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.
- includes dietary supplements and foods with therapeutic value
food - includes macronutrients (carbohydrate, fat, protein) as well as
micronutrients and is prepared in powder form.
- complex organic substances (i.e. carbon containing compounds) not made
in the body, essential in small quantities for normal functioning of the
D is an exception; it is made in the body from cholesterol if there is
is an exception too; it is synthesized in small amounts in the body from
- non-organic (i.e. no carbon atoms), homogenous substances found in the
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.
to NHANES 1999-2000, 35% of adults reported using multivitamins (Am J Epidemiol.
2004. 160. 339-349).
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.
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.
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).
1913, the first vitamin was isolated – thiamin.
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
- In the 1940’s the first multivitamin was
Paradigm: Vitamins and minerals at RDA to prevent deficiency diseases with
a short latency (i.e. rickets, scurvy, beri beri, pellagra).
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.
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).
– the effect of bioactive food components on gene expression.
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.
Williams coined the term ‘biochemical individuality’ in the 1950’s to
describe the above practice.
treatment provides the body and the brain with the best possible
this term was first used by Linus Pauling in a published article in Science in 1968.
medicine is referred to by some as megavitamin therapy, but this term is
really an oversimplification.
Proven benefits of vitamins and minerals in pharmacologic
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).
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; JAMA. 1993.
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).
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).
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).
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).
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.
E beneficial in the treatment of symptomatic PVD
- A 3
month RCT in 33 patients with severe intermittent claudication showed
that vitamin E 400 IU/day increased walking distance statistically
significantly more than placebo (Angiology.
1963. 14. 198-208).
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).
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).
picolinate 200 mcg/day shown
to lower fasting blood glucose, total cholesterol level, triglyceride
level and insulin level in Type II Diabetes. Increase in HDL cholesterol
also noted (Am J Clin
Nutr. 1983. 38. 404-410).
picolinate 1000 mcg/day
lowers fasting blood glucose and 2 hour postprandial glucose by about 35%,
lowers insulin levels, lowers glycosylated hemoglobin by 2%, and lowers
cholesterol by 6% in a 4 month double-blind, placebo-controlled study
of180 patients, conducted in China. Toxicity of this dose is unknown (Diabetes. 1997. 46. 1786-1791).
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).
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.
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
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.
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).
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)
is a strong theoretic rationale for taking anti-oxidant vitamin and
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
exposure, cigarette smoke, and environmental radiation all increase free
radical production in the body.
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.’
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).
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.
data suggests a protective role of beta-carotene with regards to lung
studies in patients with no established CAD support the protective role of
Vitamin E (see below in this outline for details of the studies).
is some data from primary prevention trials to support the use of
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).
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.
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.
the data from randomized controlled trials (RCTs) fails to show benefit of
anti-oxidant supplements and in several trials there is evidence of harm.
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).
updated Cochrane analysis of 78 RCTs (n=296,707) examining either vitamin
A, vitamin C, vitamin E, beta-carotene, selenium or combinations of these
antioxidants found that antioxidants do NOT reduce all-cause mortality in
primary or secondary prevention. In this updated analysis, 26 of the RCTs
(n=215,900) included healthy patients, and the other 52 RCTs (n=80,807)
included patients with various diseases. 56 of these RCTs, covering 82%
of the participants, were judged to have a low risk for bias. The mean
duration of supplementation was 3 years.(Cochrane Database Syst Rev. 2012.
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.
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).
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
- 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).
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.
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).
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.
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).
antioxidants in moderate to high doses cause fatigue and muscle weakness
in some individuals.
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)
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.
- 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).
- 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
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.
A study examining mineral
content of US foods from 1940-1991identified decreases of 20-77% (Nutr Health. 2003. 17. 85-115).
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.
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.
crop rotation depletes the soil of valuable nutrients.
of plant strains with higher yield per acre through sophisticated plant
breeding, which may sacrifice nutritional content.
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).
agriculture uses heavy farm equipment, which might change the ecology of the
are picked before they are ripe, so they do not acquire their full complement
of vitamins and minerals.
and storage of foods allows time for loss of some nutrients.
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
types of food processing and cooking damage or remove nutrients.
may interfere with absorption of nutrients.
of flour depletes vitamins and minerals – estimates of the loss of minerals are
of sugar depletes minerals – estimates of the loss of minerals are as follows:
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.
absorption varied more than 40-fold among “healthy” people. (Am J Clin Nutr. 1991. 53. 1443-1439).
isolated absorption defects have been described for the following nutrients:
acid (J Pediatr.
1973. 82. 450)
Biotin (N Engl
J Med. 1983. 308. 639)
Zinc (Nutr Rev. 1975. 33. 327)
(Lancet. 1983. 1. 701)
polymorphisms of the vitamin D receptor have been identified – higher doses of
vitamin D can overcome this interference with receptor binding.
with the AA allele of manganese superoxide dismutase show reduced activity of
this antioxidant enzyme
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).
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.
pharmacologic activity is expressed by some nutrients at high doses.
C: antiviral, antibacterial, antihistamine
B12: nonenzymatic degradation of sulfites
Mg: increases solubility of calcium oxalate
100 mg/day induces erythrocyte aspartate aminotransferase (increase coincides
with improvement in carpal tunnel syndrome) [Proc Natl Acad Sci. 1982. 79. 7494-8].
5 mg/day induces erythrocyte glutathione reductase (J Clin Invest. 1969. 48. 1957-1966).
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
- 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 versus liquid versus gummies
- Benefits of tablets – most stable
formulation and thus maintain potency for a longer period of time
- Drawbacks of tablets - if the
ingredients of tablets are packed under too much pressure, they will not
be absorbed; tablets more likely to contain flowing agents such as
magnesium stearate, which allow tableting machines to run faster, but
might interfere with absorption.
- Benefits of capsules (gel caps) – the
outer layer of gelatin is easily digestible, and thus the ingredients are
- Drawbacks of capsules (gel caps) –
contain fewer nutrients than liquids or powders, some gelatins are not
- Benefits of powders and liquids –
easier to swallow, more immediately bioavailable, may contain higher
amounts of nutrients per dosage
- Drawbacks of powders and liquids –
taste may be unpalatable, may contain artificial sweeteners (natural
sugar alcohols such as xylitol or sorbitol are considered best), may
contain chemical preservatives to prolong shelf life, may oxidize rapidly
- Benefits of gummies – they taste good and
are easy to digest
- Drawbacks of gummies – usually contain
sugar or artificial sweeteners (xylitol or natural berry flavoring is
- Additives - silicon dioxide, titanium dioxide,
and magnesium citrate are considered preferable to magnesium stearate and dicalcium phosphate (Natural Solutions. March 2009. 56-60).
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
- 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.
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.
of excipients include cellulose starch, corn starch, dicalcium
phosphate, magnesium stearate, maltodextrin,
methylcellulose, methylparaben, microcrystalline
cellulose, polyethylene glycol, polysorbate 80, polyvinylpyrrolidone, propylparaben,
silicon dioxide, sodium acetate, sodium benzoate, sorbitol, stearic acid,
stearate, a flowing agent, might impair immune system function.
- Propylparaben might irritate the GI tract and might
cause CNS depression
generally have fewer excipients than tablets, but many capsules are made
of gelatin, which is a beef byproduct.
be best to avoid excipients derived from dairy, wheat, corn, and yeast, because
these can be allergenic.
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.
According to NHANES III, from 1988-1994, at
least 30% of the U.S. population takes vitamin supplements regularly (Arch Fam
Med. 2000. 9. 258-262). From 2003-2006, it is estimated that 39% of the
U.S. population takes vitamin supplements regularly (NCHS Data Brief. 2011. 1-8). Spending is estimated at $1.5 billion
According to NHANES 1999-2000, 35% of U.S. adults
reported using multivitamins (Am J Epidemiol. 2004. 160. 339-349).
Data from 2003-2006 indicate that 39% of U.S.
adults reported using multivitamins (NCHS
Data Brief. 2011. 61. 1-8).
in 2003 concluded that there is no
definitive proof that taking a multivitamin daily is helpful to a healthy
In a 2013 update, USPSTF “found no evidence of an effect of nutritional doses of
vitamins or minerals on CVD, cancer, or mortality in healthy individuals… In
most cases, data are insufficient to draw any conclusion…” The authors
identified 3 RCTs of multivitamins and 24 RCTs of single or paired vitamins. In
the abstract, the authors’ state “High quality studies (k = 24, n = 324 653) of
single and paired nutrients … were scant and heterogeneous…” They state further
in the concluding paragraph of the paper, “We identified 2 multivitamin trials
(n = 27 658) that both found lower overall cancer incidence in men. Both trials
were methodologically sound, but the lack of an effect for women (albeit in 1
trial), the borderline significance in men in both trials, and the lack of
effect on CVD in either study makes it difficult to conclude that multivitamin
supplementation is beneficial” (Ann Intern Med. 2013. 159. 824-834). In
a separate article, “The USPSTF concludes that current evidence is insufficient
to assess the benefits and harms of single- or paired-nutrient supplements
(except beta-carotene and vitamin E) for the prevention of cardiovascular
disease or cancer (I statement). The USPSTF recommends against beta-carotene
and vitamin E supplements for for the prevention of
cardiovascular disease and cancer (D statement) [Ann Intern Med. 2014. 160. 558-564].
experts suggest a multivitamin daily for all adults.
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).
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).
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.
data is supportive of benefits of consumption of a daily 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)
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.
clinical trial data is mixed:
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).
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).
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).
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).
there are also negative trials
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).
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).
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).
RCT of 1708 patients (one arm of the TACT trial of chelation therapy) showed
that at a mean follow up of 55 months, “High-dose
multivitamins and multiminerals did not statistically significantly reduce
cardiovascular events in patients after MI who received standard medications (Ann Intern Med. 2013. 159. 797-804). A possible
explanation of the negative results is a combination of a high non-adherence
rate (46%) in the treatment arm, combined with 42-45% of the subjects in the
control arm were taking “ordinary dose” multivitamins (Guilliams
TG. IMCJ. 2014. 13. 18-20).
RCT of 5947 male physicians over age 65 (the Physicians’ Heath Study II) showed
that at an average duration of follow up of 8.5 years, there was no difference
in the mean cognitive change between the treatment and placebo groups (Ann Intern Med. 2013. 159. 806-814).
Centrum Silver was the multivitamin used in this study, and for approximately
70% of the 11 year study, copper in Centrum Silver was in the form of cupric
oxide, which is poorly absorbed in humans. Thus, one possible explanation for the
negative results is that the 20 mg of zinc per day in the supplement induced
copper insufficiency. In addition, several aluminum-based coloring agents are
present in Centrum Silver, and these chemicals have the potential to adversely
affect cognitive function (Gaby AR. Townsend
Letter. Feb/March 2014. 131-132). Additional potential explanations for the
negative results include that cognitive function was assessed via telephone
interview, the first cognitive assessment was conducted on average 2.5 years after
randomization to the multivitamin, and that control subjects might have been
taking supplements with a beneficial effect on cognitive function, unknown to
the researchers (Guilliams TG. IMCJ. 2014. 13. 18-20).
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.
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).
observational data in 38,772 older women in the Iowa Women’s Health Study
showed that use of multivitamins was associated with a 2.4% absolute increase in
adjusted mortality rate. In this
same study, supplemental use of folate, vitamin B6, copper, iron, magnesium,
and zinc were also associated with an increase in adjusted mortality. The association of iron with total mortality
was strong (RR 1.10) and dose-dependent. However, after adjustment for
multiplicity, only multivitamins and copper retained the significant
association with all cause mortality. Calcium and
vitamin D supplementation were associated with a lower total mortality, before
and after adjustment for multiplicity (RR 1.06, 95% CI 1.02-1.10). A potential
limitation of this study is confounding by indication [i.e. those sicker at
baseline in ways not addressed in the study, such as with asthma or migraines
self-selected to take vitamins] (Arch Intern
Med. 2011. 171. 1625-1633). Dr Alan Gaby, author of Nutritional Medicine is critical of this report, stating in an
interview published on line on PR Web, “The
authors of the study have reached an incorrect conclusion, based on the data
that were collected. They did not report the actual death rates, only the
statistically-adjusted death rates of supplement users compared to non-users.
The problem is, for every category in which they made this adjustment—caloric
intake, cigarette smoking, body mass index, blood pressure, diabetes, physical
activity, and intake of fruits and vegetables—the supplement users were in the
healthier category. Because they were healthier, they were probably less likely
to die. So the researchers must have adjusted the supplement users' death rates
upward, which may have skewed the results by over-adjusting their data. When
the data were adjusted only for age and caloric intake, there was no
statistically significant difference in death rate between the two groups.
Unfortunately, the media picked up on this story without understanding the
potential problems in the study’s statistical methods."
Data in 14,641
male US physicians initially aged 50 years or older who participated in the
Physicians' Health Study II showed that those randomized to a multivitamin
(Centrum Silver) daily had an 8% lower incidence of total cancer (HR 0.92,
p=0.04) at a mean follow up of 11.2 years. The multivitamin however did not
reduce mortality from all cancers, or total mortality. Furthermore, there was
no evidence of an association between adherence and a protective effect (JAMA.
2012. 308. 1871-1880 and editorial 1916-1917). In a separate
published report, “taking a multivitamin did not reduce major cardiovascular
events, MI, stroke, [or] CVD mortality…” (JAMA.
2012. 308. 1751-1760 and editorial 1802-1803).
of 21 RCTs (primary and secondary prevention, n=91,074, mean age, 62, mean
duration of supplementation, 43 months) showed a non-significant 2% decrease in
all-cause mortality in all trials, and a trend toward a significant reduction
in all-cause mortality in the primary prevention trials (RR=0.94, 95% CI
0.89-1.00) [Am J Clin
Nutr. 2013. 97. 437-444].
a multivitamin with mineral (if you choose to take one)
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.
aware that the information on many multivitamin labels with regard to the
percentage of daily value in the product may be based on outdated standards (Consumer Reports on Health. 10/04).
o Choose a product with no more than
3000 IU/day of pre-formed vitamin A (maximum of 2300 IU/day for women).
Additional vitamin A (in a multivitamin) in the form of beta carotene is
acceptable, as long as the beta carotene dose does not exceed 5000 IU/day.
o Choose a product with either mixed tocopherols (vitamin E) or no more than 60 IU per day of
vitamin E in the form of alpha tocopherol.
a product with little or no iron unless you are a menstruating woman. Excess iron may increase the risk of
hemochromatosis, cancer and heart disease.
for labels marked “USP” or preferably “USP-Verified.”
