Health Care Professional Information

Scientific Name
Pteroylglutamic acid
Clinical Summary

Folate and folic acid are water-soluble vitamins of the vitamin B complex. Folate is naturally available in green leafy vegetables, whereas folic acid is the synthetic supplemental form and has higher bioavailability than folate (1).

Folate is essential during pregnancy and has been shown to reduce the risk of neural tube defects (10). Data also suggest a nearly 50% reduction in risk of medulloblastoma in children born to women who took folic acid supplements during pregnancy (11). Folate supplementation may benefit women with polycystic ovary syndrome (PCOS) (42). High folate intake was also found to reduce chromosomal aberrations in sperm of healthy men (12).
In other studies, folic acid has been shown effective in decreasing levels of homocysteine, a risk factor for cardiovascular disease mortality (13) (14) (15), and reducing blood pressure in smokers (5) (16). However, trials on the risk of stroke yielded mix results (17) (18) (19) (20). Folic acid supplementation was ineffective in the treatment of chronic fatigue syndrome (21). Due to its antagonistic effects, folic acid can reduce the side effects of methotrexate when used for rheumatoid arthritis (22) (23). However, it may decrease the efficacy of methotrexate in the treatment of acute lymphoblastic leukemia (24) and psoriasis (25).
Folic acid supplementation improved cognitive function in older adults (26) and response to cholinesterase inhibitors in patients with putative Alzheimer's disease (27).
In individuals chronically exposed to arsenic, folic acid supplementation lowers blood arsenic concentrations by facilitating urinary excretion (28).

Low levels of folate in the blood are associated with certain forms of cancer (9), whereas higher levels of dietary folate have been shown to reduce the risk of breast (2), pancreatic (3) and colon cancers (4) (5) (6) (32) (35). However, folic acid supplementation does not seem to affect the risk of prostate cancer (7) or colorectal adenoma in patients with a history colorectal adenoma without carcinoma (8). A combination of folic acid, and vitamins B6 and B12 had no effect on overall of invasive cancer or breast cancer (33). Recent data, however, suggest higher cancer incidence and mortality in patients with ischemic heart disease following supplementation with vitamin B12 and folic acid (34).
In children aged 0 — 4 years, folic acid-fortification was associated with a reduction in the incidence of Wilms tumor and primitive neuroectodermal tumors (PNET), but not other childhood cancers (36).
Findings of a meta analysis indicate that folic acid supplementation does not have a significant effect on total cancer incidence, colorectal cancer, prostate cancer, lung cancer, breast cancer, or hematological malignancy, but reduces the risk of melanoma (37).

Food Sources

Main sources include fortified breakfast cereals and breads, liver, Brussels sprouts, potatoes, spinach, chickpeas, and brewer's yeast.

Purported Uses
  • Alzheimer's disease
  • Cancer prevention
  • Cardiovascular disease
  • Chronic fatigue syndrome
  • Neural tube birth defect prevention
Mechanism of Action
Folic acid plays important roles in DNA synthesis, and as a methyl donor in several metabolic and nervous system biochemical processes. The amino acid serine reacts with tetrahydrofolate, resulting in 5,10- methylenetetrahydrofolate, the derivative involved in DNA synthesis. A methyl group is donated to cobalamin (B12) by 5-methyltetrahydrofolate, forming methylcobalamin. Methylcobalamin, in turn, donates a methyl group to the amino acid metabolite homocysteine, and converts it to methionine.  Methionine is the precursor of the methyl donor, S-adenosyl-methionine (SAMe), which plays a major role in several biochemical pathways (41).


Clinical studies indicate that folic acid supplementation improves endothelial function in patients with coronary atherosclerosis (31) and in smokers (16). In addition, both oral and intravenous folate administration resulted in comparable homocysteine-lowering effects (13).
Folic acid supplementation has been shown to reduce the risk of colon cancer (32); and dietary folate intake was more strongly associated with reduced breast cancer risk in women who also consumed high levels of folate cofactors (methionine, vitamin B12, and vitamin B6) (2).

Pharmacokinetics

Folic acid was shown to have high bioavailability, with large doses of oral folic acid raising the plasma levels significantly in healthy individuals in a time- and dose-dependent manner.
After high-dose oral administration of folic acid (ranging from 25-1,000 mg/day), the red blood cell (RBC) folate levels were found to be elevated for more than 40 days following discontinuation of folic acid use.
It is poorly transported to the brain, and cleared rapidly from the central nervous system.
Elimination of absorbed folic acid was shown to be via feces (through bile) and urine.
(38) (39) (40)

Herb-Drug Interactions
  • Anticonvulsants: Concurrent use of folic acid may antagonize the effects of certain anticonvulsants (29).
  • Colestyramine, Sulfasalazine and Salicylazosulfapyridine: May reduce the absorption of folic acid (1).
Literature Summary and Critique

Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-75.
3,680 adults with cerebral infarction participated in a study of folic acid, vitamin B6 and vitamin B12 and stroke. Participants received a multivitamin containing the US recommended daily allowance of other vitamins and were randomly assigned to receive once-daily doses of either high-dose or low-dose amounts of the studied vitamins. Subjects were followed for a 2-year period. The high-dose group had a greater reduction in total homocysteine, however neither treatments lowered the risk of stroke, coronary heart disease events or death. Researchers suggest that further studies are necessary to understand the association between total homocysteine levels and vascular risk.

