vitamin

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.

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 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).
In 1913, the first vitamin was isolated – thiamin.
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 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).
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).
A3 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). 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 ug/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 ug/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 double-blind, placebo-controlled study with 180 patients. 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 (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).

Much 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).
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.

Vitamins and Minerals – reasons why supplementation (therapeutic nutrition) is clinically useful

(Pizzorno, Joseph. Integrative Medicine. 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.

o 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).

o 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).

o The USDA estimates that 75% of Americans eat less than 2/3 of the RDI for one or more nutrient.

o 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).

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).

o 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).

o A study examining mineral content of US foods from 1940-1991identified decreases of 20-77% (Nutr Health. 2003. 17. 85-115).

o 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.

o 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.

o Lack of crop rotation depletes the soil of valuable nutrients.

o Selection of plant strains with higher yield per acre through sophisticated plant breeding, which may sacrifice nutritional content.

o Most chemical fertilizers replace only the minerals essential to make the plant grow (nitrogen, potassium, and phosphorus), not all minerals which were originally in the soil. This changes the ecology of the soil (i.e. 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 low pH, waterlogging, or excessive dryness).

o Modern agriculture uses heavy farm equipment, which might change the ecology of the soil.

o Foods are picked before they are ripe, so they do not acquire their full complement of vitamins and minerals.

o Transportation and storage of foods allows time for loss of some nutrients.

o 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.

o Additives may interfere with absorption of nutrients.

o Refining of flour depletes vitamins and minerals – estimates of the loss of minerals are as follows:

§ Magnesium 85%

§ Calcium 60%

§ Potassium 77%

§ Chromium 40%

§ Manganese 86%

§ Iron 76%

§ Copper 68%

§ Zinc 78%

§ Selenium 16%

§ Thiamine 77%

§ Riboflavin 80%

§ Niacin 81%

§ Vitamin B6 72%

§ Pantothenate 50%

§ Folic acid 67%

§ Vitamin E 86%

§ Betaine 23%

§ Choline 30%

o Refining of sugar depletes minerals – estimates of the loss of minerals are as follows:

§ Magnesium 99%

§ Chromium 80%

§ Manganese 93%

§ Copper 43%

§ Zinc 60%

§ Molybdenum 100%

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.

o Beta-carotene absorption varied more than 40-fold among “healthy” people. (Am J Clin Nutr. 1991. 53. 1443-1439).

o 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)

o Genetic polymorphisms of the vitamin D receptor have been identified – higher doses of vitamin D can overcome this interference with receptor binding.

o 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.

o Vitamin C: antiviral, antibacterial, antihistamine

o Vitamin B12: nonenzymatic degradation of sulfites

o Mg: increases solubility of calcium oxalate

o Enzyme induction

o Pyridoxine 100 mg/day induces erythrocyte aspartate aminotransferase (increase coincides with improvement in carpal tunnel syndrome) [Proc Natl Acad Sci. 1982. 79. 7494-8].

o Riboflavin 5 mg/day induces erythrocyte glutathione reductase (J Clin Invest. 1969. 48. 1957-1966).

o 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 flavin mononucleotide [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

Tablet versus capsule

Tablets can contain up to twice the ingredients of capsules, but if the ingredients of tablets are packed under too much pressure, they will not be absorbed.
Tablets may be more likely to contain flowing agents such as magnesium stearate, which allow tableting machines to run faster, but may interfere with absorption.

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 methylcellulose, magnesium stearate, polyethylene glycol, sorbitol, stearic acid, and talc.
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 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 is estimated at $1.5 billion a year.

· The USPSTF in 2003 concluded that there is no definitive proof that taking a multivitamin daily is helpful to a healthy adult.

· Some experts suggest a multivitamin daily for all adults.

o "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).

o "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.

· Epidemiologic data is supportive of benefits of consumption of a daily multivitamin

o 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)

o 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:

o 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).

o 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).

o 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 suboptimally 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).

o 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).

o 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).

§ Another 4 month RCT in noninstitutionalized subjects over age 60 also found no significant difference in the incidence of infections between the multivitamin group and the placebo group (Int J Vitam Nutr Res. 1993. 63. 11-16).

§ 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).

o 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).

o 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).

o 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."

