curr Med Chem. 2004. 11. 1113-1133).
In the process of neutralizing free radicals, tocopherols become tocopheryl free radicals.
Vitamin E free radicals are reduced back to tocopherol form primarily by vitamin C, but also by coenzyme Q 10 and reduced glutathione.
Oxidized vitamin C is converted to reduced vitamin C by two molecules of glutathione. Glutathione, a tripeptide composed of cysteine, glycine, and glutamic acid, requires adequate dietary intake of these amino acids for synthesis, and requires selenium and riboflavin to cycle through its redox pathway. Tylenol (acetaminophen) may deplete the body of glutathione.
Antioxidants in the body function like a relay team – surface active antioxidants (i.e. polyphenols) shuttle free radicals from fat soluble antioxidants to water soluble antioxidants, and are then excreted in the urine (Sears, Barry. The Anti-Inflammation Zone. 2005).
An in vivo 8 week trial showed a significantly greater increase (p < 0.01) in superoxide dismutase (SOD) and endothelial constitutive nitric oxide synthase (ecNOS) in the mixed tocopherol group compared with the alpha-tocopherol group (Am J Clin Nutr. 2003. 77. 700-706).
Effects of vitamin E in animal models and cell cultures:
Alpha tocopherol reduces at atherosclerotic lesions (J Am Coll Nutr. 1992. 11. 131.138).
Alpha tocopherol reduces smooth muscle cell proliferation (Lancet. 1995. 345. 170-175).
Alpha tocopherol reduces platelet adherence and aggregation (J Am Coll Nutr. 1991. 10. 466-473).
Alpha tocopherol reduces protein kinase C activation (Diabetes Res Clin Pract. 1999. 45. 169-182).
Alpha tocotrienols is more effective than any other molecule in preventing neurodegenation in cell cultures; alpha tocotrienols protects against stroke in rodents and dogs.
Gamma tocopherol inactivates nitrogen free radicals (i.e. peroxynitrate, produced in part from nitric oxide) more effectively than alpha-tocopherol.
Gamma tocopherol is a stronger antioxidant than alpha tocopherol in humans, and it also has anti-inflammatory effects, inhibiting activation of NF-Kappa B, as well as gene regulatory activity.
Gamma tocopherol can inhibit COX-2 enzyme to a greater extent than alpha tocopherol, based on an ex-vivo study on human macrophages (Proc Natl Acad Sci USA. 2000. 97. 11494-11497).
Gamma tocopherol can improve endothelial function
Gamma and delta tocotrienols can lower cholesterol by 15-22%, lower triglycerides, and raise HDL/LDL ratios.
Effects of vitamin E in humans (basic research):
Alpha tocopherol can improve endothelial function (J Am Coll Cardiol. 2000. 36. 94-100).
Alpha tocopherol, the predominant antioxidant in the LDL particle, inhibits oxidation of LDL (JAMA. 2001. 285. 1178-1182). Animal and test tube data also show that alpha tocopherol inhibits the oxidation of LDL.
NEGATIVE EFFECT – d-alpha-tocopherol lowers HDL, and specifically HDL-2.
Gamma tocopherol supplementation in patients on dialysis lowered hs-CRP levels from 4.4 to 2.1 (p < 0.02) whereas supplementation with alpha tocopherol did not have a significant effect. Furthermore, a 61% decrease in gamma tocopherol in response to alpha tocopherol supplementation has been documented (Kidney Int. 2003. 64. 978-991).
Gamma tocopherol exhibits an anti-proliferative effect on prostate cancer cells in tissue culture (Ann N Y Acad Sci. 2004. 1031. 399-400).
Gamma tocopherol inactivates nitrogen free radicals, such as peroxynitrite (Proc Natl Acad Sci. 1997. 94. 3217-3222).
A metabolic degradation product of gamma-tocopherol appears to be a natriuretic factor (Proc Natl Acad Sci. 1996. 93. 6002-6007).
Tocotrienols partially inhibit the activity of HMG CoA reductase, involved in the biosynthesis of cholesterol.
Tocotrienols increase arterial compliance, based on a RCT in 36 healthy males (Arch Pharm Res. 2008. 31. 1212-1217).
Delta tocotrienol stops Chlamydia from entering cells via ‘lipid rafts.’
Epidemiological data indicate an inverse association between cardiovascular risk and vitamin E intake from dietary sources and/or supplements (Ann Intern Med. 1995. 123. 860-872).
Observational studies in patients without established CAD support a role of Vitamin E in atherosclerosis prevention.
Nurses’ Health Study - A prospective, observational study of 87,245 women aged 34-59. Those who took at least 100 IU/day of supplemental Vitamin E for at least 2 years had a 40% lower risk of developing coronary artery disease after 8 years than controls (New Engl J Med. 1993. 328. 1444-1449).
Health Professionals Follow-up Study – A prospective, observational study of 51,529 U.S. male health professionals aged 40-75. In the subgroup of the 39,910 who were free of diagnosed coronary heart disease, diabetes, and hypercholesterolemia at baseline, those who consumed over 60 IU/day of Vitamin E had a 36% lower risk of developing coronary artery disease after 4 years than those consuming less than 7.5 IU/day (New Engl J Med. 1993. 328. 1450-1456).
Cholesterol Lowering Atherosclerosis Study (CLAS) - of 156 men who had undergone CABG, men with self selected intake of at least 100 IU of Vitamin E/day had less coronary artery disease progression over two years by serial quantitative angiography (JAMA. 1995. 273. 1156-1162).
Established Populations for Epidemiologic Studies of the Elderly - found a decrease risk of overall mortality and mortality due to CAD among 11,178 elderly persons who had used Vitamin E supplements (Am J Clin Nutr. 1996. 64. 190-196).
NOTE THOUGH that more recent published data from the Physicians’ Health Study, a prospective observational study in 83,639 US male physicians, showed that there was no significant difference in cardiovascular disease in the 29% who were taking vitamin E, vitamin C, or a multivitamin, compared with the rest of the cohort (Arch Intern Med. 2002. 162. 1472-1476).
Early randomized controlled trials were positive with regard to Vitamin E and heart disease prevention.
CHAOS Study - natural vitamin E (d-alpha tocopherol acetate) 400-800 IU/day in 2002 patients with angiographically-confirmed CAD reduced the rate of nonfatal MI by 77%, but did not reduce cardiovascular mortality (Lancet. 1996. 347. 781-786).
HOWEVER, 8 large randomized clinical trials with a combined total of approximately 130,000 patients have failed to show a significant benefit of Vitamin E in the prevention of CAD events.
ATBC Study - 29,133 male smokers in southern Finland were assigned to receive 50 IU/day of synthetic Vitamin E or placebo and 20 mg of beta carotene or placebo. After a median treatment of 6.1 years, no significant reduction was noted in nonfatal myocardial infarction or CAD mortality (Arch Intern Med. 1998. 158. 668-675). Note though, at 19 years of follow up, men in the highest quintile of serum alpha-tocopherol (>13.5 mg/L) at baseline (i.e. before supplementation) as compared with the lowest quintile (<10 mg/L) had 16% lower mortality from CHD (p<0.02) and 37% lower mortality from ischemic stroke (p<0.02). Note that there was a correlation at baseline between the serum alpha-tocopherol levels and serum gamma-tocopherol levels (Am J Clin Nutr. 2006. 84. 1200-1207).
GISSI-Prevenzione trial - 11,324 patients were randomized within 3 months of experiencing a MI to receive 30 mg/day of synthetic Vitamin E, 1 gram/day of omega 3 fatty acids, both, or placebo. Benefit was seen for the omega 3 fatty acids, but not for vitamin E (Lancet. 1999. 354. 447-455).
HOPE Study - 2545 women and 6996 men 55 years of age or older who had documented vascular disease or diabetes plus one other coronary risk factor were randomized to receive 400 IU/day of natural vitamin E, ramipril, both, or placebo. After a mean treatment period of 4.5 years no significant differences were noted between Vitamin E and placebo with regard to rate of MI, rate of CVA, or death from cardiovascular disease. Benefits were seen with ramipril (New Engl J Med. 2000. 342. 145-153).
In the HOPE-TOO study, a 2.5 year extension of the HOPE study, 7030 of the original 9541 original study enrollees who were still alive elected to participate. After a mean of 7.2 years of follow up vitamin E did not significantly reduce the risk of a composite endpoint of including cardiovascular death, nonfatal MI, and stroke (P=0.31) or any of the individual components of this composite endpoint (JAMA. 2005. 293. 1338-1347).
HOPE-TOO also did not reduce the relative risk of total cancer incidence or cancer death (JAMA. 2005. 293. 1338-1347).
HOPE-TOO did find a statistically increased risk of heart failure in the vitamin E group (P=0.007) and an increased risk of hospitalization due to heart failure in the vitamin E group (P=0.002). This data comes from subgroup analysis; it was not a predetermined endpoint (JAMA. 2005. 293. 1338-1347).
PPP Study - 4495 men and women with one or more coronary risk factors were randomized to receive 100 mg/day of aspirin, 300 mg/day of synthetic Vitamin E, both, or placebo. The primary endpoint was cardiovascular death, nonfatal MI, or nonfatal CVA. A 29% reduction was seen with aspirin, but no reduction with vitamin E (Lancet. 2001. 357. 89-95).
HPS Study – 20,536 individuals with coronary artery disease, occlusive arterial disease, or diabetes who were randomized to receive vitamin E 600 mg daily + vitamin C 250 mg daily + beta carotene 20 mg daily or placebo. 83% in each group completed the 5 year follow up. Despite a significant increase in blood levels of the vitamins, there were no differences between the treatment and placebo groups with regard to all-cause mortality, nonfatal MI, or heart disease death (Lancet. 2002. 360. 23-33).
Women’s Health Study – 39,876 apparently healthy women aged 45 years or older were randomized to receive 600 IU of natural source alpha tocopherol every other day, and followed up for an average of 10.1 years (JAMA. 2005. 294. 56-65 with editorial 107-109).
No benefit of vitamin E was seen except in the subgroup of women over age 65.
HOWEVER, in women over age 65, there was a significant 26% reduction in relative risk for the composite endpoint of MI, CVA, or cardiovascular death. In this subgroup of women, there was a 34% reduced risk of MI (p=0.04) and a 49% reduced risk of cardiovascular death (p<0.001).
Note that vitamin E also did NOT reduce the risk of cancer in this cohort.
Note that the women in this study on average were at very low risk for CAD - only 1100 of 28,000 who were screened had a greater than 10% 10-year risk of heart disease, based on Framingham score.
Women’s Antioxidant Cardiovascular Study - 8171 female health care professionals at increased risk of cardiovascular disease (a previous event or 3 or more risk factors). A 2 x 2 x 2 design found no overall effects from vitamin E (d alpha tocopherol acetate 600 IU every other day), vitamin C 500 mg/day or beta carotene 50 mg every other day, alone or in combinations (Arch Intern Med. 2007. 167. 1610-1618).
Physicians’ Health Study II - 14,641 US male physicians who were age 50 or older at entry; only 5.1% of the cohort had prevalent cardiovascular disease at entry. The treatment group received 400 IU of vitamin E (synthetic alpha tocopherol) every other day along with 500 mg of vitamin C daily. At 8 years of follow up, neither vitamin E nor vitamin C reduced the risk of major cardiovascular events. In this trial, there was a 74% increase in the risk of hemorrhagic stroke associated with vitamin E supplementation, but no increase in the incidence of CHF (JAMA. 2008. 300. 2123-2133).
Two studies looking at changes by quantitative angiography actually show worsening when Vitamin E is given with Vitamin C.
A three year RCT in which 160 patients were assigned to one of four regimens: (1) placebo, (2) simvastatin (Zocor) plus niacin (OTC Slo Niacin or Niacor) with specific parameters for dosage titration based on LDL and HDL cholesterol levels, (3) antioxidants twice daily (total dose daily of 800 IU of d-alpha-tocopherol, 1000 mg of vitamin C, 25 mg of natural beta carotene, and 100 ug of selenium), or (4) simvastatin plus niacin plus antioxidants. This study showed that antioxidant vitamins when taken with niacin and prescription Zocor attenuated benefits in terms of HDL2 cholesterol level, clinical events, and coronary atherosclerosis by quantitative angiography (N Engl J Med. 2001. 345. 1583-1592).
WAVE trial - RCT in 423 postmenopausal women with angiographically-confirmed CAD, those who received vitamin E 400 IU twice a day and vitamin C 500 mg twice a day there was no improvement in angiographic progression at 2.8 years, and there was a actually a trend toward worse outcomes (death, nonfatal MI, stroke) in the anti-oxidant vitamin group (JAMA. 2002. 288. 2432-2440).
Vitamin E supplements in doses of 400 IU per day and higher may increase all-cause mortality, based on a meta-analysis of 19 clinical trials with 135,967 participants (Ann Intern Med. 2005. 142. 37-46). This study is critiqued in an editorial (Ann Intern Med. 2005. 142. 75-76). A superb critique is a commentary in a journal not indexed on Pub Med (Integrative Medicine: A Clinician’s Journal. 2005. 4 [1]. 14-17).
The meta-analysis may be unreliable because heterogeneous trials were combined for analysis.
