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Vitamin B9 folate

Vitamin: B9, folic acid

Daily Value: 400 mcg

Hazardous level: safe at more than 800 mg (see 2 articles on folate March 2008) See also discussion of folate question.

Average intake in US diet: 280 mcg

Function: coenzyme that transports single carbon fragments for amino acid and nucleic acid

synthesis. Aids in red blood cell formation and cell division; facilitates use of protein for energy;

reduces birth defects. A lack of folate prevents conversion of uracil to thymine, an essential base

in DNA, leading to mutations, and probably birth defects and cancer.

DOSAGE RATIONALE: want 696 mcg for lowest quintile IAW Rimm, E.B., et al, "Folate and

vitamin B6 from diet and supplements in relation to risk of coronary heart disease among

women," JAMA 279: 359-64 (1998)

KEY REFERENCES AND NOTES

Giles, W.H., Kittner, S.J., Anda, R.F., Croft, J.B., and Casper, M.L., "Serum folate and risk for ischemic

stroke. First National Health and Nutrition Examination Survey epidemiologic follow-up study", Stroke 26:

1166-70 (1995)

"A serum folate concentration < or = 9.2 nmol/L has been associated with elevated levels of plasma

homocyst(e)ine. Elevated homocyst(e)ine levels have been associated with ischemic stroke in

case-control studies...We used data from the First National Health and Nutrition Examination Survey

Epidemiologic Follow-up Study (n = 2006). ... CONCLUSIONS: These findings suggest that a folate

concentration < or = 9.2 nmol/L may be a risk factor for ischemic stroke"

Gallagher, P.M. et al , "Homocysteine and risk of premature coronary heart disease. Evidence for a common

gene mutation", Circulation 94: 2154-8 (1996 )

"Plasma homocysteine levels are modulated by nutritional and genetic factors, among which is the

enzyme methylenetetrahydrofolate reductase (MTHFR)... MTHFR, which modulates basal plasma

homocysteine concentration, is folate dependent, and dietary supplementation or fortification with folic

acid may reduce plasma homocysteine levels and consequent coronary risk in a significant proportion

of the general population. "

Swain, R.A., "The role of folic acid in deficiency states and prevention of disease", J Fam Pract 44: 138-44

(1997)

"Folic acid, a water-soluble vitamin, has been used since the 1940s to treat some cases of macrocytic

anemia without neurologic disease... the vitamin may reduce the incidence of neural tube defects by

45% in women who receive 400 mcgrams per day. It is recommended that all women of childbearing

age take 400 mcgrams of folate per day. Elevations in homocysteine levels, a metabolite intimately

associated with folate, are also being found with increasing regularity in those with cardiovascular

diseases. Homocysteine levels are reduced by folic acid administration. Therefore, there is some

biologic plausibility... for the assumption that folate supplements may prevent heart disease, stroke,

and peripheral arterial disease.

Tucker, K.L., Mahnken, B., Wilson, P.W., Jacques, P., and Selhub, J. , "Folic acid fortification of the food

supply. Potential benefits and risks for the elderly population", JAMA 276: 1879-85 (1996)

"To estimate the potential benefits and risks of food folic acid fortification for an elderly population.

Benefits are expected through the improvement of folate and homocysteine status, but there is also a

risk of masking or precipitating clinical manifestations related to vitamin B12 deficiency with

increasing exposure to folic acid.... A total of 747 subjects aged 67 to 96 years who both completed

usable food frequency questionnaires and had blood concentrations of B vitamins and homocysteine

measured. .. Percentages of this elderly population with folate intake below 400 mcg/d are projected

to drop from 66% at baseline to 49% with 140 mcg of folate per 100 g of cereal-grain product, to 32%

with 280 mcg, to 26% with 350 mcg, and to 11% with 700 mcg. Percentages with elevated

homocysteine concentrations (>14 micromol/L) are projected to drop from 26% at baseline to 21%

with 140 mcg of folate per 100 g, to 17% with 280 mcg, to 16% with 350 mcg, and to 12% with 700

mcg. "

Rimm, E.B., et al, "Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart

disease among women," JAMA 279: 359-64 (1998)

"a total of 80,082 women from the Nurses' Health Study...the relative risks of coronary heart disease

between extreme quintiles were 0.69 for folate (median intake, 696 mcg/d vs 158 mcg/d)... and 0.67

for vitamin B6 (median intake, 4.6 mg/d vs 1.1 mg/d)...These results suggest that intake of folate and

vitamin B6 above the current RDA may be important in the primary prevention of coronary heart

disease among women...".