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.
for bone development, cellular differentiation, epithelial tissue
maintenance, night vision and proper functioning of the immune system.
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.
be useful in the treatment of acne and psoriasis.
is emerging data on dangers of excess Vitamin A
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.
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.
is especially important for women in the first trimester of pregnancy to
not exceed 10,000 IU per day, secondary to an increased risk of birth
defects associated with high dosages of vitamin A.
- A Cochrane Review of “Antioxidant supplements for prevention of mortality
in healthy participants and patients with various diseases” found that vitamin A
supplements increased total mortality rate by 16% (Cochrane Database Syst
- 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).
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
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).
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).
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
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).
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
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.
15 mg = 25,000 IU
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.
carotene and lung cancer - data from prospective, observational studies
and from randomized, controlled trials is in conflict with the
epidemiologic data, for reasons unclear.
epidemiologic data shows an inverse relationship between beta carotene
intake and lung cancer risk.
Women’s Healthy Eating and Living study showed a 43% reduction in cancer
risk in women with the highest versus lowest blood carotenoid levels.
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).
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).
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).
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).
carotene and heart disease
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.
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).
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, beta-cryptoxanthin,
B complex vitamins
in energy metabolism, hematopoiesis, and other metabolic actions,
including neurotransmitter synthesis.
is increased by stress, drug or alcohol use, smoking, chronic illness,
high sugar intake.
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.
deficient in those with alcohol abuse - give 100 mg a day.
herb horsetail may deplete thiamine.
which may deplete thiamine include antibiotics, diuretics, and oral
be deficient if diet is high in fats and sugars.
is destroyed by sulfites, a common food additive, and also by excessive
Candida organisms synthesize thiaminase, which
can destroy thiamin in the gut and thus lead to thiamine deficiency.
Brussels sprouts, red beet root and tea antagonize thiamin.
is 1.1-1.4 mg for adults based on sex and pregnancy/lactation status of
to 1996 USDA data, 30.2% of Americans obtain less than the RDA of vitamin
B1 from their diet.
evidence of toxicity from oral use.
help in prevention of migraines (see above in this outline).
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.
by light, both visible and ultraviolet.
be chelated by caffeine, copper, saccharin, theophylline, tryptophan,
vitamin B3, vitamin C, and zinc.
herb psyllium may deplete riboflavin.
which may deplete riboflavin include anticholinergics, Phenobarbital, and
vitamin causes the urine to turn bright yellow.
is 1.1-1.6 mg for adults based on sex and pregnancy/lactation status of
to 1996 USDA data, 30.0% of Americans obtain less than the RDA of vitamin
B2 from their diet.
evidence of toxicity from oral use.
truly a vitamin since small amounts are synthesized in the body from
tryptophan, with iron, riboflavin, and pyridoxine as co-factors.
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
- Exists in 2 forms – nicotinic acid and niacinamide.
- Nicotonic acid:
cholesterol, raises HDL. Therapeutic dose for lowering cholesterol
is 3-6 grams/day.
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
be useful in anorexia nervosa, dyspepsia, nicotine addiction, Raynauds, those with cold extremities, Meniere's.
in gout and peptic ulcer disease.
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.
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.
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.
1200 mg twice a day may decrease the risk of elevated liver enzymes
associated in some people with consumption of high doses of niacin.
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.
form of niacin customarily included in vitamin supplements.
not produce same side effects as niacin.
a pilot double-blind trial, niacinamide 500 mg
6 times a day was effective for osteoarthritis (Inflamm Res. 1996. 45. 330-334).
be beneficial in anxiety (500 mg - 1500 mg three times a day), and
insomnia but does not lower cholesterol.
is 14-18 mg in adults based on sex and pregnancy/lactation status.
to 1996 USDA data, 26.0% of Americans obtain less than the RDA of vitamin
B3 from their diet.
which may deplete niacin include antibiotics and oral contraceptives.
Acid (Vitamin B5)
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.
cofactor in the synthesis of the neurotransmitter acetylcholine.
is the active form of this vitamin, and pantethine is available in
evidence of toxicity from oral use.
is no RDA, but adequate intake is estimated at 5 mg in adults.
B6 (Gaby AR. The
Doctor’s Guide to Vitamin B6. Rodale Press. 1984).
referred to as pyridoxine, but really a group of six related compounds,
of which pyridoxine is the most biochemically stable.
three primary forms are pyridoxine, pyridoxal, and pyridoxamine.
is the most common form seen in supplements; PLP and PMP are the
phosphorylated active coenzymes also available in some supplements.
- Pyridoxamine 5’ phosphate (PMP) prevents the formation
into an active form in the body requires zinc, ATP, and FMN
in roughly 100 enzymatic reactions, including methylation.
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
or suspected (environmental) vitamin B6 antagonists (these, if present,
competitively inhibit vitamin B6
dependent enzymes, increasing the requirement for vitamin B6).
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.
hydrazide, an herbicide sprayed on onions,
potatoes (present in potato chips), and tobacco.
acid 2,2-dimethylhydrazide, a chemical ripening agent.
- Tartrazine, a coloring agent added to food and
biphenyls (PCBs) – further use banned in the US in 1976 based on
cancer-causing effects, but residues persist in the environment.
which may deplete vitamin B6 include antibiotics, hydralazine, isoniazide, levodopa, oral contraceptives, penicillamine, phenobarbital, phenytoin,
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
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.
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
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.
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).
decrease homocysteine levels, thus MAY decrease heart disease risk.
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.
supplementation with vitamin B6 is advisable as per Alan Gaby, MD, and this may reduce the
likelihood of vitamin B6 toxicity.
supplementation is advisable with long term vitamin B6 supplementation,
as high dose vitamin B6 can occasionally trigger zinc deficiency.
above 150 mg daily may suppress lactation.
ranges from 1.2-1.7 mg in adults, based on age and sex.
to 1996 USDA data, 53.6% of Americans obtain less than the RDA of vitamin
B6 from their diet.
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)
isomers exist, but only one is biologically active.
is widely available in foods, but its bioavailability is widely variable.
egg whites can interfere with absorption of biotin. Lipoic acid might
interfere with biotin-dependent enzymes.
which may deplete biotin include carbamazepine, phenytoin, Phenobarbital,
mg a day may be helpful in the treatment of diabetes.
supplementation should be accompanied by carnitine supplementation, as
per Robert Crayhon, M.S.
factor in development of healthy hair and nails.
evidence of toxicity from oral use.
is no RDA, but adequate intake is estimated at 30 mcg in adults.
is the name given to a family of compounds (8 forms) which share a common
molecular architecture called pteroylglutamate
– the term ‘folate’ typically encompasses naturally occurring food
folates as well as synthetic folic acid.
folate in food exists in the form of polyglutamates
which must be hydrolyzed to monoglutamates in
order to be absorbed.
folate in food is about half as bioavailable as folic acid in fortified
foods and synthetic supplements.
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.
L-5-MTHF became available as a dietary supplement ~2005
molecule that can be destroyed by heat or light. Ultraviolet light exposure to the skin has a destructive
effect on folate.
alcohol can cause depletion.
which may deplete folate include antibiotics, carbamazepine, cholestryramine, colestipol,
diuretics, methotrexate, oral contraceptives, phenytoin, primidone, salicylic acid.
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.
benefits of folate supplementation
spectrum disorders prevention
from a large case-control study, Childhood Autism Risks from Genetics and
Environment (CHARGE) suggested that maternal folate status during the periconceptual period was associated with a reduced risk of
autism spectrum disorders (Am J Clin Nutr. 2012. 96. 80-89).
a study sample of 85,176 children in the population-based, prospective
Norwegian Mother and Child Cohort Study (MoBa), “use
of prenatal folic acid supplements around the time of conception was associated
with a lower risk of autistic disorder,” with an odds ratio in children of
folic acid users of 0.61 (0.41-0.90). Secondary analyses showed did not show an
association between autism and (1) fish oil supplements before and during pregnancy
and (2) folic acid use at 22 weeks’ gestation, thus suggesting that the
association of prenatal folic acid use with a lower risk of autism is NOT due
to unmeasured confounding in this observational study (JAMA. 2013. 309. 570-577 and editorial 611-613).
– improves blood flow by increasing nitric oxide production in vascular
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).
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).
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).
- 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).
- 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.
tube defect prevention - 0.4 mg/day (OTC) proven useful in prevention
(see very beginning of this outline).
tolerance – beneficial in prevention of development of nitrate tolerance
(see very beginning of this outline).
prevention – in a meta-analysis of 15 RCTs that examined the effect of
folate supplementation on stroke risk, there was an overall 8% reduction
in risk of stroke (p<0.04). In the 10 trials conducted in countries
in which there was no or minimal folic acid supplementation of food,
supplementation reduced the risk by 11% (p=0.01), whereas in the
remaining 5 trials conducted in populations in which folic acid
supplementation is widespread, supplementation had no significant effect
on stroke risk. A daily dose of 0.4 – 0.8 mg folate appeared as
protective as higher doses (Int J Clin Pract. 2012. 66.
risk of folate supplementation
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.
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.
predispose one to zinc deficiency.
increased to 400 mcg for adults, 600 mcg for pregnant women.
- Fortification of food with folate
(i.e. grains) was initiated in the U.S. in 1996 and became mandatory in
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).
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).
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.
seen in those on vegetarian diets, in some individuals over age 50, in
individuals taking medication to reduce stomach acid (H2 blockers, PPIs),
in individuals taking prescription metformin for diabetes, in individuals
with Crohn’s disease affecting the terminal ileum, and in individuals
status post gastric bypass surgery for obesity.
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.
to 1996 USDA data, 17.2% of Americans obtain less than the RDA of
vitamin B12 from their diet.
of vitamin B12 deficiency is 5% at age 65 and 20% at age 80 (Age Ageing. 2004. 33. 34-41).
absorption is common in older individuals and those on acid blockers,
because stomach acid and the digestive enzyme pepsin are required to
uncouple the vitamin B12 from the protein it is bound to in food. The National Academy of Sciences
estimates that up to 30% of adults over age 50 have impaired absorption
of protein-bound vitamin B12 in food. Seniors may require as much as 500
mcg daily of vitamin B12 in supplement form.
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.
though water soluble, vitamin B12 stores in the liver may last up to 5
years, so it can take years for deficiency to develop.
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
B12 insufficiency can be defined biochemically as a normal vitamin B12
level, associated with a high methylmalonic
acid (MMA) level. Elevated MMA is a sensitive and specific indicator of
inadequate B12 despite a normal level. Renal disease and hypovolemia can
also cause elevated MMA levels.
many as 10% of individuals with low normal B12 levels (i.e. 200-400 pg/mL) may develop neuropsychiatric symptoms of B12
deficiency in the absence of megaloblastic
dysfunction is seen in the elderly with B12 levels below 460 pg/ml (cited on pgs
751-767, chapter on diabetic neuropathy, in book Principles & Practice of Geriatric Medicine published in
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.
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.
which may deplete vitamin B12 include antibiotics, colchicine, colestipol, H2 blockers, metformin, oral
contraceptives, phenobarbital, phenytoin, proton pump inhibitors,
B12 is a more important determinant of elevated homocysteine
concentrations in older people than is folate (Age Ageing. 2004. 33. 34-41).
known toxicity for oral or parenteral use.
preservative free preparations parenterally if
chemical sensitivity is suspected.
- Cyanocobalamin is the most common, least expensive,
and commercially available, but it is not natural in the body.
is an activated form found primarily in cytoplasm where it is converted
into its active coenzyme forms – available parenterally
through compounding pharmacies.
– this is one of the active coenzyme forms – available orally and parenterally through compounding pharmacies.
is 2.4 mcg in adults.
Vitamin C (ascorbate)
[JAMA. 1999. 281.
in 3 primary forms – ascorbic acid, semidehydroascorbate,
C content in foods decreased rapidly once they have been picked or sliced.
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.
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).
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).
effects of vitamin C – antihistamine, antiviral.
animals synthesize vitamin C – exceptions are guinea pigs, monkeys, and
lack one enzyme in the 6 enzyme process of synthesizing vitamin C from
have estimated that primates lost the ability to synthesize vitamin C 20
million years ago.
Pauling asserted in the 1970’s that extrapolation of the daily quantity
of vitamin C synthesized by animals would suggest that the optimal intake
for humans is 10-30 grams per day (100 times the RDA).
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.
C and heart disease
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).
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.
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).
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).
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).
– vitamin C is an anti-histamine.
(exercise-induced) prevention – see above in this outline for reference.
disease – anecdotal data.
– may have anti-cancer effects when given at high doses intravenously –
cytotoxic effects and biological response modifier.
– 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).
disease prevention - based on NHANES III data (Arch Intern Med. 2000. 160. 931-936).
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.
metal exposure – effective in removing arsenic, cadmium, and lead from
the blood based on test tube data.
– see above in this outline for reference.
– increases interferon production and may have antiviral effects when
given at high doses intravenously.
data shows that higher intake is associated with slower progression of
– important in the synthesis of bone matrix.
cancer prevention - ineffective in the Physicians’ Health Study II (JAMA. 2009. 301. 52-62 and
sympathetic dystrophy prevention after fracture – see above in this
outline for reference.
– benefit likely based on anti-histamine properties. Vitamin C is also an anti-stress
vitamin and may counter too much adrenalin.
and pregnancy - in a RCT
of 179 pregnant smokers, in those randomized to vitamin C 500 mg daily,
there were better PFT results and less wheezing at age 1 year in infants (JAMA. 2014. 311. 2074-2082).
- vitamin C 2 grams by mouth
1 hour prior to induction of anesthesia was associated with less
post-operative self-administration of morphine (via PCA pump) in the
first 24 hours after surgery, in a randomized trial in 80 patients
undergoing laparoscopic cholysystectomy
[p=0.02] (Can J Anesth.
2012. 59. 538-543).
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.
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).
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
known toxicity but may increase risk of oxalate kidney stones in people
genetically predisposed and known as "stone formers."
doses can interfere with certain diagnostic lab tests such as tests for
occult blood in the urine or stool.
supplements are derived from corn-based material, which might thus cause
symptoms in those with a food sensitivity to corn.
the absorption of non-heme iron, which can be
problematic in those with hereditary hemochromatosis.