9 trials tested vitamin E alone and 10 trials tested vitamin E combined with other vitamins or minerals.
Beta-carotene was used in 4 of the high-dose vitamin E trials.
One trial involved use of a supplement with 80 mg of zinc oxide and 2 mg of cupric oxide – cupric oxide is very poorly absorbed as per a presentation by Dr Alan Gaby, and zinc-induced copper deficiency in this trial could be the basis of the increased mortality in this trial.
The entry criteria for the various trials in the meta-analysis were variable.
Only one trial (HOPE) used natural vitamin E, as opposed to synthetic vitamin E.
The trials that tested high dosages involved adults with chronic disease, not healthy adults.
Most of the evidence for an elevated mortality risk at high doses comes from 2 trials that administered vitamin E with beta-carotene.
Three other published meta-analyses concluded that vitamin E at doses up to 800 IU per day had no effect on either cardiovascular or all cause mortality (J Gen Intern Med. 2004. 19. 380-389; Arch Intern Med. 2004. 164. 1552-1556; Lancet. 2003. 361. 2017-2023).
Uses: Note that the USPSTF recommends in 2014 and 2022 AGAINST vitamin E supplementation for prevention of cancer or CVD in adults (JAMA. 2022. 327. 2326-2333).
Alzheimer’s disease
Prevention - most trials of supplemental vitamin E for prevention of Alzheimer’s do not show benefit.
Treatment - In the ADCS trial, Vitamin E 2000 IU/ day in showed some benefit in a 2 year RCT with 341 patients who received either alpha tocopherol 2000 IU/day, selegiline(Eldepryl)10 mg/day, both, or placebo. In analyses that included baseline MMSE score as a covariate, the median time to the primary outcome (death, institutionalization, loss of ability to perform basic activities of daily living, or severe dementia) was 440 days in the placebo group, 585 days in the combined treatment group (p = 0.049), 655 days with selegiline (p = 0.012), and 670 days with vitamin E (p = 0.001). Surprisingly though cognitive decline was not delayed in the vitamin E treatment group (New Engl J Med. 1997. 336.1216-1222). A Cochrane review found that this study was the only study of vitamin E for treatment of Alzheimer’s of sufficient quality for evaluation (Cochrane Database Syst Rev. 2000. CD002854).
Cancer
No benefit seen for breast, colon, or lung cancer in the Women’s Health Study (JAMA. 2005. 294. 56-65 with editorial 107-109).
Lower cancer mortality at 19 years of follow-up in male smokers in the ATBC trial in the highest quintile of serum alpha-tocopherol (>13.5 mg/L) at baseline (i.e. before supplementation) as compared with the lowest quintile (<10 mg/L) suggests a benefit of at least low dose supplementation. Specifically, men in the highest quintile had a 21% lower mortality from lung cancer (p<0.02) and a 32% lower mortality from prostate cancer (p<0.02) (Am J Clin Nutr. 2006. 84. 1200-1207).
Vitamin E supplementation at a dose of 400 IU/day associated with a 70% lower risk of developing advanced prostate cancer in 29,361 male smokers enrolled in the screening arm of the PLCO trial (J NCI. 2006. 98. 245-254).
The USPSTF (United States Preventive Services Task Force) in 2022 “recommends against the use of … vitamin E supplements for the prevention of cardiovascular disease or cancer” [D recommendation] (JAMA. 2022. 327. 2326-2333).
End stage liver disease (ESLD) - mixed tocotrienols, based on improvement in MELD scores noted as an unanticipated outcome of a Phase I trial to examine absorption of mixed tocotrienols (J Nutr. 2012. 142. 513-519).
Hypercholesterolemia – there is some data that gamma and delta tocotrienols lower LDL cholesterol.
Immune response – data is mixed
Vitamin E 200 mg/day for 235 days in healthy seniors is associated with significant improvements in various tests which assess the strength of the immune system, based on a RCT in 88 seniors over age 65. In this study, 200 mg/day was more beneficial than 800 mg/day (JAMA. 1997. 277. 1380-1386).
In a 441 day RCT in 652 non-institutionalized individuals over age 60, only 1.3% of whom had suboptimal alpha-tocopherol plasma concentrations at baseline, illness duration was actually worse (19 days versus 14 days, p = 0.02) in the vitamin E 200 mg/day group (JAMA. 2002. 288. 715-721).
(JAMA. 2004. 292. 828-836).
Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH)
800 IU/day d-alpha tocopherol was beneficial, with P=0.001 (and pioglitazone 30 mg/day was not beneficial) in a 96 week RCT in 247 adults without diabetes. Primary endpoint was an improvement in NAFLD activity score, based on histologic findings (N Engl J Med. 2010. 362. 1675-1685).
800 IU per day d-alpha tocopherol was somewhat beneficial in a 96 week RCT of 173 children (ages 8-17) with biopsy-proven NAFLD. Reduction in ALT levels, the primary endpoint, was statistically significantly greater in the vitamin E group at 48 weeks, but not statistically significantly different at 96 weeks (sustained reduction in 26% of those administered vitamin E vs. 16% of those administered placebo). In terms of secondary measures, the mean improvement in the NAFLD activity score was greater with vitamin E than with placebo (p=0.02) and the proportion of patients who had resolution of NASH was greater with vitamin E than with placebo (p=0.006). NOTE this study was reported in JAMA as negative based on failure to achieve significance at 96 weeks in terms of the primary endpoint (possibly due to adherence to diet and exercise recommendations in the placebo group). NOTE this was a 3 arms study, and metformin was ineffective by all measures (JAMA. 2011. 305. 1659-1668).
Mixed tocotrienols can improve and even cure NAFLD, based on 1 year data in 30 patients presented at 2010 meeting of the American Association for the Study of Liver Disease. Fifteen patients were cured (Hepatology. 2010. 52 [4 Suppl]. 642}.
Osteoarthritis (Z Orthop Ihre Grenzgeb. 1986. 124. 340-343; J Am Geriatr Soc. 1978. 26. 328-330). Rapid response to vitamin E in treatment of osteoarthritis in the small trials suggests that its effect may be from a metabolic action.
Periodontitis (chronic) - 300 IU every other day for 3 months, as an adjunct to scaling and root planning beneficial, based on a RCT of 38 patients (J Peridiontol. 2014. 85. 242-249).
Peripheral vascular disease – increases walking distance (for details of the studies, go to ‘Proven benefits of vitamins and minerals in pharmacologic doses’ near the top of this web page).
Restless legs – may be beneficial, based on a trial in 9 patients (J Applied Nutr. 1973. 25. 8-15).
Wound healing – topical application might reduce scar formation cuts or burns or surgical incisions.
Possibly effective for autoimmune diseases, diabetes, epilepsy, infertility, leg cramps, macular degeneration, multiple sclerosis, myopathy, neuropathy, premenstrual cramps and tardive dyskinesia.
Probably not effective in slowing progression of ALS, based on a RCT in 160 patients administered either vitamin E 5000 IU/day or placebo (J Neural Transm. 2005. 112. 649-660).
Probably not effective for treatment of Parkinson's disease based on data from the DATATOP study, in which 2000 IU/day did not slow progression in Parkinson's disease.
Probably not effective for treatment of hot flashes (Return to Home Page, click on "Osteoporosis", and scroll all the way to the bottom of the outline to alternative treatments for menopause.
Risks: NOTE minimal toxicity in studies of Vitamin E that have used doses as high as 3200 IU and with 10 years of follow up.
Higher all-cause mortality in a meta-analysis (see details above) – mechanism may be decreased concentrations of gamma and delta tocopherol induced by high supplemental doses of alpha tocopherol. This inverse relationship has been demonstrated in humans based on blood tests (J Nutr. 1985. 115. 807-813; J Nutr. 2003. 133. 3137-3140).
Bleeding – increased risk of minor bleeding, such as epistaxis, may be an issue. HOWEVER, there is no consistent evidence to suggest that vitamin E supplementation causes serious bleeding events, such as hemorrhagic stroke (JAMA. 2005. 294. 56-65; Arterioscler Thromb Vasc Biol. 2000. 20. 230-235). Possible excess bleeding in surgery (discontinue 2 weeks before and for 2 weeks after surgery).
HTN – in an Australian study designed around a hypothesis that vitamin E would lower BP in diabetics, the investigators unexpectedly found that both mixed tocopherols and d-alpha tocopherol increased mean daytime and nighttime BP in patients on antihypertensives (2006 presentation 16th Annual European Meeting on Hypertension). Possible mechanism – interference with metabolism of prescription medications for BP.
Prostate cancer – in the SELECT trial at 7 years of follow up, there was a statistically significant increased risk of prostate cancer in the vitamin E group (RR 1.17, p=0.008) as well as a slight, non-significant increased risk in the Vitamin E + selenium group (RR 1.05, p=0.46) [JAMA. 2011. 306. 1549-1556].
Requirements: RDA in adults is 15 mg alpha tocopherol which is equivalent to 22 IU of RRR-alpha tocopherol or 33 IU of all rac-alpha tocopherol.
Requirement for vitamin E increases in those consuming plentiful amounts of polyunsaturated fatty acids in diet.
According to 1996 USDA data, 69.4% of Americans obtain less than the RDA of vitamin E from their diet.
According to NHANES III, 92% of U.S. men and 98% of U.S. women obtain less than the RDA of vitamin E from their diet (J Am Diet Assoc. 2004. 104. 567-575).
The most recent study states that 93% of U.S. men and 96% of U.S. women obtain less than the RDA of vitamin E from their diet (Am J Clin Nutr. 2006. 84. 959-960).
Dosage:
Historically, the dose for supplementation has been chosen empirically, without actually measuring the effect of vitamin E on oxidative stress.
A study in which accepted biomarkers for lipid peroxidation were measured concluded that the dose of vitamin E required to reduce oxidative stress is 1600-3200 IU/day (Free Radical Biol Med. 2007)
Safety:
UL in 2000 defined as 1500 IU of RRR-alpha tocopherol or 1100 IU of all rac-alpha tocopherol.
Interaction with coumadin not apparent in a clinical trial (Am J Cardiol. 1996. 77. 545-546), but suspected based on an increased INR in a patient, confirmed by rechallenge (JAMA. 1974. 230. 1300-1301)
Popularity of supplements
NHANES III data shows that 11.3% of U.S. adults used supplements, leading to an intake of 400 IU/day or greater (Ann Intern Med. 2005. 143. 116-120).
A survey showed that prior to the negative publicity, 64% of health care professionals had an intake of vitamin E of 400 IU/day or greater (Arch Intern Med. 2002. 162. 1472-1476).
Sales of vitamin E supplements have dropped as the safety of this nutrient has been called into question. Sales estimated at $336 million in 2009, compared with $771 million in 2000 (Nutrition Business Journal)
Vitamin K
Vitamin K1 discovered in 1929.
Even though fat soluble, not stored in the body, so must be provided daily.
Natural Vitamin K exists in three forms
Phylloquinone or phytonadione (Vitamin K1)
Green leafy vegetables are the main dietary source of vitamin K1. Also present in plant oils, but hydrogenation of plant oils converts the vitamin K1 into a chemical form that does not function as vitamin K1 in the body.
Vitamin K1 in food is tightly bound to chlorophyll and may be difficult to absorb, such that only approximately 10% reaches the circulation (J Nutr. 1998. 128. 785-788).
Vitamin K1 in supplement form (when consumed with some fatty food) is more bioavailable than vitamin K1 in food (J Nutr. 1999. 129. 1201-1203; J Nutr. 2002. 132. 2609-2612).
Menaquinone or menatetrenone (Vitamin K2)
A family of related compounds, menaquinones 2-9.
Some menaquinones are produced by intestinal bacteria – it is estimated that intestinal bacteria produce 75% of the vitamin K that the body absorbs each day.
Small amounts of vitamin K2 are present in food - dietary sources of vitamin K2 are organ meats, butter, egg yolks, cheese, and fermented dairy products.
Natto (a fermented soy product) is a rich source of vitamin K2 as menaquinone 7.
MK-4 and MK-7 are available as OTC dietary supplements
Vitamin K2 may be more important to cardiovascular health and cancer prevention than vitamin K1.
Absorption of K2 supplements is up to 10 times greater than absorption of K1 supplements, and vitamin K2 from supplements persists in the bloodstream for up to 72 hours, whereas vitamin K1 breaks down within 8 hours of consumption (Blood. 2007. 109. 3279-3283).
Menadione (vitamin K3) is a synthetic form of vitamin K1 used as experimentally as a component of cancer chemotherapy; the FDA has banned the use of vitamin K3 in human nutritional supplements due to toxicity
Functions
Cofactor for post-translational carboxylation of glutamyl residues in specific proteins involved in blood coagulation (multiple Gla proteins). Glutamic acid is a component of at least 14 proteins.
Cofactor for the Gla protein osteocalcin, which incorporates calcium into the bone architecture.
Cofactor for matrix Gla protein (MGP), which prevents calcification in soft tissue (blood vessels, breasts, kidneys). Vitamin K2 can balance vitamin D, preventing soft tissue calcification in animals.
Vitamin K2 (MK-7) reduces calcium accumulation in vascular walls (Nutrients. 2015. 7. 6991-7011; Nutrients. 2015. 7.. 8905-8915).