Blount, B.C., et al (Ames, B.N.), "Folate deficiency causes uracil misincorporation into human DNA and

chromosome breakage: Implications for cancer and neuronal damage," PNAS USA 94: 3290-5 (1997)

"Folate deficiency causes massive incorporation of uracil into human DNA (4 million per cell) and

chromosome breaks...Both high DNA uracil levels and elevated micronucleus frequency are reversed

by folate administration. A significant proportion of the U.S. population has low folate levels...Such

breaks could contribute to the increased risk of cancer and cognitive defects associated with folate

deficiency in humans."

Cussedly, G.J., McNulty, H., and Scott, J.M., "Effect of Increasing Dietary Folate on Red-Cell Folate:

Implications for Prevention of Neural Tube Defects", Lancet 347:657-9 (1996)

Recommendations by the UK Dept. of Health suggest that protection from neural tube defects can be

achieved through intakes of an extra 400 microgram daily of folate/folic acid as...supplements.

Schwarz, R.H., and Johnston, R.B., Jr., "Folic Acid Supplementation - when and how", Obstet Gynecol

88:886-7 (1996)

Butterworth, C.E., Jr., and Bendich, A., "Folic acid and the prevention of birth defects", Annu Rev Nutr

16:73-97 (1996)

WHITE PAPER REFERENCES FOR SENIOR FORMULATION

Naurath, HJ, et al, "Effects of vitamin B12, folate, and vitamin B6 supplements in elderly people with

normal serum vitamin concentrations", Lancet 346: 85-89 (1995)

"supplement containing 1mg vitamin B12, 1.1 mg folate, and 5 mg vitamin B6" "Vitamin

supplements significantly reduced all four metabolite concentrations [related to high

homocysteine]... The response rate to vitamin supplements supports the notion that metabolic

evidence of vitamin deficiency is common in the elderly, even in the presence of normal serum

vitamin levels."- elderly deficient in folate - 1.1 mg 8x over 2 weeks IM

Selhub, J. et al, "Association between plasma homocysteine concentrations and extracranial carotid-artery

stenosis", NEJM 332: 286-92 (1995)

study of 1041 elderly subjects ages 67-96; "High plasma homocysteine concentrations and low

concentrations of folate and vitamin B6...are associated with an increased risk of extracranial

carotid-artery stenosis in the elderly." - B6 in elderly reduces risk of extracranial carotid-artery

stenosis (atherosclerosis)

Whitney, E. N., et al, Nutrition for Health and Health Care, 1996, West Publ. Co.,, Mpls.

pg 422 "One suggestion is to establish one set of RDA for those 50 to 70 years old and

another for those over 70."

pg 651 "People with renal failure...receive vitamin B6 (5-10 mg) , ...and folate (1 mg)." -

people with renal failure receive 1 mg folate

Zhang, ZF, et al "Adenocarcinomas of the esophagus and gastric cardia: the role of diet", Nutr. Cancer 27:

298-309 (1997)

"Decreased risk...was significantly associated with high ingestion of...niacin, vitamin B6, iron, and

zinc. Higher intakes of vitamin A, beta-carotene, vitamin E, folate, phosphorus, and potassium

were associated with a decreased risk..."- decreased risk of adenocarcinoma with higher intake of

folate, but not statistically significant

Alhadeff, L. et al, "Toxic effects of water-soluble vitamins", Nutr. Rev. 42: 33-40 (1984)

"it is now known that high doses of water-soluble vitamins may indeed have toxic effects"