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.
doses may cause self-limited diarrhea or bloating.
above 100 mg might be dangerous in those with chronic renal failure.
one study 500 mg daily shown to have a pro-oxidant effect on the DNA base
adenine (Nature. 1998. 392.
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.
and impact upon plasma level
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.
and 25 hydroxy vitamin D levels – a secondary
analysis of a 13 week RCT of 127 patients administered a Lactobacillus reuteri
NCIMB 30242 probiotic found that via an unknown mechanism, those
administered probiotic had an average increase of 6 ng/ml (25%) in 25 hydroxy vitamin D levels (p=0.003) [Jones ML et al. J Endocrinol Metab. Epub 4/22/13].
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).
to 1996 USDA data, 37.5% of Americans obtain less than the RDA of vitamin
C from their diet.
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.
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).
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.
limit (UL) of vitamin C in adults is considered 2 grams.
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)
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.
in the liver to 25-hydroxyvitamin D and then in the kidney to 1, 25 dihydroxyvitamin D (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
causes muscle weakness and muscle aches and pains.
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.
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).
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
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).
D appears to modulate neurotransmitter function.
D is immunoregulatory; upregulates production
of cathelicidin, a naturally occurring broad
spectrum antimicrobial substance (Altern Med Rev.
2008. 13. 6-20).
D reduces inflammation.
D may also have paracrine (around the cell) effects.
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.
(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.
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).
- vitamin D is found in relatively few foods. Vitamin D3 is found only in
animal foods; reported in 2013 that mushrooms exposed to UV light
synthesize vitamin D3.
food sources of vitamin D are high fat fish such as wild salmon and
sardines, and also egg yolks.
to the Weston Price Foundation, traditional diets contained ten times
more vitamin D than the typical modern diet.
foods – fortified with vitamin D2
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.
foods in the US
at this time include milk, cereal, orange juice, and yogurt.
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).
sunlight (290-315 nm)
exposure to sunlight can produce the equivalent of 10,000 – 25,000 IU of
vitamin D3 per day (Am J Clin Nutr. 1999. 69.
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.
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.
of SPF 8 sunscreen reduces the capacity of the skin to make vitamin D by
95% (J Cell Biochem.
2003. 88. 296-307).
vitamin D levels do not necessarily correlate with sun exposure, based
on studies in Honolulu, Miami,
(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.
pigmentation (dark skin), high latitudes, and staying indoors reduce
cutaneous production of vitamin D from sunlight.
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
- 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.
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.
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.
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.
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).
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).
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).
D requirements may be higher in those taking anticonvulsants,
cholestyramine, corticosteroids, and rifampin.
of vitamin D status - this is done primarily by monitoring
25-hydroxyvitamin D levels and serum calcium.
25 dihydroxy vitamin D levels can also be
measured, but are not considered a reliable measure of vitamin D
lab offers a vitamin D panel which measures 25 hydroxy
and 1, 25 dihydroxy vitamin D levels.
measurement of 1, 25 dihydroxy vitamin D
levels may be valuable in cancer patients on chemotherapy and in
patients with multiple chemical sensitivities.
limit of normal for 25-hydroxyvitamin D is based on serum level necessary
to protect against rickets and osteomalacia (11
- Institute of Medicine currently considers a
level of 15 ng/ml to be the minimum for sufficiency.
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).
experts, including Heaney and Holick, state
that levels should always be greater than 30 ng/ml (75 nmol/L).
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).
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”).
25 OH vitamin D levels tend to be lower in African Americans; this may
be attributable to lower levels of vitamin D-binding protein (as a
function of genetic polymorphisms), such that bioavailable 25 OH vitamin
D is similar between Caucasians and African Americans (N Engl J
Med. 2013. 369. 1991-2000 and editorial 2047-2048).
level of 60 ng/ml (150 nmol/L) may be optimal.
THIS IS CONTROVERSIAL.
is likely that levels of 50 ng/ml or higher were present throughout most
of human evolution (Am J Clin Nutr. 1999. 69.
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).
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 (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).
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.
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”).
oral intakes of Vitamin D (50,000 – 100,000 IU/day in adults) are
associated with significant 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).
D toxicity is associated with 25-hydroxy vitamin D levels >150 ng/ml.
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).
to sun does not cause Vitamin D toxicity in healthy people because of
physiologic regulation of production of Vitamin D3.
D hypersensitivity syndrome is much more common than direct vitamin D
occurs when aberrant tissue uncontrollably produces calcitriol.
hyperparathyroidism, sarcoidosis, tuberculosis, Crohn’s disease, and cancer may
cause this syndrome.
weekly measurement of serum calcium for one month, then monthly measurement in
individuals taking high dose vitamin D supplementation to monitor for vitamin D
D deficiency – global issue
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).
study of postmenopausal women admitted with hip fractures showed that 50%
were deficient (JAMA. 1999.
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].
least 62% of morbidly obese are vitamin D deficient (Obes Surg. 1993. 3. 421-424).
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).
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.
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).
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).
Americans and homebound elderly are at higher risk for deficiency.
with diseases associated with fat malabsorption (sprue,
cystic fibrosis, Crohn’s) are at especially high risk for vitamin D
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”).
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.
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.
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.
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).
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).
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.
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
2007. 92. 2130-2135).
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.
D3 supplements versus vitamin D2 supplements
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).
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
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).
Cochrane analysis (see just below) concluded that vitamin D3
supplementation reduces all cause mortality
whereas vitamin D2 supplementation does not.
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.
- High levels also associated with
increased all-cause mortality
– in the CopD Study, a J-shaped relationship
was observed between 25 hydroxy vitamin D
levels and all-cause mortality. This study followed nearly 250,000
individuals in Denmark
for a median of 3 years, and found that serum levels of 20-24 ng/ml were
associated with the lowest risk of dying. Those with a level of 56 ng/ml
had a 42% higher risk of dying during the study than those with a level
of 20 ng/ml (Durup et al. J Clin Endocrinol
- Supplementation associated with lower
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).
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
patient level pooled analysis of 70,528 patients from eight major
vitamin D trials in which vitamin D was given alone or with calcium –
statistically significant 9% decrease in all-cause mortality in those
supplemented with both vitamin D and calcium, non-significant 4%
decrease in all-cause mortality in those supplemented with vitamin D
alone (J Clin
2012. 97. 2670-2681).
meta-analysis of 22 RCTs (n=30,716) showed that overall vitamin D
supplementation did not reduce mortality, compared with placebo.
However, analysis of the 14 RCTs of vitamin D3 (n=13,637) did show a
statistically significant 11% reduction in mortality 95% CI 1% - 20%),
with a NNT of 53 (BMJ. 2014.
spondylitis – deficiency is common (Wien
2001. 113. 328-332).
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].
- However, in a 28 week RCT of 408 patients with
persistent asthma and vitamin D insufficiency, vitamin D3 100,000 IU
once, followed by 4000 IU daily did not reduce the rate of first
treatment failure or exacerbation (JAMA. 2014. 311. 2083-2091).
dermatitis – see ‘eczema’
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
of references regarding vitamin D and cancer prevention are listed on pg 364 of Mayo
Clin Proc. 2006. 81. 353-373.
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].
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).
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).
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).
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).
- A meta-analysis of four randomized controlled
trials on vitamin D supplementation and total cancer incidence, and
three randomized controlled trials on vitamin D supplementation and
total cancer mortality found that (1) vitamin D supplementation had no
significant effect on total cancer incidence, and (2) vitamin D
supplementation significantly reduced total cancer mortality by 12%.
Individual trails were typically 2-7 years and typically used does of
400-1100 IU/day vitamin D (Keum N,
Giovannucci E. Br J Cancer. Epub 6/10/2014).
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).
NHANES 2001-2004, low vitamin D levels found in 74% of 8351 adults with
cardiovascular diseases (Am J Cardiol. 2008. 102. 1540-1544).
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).
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).
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).
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.
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.
- Critique of the data by IOM
committee members (Commentary. JAMA.
2011. 305. 2565-2566).
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).
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.
a 3 month RCT of 80 infants with idiopathic cardiomyopathy, those
randomized to 1000 IU daily of vitamin D3
showed an increase in vitamin D levels from 13 ng/ml to 33 ng/ml, and
the average ejection fraction increased from 36% to 52 %, clinically and
statistically significant compared to the increase from 37% to 43% with
placebo plus standard treatment (Shedeed SA. Pediatr Cardiol. Epub
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).
– 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).
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].
a 24 week uncontrolled study of 18 patients with mild to moderate
Crohn’s disease, those who received 1000 IU per day initially, and then
escalating doses every 2 weeks until serum 25-OH vitamin D level reached
40 ng/ml or the dose was 5000 IU per day, the mean CDAI score improved
from 230 at baseline to 118 (p<0.0001) and quality of life scores
improved significantly (p=0.0004). Mean 25 OH vitamin D level increased
from 16 ng/ml at baseline to 45 ng/ml (Clin Trans Gastroenterol. 2013. 4.
(also see ‘seasonal affective disorder’ below)
likely, based on epidemiologic data, theoretical rationale, and
anecdotes, with limited controlled trial data, except for SAD (see
- 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).
RCT – 6 month RCT of 231
participants randomized to 40,000 IU vitamin D3 vs. placebo (even though
the vitamin D group’s vitamin D levels rose from 19 ng/ml to a mean
level of 59 ng/ml) [Kjærgaard M
et al. Br J Psychiatry. Epub 7/12/12].
of Prozac – an 8 week RCT of 42 patients with major depression found
that those randomized to 1500 IU of Vitamin D along with Prozac 20 mg
showed significantly greater improvement in depression symptoms at 4, 6
and 8 weeks (p<0.01). Mean serum 25 OH vitamin D level at baseline
was 23 ng/ml (Khoraminya N, et
al. Therapeutic effects of vitamin D as adjunctive therapy to
fluoxetine in patients with major depressive disorder. Aust N Z J Psychiatry. 2013. 47.
– vitamin D is important in brain detoxification pathways.
Type I prevention
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).
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).
an 18 month trial of 38 Brazilian patients with new onset type I
diabetes, 2000 IU daily of vitamin D3 slowed the progression. At the end
of the trial, fasting C-peptide levels were undetectable in 18.7% of
vitamin D patients versus 62.5% of placebo patients (p=0.01) and
stimulated C-peptide levels were undetectable in 6.2% of vitamin D patients
versus 37.5% of placebo patients (p<0.05) [Arch Pediatr Adolesc
Med. 2012. 166. 601-607].
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.
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).
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
1992. 13. 45-51).
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.
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.
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.
- Vitamin D 4000 IU daily was beneficial in a 21 day RCT (J Allergy Clin
Immunol. 2008. 122. 829-31).
– 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).
present in 50% in one study (J Rheumatol. 2001. 28. 2535-2539).
a 24 week RCT of 32 women with fibromyalgia and a 25 OH vitamin D level
of < 32 ng/ml, vitamin D supplementation (2400 IU daily for levels
< 24, otherwise 1200 IU daily) raised vitamin D levels and
significantly decrease pain severity (p = 0.03), but did not improve
overall health or overall fibromyalgia severity (Pain. 2014. 155. 261-268).
disease – deficiency present in 58% in one study (Endocrinol J. 2001. 48. 63-69).
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.
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).
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).
(information derived from Vitamin D Council Newsletter 5/16/09, written
by John Cannell, MD)
are concerned with three aspects of any influenza virus: (1) novelty,
(2) transmissibility, (3) lethality.
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.
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.”
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).
back pain – deficiency present in 83% of 360 patients in one study (Spine. 2003. 28. 177-179).
Plaquenil interferes with conversion of
vitamin D to calcitriol.
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).
a 1 year RCT of 267 patients with lupus, those randomized to receive
2000 IU daily vitamin D3 experienced a significant decrease in SLE-related
antibodies (p=0.05) and a lower probability of a flare up (10% vs.24%,
p<0.05). The 25 hydroxy vitamin D levels in
the treatment group increased from a mean of 19.8 ng/ml to 37.8 ng/ml (Abou-Raya A et al. J Rheum. Epub
degeneration (AMD) – protective effect, based on data from NHANES III (Arch Ophthamol.
2007. 125. 661-667).
loss – see ‘Cognitive Decline’ just above
is present in 48% in one study (J Neuroimmunol. 2003. 134. 128-132).
the Nurses’ Health Study and Nurses’ Health Study II, a cohort of over
95,000 women, those who took vitamin D 400 IU daily had a 40% lower risk of
developing multiple sclerosis (Neurology.
2004. 62. 60-65).
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).
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 interventional study in 12 patients with active MS who received
progressively higher doses of vitamin D3, from 28,000 IU once a week to
280,000 IU once a week for 6 weeks, along with calcium 1200 mg/day,
disease activity and disease progression did not change, but the number
of gadolinium-enhancing lesions decreased significantly (p=0.03). No
adverse effects were seen (Am J Clin Nutr. 2007. 86.
- An open-label randomized prospective controlled
52-week trial of 49 patients in which treatment patients received escalating
vitamin D doses up to 40,000 IU/day over 28 weeks to raise serum
25-hydroxyvitamin D rapidly and assess tolerability, followed by 10,000
IU/day (12 weeks), and further down-titrated to 0 IU/day (along with
Calcium 1,200 mg/day) concluded that high dose vitamin D is safe, with immunomodulatory effects. There was a trend toward
fewer relapses in the treatment group (p=0.09). No adverse effects were
seen (Neurology. 2010.
- In a 6 month RCT in 23 patients with relapsing-remitting
MS, in which the treatment group was administered 6000 IU per day
vitamin D2, and the control group was administered 1000 IU per day
vitamin D2, there were no differences between the two groups (Neurology. 2011. 77. 1611-1618).
- In a one year RCT of 66 patients, in which the
treatment group received 20,000 IU of
vitamin D3 once a week as an add-on therapy with interferon beta 1b,
those in the treatment group showed significantly fewer lesions on
brain MRI and strong trends toward lower lesion burden, reduced disability
scales, and improved ability to walk, compared to controls. 25(OH) D
levels went from 22 ng/ml to 44 ng/ml in one year (J Neurol
2012. 83. 565-71).
- In a one year RCT of 30 patients with clinically
isolated syndrome(optic neuritis), all of those randomized to vitamin D3
50,000 IU weekly delayed onset of multiple sclerosis, whereas 5 of the
11 control patients were diagnosed with multiple sclerosis (Derakhshandi H et al. Acta Neurol Belg. E pub 12/19/12).