Vitamin K2 may stabilize plaque (Atherosclerosis. 2015. 240. 10-16).
Vitamin K2 induces tumor cell apoptosis (Mol Pharmacol. 2013. 83. 613-620; J Cancer Res Clin Oncol. 2008. 134. 803-812).
Vitamin K2 restores production of mitochondrial ATP (Science. 2012. 336. 1241-1242; Science. 2012. 336. 1306-1310).
Vitamin K2 in the brain contributes to the production of myelin, independent of its carboxylation activities.
Vitamin K2 is also important for vision health and joint health.
Risk factors for deficiency include renal disease, hepatic disease, salicylate use, and malabsorption. A course of an antibiotic may increase the risk of deficiency by depleting the normal intestinal flora.
Uses:
Prevention of cancer
Theoretical benefit, based on function of inducing tumor apoptosis (see functions just above).
A prospective study of 24,340 Europeans free of cancer at baseline showed an inverse relationship between vitamin K2 intake and cancer incidence and mortality. No association was found for vitamin K1 intake (Am J Clin Nutr. 2010. 91. 1348-1358).
Prevention of osteoporotic fractures (see Osteoporosis outline on this web site).
Prevention of MI
Theoretical benefit, based on functions of reducing calcium accumulation in vascular walls and plaque stabilization (see functions just above).
Test tube data shows that 15 mg vitamin K2 three times a day in supplement form dissolves calcifications in the coronary arteries (Thromb Res. 2008. 122. 411-417). However, see information on ‘Safety’ just below
In an unpublished observational study of men aged 50-70, low vitamin K status was associated with 2.7 fold increase in the risk of severe coronary artery calcification (Fam Pract News. 2002. 32. 1-2).
In the Rotterdam Heart Study, an observational study in which 4807 subjects who were tracked for 7 years, inverse associations were found between vitamin K2 intake and severe aortic calcification, as well as all-cause mortality. 32.7 mcg/day provided protection against calcification in this study (J Nutr. 2004. 134. 3100-3105). Dietary sources of K2 include organ meats, egg yolks, cheese, and fermented dairy products, and natto. Vitamin K2 is also synthesized by intestinal microflora.
Data collected in 564 postmenopausal women by using food frequency questionnaires found less calcification of the coronary arteries in those with the highest vitamin K2 intake, whereas vitamin K1 intake was not correlated with coronary calcification (Beulens, JW et al. Atherosclerosis. 2008. epub).
Data in 16,057 postmenopausal women showed high consumption of natural vitamin K2 was correlated with reduced risk of CHD at 8 years of follow up. Consumption of vitamin K1 had no effect (Gast GC et al. Nutr Metab Cardiovasc Dis. 2009. epub).
In a 3 year RCT in 380 healthy men and women aged 60-80, those receiving a multivitamin with 500 mcg per day of vitamin K1 and with compliance with taking > 85% of the doses showed a slower rate of progression of coronary artery calcification than those in the control group taking a multivitamin without the high dose of vitamin D [p=0.03] (Am J Clin Nutr. 2009. 89. 1799-1807).
In a 1-year RCT of 243 men and women (40-70 years old), vitamin K2 as MK-7, 180 mcg daily improved arterial elasticity (Vermeer C et al. Vascul Dis Ther. 2020. 5. 1000179).
Treatment of morning sickness
Treatment of peripheral neuropathy - vitamin K2 as MK-7, at a dose of 100 mcg twice a day for 8 weeks he had a beneficial effect on those with peripheral neuropathy due to either vitamin B12 deficiency or diabetes, based on the results of a RCT of 100 participants (J Pharmacol Pharmacother. 2018. 9. 180-185).
Enhances athletic performance - menaquinone-7 at a dose of 300 mg daily for 4 weeks, followed by 150 mg daily for 4 weeks (available commercially as MyoMax, Nu Science Trading) beneficial in a RCT of 26 aerobically trained male and female athletes, with a 12% increase in maximal cardiac output measured in the treatment group [p=0.031] (Altern Ther Health Med. 2017. 23[4]. 26-32).
Safety:
Even though Vitamin K is fat soluble, toxicity is not well defined.
Vitamin K2 has been studied in a number of human trials of 1-2 years duration, with no toxicity and very few adverse effects documented.
However, in a RCT of 68 patients with diabetes and cardiovascular disease, intake of 360 mcg/day of MK-7 was associated with a nonsignificant increase in arterial calcification of the femoral artery (Zwakenberg SR et al. Am J Clin Nutr. Epub 8/16/19).
However, in a RCT of 48 patients with ESRD, on hemodialysis, intake of 360 mcg/day of MK-7 was associated with a nonsignificant increase in coronary artery calcification (Clin Kidney J. 2021. 14. 2114-2123).
Vitamin K3 triggers the production of superoxide free radicals as a consequence of its metabolism in the mitochondria (Free Radic Biol Med. 2008. 44. 768-778).
Vitamin K counteracts effects of prescription coumadin.
Laboratory assessment – most sensitive test is measurement of levels of uncarboxylated osteocalcin – high levels indicate a functional vitamin K deficiency
RDA is 90 mcg in adult females and 120 mcg in adult males.
Minerals
Forms of minerals:
The body is unable to use most minerals in their free or elemental state. The body needs them in an ionic state as found in chemical compounds.
The molecular form of a mineral may affect absorption.
Inorganic salts are the combination of a mineral with an inorganic acid (i.e. carbonate, sulfates).
Organic salts which are combinations of a mineral with an organic acid (i.e. succinates, fumarates, gluconates, citrates, picolinates) may be more easily absorbed by the body than inorganic salts.
Chelates are complicated compounds in which the mineral is held in the middle of a large organic molecule (aspartates, glycinates, selenomethionine).
These may be the best absorbed forms.
Some chelators may change the environment of the GI tract, thereby reducing or enhancing bioavailability.
There is not evidence to support the claims that colloidal minerals are superior to other forms of mineral supplements.
These are often not actual mineral suspensions and may contain levels of minerals too low to even be detected, so absorption may be less than with other forms of minerals.
These may be contaminated with toxic elements such as aluminum, lead, or strontium.
Absorption of minerals:
The form of the mineral is important, as outlined above.
Bioavailability of minerals is significantly influenced by the presence of other minerals - and excess of one mineral in a supplement can interfere with the absorption of other minerals from supplements or the diet.
Enteric coating can alter the absorption of a mineral - the acidity of the stomach can affect the extent of dissolution of the enteric coating in the stomach; a higher pH will cause greater dissolution of the enteric coating in the stomach rather than the intestines.
Time-release minerals may not be absorbed because they may bypass the absorption site in the small intestine.
Minerals and human physiology:
Approximately 18 different minerals have known physiologic function in 2004.
The functions of minerals in the body include as coenzymes, opening channels for transport across cell membranes, altering electrical currents to generate nerve impulses, and initiating muscle contraction.
Classification of minerals:
Major minerals – body needs are in excess of 100 mg per day – calcium, chloride, magnesium, phosphorous, potassium, and sodium.
Minor minerals – body needs are measured in mcg per day – arsenic, boron, chromium, cobalt, copper, fluoride, iodine, iron, manganese, molybdenum, nickel, selenium, silicon, tin, vanadium, and zinc.
Calcium
Calcium is the most abundant mineral in the body; 99% of total body calcium is found in the bones and teeth.
Functions – necessary for normal bone and tooth development, nerve impulse conduction, muscle contraction, intracellular signaling, hormonal secretion, and blood clotting.
Requirements:
RDA is currently set at 1000 mg for adults aged 19-50 and 1200 mg for women older than 50 and men older than 70. Note though that some authorities such as Walter Willett, MD, DrPH feel the RDA might be set too high.
Calcium balance studies, the basis of the RDA, may provide deceptive information because calcification of joints and artery walls and soft tissue, which is common in adults but not desirable, will contribute to the value determined for zero calcium balance.
A cross sectional study of 2310 healthy adults found that as long as there is adequate vitamin D intake (as assessed by a 25-hydroxy vitamin D level), calcium intake of 800 mg/day may be adequate for maintaining calcium homeostasis, as assessed by a normal serum intact PTH level (JAMA. 2005. 294. 2336-2341).
Requirements for a given individual will also depend on other dietary factors such as protein intake and salt intake (listed below) which affect elimination of calcium.
Average intake for U.S. adults estimated at 800 mg/day; prehistoric intake estimated at 1900 mg/day.
Supplements:
Dose is usually 500-1000 mg per day of elemental calcium.
Calcium is more efficiently absorbed if given in divided doses. Do not exceed 600 mg at one time.
Most supplements are approximately 30% absorbed; other than achlorhydria in which calcium carbonate is not well absorbed, there is little published data on differential absorption of different forms of calcium supplements.
Note that some natural calcium supplements such as dolomite and bone meal may be contaminated with lead.
There is no evidence to support claims that coral calcium is superior to other forms of calcium, and in fact in 2003 the FDA and the FTC brought charges against certain marketers for unsubstantiated claims (Los Angeles Times Health Section. 9/29/03).
Dissolution of supplements is important, especially for calcium carbonate, which can be packed so tightly in tablet form that it passes through the GI system intact – look for USP designation on the label.
Forms of calcium – as per Michael Murray, N.D. there is no single best form of calcium for everyone.
Calcium carbonate is 40% elemental calcium. This is an alkaline preparation which requires stomach acid for dissolution.
Calcium citrate or malate is 20% elemental calcium. This is an acidic preparation which can exacerbate GI symptoms due to hyperacidity. A potential benefit of these preparations is that citric acid and malic acid have been shown to chelate excess aluminum.
Calcium lactate is 13% elemental calcium.
Calcium triphosphate is 38% elemental calcium
Calcium hydroxyappetite is 25% elemental calcium.
Absorption:
Calcium is absorbed via:
An active, vitamin D dependent transcellular process in the duodenum and jejunum.
A passive, vitamin D independent paracellular process in the ileum.
Humans with vitamin D sufficiency absorb 30-40% of ingested calcium, depending in part on intake and in part on state of health (absorption is increased to as much as 80% during pregnancy and lactation). Absorption is only 10-15% with vitamin D insufficiency which often leads to secondary hyperparathyroidism.
Since calcium is absorbed in the small intestine where the pH is basic or normal, stomach acid is not needed for calcium absorption per se.
Phosphorous, phytic acid, oxalic acid (oxalate), cocoa, and excess dietary fat may interfere with calcium absorption.
Calcium absorption is enhanced by substances which increase its solubility - hydrochloric acid, ascorbic acid, citric acid, lysine, and glycine.
Some types of fiber surprisingly may actually enhance calcium absorption.
There is published data that calcium citrate malate is up to twice as absorbable as calcium carbonate (Altern Med Rev. 1999. 4. 74-85).
Distribution - bone tissue contains 95-99% of the body’s total calcium.
Utilization – “Increasing the magnesium intake improves rather than interferes with calcium utilization” (Am J Clin Nutr. 1987. 45. 1305-1312).
Elimination:
Calcium is excreted in the kidneys and also eliminated in the feces (calcium from sloughed mucosa and calcium in digestive secretions).
Excess dietary protein, sodium, glucose, and aspartame may increase renal loss of calcium. 6 mg of calcium are required to offset the urinary loss of calcium that occurs with 1 gram of protein intake.
Excess dietary fiber, caffeine, and alcohol may increase fecal elimination.
Benefits:
Blood pressure reduction. Colorectal adenomas – a meta-analysis of 3 RCTs with 1485 patients found that calcium supplements significantly reduce the rate of recurrence of adenomas (Am J Gastroenterol. 2005. 100. 390-394).
Kidney stones - in moderate amounts, contrary to conventional wisdom, may decrease risk of recurrent calcium oxalate kidney stones. Calcium citrate is the recommended form in patients with a history of kidney stones; this may actually reduce the risk of stones by reducing urinary saturation of calcium oxalate and calcium phosphate.
Mortality - prospective observational data in 38,772 older women in the Iowa Women’s Health Study showed that use of calcium and vitamin D was associated with a decreased risk of all cause mortality. Note this finding seems to contradict a meta-analysis of RCTs showing an increased risk of MI in those taking calcium supplements (Arch Intern Med. 2011. 171. 1625-1633).
Osteoporosis prevention – conflicting data in RCTs of calcium supplementation and observational studies examining calcium intake (see Osteoporosis outline on this web site for details)
PMS treatment - multi-center trial of 466 women taking 1200 mg calcium carbonate per day (Am J Obstet Gynecol. 1998. 179. 444-452).
Toxin neutralization - unabsorbed calcium in the gut lumen (which averages 90% of intake) complexes and neutralizes certain potentially harmful products of digestion, such as oxalic acid, free fatty acids, and bile acids – the effect is purely chemical and is immediate.
Weight loss - the data is mixed (J Am Diet Association. 2005. 105. 1401-1407), with the preponderance of evidence showing no effect of calcium or dairy on weight loss (Alt Med Alert. 2006. 9. 49-55). A 2 year RCT in 340 overweight or obese adults failed to show any benefit of supplementation with calcium carbonate 750 mg twice a day with meals (Ann Intern Med. 2009. 150. 821-829).