· Choosing a multivitamin with mineral (if you choose to take one)

o 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.

o Be aware that the information on many multivitamin labels with regard to the percentage of daily value in the product is often based on outdated standards (Consumer Reports on Health. 10/04).

o Choose a product with no more than 2500 IU of Vitamin A, as RDA values for vitamin A have been adjusted downward in recent years. More Vitamin A in the form of beta carotene is safe, as beta carotene is water soluble.

o Choose a product with little or no iron unless you are a menstruating woman. Excess iron may increase the risk of hemochromatosis and heart disease.

o 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.
Important for bone development, cellular differentiation, epithelial tissue maintenance, night vision and proper functioning of the immune system.
High doses (50,000 – 100,000 IU per day for one or two days) are sometimes used to treat infections. In non-pregnant women, classic toxicity does not occur acutely unless the dose exceeds 50,000 IU per day.
May be useful in the treatment of acne and psoriasis.
There is emerging data on dangers of excess Vitamin A

The National Academy of Sciences in 2001 actually reduced the RDA by about 10% to 900 mcg or 3000 IU for men and 700 mcg or 2300 IU for women.
The upper limit for safe consumption was set in 2001 at 10,000 IU for adults, 5600 IU daily for children ages 9-13, 3000 IU for children ages 4-8, and 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
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.

A nested case-control study of the incidence of hip fracture showed that the relative risk of hip fracture was 2.1 for persons with vitamin A intake greater than 1500 mcg (5000 IU) per day (Ann Intern Med. 1998. 129. 770-778).
In the Nurses' Health Study, relative risk of hip fracture was 1.64 in women with vitamin A intake greater than 1500 mcg per day, compared with those whose intake was less than 500 mcg per day (JAMA. 2002. 287. 47-54).
A prospective 30 year population-based longitudinal study in 2232 men showed an inverse relationship between serum retinol levels and hip fracture, with a relative risk of hip fracture of 2.47 in men in the highest quintile of serum retinol, as compared with the middle quintile (N Engl J Med. 2003. 348. 287-294 and 347-349).
HOWEVER, in a study of men aged 18-58 who took 25,000 IU vitamin A daily for 6 weeks, there was not an increase in bone turnover (J Nutr. 2002. 132. 1169-1172).

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.

Beta carotene

Note 15 mg = 25,000 IU
Water soluble precursors to Vitamin A; as many as 50% of individuals do not efficiently convert carotenes to vitamin A (FASEB Journal. 2009. 23. 1041-1053). Hypothyroidism interferes with the conversion of beta-carotene to vitamin A.
Beta carotene and lung cancer - data from prospective, observational studies and from randomized, controlled trials is in conflict with the epidemiologic data, for reasons unclear.

The epidemiologic data shows an inverse relationship between beta carotene intake and lung cancer risk.
The Women’s Healthy Eating and Living study showed a 43% reduction in cancer risk in women with the highest versus lowest blood carotenoid levels.
The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBCCPS) studied the effect of Vitamin E alone, beta carotene alone, and both together on the incidence of lung cancer in 29,000 male Finnish smokers, age 50-69, for 5-8 years. The investigators actually found an 18% increase in the incidence of lung cancer among the men receiving the beta carotene (New Engl J Med. 1994. 330. 1029-1035).
The Physician Health Study I - in this study, 22,000 male physicians age 40-84 were given either beta carotene supplements or placebo for 12 years. There was no effect on cancer rates from the supplements (New Engl J Med. 1996. 334. 1029-1035).
The Beta-Carotene and Retinol Efficacy Trial (CARET) studied the effect of beta carotene and retinol supplements on 18,000 adult smokers, former smokers, and workers exposed to asbestos, for 4 years. The investigators found a 28% higher incidence of lung cancer and a 17% greater mortality rate among those who received supplements (New Engl J Med. 1996. 334. 1150-1155).
The Women’s' Health Study - in this study, 40,000 women were given either beta carotene or placebo for 2 years. There was no effect on cancer rates from the supplements (J Natl Cancer Inst. 1999. 91. 2102-2106).

Beta carotene and heart disease

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).

NOTE there are nearly 750 known carotenoids, which are yellow, orange, and red plant-derived compounds. Approximately 50 of these have provitamin A activity, and all of them are antioxidants. Other carotenoids include alpha carotene, lycopene, lutein, astaxanthin, and zeaxanthin.