Table II: vitamindisorder

nicotinic acidasthma, diabetes, liver, gout, cardiac, CNS

folatemasks B12 deficiency, causes insomnia

pantothenate causes diarrhea

B1causes irritability

B6 causes convulsions, antagonizes L-dopa in

Parkinsons, neural troubles

- folate masks B12 deficiency, causes insomnia; FDA restricts vitamin manufacturers from including more than 0.4 mcg of folate per dose (1984)

Baker, H., et al, "Vitamin Profiles in elderly persons living at home or in nursing homes, versus profile in healthy young subjects," J Am Ger Soc 27:444-50 (1979)

"473 elderly persons...The circulating levels of biotin, pantothenate, riboflavin, vitamins A, B6,

B12, C, E, folate, Thiamine, nicotinate, and carotenes were determined in all groups." "Thiamine,

vitamin C and vitamin B12 levels were strikingly depressed in the non-institutional elderly... Over

30% of the institutional elderly had vitamin B6 and nicotinate hypovitaminemia...Both the

institutional and the non-institutional elderly showed depressed levels of folate and vitamin

B12...Vitamin supplementation reduced the percentage of folate and B12 deficits."- 16% of elderly

deficient in folate

Shimikawa, T. et al, "Vitamin intake: a possible determinant of plasma homocysteine among middle-aged adults", Ann Epidemiol 7: 285-93 (1997)

"Plasma homocysteine among users of vitamin supplement products was 1.5 micromol/L lower

than among nonusers." Bendich, A., Mallick, R., and Leader, S., "Potential Health Economic Benefits of Vitamin Supplementation", West J Med 166: 306-312 (1997)

"Nearly $20 billion in hospital charges were potentially avoidable with daily use of folic acid and

zinc-containing multivitamins by all women of childbearing age and daily vitamin E

supplementation by those over 50."- 400 mcg daily could dramatically reduce birth defects

Rimm, E.B., et al, "Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women," JAMA 279: 359-64 (1998)

"a total of 80,082 women from the Nurses' Health Study...the relative risks of coronary heart disease between extreme quintiles were 0.69 for folate (median intake, 696 mcg/d vs 158 mcg/d)... and 0.67 for vitamin B6 (median intake, 4.6 mg/d vs 1.1 mg/d)...These results suggest that intake of folate and vitamin B6 above the current RDA may be important in the primary prevention of coronary heart disease among women...".actual highest quintile is 774 mcg/day folate, 5.9 mg/day B6- highest quintile, lowest heart disease - intake 696 mcg folate, 4.6 mg B6 [ 696 mcg - 100 mcg (low intake) = 596 mcg]

WHITE PAPER REFERENCES FOR STAY WELL FORMULATIONS

no evidence of connection with colds, viruses, immune system

ause of possible decreased absorption by

elderly, use 150% of RDA adjusted for weight and diet.

KEY NOTES AND REFERENCES:

Benton D; Haller J; Fordy J, "The vitamin status of young British adults", Int J Vitam Nutr Res

67(1):34-40 (1997)

"thiamin, riboflavin, pyridoxine, ascorbic acid, retinol, alpha-tocopherol, folic acid,

cyanocobalanin, carotene and biotin status were assessed in a sample of 243 young

British adults... The status of ascorbic acid, cyanocobalamin, alpha-tocopherol, folic acid

and in males retinol, was adequate in the majority of cases. In the cases of riboflavin and

pyridoxine the status of a substantial minority was either borderline or deficient. The

thiamin and biotin status of a minority of both sexes, and retinol in the females, was

marginal"

.actual highest quintile is 774 mcg/day folate, 5.9 mg/day B6- highest

quintile, lowest heart disease - intake 696 mcg folate, 4.6 mg B6 [ 4.6 mg - 50%*1.6 = 3.8 mg]