Risks:
Excess calcium if not accompanied by intake of supplemental magnesium (2:1 ratio of calcium to magnesium) may predispose to magnesium deficiency (Gaby A. Preventing and Reversing Osteoporosis. 1994).
Excess calcium if not accompanied by intake of supplemental silicon (2-5 mg/day in a multimineral preparation) might predispose to silicon deficiency (Gaby 2011 presentation “Controversies in Nutrition”).
Excess calcium might interfere with conversion of Vitamin D to its active form (Willett W. Eat, Drink, and Be Healthy. 2001).
Calcium supplementation decreases the absorption of phosphorous.
Doses of calcium carbonate above 20 grams per day (above 4 grams per day in those with renal failure) can cause “milk-alkali” syndrome.
Cardiovascular disease risk - see 'MI' just below.
Dementia - "Calcium supplementation may increase the risk of dementia in elderly women with cardiovascular disease" based on prospective observational data in a cohort of 700 women (Kern J et al. Neurology. Epub 8/17/16).
Glaucoma – diagnosis significantly more likely in those who consumed > 800 mg/day of supplemental calcium (Invest Ophthalmol Vis Sci. 2012. 53. 725-731).
Kidney stones - in the WHI, in which 36,282 women were randomized to calcium carbonate 500 mg twice a day with vitamin D 200 IU twice a day, there was a 17% increased risk of kidney stones. (N Engl J Med. 2006. 354. 669-683).
See just above though (section on benefits of calcium supplementation) regarding suggestive data that calcium citrate is protective against recurrent calcium oxalate stones.
Other data suggests that higher dietary calcium intake is associated with a decreased risk of kidney stones, presumably by interfering with oxalate absorption.
It is hypothesized that the higher risk of kidney stones observed with supplemental calcium intake may be related to calcium supplements taken without food.
Macular degeneration – individuals in the highest quintile of calcium supplementation (> 800 mg/day) were 85% more likely to be diagnosed with age-related macular degeneration than those who did not consume supplements (JAMA Ophthalmol. 2015. 133. 746-754).
Myocardial infarction (MI) - data is conflicting, and there is scant evidence for biological mechanisms linking calcium supplementation to atherosclerotic heart disease.
Intake of calcium citrate supplements at a dose of 1 gram per day associated with twice the incidence of cardiovascular events (MI, CVA, and sudden death) in a 5 year RCT in 1471 healthy postmenopausal New Zealand women. There were 101 events in the treatment group, 54 events in the placebo group. Vascular event rate was higher in those with higher compliance, and higher during 30-60 months of follow up rather than initially, suggesting a causal effect. The NNT to cause one additional MI was 44 and the NNT to cause one additional stroke was 56. Possible confounding factors not addressed in the study include low intake of magnesium and/or vitamin D (BMJ. 2008. 336. 262-266).
Intake of calcium supplements >500 mg/day increases the risk for MI by 30%, but not does not increase all-cause mortality or stroke, based upon a meta-analysis of 8 RCTs (N=10,908). Trials in which vitamin D was also supplemented were excluded from this analysis (BMJ. 2010. 341. c3691). NOTE that none of these trials was designed to test the hypothesis that calcium supplementation causes MI, and borderline statistical significance (p=0.035-0.038) in this post hoc meta-analysis may be due to chance rather than a true causal relationship between calcium supplementation and MI (Gaby 2011 presentation “Controversies in Nutrition”).
A meta-analysis of both study- and patient-level data from RCTs showed that calcium supplements with or without vitamin D supplementation increased the risk for MI (RR 1.24), and CVA (RR 1.15) [BMJ. 2011. 342. d2040].
However, another meta-analysis failed to show an association between calcium supplementation with or without vitamin D supplementation on coronary heart disease events (J Bone MIner Res. 2015. 30. 165-175).
An updated systematic review and meta-analysis of randomized trials and prospective cohort and nested case-control studies showed that "Calcium intake within tolerable upper limits (2000 to 2500 mg/d) is not associated with CVD risk in generally healthy adults" (Ann Intern Med. 2016. 165. 856-866).
An expert panel convened by the National Osteoporosis Foundation and the American Society for Preventive Cardiology analyzed the data in this systematic review. Based on the findings of the expert panel, "The National Osteoporosis Foundation and the 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. In light of the evidence available to date, calcium intake from food and supplements that does not exceed the tolerable upper limit of intake (... 2000 to 2500 mg/d) should be considered safe from a cardiovascular standpoint" (Ann Intern Med. 2016. 165. 867-868).
Prostate cancer - intake of calcium above 1200-1500 mg/day is associated with an increased risk of prostate cancer.
Analysis of 2776 men in the French SU.VI.MAX Study showed a higher risk of prostate cancer in those with higher dairy and calcium intake (Br J Nutr. 2006. 95. 539-545).
Data in 47,750 males in the Health Professionals Follow-up Study showed that higher calcium intake (>1500 mg/day) was associated with an increased risk of high-grade (Gleason >7) prostate cancer and fatal prostate cancer (Cancer Epidemiol Biomarkers Prev. 2006. 15. 203-210).
A meta-analysis of 12 studies found that men with the highest intake of dairy and calcium had a higher risk of prostate cancer (J Natl Cancer Inst. 2005. 97. 1768-1777).
Supplementation dose - as a general guideline, men do not require supplemental calcium, and for women, 300 - 500 mg of elemental calcium daily is sufficient (even though some experts recommend 500 mg twice a day).
For more information, return to Home Page, click on "Osteoporosis" and scroll to "calcium."
Magnesium
Total human stores of magnesium estimated at 24 grams - bone tissue contains 53% of the body’s total magnesium, muscles contain 27%, soft tissue contains 19%.
99% of magnesium is in the cells, with only 0.3% in the serum
Functions
Cofactor in the synthesis of ATP, participates in at least 300 intermediary enzymatic reactions; essential for most energy-requiring reactions.
Calcium channel blocker, NMDA receptor antagonist (and thus relaxes muscles and relaxes nerves)
Cofactor for 1-alpha-hydroxylase, the enzyme which converts 25-OH vitamin D to its active form, 1, 25 dihydroxy vitamin D
Requirements
RDA is 400-420 mg in men, 310-320 mg in women.
According to USDA surveys, 62% of Americans fail to consume the RDA of magnesium (Consumer Reports on Health. 6/05).
NHANES III data shows that 75% of Americans don’t obtain the RDA of magnesium (Adv Data; 1994. 258: 1-28). NHANES 1999-2000 data shows that 50% of Caucasians consumed < 755 of the RDA and that magnesium intake was on average 25% lower in African Americans than in Caucasians (J Nutr. 2003. 133. 2879-2882).
Dietary magnesium intake has decreased in the US from approximately 400-500 mg per day in the early 20th Century to 200-300 mg/day in the early 21st Century (Nutr Res. 2018. 76. 526-538). Evidence from paleolithic diets suggest humans consumed four times more calcium in a paleolithic diet than in a standard Western diet (Am J Kidney Dis. 1994. 24. 737-752).
Food sources include whole grains, dark green leafy vegetables, legumes, and nuts and seeds (especially almonds, cashews and pumpkin seeds) - an estimated 80% of magnesium content is lost when whole grain flour is refined; an estimated 50% is lost when vegetables are boiled.
Absorption and utilization
As per Russell Jaffe, MD, choline citrate enhances magnesium uptake
High fat diet may decrease magnesium utilization by 50% (Seelig M, Rosanoff A. The Magnesium Factor. 2003. Pp 129-130).
Excess phosphorous (present in soda) interferes with magnesium absorption.
Oxalates in food interfere with magnesium absorption
High calcium intake can cause magnesium deficiency via interference with absorption and promotion of excretion (Am J Clin Nutr. 1987. 45. 1305-1312).
Vitamin B6 increases intracellular uptake of magnesium (Abraham G. Ann Clin Lab Sci. 1981. 11. 333-336).
Dysbiosis (based on animal data) can interfere with magnesium absorption via production of excess tricaballyate, which binds magnesium tightly in the gut.
Consumption of excess alcohol and caffeine as well as certain medications such as diuretics and digoxin depletes the body of magnesium.
Chronic sleep deprivation has been reported to cause magnesium deficiency (Clin Cardiol. 1997. 20. 265-268).
Various kinds of physical, chemical, and emotional stresses, including sleep deprivation and exposure (in animals) to excessive noise can deplete magnesium, with the effect presumably mediated by excess adrenalin secretion. This can create a viscous cycle whereby magnesium deficiency aggravates the negative effects of stress (Artery. 1981. 9. 205-211; J Am Coll Nut. 1985. 4. 165-172. Am J Otolaryngol. 1994. 15. 26-32; Clin Cardiol. 1997. 20. 265-268; Magnesium. 1986. 5. 201-210).
Forms of magnesium - inorganic forms tend to have a higher percentage of elemental magnesium, but organic forms tend to have relatively higher absorption rates (and lower relative absorption is associated with an increased possibility of GI side effects)
Magnesium aspartate – well absorbed; in some individuals, the aspartate may cause neuromuscular irritability or excitation
Magnesium carbonate - 28.9% elemental magnesium
Magnesium chloride – 25.5% elemental magnesium. NOTE applied topically.
Magnesium citrate – 11.3% elemental magnesium
Magnesium gluconate – 5.8% elemental magnesium
Magnesium glycinate – 14.1% elemental magnesium. NOTE In some individuals, the glycinate may cause neuromuscular irritability or excitation.
Magnesium hydroxide – 42% elemental magnesium; laxative
Magnesium lactate – 12% elemental magnesium
Magnesium malate - 15.5% elemental magnesium
Magnesium oxide – 60.3% elemental magnesium; commonly prescribed by physicians, may have lower bioavailability (less well absorbed than magnesium aspartate, citrate, chloride, and lactate) but clinical benefit shown with this form of magnesium in at least 6 clinical trials (Magnes Res. 2001. 14. 257-262; J Am Coll Nutr. 1990. 9. 48-55).
Magnesium succinate -
Magnesium sulfate – 10% elemental magnesium. NOTE administered parenterally
Magnesium taurinate - well absorbed (Magnes Res. 2001. 14. 257-262; J Am Coll Nutr. 1990. 9. 48-55).
Assessment of magnesium status:
Virtually all magnesium is intracellular, so serum magnesium is an insensitive test for detecting deficiency.
Rbc magnesium may be a more sensitive test (even though only 0.5% of magnesium stores are in rbc’s)
Intracellular magnesium (scraping from the frenulum of the tongue sent to Intracellular Diagnostics) considered very sensitive.
Magnesium load test (measurement of 24 hour urine magnesium before and after an oral loading dose) considered very sensitive.
Leg cramps and cold hands and feet are symptoms which suggest the possibility of a magnesium deficiency.
Safety:
Supplements can cause diarrhea or sometimes fast transit time in the absence of diarrhea - measure intestinal transit time by eating beets or corn and seeing how many hours until it appears in the stool - if transit time is less than 12 hours, decrease the dose of magnesium. 10 mg per day of pyridoxal 5’ phosphate (active form of vitamin B6) can be used to treat magnesium-induced diarrhea (as an alternative to lowering the dose).
Can accumulate in those with renal insufficiency.
Uses
Theoretical rationale and/or anecdotes and/or uncontrolled trials - anxiety, attention deficit disorder, autism, chronic fatigue syndrome, coronary artery disease, congestive heart failure, constipation (milk of magnesia, magnesium citrate), diabetes, dyspepsia (magnesium-containing antacids), epilepsy, fatigue, fibromyalgia, insomnia, nephrolithiasis prevention in chronic stone formers, osteoporosis prevention and treatment. NOTE it may take 6 weeks to 6 months to replenish body stores (Am J Health Syst Pharm. 2004. 61. 1569-1576).
Allergies - benefit seen in a one month RCT in 28 patients administered either placebo or 365 mg/day of magnesium as magnesium pidolate (Magnes Res. 1990. 3. 109-112) and a 4 month RCT in 55 patients administered either placebo or magnesium 365 mg/day as magnesium aspartate hydrochloride (Magnes Res. 1996. 9. 81).
Asthma – data is mixed
A Cochrane review of nebulized magnesium found that the addition of nebulized magnesium to nebulized beta agonist improved pulmonary function in acute asthma, with a trend toward fewer hospital admissions (Cochrane Database Syst Rev. 2005. CD003898).
A meta-analysis concluded that the addition of parenteral magnesium sulfate to standard treatment with bronchodilators and steroids is probably beneficial in the treatment of moderate to severe acute asthma in children (Arch Dis Child. 2005. 90. 74-77).
An earlier Cochrane review of parenteral magnesium sulfate for acute exacerbations of asthma treated in the emergency room concluded that it is beneficial only for the subgroup with severe acute asthma, with improvements seen in FEV1 in this subgroup with severe acute asthma (Cochrane Database Syst Rev. 2000. CD001490).
NEGATIVE STUDY – a RCT showed no benefit when oral magnesium supplementation was added to standard outpatient treatment regimen of chronic stable asthma in adults (Clin Exp Allergy. 2003. 33. 1355-1359).
Atherosclerosis prevention in those with CKD III and IV - in an open-label RCT of 125 Japanese adults, 198 mg per day of magnesium (as magnesium oxide) slowed the rate of increase in coronary artery calcium score (CAC). This score is a proxy measurement for atherosclerosis (J Am Soc Nephrology. 2019. 30. 1073-1085).