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)

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.
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.
Thiamin is destroyed by sulfites, a common food additive, and also by excessive cooking.
Some Candida organisms synthesize thiaminase, which can destroy thiamin in the gut and thus lead to thiamine deficiency.
Blueberries, Brussels sprouts, red beet root and tea antagonize thiamin.
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)

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)

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 and niacinamide.
Nicotonic acid:

Lowers cholesterol, raises HDL. 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, Raynauds, those with cold extremities, Meniere's.
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.
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:

The form of niacin customarily included in vitamin supplements.
Does not produce same side effects as niacin.
In a pilot double-blind trial, niacinamide 500 mg 6 times a day was effective for osteoarthritis (Inflamm Res. 1996. 45. 330-334).
May be beneficial in anxiety (500 mg - 1500 mg three times a day), and insomnia but does not lower cholesterol.

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)

500-1000 mg/day may be beneficial in the treatment of adrenal dysfunction, allergies, Alzheimer’s, environmental toxicity, fatigue, high cholesterol, nausea from formaldehyde, Parkinson’s, recurrent infections, rheumatoid arthritis, and ulcerative colitis.
Important cofactor in the synthesis of the neurotransmitter acetylcholine.
Pantethine is the active form of this vitamin, and pantethine 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.

Vitamin B6 (Gaby AR. The Doctor’s Guide to Vitamin B6. Rodale Press. 1984).

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.
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 Clin Nutr. 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 Phys Med 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)

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.
10-16 mg a day may be helpful in the treatment of diabetes.
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.
There is no RDA, but adequate intake is estimated at 30 mcg in adults.

Folate (Vitamin B9)

This is the name given to a family of compounds which share a common molecular architecture called pteroylglutamate – the term ‘folate’ typically encompasses naturally occurring food folates as well as synthetic folic acid.
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).
Bioactive L-5-MTHF became available as a dietary supplement ~2005

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.
Drugs which may deplete folate include antibiotics, carbamazepine, cholestryramine, colestipol, diuretics, methotrexate, oral contraceptives, phenytoin, primidone, salicylic acid.
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.
Potential benefits of folate supplementation

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).
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 - 0.4 mg/day (OTC) proven useful in prevention (see very beginning of this outline).
Nitrate tolerance – beneficial in prevention of development of nitrate tolerance (see very beginning of this outline).

Potential risk of folate 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 dilantin and might interfere with absorption of zinc.
May predispose one to zinc deficiency.

RDA increased to 400 mcg for adults, 600 mcg for pregnant women.

Fortification of food with folate (i.e. grains) began in 1996 and was mandatory in the U.S. in 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 folate (Am J Public Health. 2006. 96. 2040-2047).
Consider as a diagnostic tool in an individual a peripheral smear to count the percent of hypersegmented PMNs (>10% diagnostic of folate insufficiency as per Dr. Jonathan Wright).

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)

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 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.
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. As many as 10% of individuals with low normal B12 levels (i.e. 200-400 pg/mL) may develop neuropsychiatric sequelae of B12 deficiency in the absence of megaloblastic anemia. Renal disease and hypovolemia can also cause elevated MMA levels.
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.
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.
Three forms:

Cyanocobalamin is the most common, least expensive, and commercially available, but it is not natural in the body.
Hydroxocobalamin is an activated form found primarily in cytoplasm where it is converted into its active coenzyme forms – available parenterally through compounding pharmacies.
Methylcobalamin – this is one of the active coenzyme forms – available orally and parenterally through compounding pharmacies.

RDA is 2.4 mcg in adults.

Vitamin C (ascorbate) [JAMA. 1999. 281. 1415-1423]

Discovered in 1932.
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.
All animals other than primates (humans are a primate) synthesize vitamin C.