WHITE PAPER REFERENCES FOR STAY WELL FORMULATIONS

Chandra, R. K., "Effect of vitamin and trace-element supplementation on immune responses and

infection in elderly subjects", Lancet 340: 1124-27 (1992)

study of 96 people, had 23 vs. 48 days of illness, recipe 400 iu retinol, 16 mg beta-carotene, 2.2

mg thiamin, 1.5 mg riboflavin, 16 mg niacin, 3 mg B6, 400 mcg folate, 4 mcg B12, 80 mg C, 4

mcg D, 44 mg E, 16 mg Iron, 200 mg Ca, 100 mg Mg

Gridley, DS, Shultz, TD, Stickney, DR, and Slater, JM, "In vivo and in vitro stimulation of cell-mediated

immunity by vitamin B6", Nutr Res 8: 201-7 (1988)

"These data suggest that vitamin B6 (7.7mg/kg) is an important in vivo and in vitro modulator of

immune function and that dietary supplementation with this vitamin can enhance cellular

immune mechanisms"

ein, and carbohydrate metabolism

DOSAGE RATIONALE: Safe, so goal is at least 150% of RDA including dietary intake

KEY NOTES AND REFERENCES:

Alhadeff, L. et al, "Toxic effects of water-soluble vitamins", Nutr. Rev. 42: 33-40 (1984)

"it is now known that high doses of water-soluble vitamins may indeed have toxic effects"

Table II: vitamin disorder

nicotinic acid asthma, diabetes, liver, gout, cardiac, CNS

folate masks B12 deficiency, causes insomnia

pantothenate causes diarrhea

B1 causes irritability

B6 causes convulsions, antagonizes L-dopa in Parkinsons, neural troubles

- promotes diarrhea at 10g / day

WHITE PAPER REFERENCES FOR STAY WELL FORMULATIONS

no evidence of connection with colds, viruses, immune system

s...The circulating levels of biotin, pantothenate, riboflavin, vitamins A, B6,

B12, C, E, folate, Thiamine, nicotinate, and carotenes were determined in all groups."

"Thiamine, vitamin C and vitamin B12 levels were strikingly depressed in the non-institutional

elderly... Over 30% of the institutional elderly had vitamin B6 and nicotinate

hypovitaminemia...Both the institutional and the non-institutional elderly showed depressed

levels of folate and vitamin B12...Vitamin supplementation reduced the percentage of folate and

B12 deficits." - 29% of elderly were deficient

WHITE PAPER REFERENCES FOR STAY WELL FORMULATIONS

Chandra, R. K., "Effect of vitamin and trace-element supplementation on immune responses and

infection in elderly subjects", Lancet 340: 1124-27 (1992)

study of 96 people, had 23 vs. 48 days of illness, recipe 400 iu retinol, 16 mg beta-

carotene, 2.2 mg thiamin, 1.5 mg riboflavin, 16 mg niacin, 3 mg B6, 400 mcg folate, 4

mcg B12, 80 mg C, 4 mcg D, 44 mg E, 16 mg Iron, 200 mg Ca, 100 mg Mg

"thiamin, riboflavin, pyridoxine, ascorbic acid, retinol, alpha-tocopherol, folic acid,

cyanocobalanin, carotene and biotin status were assessed in a sample of 243 young

British adults... The status of ascorbic acid, cyanocobalamin, alpha-tocopherol, folic acid

and in males retinol, was adequate in the majority of cases. In the cases of riboflavin and

pyridoxine the status of a substantial minority was either borderline or deficient. The

thiamin and biotin status of a minority of both sexes, and retinol in the females, was

marginal" In riboflavin the status of a substantial minority of 243 British students was

either borderline or deficient.

WHITE PAPER REFERENCES FOR STAY WELL FORMULATIONS

Chandra, R. K., "Effect of vitamin and trace-element supplementation on immune responses and

infection in elderly subjects", Lancet 340: 1124-27 (1992)

study of 96 people, had 23 vs. 48 days of illness, recipe 400 iu retinol, 16 mg beta-

carotene, 2.2 mg thiamin, 1.5 mg riboflavin, 16 mg niacin, 3 mg B6, 400 mcg folate, 4

mcg B12, 80 mg C, 4 mcg D, 44 mg E, 16 mg Iron, 200 mg Ca, 100 mg Mg