Athletic performance - 300 mg/day magnesium oxide beneficial in a 12 week trial of 139 healthy elderly women, with those in the treatment group scoring better on the Short Physical Performance Battery (p-0.03), chair stand time (p<0.001), and 4-meter walking speed (p=0.006). Benefits more evident in individuals with magnesium intake below the RDI (Am J Clin Nutr. 2014. 100. 974-981).
Atrial fibrillation for rate and rhythm control – efficacy reported for intravenous magnesium in a meta-analysis of 8 RCTs (n=476), using doses of Mg sulfate in the range of 1.2 to 10 grams, with infusions over 1 to 30 minutes. Adverse effect profile of magnesium similar to that of placebo (Am J Cardiol. 2007.99. 1726-1732).
Dysmenorrhea – shown beneficial in a Cochrane review of 3 small trials (Cochrane Database Syst Rev. 2001. CD002124).
Eclampsia
Treatment – parenteral magnesium has been t he standard of care for decades; benefit shown in two Cochrane reviews (Cochrane Database Syst Rev. 2003. CD000128; Cochrane Database Syst Rev. 2001. CD002960).
Prevention in those with pre-eclampsia – benefit shown in a Cochrane review (Cochrane Database Syst Rev. 2003. CD000025) and an additional study (N Engl J Med. 2003. 348. 304-311).
Hypertension - a meta-analysis of RCTs found that oral magnesium supplementation resulted in small overall reductions in BP in a dose dependent manner in hypertensive patients (Am J Hypertens. 2002. 15. 691-696).
Insomnia - 250 mg twice a day of magnesium oxide beneficial in an 8 week RCT of 46 individuals with moderate or severe insomnia and a mean dietary magnesium intake of 194 mg magnesium per day, with an increase in mean sleep time (p=0.002) and sleep efficiency (p=0.03), as well as improvement in mean score on the Insomnia Severity Index (p=0.006) [J Res Med Sci. 2012. 17. 1161-1169].
Leg cramps in pregnant women – shown beneficial in a Cochrane review (Cochrane Database Syst Rev. 2002. CD000121).
Metabolic syndrome prevention:
Cross-sectional analysis of 11,686 women over age 45 in the Women’s Health Study suggests that magnesium intake is inversely associated with systemic inflammation and prevalence of metabolic syndrome (Diabetes Care. 2005. 28. 1438-1444).
Data from 4637 young adults in the CARDIA Study without metabolic syndrome or diabetes at baseline showed a 30% reduction in metabolic syndrome at 15 years of follow-up in those in the highest quartile of magnesium intake compared those in the lowest quartile of magnesium intake, based on food frequency questionnaires (Circulation. 2006. 113. 1675-1682).
Migraine headaches – data is MIXED
Magnesium (trimagnesium dicitrate) 600 mg/day effective in reducing the frequency and severity of migraines, based on a 12 week RCT with 81 patients. At month 2, treatment patients had 2 migraines per month compared to 3 per month in the placebo group, and treatment patients experienced 2.4 headache days per month compared to 4.7 headache days in the treatment group (Cephalagia. 1996. 16. 257-263).
Magnesium 360 mg/day during the luteal phase significantly reduces the number of headache days by 50% compared with placebo, in a small study in 20 women with menstrual migraines (Headache. 1991. 31. 298-301).
Two other RCTs showed mixed results (Cephalagia. 1996. 16. 436-440; Headache. 2003. 43. 601-610).
Mitral valve prolapse treatment
Hypomagnesemia demonstrated in 60% of patients with MVP.
Double-blind trial: Mg (510 mg/day) improved weakness, chest pain, dyspnea, palpitations, anxiety (Am J Cardiol. 1997. 79. 768-772).
Long-term supplementation (1-3 years) reversed valvular pathology in 20-40% of cases (Magnes Res. 2005. 18. 35-52; Magnesium. 1986. 5. 175-181).
Physical performance – magnesium oxide 300 mg daily associated with improved physical performance in a 12 wek RCT of 139 healthy elderly women, mean age 71.5 years (Veronese N et al. Am J Clin Nutr. Epub 7/9/14).
PMS – benefit seen in two trials (Obstet Gynecol. 1991. 78. 177-181; J Womens Health. 1998. 7. 1157-1165).
Torsade de pointes treatment (J Cardiovasc Electrophysiol. 1993. 4. 206-210).
Phosphorous
The source of metabolic energy, which is stored in phosphate bonds. Important role also in forming mineral matrix of bone.
Second most abundant mineral found in the body.
Regulates enzymes and participates in buffer systems in the body.
Dietary protein is the main source of dietary phosphorous.
Soft drinks are a source of excess phosphorous in the diet.
Processed foods are another source of excess phosphorous in the diet – phosphorous is added during food processing as a generally recognized as safe (GRAS) ingredient, with the quantity not always specified, as disclosure of the quantity of added phosphorous is not a regulatory requirement. Furthermore, phosphorous in food additives is rapidly and almost completely absorbed, in contrast to food-bound phosphorous, which is more slowly and less efficiently abosrbed (Review Article. Pizzorno, Lara. Canaries in the phosphate-toxicity coal mine.” IMCJ. 2014. 13[6]. 24-32).
Most of the population obtains adequate (or too much) phosphorous from the diet.
Based on data from NHANES 2005-2006, >50% of young and middle-aged men consume 1600 mg per day of phosphorous or more, and > 50% of young and middle-aged women consume 1200 mg per day of phosphorous or more, as compared with an RDA of 700 mg/day.
However it is estimated that 10% of women over age 60 and 15% of women over age 80 have a phosphorous intake less than 2/3 of the RDA.
Over-consumption of antacids can cause phosphorous deficiency since aluminum present in many antacids interferes with phosphorous absorption.
Excess phosphorous intake is associated with excess mortality, based on data in 9686 healthy adults in NHANES III (1988-1994). Dietary phosphorous intake was assessed using a 24 hour dietary recall (Am J Clin Nutr. 2014. 99. 320-327).
Dietary guidelines recommend calcium: phosphorous intake in a 1.5:1 ratio.
Calcium carbonate and calcium citrate supplements will bind dietary phosphorous and thus inhibit absorption.
Potassium
Increases natriuresis (sodium excretion), modulates baroreflex sensitivity, vasodilates blood vessels, decreases sensitivity to catecholamines, reduces intracellular sodium, improves insulin sensitivity, and decreases ADMA (Curr Hypertens Rep. 2011. 13. 309-317).
Average US dietary intake is 45 mmol/day, with a dietary potassium: sodium ratio of 1:2; optimal intake is considered 120 mmol/day (4700 mg/day) with a potassium: sodium ratio of 4-5:1 (Curr Hypertens Rep. 2011. 13. 309-317; J Clin Hypertens. 2008. 10[suppl 2]. 3-11).
As per Consumer Reports on Health (September 2020), 98% of Americans don’t obtain the RDA of potassium.
Those with kidney disease may need to restrict potassium in the diet, especially if on certain medications such as ACE inhibitors, ARB or potassium sparing diuretics.
Sodium
Increases platelet reactivity, increases sympathetic nervous system activity (Arch Intern Med. 1997. 157. 2449-2452), may increase blood pressure (but modest intakes may also protect against stroke via poorly understood mechanisms.
Average US dietary intake is 5000 mg/day, with some areas of the country consuming 15,000 – 20,000 mg/day; minimum requirement for sodium is probably about 500 mg/day (Circulation. 1998. 98. 613-617).
Boron
Usual supplemental dose is 1-3 mg per day.
Not recognized as an essential nutrient until recently.
May enhance conversion of vitamin D to 1,25-dihydroxyvitamin D.
Shown to increase estradiol and testosterone levels in postmenopausal women.
May build muscle mass and may increase bone density.
Chromium
Usual supplemental dose is 200-1000 micrograms per day.
Required for normal glucose metabolism; potentiates the action of insulin, probably by facilitating the binding of insulin to its receptor (Med Clin North Am. 1976. 60. 739-744; J Am CollNutr. 1998. 17. 544-547). May have antioxidant effects, and in humans alters the sensitivity of brain 5-HT2A receptors (Psychopharmacology. 2002. 159. 432-436).
Uses:
Treatment of diabetes - 200-500 mcg twice a day (see specifics with references at the beginning of this outline). Summary article (Role of chromium in human health and in diabetes.Diabetes Care. 2004. 27. 2741).
Reversal of hyperglycemia in patients receiving hyperalimentation (J Am Coll Nutr. 1998. 17. 548).
Reversal of corticosteroid-induced diabetes (Diabet Med. 1999. 16. 164-167).
Treatment of atypical depression, which is clinically characterized by mood reactivity, increased appetite, weight gain, and hypersomnia (Biol Psychiatry. 2003. 53. 261-264), especially if accompanied by carbohydrate cravings (J Psychiatr Pract. 2005. 11. 302-314).
May be useful in treatment of reactive hypoglycemia (12 week trial in 8 women published in Metabolism. 1987. 36. 351-355; Am J Clin Nutr. 1985. 41. 841) and carbohydrate cravings.
Reported in some trials to facilitate weight loss and improve muscle mass but a meta-analysis failed to identify benefit (Int J Obes Relat Metab Disord. 2003. 27. 522).
Evidence is mixed with regard to a beneficial effect on the lipid profile, with positive studies (Am J Clin Nutr. 1981. 34. 2670-2678; West J Med. 1990. 152. 41-45) and a negative study (J Gerontol A Biol Sci Med Sci. 2000. 55. M260-M263).
May be best to take this on an empty stomach.
Supplemental chromium exists in several forms.
Chromium GTF is the natural form of chromium. Supplements are derived from brewer’s yeast. The precise structure of chromium has not been determined as of 2006. BEWARE some products marketed as GTF chromium on analysis had no GTF activity (unpublished data).
Chromium picolinate, chromium polynicotinate, and chromium aspartate are all believed to be effective; chromium chloride may be less effective.
Chromium picolinate is better absorbed than chromium present in many foods, including whole grains, nuts, meat, broccoli, and green beans.
There is controversy in the literature regarding whether chromium picolinate and polynicotinate are better absorbed than chromium GTF – this controversy might be a function of mislabeling of chromium GTF (see just above).
May cause insomnia or increased dream activity as an adverse effect.
Safety
No data on long term safety.
High concentrations of chromium picolinate can be mutagenic in vitro, but no damage to DNA has been reported in vivo (The Medical Letter. 2006. 48. 7-8).
Appears safe in the short term in doses up to 1000 mcg/day (Dietary Supplements: A Framework for Evaluating Safety. Institute of Medicine. Washington, DC. 2004).
Copper
Important in a number of enzyme systems and for normal energy production, connective tissue formation, and iron metabolism; may have anti-inflammatory effects.
Dietary intake is likely lower than 50-100 years ago
The average copper content of fruits and vegetables declined by 81% between 1940 and 2000 (J Altern Complement Med. 2001. 7. 161-173).
68% of the copper content is lost when whole wheat flour is refined to white flour (Am J Clin Nutr. 1971. 24. 562-573).
Absorption occurs in the small intestine, and is dependent upon stomach acid, so use of H2 blockers or PPIs can predispose to copper deficiency.
Vitamin C supplementation may interfere with copper utilization.
Long-term NAC supplementation can predispose to copper deficiency.
Cupric oxide is very poorly absorbed (J Nutr. 1999. 129. 2278-2279).Deficiency can cause anemia which mimics iron deficiency anemia with the exception that copper deficiency is characterized by neutropenia too. Deficiency might cause myelodysplasia.
Shares an absorption carrier with zinc and calcium.
Zinc may protect us from high copper levels by interfering with absorption of copper in the gut.
Conversely, zinc supplementation can predispose to copper deficiency. Supplemental doses of zinc should be accompanied by supplemental doses of copper in a ratio of 15 mg: 2 mg (Advanced Nutrition and Human Metabolism. 3rd ed. Chapter 12: Microminerals. 2000. 401-470).
Uses - typical supplemental dose is 2 mg daily
Copper bracelets have shown efficacy in treatment of rheumatoid arthritis (Agents Actions. 1976. 6. 454-459).
May protect against aortic aneurysms, and may be important in bone health, based on test tube and animal data.
Copper and depression - a systematic review and meta-analysis of observational studies reports that elevated serum copper levels may be a biomarker of depression (Psychiatry Res. 2018; 267:506-515).
Copper and aggressive behavior - in a study of young males with a history of assaultive behaviors, the copper zinc ratio was significantly higher than in normal controls (Physiol Behav. 1997; 62(2):327-329).
Copper in high doses/at high levels by blood test can act as an ‘anti-mineral’ (toxicity can cause various psychiatric problems, including anxiety, phobias, and in the extreme, paranoia and hallucinations).
High levels can arise from copper leaching into the water out of copper pipes, absorption of copper from copper cookware, absorption of copper from a copper IUD for birth control.
Birth control pills (oral contraceptives) can raise copper levels.