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)
Proc. 2003. 78. 1463-1470].
data showed slower progression of knee osteoarthritis symptoms in those
with higher 25-hydroxyvitamin D levels (Ann Intern Med. 1996. 125. 353-359). However, other epidemiologic
studies have failed to link vitamin D intake or levels to the incidence
or prevalence of osteoarthritis (Alt
Med Alert. 2008. 11. 85-90).
- Negative RCT - in a 2 year RCT
of 146 participants with symptomatic knee OA, vitamin D3 2000 IU per
day, with dose escalation to achieve a serum 25 hydroxy
vitamin D level of > 36 ng/ml, was not associated with reduction in
knee pain or cartilage volume loss (JAMA.
2013. 309. 155-162).
- Positive RCT – in a 1 year RCT
of 103 patients, conducted in India, and with all patients with a
baseline 25 OH level below 20 ng/ml,
there was a greater decrease in WOMAC scores in the treatment group (p
<0.001), and greater improvements in physical function in the
treatment group (p <0.001). The treatment group received 60,000 IU of
vitamin D for 10 days and then 60,000 IU once a month for a year (Sanghi D et al. Does Vitamin D Improve Osteoarthritis of
the Knee: A Randomized Controlled Pilot Trial. Clin Orthop Relat Res. 2013).
– may decrease the risk of nonvertebral
fractures and the incidence of falls. For specifics, return to Home Page,
click on "Osteoporosis" and scroll to "Vitamin D."
– in an uncontrolled 12 week trial in Iran of 62 adult patients with chronic pain and
treated with 50,000 IU/week of vitamin D3 and 1,000 mg of calcium/day,
the researchers found that 53 of the 62 patients (85.5%) responded to
treatment, with pain scores diminishing more than 60%. In 47 (75.8%)
patients, the pain subsided completely. At baseline, 95% of the patients
had levels less than 20 ng/ml (Abbasi M et al. Global J Health Sci. 2013. 5).
disease – in a 12 month RCT of 112 patients randomized to 1200 IU vitamin
D3 or placebo, vitamin D3 prevented progression. There was no worsening
of scores in the treatment group on the HY scale, whereas the disease
progressed in the placebo group (p=0.005). In addition, there was no
worsening of scores in the treatment group on the UPDRS part II, whereas the disease progressed in the
placebo group (p=0.004). 25 OH vitamin D levels rose from 22.5 ng/ml to 41.7 ng/ml in
the treatment group (Am J Clin Nutr. 2013. 97. 1004-1013).
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.
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).
cancer – 44 men with low risk prostate cancer (Gleason score of 6 or
less, PSA of 10 or less, clinical stage T1c or T2a) who elected active
surveillance were administered 4000 IU per day vitamin D3 for one year.
As compared with 19 historical controls, the proportion of patients who
showed progression was lower in the vitamin D supplementation group (34%
vs. 63%, p=0.025). Men in the vitamin D supplementation group with a
baseline 25 OH vitamin D level of < 20 ng/ml seemed to benefit less
from supplementation than those with a higher baseline vitamin D level (J Clin Endocrinol Metab. 2012.
– calcitriol inhibits proliferation of human keratinocytes, and vitamin D
analogues are available by prescription to treat this condition.
meta-analysis of 5 RCTs found that the
combined relative risk for a respiratory infection was 0.58 for those
taking vitamin D. The dose of vitamin D in the five trials ranged from
400 IU/day to 2,000 IU/day, with one using a single dose of 100,000 IU.
The length of the trials ranged from 3 months to three years (J Pharmacol
Pharmacother. 2012; 3:300-303).
meta-analysis of 11 RCTs, conducted by the Karolinska
Institute in Stockholm found a protective effect, with an odds ratio
(OR) of 0.64 for taking a vitamin D supplement rather than a placebo.
The protective effect was larger in studies using once-daily dosing
compared to bolus doses (OR = 0.51 vs. OR = 0.86, p = 0.01).The doses of
vitamin D in the studies was variable, and the studies were
heterogeneous. The authors conclude “Aggregated evidence from 11
randomized controlled trials indicates that supplementation with vitamin
D could be an effective means of preventing respiratory tract
infection.” (Bergman P et
al. PLOS One. 2013).
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).
the Iowa Women’s Health Study, vitamin D intake correlated inversely
with disease prevalence (Arthritis
Rheum. 2004. 50. 72-77).
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).
- High dose vitamin D supplementation
may be harmful – in a one year RCT of 22 patients, all with baseline
25 OH vitamin D levels < 25 ng/ml, vitamin D treatment was associated
with a significant worsening of the Patient Assessment of Global Health
(p=0.02) and Patient Global Assessment of RA (p=0.01). Treatment group
received vitamin D2 50,000 IU 3 times per week for 4 weeks, then 50,000
IU twice a month, with dose increased to 50,000 IU weekly if 25 OH
vitamin D level at 2 or 5 months was < 25 ng/ml (J Clin Rheum. 2014. 20. 112-114).
affective depression – supplementation with 400-800 IU vitamin D3 improved
mood in a study of 44 patients (Psychopharmacology.
1998. 135. 319-323).
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).
– 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).
- 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).
brain injury – a 3 month, 3-arm RCT of 60 patients in Iran showed benefit
in the group randomized to receive one
mg/kg of progesterone intramuscularly every 12 hours for 5 days and also
200 IU/kg of vitamin D once-a-day for 5 days. At 3 months, 35% of
patients in the progesterone + vitamin D group made “Good Recovery,” as
assessed by the Glasgow Outcome Scale, while only 25% met this assessment
in the progesterone group and only 15% in the placebo group (p=.03).
Ten-percent died in the progesterone + vitamin D group, compared to 20%
in the progesterone group and 40% in the placebo group (p=.03) [Aminmansour B et al. Adv Biomed Res.
– 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).
respiratory infections (also see ‘respiratory infections’ just above)
studies have reported an inverse association between serum 25 hydroxy vitamin D levels and incidence of upper
RCT: An 18 month RCT of 322 healthy adults with a mean baseline serum 25
hydroxy vitamin D level of 29 ng/ml showed
that monthly administration of 100,000 IU of vitamin D3 did not reduce
the incidence or severity of URI’s in healthy adults, even though the
serum level was increased to 48 ng/ml in the treatment group (JAMA. 2012. 308. 1333-1339 and
D supplementation – sales estimated at $425 million in 2009, compared with
$40 million in 2000 (Nutrition
D2 (ergocalciferol) is produced by exposing ergosterol from yeast to UVB radiation.
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.
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.
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).
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.
experts recommend administering 4000 IU per day to all pregnant women (Am J Clin Nutr. 2004. 79. 717-726).
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).
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).
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)
of a group of 8 molecules, 4 tocopherols and 4 tocotrienols, each named alpha, beta, gamma, and
delta, which function as lipid-soluble antioxidants.
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).
tocopherols differ from the tocotrienols
with regard to the chemical structure of the tail of the molecule (i.e.
the number of double bonds).
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.
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).
in 1924 as a missing factor in the diet that was making male rats
on this, main function of vitamin E was thought to be support of
tocopherol was isolated in 1936, beta and gamma tocopherols
in 1937, delta tocopherol at a later date, the tocotrienols
not until the 1950s.
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).
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.
scientists learn of the multiple functions of the various tocopherols and tocotrienols
in the body, potency becomes somewhat irrelevant, as potency is useful
only for comparing compounds with the same function. Tocotrienols
may be 40-60 times morpotent than tocopherols in their antioxidant capacity, and up to 70 fold more bioavailable
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.
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.
equivalents for vitamin E (Papas A. The Vitamin E Factor. 1999.
alpha tocopherol 1.49 IU/mg
alpha tocopheryl acetate 1.36 IU/mg
alpha tocopheryl succinate 1.21 IU/mg
alpha tocopherol 1.10 IU/mg
alpha tocopheryl acetate 1.0 IU/mg
alpha tocopheryl succinate 0.89 IU/mg
food sources include oils of vegetables, nuts, and seeds.
fruit oil (not to be confused with palm kernel oil) is the only common
and complete source of all 4 tocotrienols.
or processing foods can substantially lower vitamin E amounts.
tocopherol is the predominant form of vitamin E in food.
forms of vitamin E (The Vitamin E
Factor (1999) by Andreas Papas, PhD. Ch 3-4)
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
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
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.
(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.
tocopherols – beware these may contain filler
oil as 33-50% of the product, and the filler oil may be subject to
tocopherols and tocotrienols.
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).
the process of neutralizing free radicals, tocopherols
become tocopheryl free radicals.
E free radicals are reduced back to tocopherol form primarily by vitamin
C, but also by coenzyme Q 10 and reduced glutathione.
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.
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.
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).
of vitamin E in animal models and cell cultures:
tocopherol reduces at atherosclerotic lesions (J Am Coll Nutr.
1992. 11. 131.138).
tocopherol reduces smooth muscle cell proliferation (Lancet. 1995. 345. 170-175).
tocopherol reduces platelet adherence and aggregation (J Am Coll Nutr. 1991. 10. 466-473).
tocopherol reduces protein kinase C activation (Diabetes Res Clin Pract. 1999. 45. 169-182).
tocotrienols is more effective than any other
molecule in preventing neurodegenation in cell
cultures; alpha tocotrienols protects against
stroke in rodents and dogs.
tocopherol inactivates nitrogen free radicals (i.e. peroxynitrate,
produced in part from nitric oxide) more effectively than
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.
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.
tocopherol can improve endothelial function
and delta tocotrienols can lower cholesterol by
15-22%, lower triglycerides, and raise HDL/LDL ratios.
of vitamin E in humans (basic research):
tocopherol can improve endothelial function (J Am Coll Cardiol.
2000. 36. 94-100).
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.
EFFECT – d-alpha-tocopherol lowers HDL, and specifically HDL-2.
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).
tocopherol exhibits an anti-proliferative effect on prostate cancer cells
in tissue culture (Ann N Y Acad Sci. 2004. 1031. 399-400).
tocopherol inactivates nitrogen free radicals, such as peroxynitrite (Proc Natl Acad Sci. 1997. 94. 3217-3222).
metabolic degradation product of gamma-tocopherol appears to be a
natriuretic factor (Proc Natl Acad Sci. 1996. 93. 6002-6007).
- Tocotrienols partially inhibit the activity of HMG
CoA reductase, involved in the biosynthesis of cholesterol.
- Tocotrienols increase arterial compliance, based on a
RCT in 36 healthy males (Arch Pharm
Res. 2008. 31. 1212-1217).
tocotrienol stops Chlamydia from entering cells
via ‘lipid rafts.’
data indicate an inverse association between cardiovascular risk and
vitamin E intake from dietary sources and/or supplements (Ann Intern Med. 1995. 123.
studies in patients without established CAD support a role of Vitamin E in
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).
Professionals Follow-up Study – A prospective, observational study of
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).
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).
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).
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).
randomized controlled trials were positive with regard to Vitamin E and
heart disease prevention.
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).
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.
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).
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).
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.
also did not reduce the relative risk of total cancer incidence or cancer death (JAMA.
2005. 293. 1338-1347).
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).
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).
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).
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
benefit of vitamin E was seen except in the subgroup of women over age
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).
that vitamin E also did NOT reduce the risk of cancer in this
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
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).
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.
studies looking at changes by quantitative angiography actually show
worsening when Vitamin E is given with Vitamin C.
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.
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).
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 . 14-17).
meta-analysis may be unreliable because heterogeneous trials were
combined for analysis.
trials tested vitamin E alone and 10 trials tested vitamin E combined
with other vitamins or minerals.
was used in 4 of the high-dose vitamin E trials.
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.
entry criteria for the various trials in the meta-analysis were
one trial (HOPE) used natural vitamin E, as opposed to synthetic vitamin
trials that tested high dosages involved adults with chronic disease, not
of the evidence for an elevated mortality risk at high doses comes from 2
trials that administered vitamin E with beta-carotene.
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).
- most trials of supplemental vitamin E for prevention of Alzheimer’s do
not show benefit.
- 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).
benefit seen for breast, colon, or lung cancer in the Women’s Health
Study (JAMA. 2005. 294. 56-65
with editorial 107-109).
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).
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.
stage liver disease (ESLD) - mixed tocotrienols,
based on improvement in MELD scores noted as an unanticipated outcome of
a Phase I trial to examine absorption of mixed tocotrienols
2012. 142. 513-519).
– there is some data that gamma and delta tocotrienols
lower LDL cholesterol.
response – data is mixed
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).
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).
fatty liver disease (NAFLD) and nonalcoholic steatohepatitis
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).
IU per day d-alpha tocopherol was somewhat beneficial in a 96 week RCT of 173
children (ages 8-17) with biopsy-proven NAFLD.
Reduction in ALT levels, the primary endpoint, was statistically
significantly greater in the vitamin E group at 48 weeks, but not statistically
significantly different at 96 weeks (sustained reduction in 26% of those
administered vitamin E vs. 16% of those administered placebo). In terms of
secondary measures, the mean improvement in the NAFLD activity score was
greater with vitamin E than with placebo (p=0.02) and the proportion of
patients who had resolution of NASH was greater with vitamin E than with
placebo (p=0.006). NOTE this study was reported in JAMA as negative based on failure to achieve significance at 96
weeks in terms of the primary endpoint (possibly due to adherence to diet and
exercise recommendations in the placebo group). NOTE this was a 3 arms study,
and metformin was ineffective by all measures (JAMA. 2011. 305. 1659-1668).
tocotrienols can improve and even cure NAFLD, based
on 1 year data in 30 patients presented at 2010 meeting of the American
Association for the Study of Liver Disease. Fifteen patients were cured (Hepatology. 2010.
52 [4 Suppl]. 642}.
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.
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).
legs – may be beneficial, based on a trial in 9 patients (J Applied Nutr.
1973. 25. 8-15).
healing – topical application might reduce scar formation cuts or burns
or surgical incisions.
effective for autoimmune diseases, diabetes, epilepsy, infertility, leg
cramps, macular degeneration, multiple sclerosis, myopathy, neuropathy,
premenstrual cramps and tardive dyskinesia.
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).
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
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.
NOTE minimal toxicity in studies of Vitamin E that have used doses as high
as 3200 IU and with 10 years of follow up.