Humans lack the last enzyme in the vitamin C biosynthetic pathway.
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 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 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 anti-histamine.
Asthma (exercise-induced) prevention – see above in this outline for reference.
Autoimmune disease – anecdotal data.
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, and one controlled trial showing that vitamin C supplementation enhances recovery from depression (Brit J Psychiat. 1963. 109. 294-299).
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). Previous studies have shown that vitamin C supplementation lowers uric acid levels via a uricosuric effect (Am J Med. 1977. 62. 71-76; Ann Intern Med. 1976. 84. 385-388).
Heavy metal exposure – effective in removing arsenic, cadmium, and lead from the blood based on test tube data.
Hypertension – see above in this outline for reference.
Infections – increases interferon production and may have antiviral effects when given at high doses intravenously.
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.
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).

1. In one positive study in young adults, the dose of vitamin C was 1000 mg per hour for six hours at onset of symptoms, followed by 1000 mg tid (J Manipulative Physiol Ther. 1999. 22. 530-533).

2. In a 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%.

Risks:

No known toxicity but may increase risk of oxalate kidney stones in people genetically predisposed and known as "stone formers."
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, which can be problematic 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.
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). 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 Acad Sci. 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 Biol Chem. 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) www.vitamindcouncil.org

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. It is found only in animal foods.

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.
Fortified foods in the US at this time include milk, cereal, orange juice, and yogurt.
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).

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.

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-hydroxyvitamin 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

Quest lab offers a vitamin D panel which measures 25 hydroxy and 1, 25 dihydroxy vitamin D levels.
Anecdotally, measurement of 1, 25 dihydroxy vitamin D levels may be valuable in cancer patients on chemotherapy and in patients with multiple chemical sensitivities.

Lower limit of normal for 25-hydroxyvitamin D is based on serum level necessary to protect against rickets and osteomalacia (11 ng/ml)

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-hydroxyvitamin D level of at least 20 ng/ml (50 nmol/L) is necessary (Am J Clin Nutr. 2002. 76. 187-192).
Many experts, including Heaney and Holick, state that levels should always be greater than 30 ng/ml (75 nmol/L).
Levels less than 40 ng/ml (100 nmol/L) indicate vitamin D insufficiency, based on data that serum PTH levels start to rise when 25-hydroxyvitamin D levels fall below 45-50 ng/ml (Am J Clin Nutr. 1997. 65. 67-71; Am J Clin Nutr. 1998. 67. 342-348).
NOTE 25-hydroxyvitamin 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 2011 presentation “Controversies in Nutrition”).

A level of 60 ng/ml (150 nmol/L) may be optimal. THIS IS CONTROVERSIAL.

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.

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 2011 presentation “Controversies in Nutrition”).

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 Clin Endocrinol 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 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.
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.
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.
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).

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 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).
A Cochrane analysis (see just below) concluded that vitamin D3 supplementation reduces all cause mortality whereas vitamin D2 supplementation does not.

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 Clin Nutr. 2010. 92. 841-848].
Supplementation associated with lower total mortality

Data from 18 independent RCTs (n=57,311 participants) 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).
Data from 32 trials including nearly 75,000 patients shows that vitamin D3 supplementation was associated with a RR 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).

Ankylosing spondylitis – deficiency is common (Wien Klin Wochenschr. 2001. 113. 328-332).
Athletic performance – there is 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).
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].
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.
Dozens of references regarding vitamin D and cancer prevention are listed on pg 364 of Mayo Clin Proc. 2006. 81. 353-373.
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].
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).
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).
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. RCT negative – WHI Trial in which supplemental calcium and vitamin D were administered, and follow up was 8 years (N Engl J Med. 2006. 354. 684-696).
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).

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).
In NHANES 2001-2004, low vitamin D levels found in 74% of 8351 adults with cardiovascular diseases (Am J Cardiol. 2008. 102. 1540-1544).
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 hydroxy vitamin D level < 10 ng/ml (Circulation. 2008. 117. 503-511).
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).
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).
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).
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).
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 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).
Critique of the data by IOM committee members (Commentary. JAMA. 2011. 305. 2565-2566).

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).

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).
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).
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].
Depression

Benefit likely, based on epidemiologic data, theoretical rationale, and anecdotes, with limited controlled trial data, except for SAD (see below).
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).
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).

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).