Note Wilson’s disease is a genetically inherited condition in which there is a metabolic aberration which leads to excessive accumulation of copper in the tissues - many patients with this condition present with irritability and aggressiveness (Arch Gen Psychiatry. 1989; 46(12):1126-1134); chelation strategies (vitamin C, zinc, prescription Penicillamine) to reduce copper in these patients often lead to a lessening of psychiatric and neurologic symptoms (Eur Neurol. 1989; 29(6):301-305).
Safety: may act as an emetic in high doses (60 mg).
Iodide
Iodine is the oxidized form of this mineral, iodide is the reduced form
Current understanding is that iodine is reduced to iodide in the gut for intestinal absorption.
Iodine is used primarily in the synthesis of thyroid hormones.
Iodine supplementation should be accompanied by selenium supplementation, as per Robert Crayhon, M.S.
Added to most salt, but the amount in sea salt is minimal.
Kelp and seaweed are rich in iodine.
Bromide, a ubiquitous food additive and industrial chemical, competes with iodine for intracellular absorption, and may lead to iodine insufficiency in a significant proportion of population.
Fluoride added to the water supply competes with iodine for uptake into thyroid hormones, and may thus contribute to the rising incidence of hypothyroidism.
In a study in New Zealand in 184 children, ages 10-13, with mild iodine deficiency, based on a urine iodine concentration, four tests of cognitive function showed improvement in those randomized to supplementation with 150 mcg/day (Am J Clin Nutr. 2009. 90. 1264-1271).
RDA is 150 mcg daily, upper limit is 1100 mcg daily. However there are individuals such as Guy E. Abraham, MD who assert that the human need is on the order of 5 mg daily and that doses of 50 mg/day are needed to replenish body stores (urine excretion of 90% of an administered dose is the measure advocated by these authorities for determining adequate body iodide stores).
Iron
Iron is one of the few minerals we cannot eliminate from the body if we consume too much.
Men and postmenopausal women need very little iron and unless vegan should obtain plenty from the diet.
Iron deficiency is common in menstruating women; according to USDA surveys, 39% of Americans fail to consume the RDA (Consumer Reports on Health. 6/05).
Non-heme iron, the form found in green leafy vegetables and grains, is best absorbed in an acidic environment, so eating fruits with vegetables or taking vitamin C with meals facilitates the absorption of iron from non-meat food sources. Cysteine also helps with iron absorption.
Iron absorption may be inhibited by hypochlorhydria, phytic acid, polyphenolic compounds, calcium, tannins in tea, and partially digested proteins. It may also be impaired status post gastric bypass surgery for obesity.
Tea affects iron absorption only if consumed at the same time as food with iron (Nutr Res. 1997. 17. 1303-1310); milk does not alter this inhibition (Br J Nutr. 1999. 81. 289-295).
Herbal infusions of peppermint, pennyroyal, cocoa, vervain, lime flower, and chamomile (commonly referred to as teas) also inhibit iron absorption (Br J Nutr. 1999. 81. 289-295).
Benefits of iron (in those who are iron deficient)
Anxiety - in a 3 month open label study of 207 women, significant improvements were seen in the Beck Anxiety Inventory and the Female Sexual Function Index (J Sex Med. 014. 11. 1042-1046).
Cognitive function – iron deficiency is associated with impairment of cognitive function and scholastic performance in children (J Pediatr. 1973; 82:827–830); iron supplementation is associated with improved cognitive function and scholastic performance in children (Am J Clin Nutr. 1989; 50:675–686; Am J Clin Nutr. 1989; 50:698–702; Lancet. 1996; 348:992-996; Review article. Public Health Nutrition. 2005; 8:117-32; Arzneimittel-Forschung. 2009; 59:303-510) and in young women, aged 18-35 (Am J Clin Nutr. 2007; 85:778-787).
Cough – Ferrous sulfate 330 mg once or twice a day (dependent upon body weight) beneficial in a 2 month trial of 20 nonsmoking women with a chronic unexplained cough and a ferritin < 15 ng/ml (Int J Clin Pract. 2012. 66. 1095-1100).
Fatigue – in a 12 week RCT of 198 women, aged 18-53, with fatigue, a serum ferritin < 50 mcg/L (low normal) and a hemoglobin > 12.0 g/dl (not anemic), those randomized to prolonged release ferrous sulfate, 80 mg/day showed a 48% improvement in score on the Current and Past Psychological Scale for Fatigue, as compared with a 28.8% improvement in the placebo group (p=0.02). Compared with placebo, iron increased hemoglobin by 0.32 g/dl (p=0.002) and ferritin by 11.4 mcg/L (p<0.001) [CMAJ. 2012. 184. 1247-1254].
Heart failure - in a 1 year trial of 304 patients with symptomatic heart failure and EF < 45%, in which those with a ferritin < 100 ng/ml or a ferritin of 100-300 ng/ml with transferrin saturation < 20% were randomized to intravenous iron at a dosage and freequency based on initial body weight and Hb, those in the intravenous iron supplementation group showed sustained improvement in functional capacity, symptoms, and QOL. In addition, the rate of hospitalization for worsening heart failure was 61% lower in the treatment group [p<0.01] (Ponikowski P et al. Eur Heart J. Epub 8/31/14).
Additional benefits of iron supplementation include improved fertility, immune function, physical performance, thermoregulation, and restless leg syndrome (Review article. American Journal of Nephrology. 27(6):565-71, 2007).
Risks of iron
High iron stores, measured by serum ferritin, are associated with an increased risk of heart disease in two studies (Circulation. 1992. 86. 803-811; N Engl J Med. 1994. 331. 1159-1160), but not in a third study (Circulation. 1999. 99. 852-854).
Prospective observational data in 38,772 older women in the Iowa Women’s Health Study showed that use of iron was associated with an increase in total mortality (RR 1.10), with the relationship dose-dependent (Arch Intern Med. 2011. 171. 1625-1633).
Intravenous iron
Iron isomaltoside (renamed in June 2019 as ferric derisomaltose) 1000 mg over 20 minutes as a single infusion rapidly corrects iron deficiency anemia, and in two RCTsof a total of 245 patients was associated with a lower risk of hypophosphatemia over 35 days, of uncertain clinical significance (JAMA. 2020. 323. 432-443).
Ferric carboxymaltose 750 mg on two occasions, 1 week apart corrects iron deficiency anemia, but is associated with hypophosphatemia in 75% of recipients over 25 days, of uncertain clinical significance (JAMA. 2020. 323. 432-443).
It is best for men and postmenopausal women to choose a multivitamin which does not contain iron.
Lithium
While in 2022 not yet characterized as an essential micronutrient, there is data that small quantities, approximately 1 mg daily are essential to health (J Am Coll Nutr. 2002; 21(1):14-21).
Usual supplemental dose is lithium orotate 5 mg daily (maximum of 20 mg daily)
Published studies demonstrating benefits of low dose lithium intake
Data in Texas indicates that in those regions with higher concentration of lithium in the drinking water, mental health hospital admissions are lower (Dis Nerv Syst. 1970; 31(12):811-820).
A study in Japan found reduced rates of suicide in municipalities with higher levels of lithium in the drinking water (Br J Psychiatry. 2009;194(5):464-446).
A study in Greece found reduced rates of homicide correlated with quantities of lithium in the drinking water (Biol Trace Elem Res. 2015; 164(2):165-168).
A cross sectional study in Japan found an inverse association between levels of lithium and drinking water and crime (BJPsych Open. 2020; 6(6):e122).
A meta-analysis of 14 studies including 94 million people found that higher lithium concentrations in drinking water were associated with lower suicide rates (P < 0.001) and a separate meta-analysis of 2 studies including 5 million people found that higher lithium concentrations and drinking water were associated with fewer hospital admissions for psychiatric disorders (P=0.035) [Aust N Z J Psychiatry. 2021. 55. 139-152].
Manganese
Important in a wide variety of metabolic functions.
Absorption is inhibited by iron and phytates.
Tissue stores are reduced by aluminum, and may be reduced by cadmium.
EDTA, a common food preservative, inhibits the absorption of manganese.
Typical supplemental dose is 5 - 20 mg a day.
May be useful in treatment of tardive dyskinesia (25 mg daily).
Toxicity (seen in miners of manganese ore) manifests as disorientation, memory loss, delusions, hallucinations, anxiety, and emotional lability.
Molybdenum
Primary role is as a coenzyme. Required in particular for detoxification of sulfite.
Low uric acid on a blood test suggests molybdenum deficiency, as per Jonathan Wright, MD.
May be useful in treatment of autism if Phase II detoxification via sulfation is impaired.
Typical supplemental dose is 500 mcg.
Very safe.
Potassium
Most Western diets provide suboptimal amounts of potassium, but contrary to the folk wisdom of no risk of excessive potassium intake in those with normal renal function, there are case reports of life-threatening hyperkalemia, including 3 case reports of death, associated with high oral potassium intake in those with normal renal function and also not taking medications which might cause potassium retention (Eur J Clin Nutr. 2019. 73. 38-45).
Selenium
RDA is 55 mcg/day in women and 70 mcg/day in men, and UL is 400 mcg/day in 2000.
Usual supplemental dose is 200 micrograms per day. May be toxic in amounts in excess of 750 - 900 micrograms daily.
Selenium supplementation should be accompanied by iodine supplementation, as per Robert Crayhon, M.S.
Much glutathione peroxidase is dependent upon selenium as a cofactor.
Conversion of T4 to T3 is selenium-dependent.
Enhances immune function, and may decrease symptoms in rheumatoid arthritis.
Selenium in food is in the form of seleno amino acids such as selenomethionine or selenocysteine.
Brazil nuts, butter, and wheat germ are excellent food sources.
There is some data that acid rain interferes with selenium uptake from the soil into the roots of plants.
Selenium and mortality
Higher serum selenium levels, up to 150 ng/ml, associated with lower all-cause and cancer mortality, based on data from 13,887 adult participants in NHANES III who had serum selenium levels measured (Arch Intern Med. 2008. 168. 404-410).
In a RCT in Denmark in which 491 volunteers ages 60-74 were dosed with supplemental selenium 100 mcg, 200 mcg or 300 mcg daily for 5 years, mortality was 60% higher in those supplemented with 300 mcg selenium daily at the end of 5 years (not statistically significant) and this 60% increase in mortality persisted 10 years after the end of he 5-year study (statistically signficant at this juncture) [Rayman MP et al. Free Radic Biol Med. Epub 2/14/18].
Benefits of supplementation
Grave’s disease - sodium selenite 100 mcg twice a day significantly improved quality of life, reduced ocular involvement, and slowed progress in a 6 month RCT in 159 patients with mild Grave’s orbitopathy (N Engl J Med. 2011. 364. 1920-1931).
Hyperlipidemia - supplementation had modestly beneficial effects on the lipid profile in a 6 month RCT in 501 volunteers. This was a 4 arm trial – placebo, 100 mcg/day high selenium yeast, 200 mcg/day high selenium yeast, and 300 mcg/day high selenium yeast. Total cholesterol and LDL improved, and higher doses raised HDL (Ann Intern Med. 2011. 154. 656-665).
Lymphedema associated with breast cancer - 500 mcg intravenous on 5 occasions over 2 weeks beneficial in a RCT of 26 women, with improvement from stage III lymphedema to stage II lymphedema in 84.3% of the selenium infusion group and only 10% of the manual lymph therapy only group (p=0.002). Mechanism of action is unknown (Nutrients. 2019. 11. E1021).
Modest supplementation theoretically may decrease the likelihood of colon, esophageal, stomach, and lung cancer. Mechanism may be related to initiation of DNA repair through activation of p53 (J Natl Cancer Inst. 2003. 95. 98-100). HOWEVER, ineffective for prostate cancer prevention in the SELECT trial (JAMA. 2009. 301. 39-51 and editorial 102-103; JAMA. 2011. 306. 1549-1556).
Risks of supplementation
May increase the risk of diabetes - data is conflicting
Retrospective analysis of data in 1202 individuals who did not have diabetes at baseline in a RCT of selenium yeast 200 mcg daily for skin cancer prevention (the Nutrition Prevention of Cancer trial; n=1312) showed that at mean follow up of 7.7 years, the hazard ratio for the development of diabetes was 1.55 (95% CI 1.03 – 2.33) in the group randomized to selenium supplementation. Within the group randomized to selenium supplementation, those in the highest tertile of baseline plasma selenium level (>121.6 ng/ml) had a hazard ratio for development of diabetes of 2.70 (95% CI 2.70 – 5.61) [Ann Intern Med. 2007. 147. 217-223 and editorial 271-272].
Corroborative epidemiologic evidence - in NHANES III, participants in the highest quintile of serum selenium levels (>137.7 ng/ml) had an increased prevalence of diabetes compared with those in the lowest quintile (<111.6 ng/ml) [Diabetes Care. 2007. 30. 829-834]; an observational analysis within the SU.VI.MAX trial also found a positive association between baseline plasma selenium levels and fasting plasma glucose levels (Am J Clin Nutr. 2006. 84. 395-399).
In the SELECT trial, those who consumed selenium supplements alone had an increased risk of diabetes, although the increase did not reach statistical significance. However, in the SELECT patients taking selenium and vitamin E had no increased risk of diabetes (JAMA. 2009. 301. 39-51 and editorial 102-103).