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).
– 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
– in an Australian study designed around a hypothesis that vitamin E would
lower BP in diabetics, the investigators unexpectedly found that both
mixed tocopherols and d-alpha tocopherol
increased mean daytime and nighttime BP in patients on antihypertensives (2006 presentation 16th
Annual European Meeting on Hypertension). Possible mechanism –
interference with metabolism of prescription medications for BP.
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].
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
for vitamin E increases in those consuming plentiful amounts of
polyunsaturated fatty acids in diet.
to 1996 USDA data, 69.4% of Americans obtain less than the RDA of vitamin
E from their diet.
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.
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).
the dose for supplementation has been chosen empirically, without
actually measuring the effect of vitamin E on oxidative stress.
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
in 2000 defined as 1500 IU of RRR-alpha tocopherol or 1100 IU of all rac-alpha tocopherol.
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)
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).
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.
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
though fat soluble, not stored in the body, so must be provided daily.
Vitamin K exists in three forms
o Phylloquinone or phytonadione
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.
K1 in food is tightly bound to chlorophyll and may be difficult to absorb (J Nutr. 1998.
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
family of related compounds, menaquinones 2-9.
menaquinones are produced by intestinal bacteria – it
is estimated that intestinal bacteria produce 75% of the vitamin K that the
body absorbs each day.
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).
K2 may be more important to cardiovascular health and cancer prevention than
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.
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
for post-translational carboxylation of glutamyl
residues in specific proteins involved in blood coagulation (multiple Gla proteins) and bone metabolism (via carboxylation of
osteocalcin). Glutamic acid is a component of at least 14 proteins
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.
K2 in the brain contributes to the production of myelin, independent of its
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.
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).
of osteoporotic fractures (see Osteoporosis outline on this web site).
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).
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
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).
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).
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).
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.
of morning sickness.
treatment of leukemia, liver cancer, lung cancer (very preliminary data, much
of the research is in animals).
prevention or reversal of coumadin-induced arterial
calcification, based on animal research showing reversal in rats (Blood. 2007. 109. 2823-2831).
though Vitamin K is fat soluble, toxicity is not well defined.
K2 has been studied in a number of human trials of 1-2 years duration, with no
toxicity and very few adverse effects documented.
K3 triggers the production of superoxide free radicals as a consequence of its
metabolism in the mitochondria (Free Radic Biol Med. 2008. 44.
K counteracts effects of prescription coumadin.
assessment – most sensitive test is measurement of levels of uncarboxylated osteocalcin – high levels indicate a
functional vitamin K deficiency
is 90 mcg in adult females and 120 mcg in adult males.
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
molecular form of a mineral may affect absorption.
salts are the combination of a mineral with an inorganic acid (i.e.
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.
are complicated compounds in which the mineral is held in the middle of
a large organic molecule (aspartates, glycinates,
may be the best absorbed forms.
chelators may change the environment of the
GI tract, thereby reducing or enhancing bioavailability.
is not evidence to support the claims
that colloidal minerals are superior to other forms of mineral
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.
may be contaminated with toxic elements such as aluminum, lead, or
form of the mineral is important, as outlined above.
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.
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.
minerals may not be absorbed because they may bypass the absorption site
in the small intestine.
and human physiology:
18 different minerals have known physiologic function in 2004.
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.
minerals – body needs are in excess of 100 mg per day – calcium,
chloride, magnesium, phosphorous, potassium, and sodium.
minerals – body needs are measured in mcg per day – arsenic, boron,
chromium, cobalt, copper, fluoride, iodine, iron, manganese, molybdenum,
nickel, selenium, silicon, tin, vanadium, and zinc.
– necessary for normal bone and tooth development, nerve impulse conduction,
muscle contraction, and blood clotting.
is currently set at 1000 mg for adults aged 19-50 and 1200 mg for adults over
age 50, but some authorities such as Walter Willett, MD, DrPH
feel the RDA might be set too high.
balance studies, the basis of the RDA, may provide deceptive information
because calcification of joints and artery walls and soft tissue, which is
common in adults but not desirable, will contribute to the value determined for
zero calcium balance.
cross sectional study of 2310 healthy adults found that as long as there is
adequate vitamin D intake (as assessed by a 25-hydroxy vitamin D level),
calcium intake of 800 mg/day may be adequate for maintaining calcium
homeostasis, as assessed by a normal serum intact PTH level (JAMA. 2005. 294. 2336-2341).
for a given individual will also depend on other dietary factors such as
protein intake and salt intake (listed below) which affect elimination of
intake for U.S.
adults estimated at 800 mg/day; prehistoric intake estimated at 1900 mg/day.
is usually 500-1000 mg per day of elemental
is more efficiently absorbed if given in divided doses. Do not exceed 600
mg at one time.
supplements are approximately 30% absorbed; other than achlorhydria
in which calcium carbonate is not well absorbed, there is little published data
on differential absorption of different forms of calcium supplements.
that some natural calcium supplements such as dolomite and bone meal may
be contaminated with lead.
is no evidence to support claims that coral calcium is superior to other
forms of calcium, and in fact in 2003 the FDA and the FTC brought charges
against certain marketers for unsubstantiated claims (Los Angeles Times Health Section. 9/29/03).
o Dissolution of supplements is important,
especially for calcium carbonate, which can be packed so tightly in tablet form
that it passes through the GI system intact – look for USP designation on the
of calcium – as per Michael Murray, N.D. there is no single best form of
calcium for everyone.
carbonate is 40% elemental calcium. This is an alkaline preparation which
requires stomach acid for dissolution.
citrate or malate is 20% elemental calcium. This is an acidic preparation which
can exacerbate GI symptoms due to hyperacidity. A potential benefit of these
preparations is that citric acid and malic acid have been shown to chelate
lactate is 13% elemental calcium.
triphosphate is 38% elemental calcium
hydroxyappetite is 25% elemental calcium.
is absorbed via:
active, vitamin D dependent transcellular process in
the duodenum and jejunum.
passive, vitamin D independent paracellular process
in the ileum.
with vitamin D sufficiency absorb 30-40% of ingested calcium, depending in part
on intake and in part on state of health (absorption is increased to as much as
80% during pregnancy and lactation). Absorption is only 10-15% with vitamin D
insufficiency which often leads to secondary hyperparathyroidism.
calcium is absorbed in the small intestine where the pH is basic or normal,
stomach acid is not needed for calcium absorption per se.
phytic acid, oxalic acid (oxalate), cocoa, and excess
dietary fat may interfere with calcium absorption.
absorption is enhanced by substances which increase its solubility -
hydrochloric acid, ascorbic acid, citric acid, lysine, and glycine.
types of fiber surprisingly may actually enhance calcium absorption.
is published data that calcium citrate malate is up to twice as absorbable as
calcium carbonate (Altern Med Rev. 1999. 4. 74-85).
- bone tissue contains 95-99% of the body’s total calcium.
– “Increasing the magnesium intake improves rather than interferes with
calcium utilization” (Am J Clin Nutr. 1987. 45.
is excreted in the kidneys and also eliminated in the feces (calcium from
sloughed mucosa and calcium in digestive secretions).
dietary protein, sodium, glucose, and aspartame may increase renal loss of
calcium. 6 mg of calcium are required to
offset the urinary loss of calcium that occurs with 1 gram of protein intake.
dietary fiber, caffeine, and alcohol may increase fecal elimination.
pressure reduction. Colorectal adenomas – a meta-analysis of 3 RCTs with 1485
patients found that calcium supplements significantly reduce the rate of
recurrence of adenomas (Am J Gastroenterol. 2005. 100. 390-394).
stones - in moderate amounts, contrary to conventional wisdom, may decrease
risk of recurrent calcium oxalate kidney stones. Calcium citrate is the
recommended form in patients with a history of kidney stones; this may actually
reduce the risk of stones by reducing urinary saturation of calcium oxalate and
Mortality - prospective observational data in 38,772 older women in the Iowa Women’s
Health Study showed that use of calcium and vitamin D was associated with a
decreased risk of all cause mortality. Note this
finding seems to contradict a meta-analysis of RCTs showing an increased risk
of MI in those taking calcium supplements (Arch
Intern Med. 2011. 171. 1625-1633).
prevention – benefit seen in clinical trials of 2-3 year duration, but not seen
in long term observational studies, suggesting that once a calcium deficit is
corrected, total daily intake of 800 mg/day is probably sufficient (as long as
vitamin D status is replete!).
treatment - multi-center trial of 466 women taking 1200 mg calcium carbonate
per day (Am J Obstet
Gynecol. 1998. 179. 444-452).
neutralization - unabsorbed calcium in the
gut lumen (which averages 90% of intake) complexes and neutralizes
certain potentially harmful products of digestion, such as oxalic acid, free
fatty acids, and bile acids – the effect is purely chemical and is immediate.
loss - the data is mixed (J Am Diet
Association. 2005. 105. 1401-1407), with the preponderance of evidence
showing no effect of calcium or dairy on weight loss (Alt Med Alert. 2006. 9. 49-55). A 2 year RCT in 340 overweight or
obese adults failed to show any benefit of supplementation with calcium
carbonate 750 mg twice a day with meals (Ann
Intern Med. 2009. 150. 821-829).
calcium if not accompanied by intake of supplemental magnesium (2:1 ratio of
calcium to magnesium) may predispose to magnesium deficiency (Gaby A. Preventing and Reversing Osteoporosis.
calcium if not accompanied by intake of supplemental silicon (2-5 mg/day in a
multimineral preparation) might predispose to silicon deficiency (Gaby 2011
presentation “Controversies in Nutrition”).
calcium might interfere with conversion of Vitamin D to its active form
(Willett W. Eat, Drink, and Be Healthy.
supplementation decreases the absorption of phosphorous.
of calcium carbonate above 20 grams per day (above 4 grams per day in those
with renal failure) can cause “milk-alkali” syndrome.
of calcium above 1200-1500 mg/day is associated with an increased risk of
of 2776 men in the French SU.VI.MAX Study showed a higher risk of prostate
cancer in those with higher dairy and calcium intake (Br J Nutr. 2006. 95. 539-545).
in 47,750 males in the Health Professionals Follow-up Study showed that higher
calcium intake (>1500 mg/day) was associated with an increased risk of
high-grade (Gleason >7) prostate cancer and fatal prostate cancer (Cancer Epidemiol
Biomarkers Prev. 2006. 15. 203-210).
meta-analysis of 12 studies found that men with the highest intake of dairy and
calcium had a higher risk of prostate cancer (J Natl Cancer Inst. 2005. 97. 1768-1777).
of calcium supplements might increase the risk for MI
of calcium supplements >500 mg/day increases the risk for MI by 30%, but not
does not increase all-cause mortality or stroke, based upon a meta-analysis of
8 RCTs (N=10,908). Trials in which vitamin D was also supplemented were
excluded from this analysis. (BMJ.
2010. 341. c3691). NOTE that none of these trials was designed to test the
hypothesis that calcium supplementation causes MI, and borderline statistical
significance (p=0.035-0.038) in this post hoc meta-analysis may be due to
chance rather than a true causal relationship between calcium supplementation
and MI (Gaby 2011 presentation “Controversies in Nutrition”).
of calcium citrate supplements at a dose of 1 gram per day associated with
twice the incidence of cardiovascular events (MI, CVA, and sudden death) in a 5
year RCT in 1471 healthy postmenopausal New Zealand women. There were 101
events in the treatment group, 54 events in the placebo group. Vascular event
rate was higher in those with higher compliance, and higher during 30-60 months
of follow up rather than initially, suggesting a causal effect. The NNT to cause one additional MI was 44 and
the NNT to cause one additional stroke was 56. Possible confounding factors not
addressed in the study include low intake of magnesium and/or vitamin D (BMJ. 2008. 336. 262-266).
trial – 1200 mg/day of calcium for 5 years was associated with a nonsignificant 6% decrease
in cardiovascular disease-related death or hospitalization in elderly women (J Bone Res. 2011. 26. 35-41).
the WHI, in which 36,282 women were randomized to calcium carbonate 500 mg
twice a day with vitamin D 200 IU twice a day, there was a 17% increased risk
of kidney stones. (N Engl
J Med. 2006. 354. 669-683).
just above though regarding suggestive data that calcium citrate is protective
against recurrent calcium oxalate stones.
data suggests that higher dietary calcium intake is associated with a decreased
risk of kidney stones, presumably by interfering with oxalate absorption. It is
hypothesized that the higher risk of kidney stones observed with supplemental
calcium intake may be related to calcium supplements taken without food.
more information, return to Home Page, click on "Osteoporosis"
and scroll to "calcium."
dose is usually 400 mg – 600 mg per day.
to USDA surveys, 62% of Americans fail to consume the RDA of magnesium (Consumer Reports on Health. 6/05).
III data shows that 75% of Americans don’t obtain the RDA of magnesium (Adv Data; 1994. 258: 1-28). NHANES
1999-2000 data shows that 50% of Caucasians consumed < 755 of the RDA
and that magnesium intake was on average 25% lower in African Americans
than in Caucasians (J Nutr. 2003. 133. 2879-2882).
in at least 300 intermediary enzymatic reactions; essential for most energy-requiring reactions.
sources include whole grains, green leafy vegetables, legumes, almonds,
cashews - an estimated 80% of magnesium content is lost when whole grain
flour is refined; an estimated 50% is lost when vegetables are boiled.
fat diet may decrease magnesium utilization by 50% (Seelig
M, Rosanoff A. The Magnesium Factor. 2003. Pp 129-130).
phosphorous (present in soda) interferes with magnesium absorption.
in food interfere with magnesium absorption
calcium intake can cause magnesium deficiency via interference with
absorption and promotion of excretion (Am
J Clin Nutr. 1987.
B6 increases intracellular uptake of magnesium (Abraham G. Ann Clin Lab
Sci. 1981. 11. 333-336).
(based on animal data) can interfere with magnesium absorption via
production of excess tricaballyate, which binds
magnesium tightly in the gut.
of excess alcohol and caffeine as well as certain medications such as
diuretics and digoxin depletes the body of magnesium.
sleep deprivation has been reported to cause magnesium deficiency (Clin Cardiol.
1997. 20. 265-268).
kinds of physical, chemical, and emotional stresses, including sleep
deprivation and exposure (in animals) to excessive noise can deplete
magnesium, with the effect presumably mediated by excess adrenalin
secretion. This can create a viscous cycle whereby magnesium deficiency
aggravates the negative effects of
stress (Artery. 1981. 9. 205-211; J Am Coll
Nut. 1985. 4. 165-172. Am J Otolaryngol.