Diabetes Type II

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).
In the Framingham Offspring study in 808 non-diabetic individuals, there was a strong inverse correlation between serum 25-hydroxy vitamin D levels and both plasma glucose and fasting insulin, and a strong positive correlation between serum 25-hydroxy vitamin D levels and insulin sensitivity (J Nutr. 2009. 139. 329-334).
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 systematic review of 6 prospective observational studies in 4 cohorts found that there was an increased risk for diabetes in those with low vitamin D intake or low serum vitamin D levels in 3 of the 6 analyses; the methods of the original studies were too heterogeneous to consider pooling across studies. This same review reported that 8 trials found no effect of vitamin D supplementation on glycemia or incident diabetes (Ann Intern Med. 2010.152. 307-314).
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).
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).
Critique of the data by IOM committee members (Commentary. JAMA. 2011. 305. 2565-2566).

§ 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 - Vitamin D 4000 IU daily was beneficial in a 21 day RCT (J Allergy Clin Immunol. 2008. 122. 829-31).

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).
Fibromyalgia - deficiency present in 50% in one study (J Rheumatol. 2001. 28. 2535-2539).
Grave’s disease – deficiency present in 58% in one study (Endocrinol J. 2001. 48. 63-69).
HTN

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 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).

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.
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.
“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.”
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).

Low back pain – deficiency present in 83% of 360 patients in one study (Spine. 2003. 28. 177-179).
Lupus

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).
Plaquenil interferes with conversion of vitamin D to calcitriol.

Macular degeneration (AMD) – protective effect, based on data from NHANES III (Arch Ophthamol. 2007. 125. 661-667).
Memory loss – see ‘Cognitive Decline’ just above
Multiple sclerosis

Deficiency is present in 48% in one study (J Neuroimmunol. 2003. 134. 128-132).
In the Nurses’ Health Study and Nurses’ Health Study II higher intake of vitamin D was associated with a 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 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).
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 downtitrated to 0 IU/day (along with Calcium 1,200 mg/day) concluded that high dose vitamin D is safe, with immunomodulatory effects. Treatment group patients appeared to have fewer relapse events (Neurology. 2010. 74. 1852-1859)

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).
Osteoporosis – decreases the risk of nonvertebral fractures and the incidence of falls. For specifics, return to Home Page, click on "Osteoporosis" and scroll to "Vitamin D."
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.
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).
In the Iowa Women’s Health Study, vitamin D intake correlated inversely with disease prevalence (Arthritis Rheum. 2004. 50. 72-77).
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).

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 – 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).
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).

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).

Vitamin D supplementation – sales estimated at $425 million in 2009, compared with $40 million in 2000 (Nutrition Business Journal)

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.
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 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.
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.

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.

Function 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).
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
Tocotrienols may be 40-60 times more effective than tocopherols in their antioxidant capacity, and up to 70 fold more bioavailable.
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.
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:

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 arem of the PLCO trial (J NCI. 2006. 98. 245-254).

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 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).

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.
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 16^th Annual European Meeting on Hypertension). Possible mechanism – interference with metabolism of prescription medications for BP.

o Prostate cancer – in the SELECT trial at in7 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

Discovered in 1930.
Even though fat soluble, not stored in the body, so must be provided daily.
Natural Vitamin K exists in three forms

o 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 (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).

o 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, fermented dairy products, and natto (a fermented soy product which is specifically a dietary source of menaquinone 7, which has a half life much longer than menaquinone 4).

§ 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).

o 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

o Post-translational carboxylation of glutamyl residues in specific proteins involved in blood coagulation (multiple Gla proteins) and bone metabolism (via carboxylation of osteocalcin).

o Carboxylation of matrix Gla protein (MGP) prevents calcification in soft tissue (blood vessels, breasts, kidneys). Vitamin K2 can balance vitamin D, preventing soft tissue calcification in animals.

o Vitamin K2 in the brain contributes to the production of myelin, independent of its carboxylation activities.

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:

o Prevention of cancer – 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).

o Prevention of osteoporotic fractures (see Osteoporosis outline on this web site).

o Prevention of MI

§ 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).

§ 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).

§ 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).

o Treatment of morning sickness.

o POSSIBLY treatment of leukemia, liver cancer, lung cancer (very preliminary data, much of the research is in animals).

o POSSIBLY prevention or reversal of coumadin-induced arterial calcification, based on animal research showing reversal in rats (Blood. 2007. 109. 2823-2831).

Safety:

o Even though Vitamin K is fat soluble, toxicity is not well defined.

o 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.

o 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,