However, in a RCT of 409 volunteers in Denmark (a population with moderately low selenium status), 100 mcg, 200 mcg and 300 mcg daily of selenium (as selenium-enriched yeast) was not associated with significant changes in HbA1c (and there was a nonsignificant trend suggesting benefit of selenium supplementation on HbA1c levels) [Diabetes Obes Metab. 2019. 21. 541-549].
May increase the risk of prostate cancer - in the SELECT trial, a RCT in 35,533 men from 427 participating sites in the US and Canada, examining 200 mcg per day of selenium from L-selenomethionine, at 7 years of follow up, the risk of prostate cancer in the selenium group was nonsignificantly increased (RR 1.09, p = 0.18) [JAMA. 2011. 306. 1549-1556].
Selenium is available in several different forms for supplementation.
Selenium yeast formulations have been used in a number of studies, and as per Dr Alan Gaby, this may be the best form with which to supplement.
Sodium selenite – published data shows that this form boosts immune system function in those with borderline low selenium status (Am J Clin Nutr. 2004. 80. 154-162), protects against radiation-induced inflammation and swelling (Int J Radiat Oncol Biol Phys. 2003. 56. 40-49), and reduces post-operative swelling (Biol Trace Elem Res. 2005. 106. 193-203).
Selenodiglutathione, a natural metabolite of selenium, may have a cancer chemopreventive effect (Nutr Cancer. 2001. 40. 42-49).
L-selenomethionine is a selenium-containing amino acid supplement associated in one study with an increased risk of prostate cancer, and thus as per Dr Alan Gaby, may be best to avoid this form of supplement.
Se-methylselenocysteine is a selenium-containing amino acid supplement which may be beneficial in treatment of established cancers (J Trace Elem Med Biol. 2005. 19. 141-150).
Silicon
Second most abundant mineral in the Earth’s crust, but little exists in a form that humans can absorb and utilize.
Dietary silicon compounds must be solubilized by stomach acid into orthosilicic acid before they can be absorbed.
Some experts believe that choline-stabilized orthosilicic acid (ch-OSA) is the ideal chemical form with which to supplement silicon.
Stimulates collagen synthesis and thus may improve bone strength and may be beneficial in those with brittle hair and nails.
NOTE high dose calcium supplementation might cause a silicon deficiency.
NOTE as per Wikipedia, “Silica gel is an amorphous and porous form of silicon dioxide, consisting of an irregular tridimensional framework of alternating silicon and oxygen atoms with nanometer-scale voids and pores. The voids may contain water or some other liquids, or may be filled by gas or vacuum.”
Strontium
High doses (as much as 1.7 grams per day) in a few studies shown to be beneficial in treatment of osteoporosis and cancer metastatic to bone.
Strontium may be administered as strontium lactate, strontium gluconate, strontium carbonate, or strontium ranelate.
For decades in the first half of the 20th Century, strontium salts were administered therapeutically in doses of 200-400 mg/day without toxic effects. As late as 1955, strontium products were listed in the Dispensatory of the U.S.
Do not confuse stable strontium with radioactive strontium-90, which spread through the environment in the 1950’s as a result of above ground nuclear testing. Radioactive strontium-90 spread throughout the environment, contaminating meat and dairy products, and eventually accumulating in bones of children and adults.
Vanadium
Usual supplemental dose is 5-15 mg per day (but as per Institute of Medicine, UL is 1.8 mg.
Insulin signal enhancer and demonstrates insulin like effects on glucose metabolism.
Viewed only recently as an essential nutrient.
Zinc
RDA in 2017 is 8 mg for women and 11 mg for men (it was 15 mg in the past and lowered in the 1980s) - there is published evidence that the RDA for zinc should be increased by 50%, based on nutrient intake data from NHANES 2009-2010 and specifically average phytate intake, as phytates in the diet inhibit the absorption of zinc (J Nutr. 2016. 146. 1276-1280).
Supplemental dose is usually 15-40 mg per day of elemental zinc.
Dietary Sources of zinc
Beef, poultry, seafood, egg yolks, dairy products
Whole grains
Legumes
Almonds, Brazil nuts, pecans, pumpkin seeds, walnuts, peanuts
Therapeutic uses
Acne – anecdotes of benefit, with clinical trial data mixed. In a RCT minocycline was twice as effective (Dermatology. 2001. 203. 135-140).
AIDS - theoretical rationale, based on rapid progression of zinc deficiency in those with HIV, but RCTs of zinc supplementation fail to show benefit.
Anosmia – theoretical rationale and anecdotal evidence.
Autism – theoretical rationale, based on unpublished reports of increased copper to zinc ratios in 85% of autistics; anecdotal evidence of benefit.
BPH - theoretical rationale, as zinc inhibits the activity of the enzyme 5-alpha-reductase, which converts testosterone to dihydrotestosterone (DHT), and also inhibits binding of DHT to its receptors. An old clinical trial shows benefit (Fed Proc. 1976. 35. 361).
Depression. In a 12 week RCT of 37 patients with major depression, all on a SSRI prescription medication, those randomized to zinc 25 mg daily (as zinc sulfate) scored lower at 6 weeks (17 vs. 25, p<0.05) and 12 weeks (11 vs. 23, p<0.01) on the Hamilton Depression Rating Scale (Nutr Neurosci. 2014. 17. 65-71).
Diarrhea – uncertain from data whether beneficial effect is a direct effect versus indirect effect of zinc repletion in those with zinc deficiency.
A meta-analysis of 22 RCTs of zinc supplements for treatment of diarrhea in children from developing countries found an 18% reduction of diarrhea symptoms (Pediatrics. 2008. 121. 326-336).
A meta-analysis of 15 RCTs of zinc supplements for prevention of diarrhea in children from developing countries found a14% reduction in risk (Pediatrics. 2007. 119. 1120-1130).
Eating disorders – theoretical rationale, and a published study in which 100 mg zinc gluconate facilitated weight gain (Int J Eat Disord. 1994. 15. 251-255)
Infection prevention - in a RCT in 50 healthy persons aged 55-87, zinc gluconate providing 45 mg of elemental zinc per day was associated with a lower incidence of infection (29% vs. 88%), higher plasma zinc levels, and lower serum levels of inflammatory markers (Am J Clin Nutr. 2007. 85. 837-844).
Macular degeneration – prevention of progression (no studies on zinc for primary prevention, and results of cohort studies are mixed)
In a randomized trial with 4753 patients with age-related macular degeneration (AREDS), a supplement containing vitamin C 500 mg, vitamin E 400 IU, beta-carotene 15 mg, zinc oxide 80 mg, and cupric oxide 2 mg was associated with a 27% reduction in worsening of visual acuity (p=0.008), but with increased hospitalizations for UTI and nephrolithiasis (Arch Ophthalmol. 2001. 119. 1417-1436).
Supplementation was also associated with a 27% lower mortality rate (Arch Ophthalmol. 2004. 122. 716-726).
Osteoporosis – theoretical rationale; important in the formation of osteoblasts and osteoclasts and various proteins found in bone tissue.
Peptic ulcer disease
Protects against endoscopic recurrence of peptic ulcers, based on a 12 month RCT of zinc acexamate (48 mg of elemental zinc) once daily in 146 patients initially treated with prescription medication for PUD (Rev Esp Enferm Dig. 1991. 80. 91-94).
Protects against NSAID induced GI damage – in a multicenter 4 week clinical trial in 276 patients, 88% of the patients who received zinc acexamate (48 mg of elemental zinc) once daily had a normal endoscopy, compared with 66% of the placebo patients (J Rheumatol. 1994. 21. 927-933).
Facilitates healing of acute ulcers - in a 4 week RCT in 199 patients with endoscopically verified acute duodenal ulcers, symptom improvement and endoscopic improvement were statistically identical in the group receiving zinc acexamate (48 mg of elemental zinc) twice a day, as compared with Pepcid 40 mg daily (Rev Esp Enferm Dig. 1996. 88. 757-762).
Schizophrenia – anecdotal evidence.
Upper respiratory infections – also see section just below for information on zinc and the common cold
A meta-analysis of 12 RCTs (n=5512) of children in developing countries found a reduction in URI incidence in those using zinc supplements (Pediatrics. 2007. 119. 1120-1130).
A meta-analysis of 8 RCTs (n=890) of zinc lozenges for treatment of URI in adults in industrialized countries found no evidence of statistically significant benefit, but many of the studies had methodologic problems (J Nutr. 2000. 130. 1512S-1515S).
Wilson’s disease – zinc acetate is approved by the FDA for maintenance therapy (J Lab Clin Med. 1998. 132. 264-278).
Wound healing – strong theoretical rationale, but a meta-analysis of 6 RCTs of oral zinc sulfate (n=181) for venous or arterial leg ulcers failed to show benefit (Arch Dermatol. 1998. 134. 1556-1560).
Functions of zinc
Anti-inflammatory - stabilizes membranes of mast cells, and thus is anti-inflammatory (Life Sci. 1991. 49. L189-194).
Antioxidant – cofactor for the enzyme superoxide dismutase (SOD)
Digestion - cofactor in protein digestion and production of hydrochloric acid (i.e. stomach acid); necessary for fatty acid absorption
GI protection – involved in intestinal epithelial cell regeneration (Eur J Clin Invest. 2000. 30. 419-428).
Heavy metals
Zinc deficiency predisposes to excess absorption of aluminum.
Zinc upregulates metallothionein, the enzyme which facilitates clearance of heavy metals from the cells of our bodies.
Hormonal effects
Cofactor in synthesis of melatonin from serotonin
Inhibits the activity of the enzyme 5-alpha-reductase, which converts testosterone to dihydrotestosterone (DHT)
May promote growth hormone secretion.
Immune system effects – protects against infection, and anti-inflammatory - zinc is a cofactor for thymulin, a thymic hormone essential for T cell maturation (Int J Immunopharmacol. 1995. 17. 703-718).
Prostate health – zinc deficiency predisposes to BPH, but excess zinc (greater than 100 mg daily) is associated with an increased risk of prostate cancer.
Wound repair – zinc deficiency is associated with impaired wound healing.
Measurement
Serum zinc levels are not considered a reliable measure of zinc stores.
RBC zinc is considered a more sensitive indicator of zinc status than a serum level.
The zinc taste test is considered a good surrogate for zinc status, as per Jeff Bland, PhD
This test involves assessing the taste tolerance to a 0.1% solution of zinc sulfate in water (Am J Clin Nutr. 1978. 31. 633-637).
The clinical accuracy of this test is improved by using a taste-intensity visual analogue scale (Integr Med. 2015. 14. 34-38).
Zinc deficiency
Very common in developing countries, due to malnutrition, and associated with growth retardation.
According to NHANES III, 91% of U.S. children, 49% of 51-70 year olds, and 57% of elderly obtain less than the RDA of zinc from their diet (J Nutr. 2000. 130. 1367S-1375S).
According to USDA surveys, 73% of Americans fail to consume the RDA (Consumer Reports on Health. 6/05).
Zinc deficiency is a clinical concern in
Individuals switching to a vegetarian diet
Individuals with pyrolluria, (Holford, Patrick. Optimum Nutrition for the Mind. 2000. Pgs. 211-215)
Individuals with histadelia (Holford, Patrick. Optimum Nutrition for the Mind. 2000. Pg. 186).
Symptoms and signs which suggest zinc insufficiency include anorexia, dandruff, slow wound healing, and white spots on fingernails.
Low alkaline phosphatase on a blood test suggests zinc deficiency, as per Jonathan Wright, MD.
Zinc absorption and excretion
Phytates in grains and legumes can interfere with zinc absorption.
Calcium and iron supplements can interfere with zinc absorption.
Coffee can decrease zinc absorption by 50%.
Intestinal absorption of zinc is inhibited by estrogen.
The yellow food dye tartrazine can cause zinc depletion by increasing urinary losses.
Medications which can deplete zinc include thiazide diuretics, corticosteroids, methotrexate, tetracyclanes, and fluoroquinolones.
Potential environmental zinc antagonists
6-chloropicolinic acid (a degradation product of nitrapyrin, which is applied to soil to increase crop yields).
4-amino-3,5,6-trichloropicolinic acid (an herbicide).
Zinc supplements
The amount of elemental zinc contained in various zinc salts differs
Zinc acetate is 30% zinc.
Zinc chloride is 50% zinc.
Zinc gluconate is 14.3% zinc.
Zinc sulfate is 23% zinc.
Zinc oxide is 80% zinc.
The extent of absorption of zinc in supplement form will vary based on the salt with which the elemental zinc is combined.
Zinc picolinate or citrate or chelated zinc are the preferred forms.
Zinc sulfate is probably not as well absorbed orally and may cause gastric irritation.
Zinc oxide is useful topically but not well absorbed orally.
Adverse effects from excessive intake of supplemental zinc
Symptoms include metallic taste, nausea, vomiting, and abdominal cramping.
Prolonged exposure may suppress immunity, decrease HDL, and cause a microcytic anemia due to copper deficiency (Am J Clin Nutr. 1990. 51. 225-227).
Intake of elemental zinc in amounts of 100 mg per day or more associated with an increased relative risk of 2.3 for advanced prostate cancer in men, based on data in 46,974 men in the Health Professionals Follow-up Study (J Natl Cancer Inst. 2003. 95. 1004-1007).