1994. 15. 26-32; Clin Cardiol.
1997. 20. 265-268; Magnesium.
1986. 5. 201-210).
cramps and cold hands and feet are symptoms which suggest the possibility
of a magnesium deficiency.
tissue contains 60% of the body’s total magnesium, and muscles contain
20%. 99% of magnesium is in the cells, with only 1% in the bloodstream.
rationale and/or anecdotes and/or uncontrolled trials - anxiety,
attention deficit disorder, autism, chronic fatigue syndrome, coronary
artery disease, congestive heart failure, constipation (milk of magnesia,
magnesium citrate), diabetes, dyspepsia (magnesium-containing antacids),
epilepsy, fatigue, fibromyalgia, insomnia, nephrolithiasis prevention in
chronic stone formers, osteoporosis prevention and treatment. NOTE it may
take 6 weeks to 6 months to replenish body stores (Am J Health Syst Pharm. 2004. 61.
- benefit seen in a one month RCT in 28 patients administered either
placebo or 365 mg/day of magnesium as magnesium pidolate
(Magnes Res. 1990. 3. 109-112) and a 4
month RCT in 55 patients administered either placebo or magnesium 365
mg/day as magnesium aspartate hydrochloride (Magnes Res. 1996. 9. 81).
– data is mixed
Cochrane review of nebulized magnesium found that the addition of
nebulized magnesium to nebulized beta agonist improved pulmonary
function in acute asthma, with a trend toward fewer hospital admissions
(Cochrane Database Syst Rev. 2005. CD003898).
meta-analysis concluded that the addition of parenteral magnesium
sulfate to standard treatment with bronchodilators and steroids is
probably beneficial in the treatment of moderate to severe acute asthma
in children (Arch Dis Child.
2005. 90. 74-77).
earlier Cochrane review of parenteral magnesium sulfate for acute
exacerbations of asthma treated in the emergency room concluded that it
is beneficial only for the subgroup with severe acute asthma, with
improvements seen in FEV1 in this subgroup with severe acute asthma (Cochrane Database Syst
Rev. 2000. CD001490).
STUDY – a RCT showed no benefit when oral magnesium supplementation was
added to standard outpatient treatment regimen of chronic stable asthma
in adults (Clin Exp
Allergy. 2003. 33. 1355-1359).
fibrillation for rate and rhythm control – efficacy reported for
intravenous magnesium in a meta-analysis of 8 RCTs (n=476), using doses
of Mg sulfate in the range of 1.2 to 10 grams, with infusions over 1 to
30 minutes. Adverse effect profile of magnesium similar to that of
placebo (Am J Cardiol.
– shown beneficial in a Cochrane review of 3 small trials (Cochrane Database Syst
Rev. 2001. CD002124).
– parenteral magnesium has been t he standard
of care for decades; benefit shown in two Cochrane reviews (Cochrane Database Syst
Rev. 2003. CD000128; Cochrane
Database Syst Rev. 2001. CD002960).
in those with pre-eclampsia – benefit shown in a Cochrane review (Cochrane Database Syst
Rev. 2003. CD000025) and an additional study (N Engl J Med. 2003. 348. 304-311).
- a meta-analysis of RCTs found that oral magnesium supplementation
resulted in small overall reductions in BP in a dose dependent manner in
hypertensive patients (Am J Hypertens. 2002. 15. 691-696).
cramps in pregnant women – shown beneficial in a Cochrane review (Cochrane Database Syst
Rev. 2002. CD000121).
Cross-sectional analysis of 11,686 women over
age 45 in the Women’s Health Study suggests that magnesium intake is inversely
associated with systemic inflammation and prevalence of metabolic syndrome (Diabetes Care. 2005. 28. 1438-1444).
Data from 4637 young adults in the CARDIA Study
without metabolic syndrome or diabetes at baseline showed a 30% reduction in
metabolic syndrome at 15 years of follow-up in those in the highest quartile of
magnesium intake compared those in the lowest quartile of magnesium intake,
based on food frequency questionnaires (Circulation.
2006. 113. 1675-1682).
Migraine headaches – data is MIXED
dicitrate) 600 mg/day effective in reducing the
frequency and severity of migraines, based on a 12 week RCT with 81 patients.
At month 2, treatment patients had 2 migraines per month compared to 3 per
month in the placebo group, and treatment patients experienced 2.4 headache
days per month compared to 4.7 headache days in the treatment group (Cephalagia. 1996. 16. 257-263).
Magnesium 360 mg/day during the luteal phase
significantly reduces the number of headache days by 50% compared with placebo,
in a small study in 20 women with menstrual migraines (Headache. 1991.
Two other RCTs showed mixed results (Cephalagia. 1996. 16. 436-440; Headache.
2003. 43. 601-610).
Mitral valve prolapse treatment
demonstrated in 60% of patients with MVP.
Double-blind trial: Mg (510 mg/day) improved
weakness, chest pain, dyspnea, palpitations, anxiety (Am J Cardiol. 1997. 79. 768-772).
Long-term supplementation (1-3 years) reversed valvular pathology in 20-40% of cases (Magnes Res. 2005. 18. 35-52; Magnesium.
1986. 5. 175-181).
Physical performance – magnesium oxide 300 mg
daily associated with improved physical performance in a 12 wek
RCT of 139 healthy elderly women, mean age 71.5 years (Veronese N et al. Am J Clin Nutr. Epub 7/9/14).
PMS – benefit seen in two trials (Obstet Gynecol. 1991. 78. 177-181; J Womens Health.
1998. 7. 1157-1165).
Torsade de pointes treatment (J Cardiovasc Electrophysiol. 1993. 4. 206-210).
of magnesium status:
all magnesium is intracellular, so serum magnesium is an insensitive test
for detecting deficiency.
- Rbc magnesium may be a more sensitive test.
magnesium (scraping from the frenulum of the tongue sent to Intracellular
Diagnostics) considered very sensitive.
load test (measurement of 24 hour urine magnesium before and after an
oral loading dose) considered very sensitive.
can cause diarrhea or sometimes fast transit time in the absence of
diarrhea - measure intestinal transit time by eating beets or corn and
seeing how many hours until it appears in the stool - if transit time is less than 12 hours, decrease the dose of
magnesium. 10 mg per day of pyridoxal 5’ phosphate (active form of
vitamin B6) can be used to treat magnesium-induced diarrhea (as an
alternative to lowering the dose).
accumulate in those with renal insufficiency.
of magnesium: As per Russell Jaffe, MD, choline citrate enhances magnesium
aspartate – well absorbed; in some individuals, the aspartate may cause
neuromuscular irritability or excitation
chloride – 12% elemental magnesium; absorbed topically.
citrate – 16.2% elemental magnesium, well absorbed
gluconate – 5.8% elemental magnesium
glycinate – 50% elemental magnesium, hypothesized to have high
bioavailability. In some individuals, the glycinate may cause
neuromuscular irritability or excitation.
hydroxide – 42% elemental magnesium; laxative, very little absorption.
lactate – 12% elemental magnesium, well absorbed
malate - well absorbed
oxide – 60.3% elemental magnesium; commonly prescribed by physicians, may
have lower bioavailability (less well absorbed than magnesium aspartate,
citrate, chloride, and lactate) but clinical benefit shown with this form
of magnesium in at least 6 clinical trials (Magnes Res. 2001. 14. 257-262; J
Am Coll Nutr.
1990. 9. 48-55).
succinate - well absorbed
sulfate – 10% elemental magnesium, administered parenterally
taurinate - well absorbed (Magnes Res. 2001. 14. 257-262; J
Am Coll Nutr.
1990. 9. 48-55).
source of metabolic energy, which is stored in phosphate bonds. Important role also in forming mineral
matrix of bone.
most abundant mineral found in the body.
enzymes and participates in buffer systems in the body.
protein is the main source of dietary phosphorous.
drinks are a source of excess phosphorous in the diet.
foods are another source of excess phosphorous in the diet – phosphorous
is added during food processing as a generally recognized as safe (GRAS)
ingredient, with the quantity not always specified, as disclosure of the
quantity of added phosphorous is not a regulatory requirement.
Furthermore, phosphorous in food additives is rapidly and almost
completely absorbed, in contrast to food-bound phosphorous, which is more
slowly and less efficiently abosrbed (Review
Article. Pizzorno, Lara. Canaries in the
phosphate-toxicity coal mine.” IMCJ.
2014. 13. 24-32).
of the population obtains adequate (or too much) phosphorous from the
on data from NHANES 2005-2006, >50% of young and middle-aged men
consume 1600 mg per day of phosphorous or more, and > 50% of young and
middle-aged women consume 1200 mg per day of phosphorous or more, as
compared with an RDA of 700 mg/day.
However it is estimated that10% of women over
age 60 and 15% of women over age 80 have a phosphorous intake less than 2/3 of
Over-consumption of antacids can cause
phosphorous deficiency since aluminum present in many antacids interferes with
- Excess phosphorous intake is
associated with excess mortality, based on data in 9686 healthy adults
in NHANES III (1988-1994). Dietary phosphorous intake was assessed using a
24 hour dietary recall (Am J Clin Nutr. 2014. 99.
guidelines recommend calcium: phosphorous intake in a 1.5:1 ratio.
carbonate and calcium citrate supplements will bind dietary phosphorous
and thus inhibit absorption.
(sodium excretion), modulates baroreflex sensitivity,
vasodilates blood vessels, decreases sensitivity to
catecholamines, reduces intracellular sodium, improves insulin sensitivity, and
decreases ADMA (Curr Hypertens Rep.
2011. 13. 309-317).
Average US dietary intake is 45 mmol/day, with a dietary potassium: sodium ratio of 1:2;
optimal intake is considered 120 mmol/day (4700
mg/day) with a
ratio of 4-5:1 (Curr Hypertens Rep.
2011. 13. 309-317; J Clin
Hypertens. 2008. 10[suppl
Increases platelet reactivity, increases
sympathetic nervous system activity (Arch
Intern Med. 1997. 157. 2449-2452), may increase blood pressure (but modest
intakes may also protect against stroke via poorly understood mechanisms.
Average US dietary intake is 5000 mg/day, with
some areas of the country consuming 15,000 – 20,000 mg/day; minimum requirement
for sodium is probably about 500 mg/day (Circulation.
1998. 98. 613-617).
supplemental dose is 1-3 mg per day.
recognized as an essential nutrient until recently.
enhance conversion of vitamin D to 1,25-dihydroxyvitamin D.
to increase estradiol and testosterone levels in postmenopausal women.
build muscle mass and may increase bone density.
supplemental dose is 200-1000 micrograms per day.
for normal glucose metabolism; potentiates the action of insulin, probably
by facilitating the binding of insulin to its receptor (Med Clin
North Am. 1976. 60. 739-744; J
Am Coll Nutr.
1998. 17. 544-547). May have antioxidant effects, and in humans alters the
sensitivity of brain 5-HT2A
2002. 159. 432-436).
of diabetes - 200-500 mcg twice a day (see specifics with references at the
beginning of this outline). Summary article (Role of chromium in human health
and in diabetes. Diabetes Care. 2004.
of hyperglycemia in patients receiving hyperalimentation
(J Am Coll Nutr. 1998. 17. 548).
of corticosteroid-induced diabetes (Diabet Med. 1999.
of atypical depression, which is clinically characterized by mood reactivity,
increased appetite, weight gain, and hypersomnia (Biol Psychiatry. 2003. 53. 261-264), especially if accompanied by
carbohydrate cravings (J Psychiatr Pract. 2005. 11.
be useful in treatment of reactive hypoglycemia (12 week trial in 8 women
published in Metabolism. 1987. 36.
351-355; Am J Clin
Nutr. 1985. 41. 841) and carbohydrate cravings.
in some trials to facilitate weight loss and improve muscle mass but a
meta-analysis failed to identify benefit (Int J Obes Relat Metab Disord. 2003. 27. 522).
is mixed with regard to a beneficial effect on the lipid profile, with positive
studies (Am J Clin
Nutr. 1981. 34. 2670-2678; West J Med. 1990. 152. 41-45) and a negative study (J Gerontol A Biol Sci Med Sci. 2000. 55.
be best to take this on an empty stomach.
chromium exists in several forms.
GTF is the natural form of chromium. Supplements are derived from brewer’s
yeast. The precise structure of chromium has not been determined as of 2006.
BEWARE some products marketed as GTF chromium on analysis had no GTF activity
picolinate, chromium polynicotinate, and chromium
aspartate are all believed to be effective; chromium chloride may be less
picolinate is better absorbed than chromium present in many foods, including
whole grains, nuts, meat, broccoli, and green beans.
is controversy in the literature regarding whether chromium picolinate and polynicotinate are better absorbed than chromium GTF – this
controversy might be a function of mislabeling of chromium GTF (see just
cause insomnia or increased dream activity as an adverse effect.
data on long term safety.
concentrations of chromium picolinate can be mutagenic in vitro, but no damage to DNA has been reported in vivo (The Medical Letter. 2006. 48. 7-8).
safe in the short term in doses up to 1000 mcg/day (Dietary Supplements: A Framework for Evaluating Safety. Institute of Medicine. Washington, DC.
in a number of enzyme systems; important for normal energy production and
occurs in the small intestine, and is dependent upon stomach acid, so use
of H2 blockers or PPIs can predispose to copper deficiency.
can cause anemia which mimics iron deficiency anemia with the exception
that copper deficiency is characterized by neutropenia too. Deficiency
might cause myelodysplasia.
an absorption carrier with zinc and calcium. Zinc may protect us from high
copper levels by interfering with absorption of copper in the gut.
bracelets have shown efficacy in treatment of rheumatoid arthritis.
protect against aortic aneurysms, and may be important in bone health,
based on test tube and animal data.
that zinc supplementation can create copper deficiency. Supplemental doses
of zinc should be accompanied by supplemental doses of copper in a ratio
of 15 mg: 2 mg (Advanced Nutrition
and Human Metabolism. 3rd ed. Chapter 12: Microminerals. 2000. 401-470).
C supplementation may interfere with copper utilization.
NAC supplementation can predispose to copper deficiency.
oxide is very poorly absorbed (J Nutr. 1999. 129. 2278-2279).
in high doses can act as an ‘anti-mineral’ – excess levels can arise from
copper leaching into the water out of copper pipes, absorption of copper
from copper cookware, absorption of copper from a copper IUD for birth
control. Birth control pills also can raise copper levels.
may act as an emetic in high doses (60 mg). Toxicity can cause various psychiatric
problems (anxiety, phobias, and in the extreme, paranoi
is the oxidized form of this mineral, iodide is the reduced form
understanding is that iodine is reduced to iodide in the gut for
is used primarily in the synthesis of thyroid hormones.
supplementation should be accompanied by selenium supplementation, as per
Robert Crayhon, M.S.
to most salt, but the amount in sea salt is minimal.
and seaweed are rich in iodine.
a ubiquitous food additive and industrial chemical, competes with iodine
for intracellular absorption, and may lead to iodine insufficiency in a
significant proportion of population.
added to the water supply competes with iodine for uptake into thyroid
hormones, and may thus contribute to the rising incidence of
a study in New Zealand
in 184 children, ages 10-13, with mild iodine deficiency, based on a urine
iodine concentration, four tests of cognitive function showed improvement
in those randomized to supplementation with 150 mcg/day (Am J Clin Nutr. 2009. 90. 1264-1271).
is 150 mcg daily, upper limit is 1100 mcg daily. However there are individuals such as
Guy E. Abraham, MD who assert that the human need is on the order of 5 mg
daily and that doses of 50 mg/day are needed to replenish body stores
(urine excretion of 90% of an administered dose is the measure advocated by
these authorities for determining adequate body iodide stores).
is one of the few minerals we cannot eliminate from the body if we consume
and postmenopausal women need very little iron and unless vegan should
obtain plenty from the diet.
deficiency is common in menstruating women; according to USDA surveys, 39%
of Americans fail to consume the RDA (Consumer
Reports on Health. 6/05).
- Non-heme iron, the form found in green leafy vegetables
and grains, is best absorbed in an acidic environment, so eating fruits
with vegetables or taking vitamin C with meals facilitates the absorption
of iron from non-meat food sources.
Cysteine also helps with iron absorption.
absorption may be inhibited by hypochlorhydria, phytic
acid, polyphenolic compounds, calcium, tannins in tea, and partially
digested proteins. It may also be impaired status post gastric bypass
surgery for obesity.
affects iron absorption only if consumed at the same time as food with iron (Nutr Res. 1997. 17. 1303-1310); milk does
not alter this inhibition (Br J Nutr. 1999. 81. 289-295).
infusions of peppermint, pennyroyal, cocoa, vervain,
lime flower, and chamomile (commonly referred to as teas) also inhibit iron
absorption (Br J Nutr.
1999. 81. 289-295).
of iron (in those who are iron deficient)
function – iron deficiency is associated with impairment of cognitive function
and scholastic performance in children (J Pediatr. 1973; 82:827–830); iron supplementation is
associated with improved cognitive function and scholastic performance in
children (Am J Clin
Nutr. 1989; 50:675–686; Am J Clin Nutr.
1989; 50:698–702; Lancet.
1996; 348:992-996; Review article. Public Health Nutrition. 2005;
2009; 59:303-510) and in young women, aged 18-35
(Am J Clin Nutr. 2007; 85:778-787).
– Ferrous sulfate 330 mg once or twice a day (dependent upon body weight)
beneficial in a 2 month trial of 20 nonsmoking women with a chronic unexplained
cough and a ferritin < 15 ng/ml (Int J Clin Pract. 2012. 66.
– in a 12 week RCT of 198 women, aged 18-53, with fatigue, a serum ferritin
< 50 mcg/L (low normal) and a hemoglobin > 12.0 g/dl (not anemic), those
randomized to prolonged release ferrous sulfate, 80 mg/day showed a 48%
improvement in score on the Current and Past Psychological Scale for Fatigue,
as compared with a 28.8% improvement in the placebo group (p=0.02). Compared
with placebo, iron increased hemoglobin by 0.32 g/dl (p=0.002) and ferritin by
11.4 mcg/L (p<0.001) [CMAJ. 2012.
benefits of iron supplementation include improved fertility, immune function,
physical performance, thermoregulation, and restless leg syndrome (Review
article. American Journal of Nephrology.
iron stores, measured by serum ferritin, are associated with an increased risk
of heart disease in two studies (Circulation.
1992. 86. 803-811; N Engl
J Med. 1994. 331. 1159-1160), but not in a third study (Circulation. 1999. 99. 852-854).
o Prospective observational data in
38,772 older women in the Iowa Women’s Health Study showed that use of iron was
associated with an increase in total mortality (RR 1.10), with the relationship
dose-dependent (Arch Intern Med.
2011. 171. 1625-1633).
is best for men and postmenopausal women to choose a multivitamin which
does not contain iron.
in a wide variety of metabolic functions.
is inhibited by iron and phytates.
stores are reduced by aluminum, and may be reduced by cadmium.
a common food preservative, inhibits the absorption of manganese.
be useful in treatment of tardive dyskinesia (25 mg daily).
(seen in miners of manganese ore) manifests as disorientation, memory
loss, delusions, hallucinations, anxiety, and emotional lability.
role is as a coenzyme. Required in
particular for detoxification of sulfite.
- Low uric acid on a blood test
suggests molybdenum deficiency, as per Jonathan Wright, MD.
be useful in treatment of autism if Phase II detoxification via sulfation
is 55 mcg/day in women and 70 mcg/day in men, and UL is 400 mcg/day in
supplemental dose is 200 micrograms per day. May be toxic in amounts in excess of 750
- 900 micrograms daily.
supplementation should be accompanied by iodine supplementation, as per
Robert Crayhon, M.S.
glutathione peroxidase is dependent upon selenium as a cofactor.
of T4 to T3 is selenium-dependent.
serum selenium levels, up to 150 ng/ml, associated with lower all-cause
and cancer mortality, based on data from 13,887 adult participants in
NHANES III who had serum selenium levels measured (Arch Intern Med. 2008. 168. 404-410).
immune function, and may decrease symptoms in rheumatoid arthritis.
in food is in the form of seleno amino acids
such as selenomethionine or selenocysteine.
nuts, butter, and wheat germ are excellent food sources.
is some data that acid rain interferes with selenium uptake from the soil
into the roots of plants.
disease - sodium selenite 100 mcg twice a day significantly improved quality of
life, reduced ocular involvement, and slowed progress in a 6 month RCT in 159
patients with mild Grave’s orbitopathy (N Engl J Med. 2011. 364. 1920-1931).
- supplementation had modestly beneficial effects on the lipid profile in a 6
month RCT in 501 volunteers. This was a 4 arm trial – placebo, 100 mcg/day high
selenium yeast, 200 mcg/day high selenium yeast, and 300 mcg/day high selenium
yeast. Total cholesterol and LDL improved, and higher doses raised HDL (Ann Intern Med. 2011. 154. 656-665).
supplementation theoretically may decrease the likelihood of colon, esophageal,
stomach, and lung cancer. Mechanism may be related to initiation of DNA repair
through activation of p53 (J Natl Cancer
Inst. 2003. 95. 98-100). HOWEVER, ineffective for prostate cancer
prevention in the SELECT trial (JAMA.
2009. 301. 39-51 and editorial 102-103; JAMA.
2011. 306. 1549-1556).
may increase the risk of diabetes
in 1202 individuals who did not have diabetes at baseline in a RCT of selenium
yeast 200 mcg daily for skin cancer prevention (the Nutrition Prevention of
Cancer trial; n=1312) showed that at mean follow up of 7.7 years, the hazard
ratio for the development of diabetes was 1.55 (95% CI 1.03 – 2.33) in the
group randomized to selenium supplementation. Within the group randomized to selenium
supplementation, those in the highest tertile of baseline plasma selenium level
(>121.6 ng/ml) had a hazard ratio for development of diabetes of 2.70 (95%
CI 2.70 – 5.61) [Ann Intern Med.
2007. 147. 217-223 and editorial 271-272].
epidemiologic evidence - in NHANES III, participants in the highest quintile of
serum selenium levels (>137.7 ng/ml) had an increased prevalence of diabetes
compared with those in the lowest quintile (<111.6 ng/ml) [Diabetes Care. 2007. 30. 829-834]; an observational
analysis within the SU.VI.MAX trial also found a positive association between
baseline plasma selenium levels and fasting plasma glucose levels (Am J Clin Nutr. 2006. 84. 395-399).
the SELECT trial, those who consumed selenium supplements alone had an
increased risk of diabetes, although the increase did not reach statistical
significance. However, in the SELECT patients taking selenium and vitamin E had
no increased risk of diabetes (JAMA.
2009. 301. 39-51 and editorial 102-103).
is available in several different forms for supplementation.
yeast formulations have been used in a number of studies, and as per Dr Alan
Gaby, this may be the best form with which to supplement.
selenite – published data shows that this form boosts immune system function in
those with borderline low selenium status (Am
J Clin Nutr. 2004. 80.
154-162), protects against radiation-induced inflammation and swelling (Int J Radiat Oncol Biol Phys. 2003. 56.
40-49), and reduces post-operative swelling (Biol Trace Elem Res. 2005. 106. 193-203).
o Selenodiglutathione, a natural metabolite of selenium, may
have a cancer chemopreventive effect (Nutr Cancer. 2001. 40. 42-49).
o L-selenomethionine is a selenium-containing amino acid
supplement associated in one study with an increased risk of prostate cancer,
and thus as per Dr Alan Gaby, may be best to avoid this form of supplement.
o Se-methylselenocysteine is a selenium-containing amino acid
supplement which may be beneficial in treatment of established cancers (J Trace Elem Med Biol. 2005. 19.
- Second most abundant mineral in the Earth’s crust,
but little exists in a form that humans can absorb and utilize.
- Dietary silicon compounds must be solubilized by
stomach acid into orthosilicic acid before they
can be absorbed.
- Some experts believe that choline-stabilized orthosilicic acid (ch-OSA)
is the ideal chemical form with which to supplement silicon.
- Stimulates collagen synthesis and thus may improve
bone strength and may be beneficial in those with brittle hair and nails.
- NOTE high dose calcium supplementation might cause a
doses (as much as 1.7 grams per day) in a few studies shown to be
beneficial in treatment of osteoporosis and cancer metastatic to bone.
may be administered as strontium lactate, strontium gluconate, strontium
carbonate, or strontium ralenate.
decades in the first half of the 20th Century, strontium salts
were administered therapeutically in doses of 200-400 mg/day without toxic
effects. As late as 1955, strontium products were listed in the
Dispensatory of the U.S.
not confuse stable strontium with radioactive strontium-90, which spread
through the environment in the 1950’s as a result of above ground nuclear
testing. Radioactive strontium-90 spread throughout the environment,
contaminating meat and dairy products, and eventually accumulating in
bones of children and adults.
supplemental dose is 5-15 mg per day (but as per Institute of Medicine, UL
is 1.8 mg.
signal enhancer and demonstrates insulin like effects on glucose
only recently as an essential nutrient.
dose is usually 15-40 mg per day of elemental zinc.
Sources of zinc
poultry, seafood, egg yolks
Brazil nuts, pecans, pumpkin seeds, walnuts
– anecdotes of benefit, with clinical trial data mixed. In a RCT
minocycline was twice as effective (Dermatology.
2001. 203. 135-140).
- theoretical rationale, based on rapid progression of zinc deficiency in
those with HIV, but RCTs of zinc supplementation fail to show benefit.
– theoretical rationale and anecdotal evidence.
– theoretical rationale, based on unpublished reports of increased copper
to zinc ratios in 85% of autistics; anecdotal evidence of benefit.
- theoretical rationale, as zinc inhibits the activity of the enzyme
5-alpha-reductase, which converts testosterone to dihydrotestosterone
(DHT), and also inhibits binding of DHT to its receptors. An old clinical
trial shows benefit (Fed Proc.
1976. 35. 361).
– uncertain from data whether beneficial effect is a direct effect versus
indirect effect of zinc repletion in those with zinc deficiency.
meta-analysis of 22 RCTs of zinc supplements for treatment of diarrhea
in children from developing countries found an 18% reduction of diarrhea
symptoms (Pediatrics. 2008.
meta-analysis of 15 RCTs of zinc supplements for prevention of diarrhea
in children from developing countries found a14% reduction in risk (Pediatrics. 2007. 119.
disorders – theoretical rationale, and a published study in which 100 mg
zinc gluconate facilitated weight gain (Int J Eat Disord. 1994. 15. 251-255)
prevention - in a RCT in 50 healthy persons aged 55-87, zinc gluconate
providing 45 mg of elemental zinc per day was associated with a lower
incidence of infection (29% vs. 88%), higher plasma zinc levels, and
lower serum levels of inflammatory markers (Am J Clin Nutr.
2007. 85. 837-844).
degeneration – prevention of progression (no studies on zinc for primary
prevention, and results of cohort
studies are mixed)
a randomized trial with 4753 patients with age-related macular degeneration
(AREDS), a supplement containing vitamin C 500 mg, vitamin E 400 IU,
beta-carotene 15 mg, zinc oxide 80 mg, and cupric oxide 2 mg was associated
with a 27% reduction in worsening of visual acuity (p=0.008), but with
increased hospitalizations for UTI and nephrolithiasis (Arch Ophthalmol. 2001. 119. 1417-1436).
was also associated with a 27% lower
mortality rate (Arch Ophthalmol. 2004. 122. 716-726).
– theoretical rationale; important in the formation of osteoblasts and
osteoclasts and various proteins found in bone tissue.
against endoscopic recurrence of peptic ulcers, based on a 12 month RCT of zinc
acexamate (48 mg of elemental zinc) once daily in 146
patients initially treated with prescription medication for PUD (Rev Esp Enferm Dig. 1991. 80. 91-94).
against NSAID induced GI damage – in a multicenter 4 week clinical trial in 276
patients, 88% of the patients who received zinc acexamate
(48 mg of elemental zinc) once daily had a normal endoscopy, compared with 66%
of the placebo patients (J Rheumatol. 1994. 21. 927-933).
healing of acute ulcers - in a 4 week RCT in 199 patients with endoscopically verified acute duodenal ulcers,
symptom improvement and endoscopic improvement were statistically
identical in the group receiving zinc acexamate
(48 mg of elemental zinc) twice a day, as compared with Pepcid 40 mg
daily (Rev Esp
Enferm Dig. 1996. 88. 757-762).