Zinc and other supplements
Chronic administration of supplemental NAC (N acetyl cysteine) can predispose to zinc deficiency via increased urinary excretion of zinc.
Zinc and copper compete for absorption – as general principle, supplemental doses of zinc should be accompanied by supplemental doses of copper in a ratio of 15 mg: 2 mg (Advanced Nutrition and Human Metabolism. 3rd ed. Chapter 12: Microminerals. 2000. 401-470).
Zinc and medications – zinc supplements may inhibit absorption of penicillamine, tetracyclanes, and quinolones.
Zinc and upper respiratory infections
Positive Cochrane review of 15 trials (n=966) evaluating 5 or more days of zinc, initiated within one day of symptom onset decreased the severity and duration of the common cold (Cochrane Database Syst Rev. 2011:CD001364).
A 2020 systematic review and meta-analysis concluded that zinc supplementation may reduce the duration of URIs by an average of 2.25 days (Am J Tropical Med Hyg. 2020. 103(1). 86–99).
A meta-analysis of 28 clinical trials, either randomized or quasi-randomized (N=5446 adults unlikely to be zinc deficient) concluded that oral or intranasal zinc supplementation can reduce the incidence and severity of viral upper respiratory infections. In this meta-analysis, Cochrane protocols for data analysis were followed (Hunter J et al. BMJ Open. November 2021).
A summary article reporting on a novel approach to analyze the effect of treatment on illness duration concludes that zinc lozenges reduce the duration and severity of the common cold (Front Pharmacol. 2022. 13. 817522).
Differences in the zinc salts used in the various trials, differences in dosages, and differences in bioavailability may account for the conflicting results – the best available data in 2005 is that lozenge efficacy or lack of efficacy is directly related to the total daily positively charged zinc administered and unrelated to the total dosage of zinc (Biosci Rep. 2004. 24. 23-39; Ann Pharmacother. 1996. 30. 1336-1338). As per Alan Gaby MD, negative studies typically contained flavoring agents or excipients such as citric acid, mannitol, sorbitol, and tartrate that may chelate zinc and prevent it from ionizing in the mouth.
Proposed mechanism - ionic zinc binds specifically to intracellular adhesion molecule-1 (ICAM-1) receptors on nasal epithelial cells, and this binding is hypothesized to prevent the rhinovirus from binding to this receptor (J Am Pharmacists Assoc. 2004. 44. 594-603).
A mouth-nose biologically closed electric circuit (BCEC) with a voltage of 60-120 millivolts moves positively charged particles such as ionic zinc from the mouth to the nose.
NOTE that the electrical resistance between the mouth and the nose varies from individual to individual, and unpublished data suggests that those with the lowest electrical resistance (1-10 Kohms) experience frequent colds, allergies, and rhinitis whereas those with the highest electrical resistance (100-500 Kohms) are immune to common colds.
Zinc acetate releases virtually 100% as zinc ion, regardless of pH; zinc gluconate, zinc sulfate, and zinc chloride are also highly ionizable, BUT zinc is tightly bound in the following forms, and thus not available in the pharynx as ionic zinc: zinc aspartate, zinc citrate, zinc orotate, zinc picolinate.
Side effects of zinc gluconate lozenges include unpalatable taste, mouth irritation, taste distortion, mouth sores, vomiting, diarrhea, headache. Zinc acetate may be more palatable than zinc gluconate.
Intranasal administration of ionic zinc
At least one published study showing benefit (QJM: An International Journal of Medicine. 2002. 96. 35-43), but case reports of persistent anosmia in humans associated with intranasal administration of ionic zinc (J Ped. 1938. 13. 60-62; JAMA. 1938. 110. 2024; Chem Senses. 2000. 5. 659; Am J Rhinol. 2004. 18. 137-141) indicate that this route of administration is not risk free.
An understanding of biologically closed electric circuits (BCECs) as described by BE Nordenstrom (Nordic Medical Publications. 1983. 112-172) combined with unpublished data of a mouth-nose BCEC (cited on pg 37, column 1 in Altern Ther Health Med. 2006. 12. 34-38), leads to the conclusion that positively charged zinc introduced into the nasal passages is repelled by the like charge of the nasal tissues, and is thus poorly absorbed in the nose (except perhaps in the olfactory region on direct contact) and passes into the throat and then stomach with nasal mucous, thus lacking therapeutic efficacy against rhinoviruses when administered intranasally.
GENERAL GUIDELINES FOR CONSUMERS
Watch for time release preparations (except iron), as they may be less efficiently absorbed.
Take with food (except amino acids and possibly chromium).
Store at room temperature.
Don't store in a bathroom; the humidity is too high.
LEVEL PLAYING FIELD (Goodwin JS and Tangum MR. Battling quackery: attitudes about micronutrient supplements in American academic medicine. Arch Intern Med. 1998. 158. 2187-2191)
Uncritical acceptance of news of toxicity - high dose Vitamin C and kidney stones - review articles and book chapters cite abstracts, letters, and other review articles, but no articles in peer reviewed journals based upon a literature search (in 1998 - see citation in vitamin C section for prospective cohort analysis published in 2016)
Scornful, dismissive tone - Harrison's Principles of Internal Medicine - in the section on multivitamins, words used in the text include the following: "massive, carelessness, useless, indiscriminate, false, indefensible, wasteful, unnecessary, deplored, poor medical practice."
Ignoring claims of efficacy - Vitamin E and intermittent claudication - four randomized, controlled trials (3 positive).
Over-emphasis on anecdotal case reports of harm associated with natural supplements, or interactions of natural supplements with prescription medications, such as Coumadin.
Cranberry – Based upon several unpublished reports of an interaction between cranberry juice and warfarin, the UK Committee on Safety of Medicines in 9/03 alerted clinicians to a potential interaction. Subsequently, based upon additional unpublished case reports, the UK Committee on Safety of Medicines in 10/04 recommended against concurrent use of cranberry juice and warfarin unless health benefits outweighed the risks. Subsequent to this second “warning” several case reports were published. In 2005, the US FDA mandated a precautionary potential interaction label on warfarin. In 2008, JCAHO established guidelines that hospitals should advise patients taking warfarin to avoid cranberry juice. However, analysis of the 6 published case reports shows that only two cases had a validation scale suggesting “probable” interaction, and even in both these cases, there were other potential explanations for the alteration in INR. Additionally, small RCTs in patients on stable anticoagulation showed that the addition of 8 ounces of cranberry juice daily did NOT affect the INR (J Am Diet Assoc. 2006. 106. 2057-2061; J Thrombos Thrombolysis. 2008. 25. 112). The authors of a review article “conclude that the initial precautionary warnings … represent misleading conclusions” (Zikria J et al. Cranberry Juice and Warfarin: When Bad Publicity Trumps Science. Am J Med. 2010. 123. 384-392).
Ginkgo biloba - there are published case reports of subdural hematoma, hyphema, subarachnoid hemorrhage, and intracerebral hemorrhage with gingko. HOWEVER, in a 14 day RCT in 32 healthy volunteers, Ginkgo biloba extract (EGb 761) at daily doses of 120 mg, 240 mg, and 480 mg did NOT alter platelet function or coagulation (Clin Lab Haematol. 2003. 25. 251-253).
Skullcap – based upon case reports of hepatoxicity, this herb is listed in Consumer Reports 5/04 ‘Dirty Dozen.’ Case reports of hepatotoxicity attributed to skullcap appear to be associated with skullcap products adulterated with germander, a known hepatotoxin (Teucrium chamaedrys) [Botanical Safety Handbook. 1997; Pharmaceut J. 1984. 233. 80-82; Ann Intern Med. 1992. 117. 165-166].
Prescription and even some OTC medications are far from totally safe:
A meta-analysis of 39 prospective studies in U.S. hospitals found that in 1994, 2,216,000 hospitalized patients had an adverse drug reaction, and 106,000 had fatal adverse drug reactions (JAMA. 1998. 279. 1200-1205).
Surveillance data from 2017-2019 shows that approximately 2 million Americans visit an ED each year because of an adverse effect of a medication (JAMA. 2021. 326. 1299-1309).
There are 16,000 deaths and 100,000 hospitalizations in the U.S. each year from NSAID's (Am J Med. 1998. 105. 31S-38S, as referenced in New Engl J Med. 1999. 340. 1888-1899). It is estimated that only 1 in 5 individuals who GI bleed from a NSAID have any warning symptoms.
Proton pump inhibitor usage is associated with increased risk of fracture, C difficile infections, and pneumonia. An editorial concludes that “…for most patients, the adverse effects of PPIs outweigh the benefits.” (Arch Intern Med. 2010. 170. 747-748).
Published peer-reviewed literature often does NOT reflect the state of knowledge about a given pharmaceutical agent, due to publication bias and lack of submission of negative industry sponsored trials for publication. Furthermore, when negative industry sponsored trials are published, they are often written in a way that emphasizes the positive. A published study in which compared the independent FDA medical reviews of the primary results of 74 trials of 12 antidepressant agents with the published literature on these 74 trials found that (N Engl J Med. 2008. 358. 252-260):
Of the 38 trials viewed as positive by the independent FDA analysis, 37 were published.
Of the 36 trials viewed as negative or questionable by the independent FDA analysis, only 14 were published (29%), and 11 of the 14 were published in a way that conveyed more positive findings than appeared in the FDA review.
It would appear from the published literature that 94% of the antidepressant trials were positive, whereas only 51% were positive from the standpoint of the of independent FDA medical reviews.
Much of conventional medicine is not based on data from RCTs
A Congressional Office of Technology Assessment report in 1978 which indicated that only 10-20% of conventional medical practice was based on controlled studies (Office of Technology Assessment. Assessing the Efficacy and Safety of Medical Technologies. Washington, D.C.: U.S. Govt. Printing Office; 1978).
In a study of 109 patients on a university medical service, only 53% of the primary treatments were supported by data from randomized, controlled trials (Ellis J et al. Inpatient general medicine is evidence based. Lancet. 1995. 346. 407-409).
In a study at a suburban training general practice, only 30% of 101 therapeutic decisions were supported by data from randomized, controlled trials (Gill P. et al. Br Med J. 1996. 312. 819-821).
A 2003 study concluded that only about half of medical treatments are supported by evidence (Hardern RD et al. How evidence based are therapeutic decisions taken on a medical admissions unit? Emerg Med J. 2003. 20. 447-448).
ACC/AHA Guidelines and level of supporting evidence
In 2009, an analysis of the level of evidence supporting the guidelines examined 16 guidelines and 2711 recommendations and found that only 11% were classified as Level A. Furthermore, for class I recommendations, only 19% were supported by Level A evidence (JAMA. 2009. 301. 831-841).
In 2019, an analysis of the level of evidence supporting the guidelines examined 26 guidelines and 2930 recommendations and found that only 8.5% were classified as Level A (supported by multiple RCTs). 50% were supported by Level B (supported by observational studies or a single RCT) and 41.5% were supported only by Level C (expert opinion) [JAMA. 2019. 321. 1069-1080 and editorial 1053-1054].
References
The Vitamin Revolution. Michael Janson, M.D. 1996.
The Vitamin E Factor. Andreas Papas, Ph.D. 1999.
ConsumerLab.com’s Guide to Buying Vitamins and Supplements: What’s really in the bottle? 2003.
The UV Advantage. Michael Holick, M.D. 2004.
Fortify Your Life: Your Guide to Vitamins, Minerals, and More. Tieraona Low Dog, M.D. 2016.
Goodwin JS and Tangum MR. Battling quackery: attitudes about micronutrient supplements in American academic medicine. Arch Intern Med. 158; 1998: 2187-2191.
Han-Yao H et al. The Efficacy and Safety of Multivitamin and Mineral Supplement Use To Prevent Cancer and Chronic Disease in Adults: A Systematic Review for a National Institutes of Health State-of-the-Science Conference. Ann Intern Med. 2006. 145. 372-385.
NIH State-of-the-Science Panel. National Institutes of Health State-of-the-Science Conference Statement: Multivitamin/Mineral Supplements and Chronic Disease Prevention. Ann Intern Med. 2006. 145. 364-371.
www.cfsan.fda.gov – FDA Center for Applied Food Safety and Applied Nutrition. Useful consumer information.
www.cc.nih.gov/ccc/supplements - NIH web site
www.navigator.tufts.edu - Tufts University. This site also contains quality ratings for other sites.
www.consumerlab.com - provides independent analysis of the quality of dietary supplements.
www.nnfa.org - web site includes a list of companies certified by NNFA GMP Program.
www.nsf.org/certified/dietary - allows one to search for products and companies certified by NSF.
www.uspverified.org – list of products verified by USP.
www.drugstore.com - this provides information on dietary supplements by disease.
http://nccam.nih.gov/health - fact sheets, alerts and advisories, treatment information.
http://ods.od.nih.gov/databases/ibids.html - NIH Office of Dietary Supplements International Bibliographic Information on Dietary Supplements (IBIDS) [over 730,000 scientific citations and links to more than 1600 journal web sites, as of 2004]
https://dietarysupplementdatabase.usda.nih.gov/Conversions.php - unit conversion chart from IU to mcg to new DV unit required in 2020
Page Updated January 27, 2024