– anecdotal evidence.
respiratory infections – also see section just below for information on
zinc and the common cold
meta-analysis of 12 RCTs (n=5512) of children in developing countries
found a reduction in URI incidence in those using zinc supplements (Pediatrics. 2007. 119.
meta-analysis of 8 RCTs (n=890) of zinc lozenges for treatment of URI in
adults in industrialized countries found no evidence of statistically
significant benefit, but many of the studies had methodologic problems (J Nutr.
2000. 130. 1512S-1515S).
disease – zinc acetate is approved by the FDA for maintenance therapy (J Lab Clin
Med. 1998. 132. 264-278).
healing – strong theoretical rationale, but a meta-analysis of 6 RCTs of
oral zinc sulfate (n=181) for venous or arterial leg ulcers failed to
show benefit (Arch Dermatol. 1998. 134. 1556-1560).
- stabilizes membranes of mast cells, and thus is anti-inflammatory (Life Sci. 1991. 49. L189-194).
– cofactor for the enzyme superoxide dismutase (SOD)
- cofactor in protein digestion and production of hydrochloric acid (i.e.
stomach acid); necessary for fatty acid absorption
protection – involved in intestinal epithelial cell regeneration (Eur J Clin
Invest. 2000. 30. 419-428).
deficiency predisposes to excess absorption of aluminum.
upregulates metallothionein, the enzyme which
facilitates clearance of heavy metals from the cells of our bodies.
in synthesis of melatonin from serotonin
the activity of the enzyme 5-alpha-reductase, which converts
testosterone to dihydrotestosterone (DHT)
promote growth hormone secretion.
system effects – protects against infection, and anti-inflammatory - zinc
is a cofactor for thymulin, a thymic hormone essential for T cell maturation (Int J Immunopharmacol.
1995. 17. 703-718).
health – zinc deficiency predisposes to BPH, but excess zinc (greater
than 100 mg daily) is associated with an increased risk of prostate
repair – zinc deficiency is associated with impaired wound healing.
zinc levels are not considered a reliable measure of zinc stores.
zinc is considered a more sensitive indicator of zinc status than a serum
common in developing countries, due to malnutrition, and associated with
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).
to USDA surveys, 73% of Americans fail to consume the RDA (Consumer Reports on Health. 6/05).
deficiency is a clinical concern in
switching to a vegetarian diet
with pyroluria, (Holford, Patrick. Optimum Nutrition for the Mind.
2000. Pgs. 211-215)
with histadelia (Holford,
Patrick. Optimum Nutrition for the
Mind. 2000. Pg. 186).
- Symptoms and signs which suggest
zinc insufficiency include anorexia, dandruff, slow wound healing, and
white spots on fingernails.
- Low alkaline phosphatase on a
blood test suggests zinc deficiency, as per Jonathan Wright, MD.
absorption and excretion
- Phytates in grains and legumes can interfere with
and iron supplements can interfere with zinc absorption.
can decrease zinc absorption by 50%.
absorption of zinc is inhibited by estrogen.
yellow food dye tartrazine can cause zinc
depletion by increasing urinary losses.
which can deplete zinc include thiazide diuretics, corticosteroids,
methotrexate, tetracyclanes, and fluoroquinolones.
environmental zinc antagonists
acid (a degradation product of nitrapyrin,
which is applied to soil to increase crop yields).
acid (an herbicide).
amount of elemental zinc contained in various zinc salts differs
acetate is 30% zinc.
chloride is 50% zinc.
gluconate is 14.3% zinc.
sulfate is 23% zinc.
oxide is 80% zinc.
extent of absorption of zinc in supplement form will vary based on the
salt with which the elemental zinc is combined.
picolinate or citrate or chelated zinc are the preferred forms.
sulfate is probably not as well absorbed orally and may cause gastric
oxide is useful topically but not well absorbed orally.
effects from excessive intake of supplemental zinc
include metallic taste, nausea, vomiting, and abdominal cramping.
exposure may suppress immunity, decrease HDL, and cause a microcytic
anemia due to copper deficiency (Am
J Clin Nutr.
1990. 51. 225-227).
of elemental zinc in amounts of 100 mg per day or more associated with an
increased relative risk of 2.3 for advanced prostate cancer in men, based
on data in 46,974 men in the Health Professionals Follow-up Study (J Natl Cancer Inst. 2003. 95.
and other supplements
administration of supplemental NAC (N acetyl cysteine) can predispose to
zinc deficiency via increased urinary excretion of zinc.
and copper compete for absorption – as general principle, supplemental
doses of zinc should be accompanied by supplemental doses of copper in a
ratio of 15 mg: 2 mg (Advanced
Nutrition and Human Metabolism. 3rd ed. Chapter 12: Microminerals. 2000. 401-470).
and medications – zinc supplements may inhibit absorption of penicillamine, tetracyclanes,
and the common cold
clinical trial data is mixed; with a positive
Cochrane review of 15 trials
(n=966) evaluating 5 or more days of zinc, initiated within one day of
symptom onset decreased the severity and duration of the common cold (Cochrane Database Syst
of the positive studies are referenced at the top of this outline “Proven benefits of vitamins and minerals in pharmacologic doses.”
- The first study to report a benefit
was published in Antimicrob Agents Chemother.
1984. 25. 20-24.
review article found that three trials of comparable design and outcome
measurement found zinc effective in reducing the duration of colds, if
started within 24 hours (J Am
Pharmacists Assoc. 2004. 44. 594-603).
in the zinc salts used in the various trials, differences in dosages, and
differences in bioavailability may account for the conflicting results – the best available data in 2005 is that
lozenge efficacy or lack of efficacy is directly related to the total
daily positively charged zinc
administered and unrelated to the total dosage of zinc (Biosci Rep. 2004. 24. 23-39; Ann Pharmacother.
1996. 30. 1336-1338).
mechanism - ionic zinc binds specifically to intracellular adhesion
molecule-1 (ICAM-1) receptors on nasal epithelial cells, and this
binding is hypothesized to prevent the rhinovirus from binding to this
receptor (J Am Pharmacists Assoc.
2004. 44. 594-603).
mouth-nose biologically closed electric circuit (BCEC) with a voltage of
60-120 millivolts moves positively charged particles such as ionic zinc
from the mouth to the nose.
that the electrical resistance between the mouth and the nose varies
from individual to individual, and unpublished data suggests that those
with the lowest electrical resistance (1-10 Kohms)
experience frequent colds, allergies, and rhinitis whereas those with
the highest electrical resistance (100-500 Kohms)
are immune to common colds.
acetate releases virtually 100% as zinc ion, regardless of pH; zinc
gluconate, zinc sulfate, and zinc chloride are also highly ionizable.
effects of zinc gluconate lozenges include unpalatable taste, mouth
irritation, taste distortion, mouth sores, vomiting, diarrhea, headache.
Zinc acetate may be more palatable than zinc gluconate.
administration of ionic zinc
least one published study showing benefit (QJM: An International Journal of Medicine. 2002. 96. 35-43),
but case reports of persistent anosmia in humans associated with
intranasal administration of ionic zinc (J Ped. 1938. 13. 60-62; JAMA. 1938. 110. 2024; Chem Senses. 2000. 5. 659; Am J Rhinol.
2004. 18. 137-141) indicate that this route of administration is not
understanding of biologically closed electric circuits (BCECs) as
described by BE Nordenstrom (Nordic Medical Publications.
1983. 112-172) combined with unpublished data of a mouth-nose BCEC
(cited on pg 37, column 1 in Altern Ther
Health Med. 2006. 12. 34-38), leads to the conclusion that
positively charged zinc introduced into the nasal passages is repelled
by the like charge of the nasal tissues, and is thus poorly absorbed in
the nose (except perhaps in the olfactory region on direct contact) and
passes into the throat and then stomach with nasal mucous, thus lacking
therapeutic efficacy against rhinoviruses when administered intranasally.
GENERAL GUIDELINES FOR CONSUMERS
for time release preparations (except iron), as they may be less
with food (except amino acids and possibly chromium).
at room temperature.
store in a bathroom; the humidity is too high.
LEVEL PLAYING FIELD (Arch Intern Med. 1998. 158. 2187-2191)
acceptance of news of toxicity - high dose Vitamin C and kidney stones -
review articles and book chapters cite abstracts, letters, and other
review articles, but no articles in peer reviewed journals based upon a
dismissive tone - Harrison's and multivitamins - words such
as "massive, carelessness, useless, indiscriminate, false,
indefensible, wasteful, unnecessary, deplored, poor medical
claims of efficacy - Vitamin E and intermittent claudication - four
randomized, controlled trials (3 positive).
on anecdotal case reports of harm associated with natural supplements, or
interactions of natural supplements with prescription medications, such as
– Based upon several unpublished reports of an interaction between
cranberry juice and warfarin, the UK Committee on Safety of Medicines in
9/03 alerted clinicians to a potential interaction. Subsequently, based
upon additional unpublished case reports, the UK Committee on Safety of
Medicines in 10/04 recommended against concurrent use of cranberry juice
and warfarin unless health benefits outweighed the risks. Subsequent to
this second “warning” several case reports were published. In 2005, the
US FDA mandated a precautionary potential interaction label on warfarin.
In 2008, JCAHO established guidelines that hospitals should advise
patients taking warfarin to avoid cranberry juice. However, analysis of
the 6 published case reports shows that only two cases had a validation
scale suggesting “probable” interaction, and even in both these cases,
there were other potential explanations for the alteration in INR.
Additionally, small RCTs in patients on stable anticoagulation showed
that the addition of 8 ounces of cranberry juice daily did NOT affect the
INR (J Am Diet Assoc. 2006.
106. 2057-2061; J Thrombos Thrombolysis. 2008. 25. 112). The
authors of a review article “conclude that the initial precautionary
warnings … represent misleading conclusions” (Zikria
J et al. Cranberry Juice and Warfarin: When Bad Publicity Trumps Science.
Am J Med. 2010. 123. 384-392).
biloba - there are published case reports of subdural hematoma, hyphema, subarachnoid hemorrhage, and intracerebral
hemorrhage with gingko. HOWEVER,
in a 14 day RCT in 32 healthy volunteers, Ginkgo biloba extract (EGb 761) at daily doses of 120 mg, 240 mg, and 480 mg
did NOT alter platelet function or coagulation (Clin Lab Haematol. 2003. 25. 251-253).
– based upon case reports of hepatoxicity, this
herb is listed in Consumer Reports
5/04 ‘Dirty Dozen.’ Case reports of hepatotoxicity attributed to skullcap
appear to be associated with skullcap products adulterated with
germander, a known hepatotoxin (Teucrium chamaedrys)
[Botanical Safety Handbook.
1997; Pharmaceut J. 1984. 233. 80-82; Ann Intern Med. 1992. 117. 165-166].
and even some OTC medications are far from totally safe:
meta-analysis of 39 prospective studies in U.S. hospitals found that in
1994, 2,216,000 hospitalized patients had an adverse drug reaction, and
106,000 had fatal adverse drug reactions (JAMA. 1998. 279. 1200-1205).
are 16,000 deaths and 100,000 hospitalizations in the U.S. each year from NSAID's (Am J Med. 1998. 105. 31S-38S, as
referenced in New Engl J Med. 1999. 340. 1888-1899). It is
estimated that only 1 in 5 individuals who GI bleed from a NSAID have any
pump inhibitor usage is associated with increased risk of fracture, C
difficile infections, and pneumonia. An editorial concludes that “…for
most patients, the adverse effects of PPIs outweigh the benefits.” (Arch Intern Med. 2010. 170.
peer-reviewed literature often does NOT reflect the state of knowledge
about a given pharmaceutical agent, due to publication bias and lack of
submission of negative industry sponsored trials for publication.
Furthermore, when negative industry sponsored trials are published, they
are often written in a way that emphasizes the positive. A published study
in which compared the independent FDA medical reviews of the primary
results of 74 trials of 12 antidepressant agents with the published
literature on these 74 trials found that (N Engl J Med. 2008. 358. 252-260):
the 38 trials viewed as positive by the independent FDA analysis, 37 were
the 36 trials viewed as negative or questionable by the independent FDA
analysis, only 14 were published (29%), and 11 or the 14 were published
in a way that conveyed more positive findings than appeared in the FDA
would appear from the published literature that 94% of the antidepressant
trials were positive, whereas only 51% were positive from the standpoint
of the of independent FDA medical reviews.
- The Vitamin Revolution. Michael
- The Vitamin E Factor. Andreas
Papas, Ph.D. 1999.
- Encyclopedia of Natural Medicine.
Michael Murray, N.D. and Joseph Pizzorno, N.D.
- ConsumerLab.com’s Guide to Buying Vitamins and
Supplements: What’s really in the bottle? 2003.
- The UV Advantage. Michael Holick, M.D. 2004.
JS and Tangum MR. Battling quackery: attitudes
about micronutrient supplements in American academic medicine. Arch Intern Med. 158; 1998:
- Han-Yao H et al. The
Efficacy and Safety of Multivitamin and Mineral Supplement Use To Prevent
Cancer and Chronic Disease in Adults: A Systematic Review for a National
Institutes of Health State-of-the-Science Conference. Ann Intern Med. 2006. 145. 372-385.
State-of-the-Science Panel. National Institutes of Health
State-of-the-Science Conference Statement: Multivitamin/Mineral
Supplements and Chronic Disease Prevention. Ann Intern Med. 2006. 145. 364-371.
- www.cfsan.fda.gov – FDA Center for Applied Food Safety and
Applied Nutrition. Useful consumer information.
- NIH web site
- www.navigator.tufts.edu - Tufts University. This site also
contains quality ratings for other sites.
- www.consumerlab.com - provides
independent analysis of the quality of dietary supplements.
- www.nnfa.org - web site includes a list of companies
certified by NNFA GMP Program.
- www.nsf.org/certified/dietary - allows one to search for products and
companies certified by NSF.
- www.uspverified.org – list of
products verified by USP.
- www.drugstore.com - this provides
information on dietary supplements by disease.
- http://nccam.nih.gov/health - fact
sheets, alerts and advisories, treatment information.
- NIH Office of Dietary Supplements International Bibliographic
Information on Dietary Supplements (IBIDS) [over 730,000 scientific
citations and links to more than 1600 journal web sites, as of 2004]
[Last Updated March 20, 2015]
to List of Topics]