Van Guelpen B, Hultdin J, Johansson I, et al. Low folate levels may protect against colorectal cancer. Gut 2006;55(10):1461-6.
This prospective study was conducted to determine the association between folate levels and the risk of developing colorectal cancer. This is the first study to look at the plasma folate levels unlike the earlier ones that examined the benefits of oral folic acid supplementation. The study involved 226 persons with colorectal cancer and 437 matched controls from the Northersn Sweden Health and Disease Cohort. Researchers observed a bell-shaped association between plasma folate levels and the risk of colorectal cancer. Persons in the highest folate quintile were four times as likely to develop colorectal cancer compared to those in the lowest quintile. These results contradict the data available so far, but the low folate status of the subjects may be the reason. Further studies with long-term follow up are needed to confirm the benefits of folic acid supplementation.

Durga J, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet 2007;369(9557):208-216.
In the Folic Acid and Carotid Intima-media Thickness (FACIT) trial, 818 participants (50-70 years of age) with homocysteine concentrations ranging from 13-26 ìmol/L randomly received placebo or folic acid (800 ìg daily) for 3 years during which cognitive function was assessed by 5 separate tests including memory, word fluency, and sensorimotor, complex, and information processing speeds. Participants that received folic acid experienced benefits in memory, speed of information processing, and sensorimotor speed as compared to those receiving placebo, indicating that folic acid supplementation may improve cognitive function in older adults. Further studies are necessary to determine if individuals with low or high homocysteine levels would also benefit in folic acid supplementation.

Connelly PJ, et al. A randomised double-blind placebo-controlled trial of folic acid supplementation of cholinesterase inhibitors in Alzheimer's disease. Int J Geriatr Psychiatry 2008;23(2):155-160.A pilot randomized, double-blind, placebo-controlled study of 57 participants with Alzheimer's disease sought to determine if folic acid supplementation could improve the patients' response to cholinesterase inhibitors. Consecutive patients were either given placebo or folic acid (1 mg daily) and their Mini-Mental State Examination (MMSE) and Instrumental Activities of Daily Living (IADL) and Social Behavior (SB) scores as well as homocysteine levels were assessed at baseline and 3 and 6 months after treatment initiation. Although MMSE scores were not affected by folic acid supplementation, IADL and IADL/SB scores were. Further studies of larger population sizes will confirm whether folic acid supplementation is beneficial in the treatment of Alzheimer's disease.

Dosage (Inside MSKCC Only)
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References
  1. Gregory JF, III. Case study: folate bioavailability. J Nutr 2001;131:1376S-82S.
  2. Shrubsole MJ, Jin F, Dai Q, Shu XO, Potter JD, Hebert JR et al. Dietary folate intake and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Res 2001;61:7136-41.
  3. Stolzenberg-Solomon RZ, Pietinen P, Barrett MJ, Taylor PR, Virtamo J, Albanes D. Dietary and other methyl-group availability factors and pancreatic cancer risk in a cohort of male smokers. Am J Epidemiol 2001;153:680-7.
  4. Fuchs CS, Willett WC, Colditz GA, Hunter DJ, Stampfer MJ, Speizer FE et al. The influence of folate and multivitamin use on the familial risk of colon cancer in women. Cancer Epidemiol Biomarkers Prev 2002;11:227-34.
  5. Su LJ,.Arab L. Nutritional status of folate and colon cancer risk: evidence from NHANES I epidemiologic follow-up study. Ann.Epidemiol 2001;11:65-72.
  6. Van Guelpen B, Hultdin J, Johansson I, et al. Low folate levels may protect against colorectal cancer. Gut 2006;55(10):1461-6.
  7. Stevens VL, et al. Folate nutrition and prostate cancer incidence in a large cohort of US men. Am J Epidemiology 2006; 163(11):989-996.
  8. Cole BF, Baron JA, Sandler RS. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007 ;297(21):2351-9.
  9. Lashner BA. Red blood cell folate is associated with the development of dysplasia and cancer in ulcerative colitis. J Cancer Res Clin Oncol 1993;119:549-54.
  10. Berry RJ, Li Z, Erickson D, et al. Prevention of neural-tube defects with folic acid in China. N Engl J Med 1999;341(20):1485-1490.
  11. Bunin GR, Gallagher PR, Rorke-Adams LB, et al. Maternal supplement, micronutrient, and cured meat intake during pregnancy and risk of medulloblastoma during childhood: A children's oncology group study. Cancer Epidemiol Biomarkers Prev 2006; 15(9): 1660-7.
  12. Young SS, Eskenazi B, Marchetti FM, et al. The association of folate, zinc and antioxidant intake with sperm aneuploidy in healthy non-smoking men. Hum Reprod. 2008;23(5):1014-22. Epub 2008 Mar 19.
  13. Ducloux D, Aboubakr A, Motte G, Toubin G, Fournier V, Chalopin JM et al. Hyperhomocysteinaemia therapy in haemodialysis patients: folinic versus folic acid in combination with vitamin B6 and B12. Nephrol.Dial.Transplant. 2002;17:865-70.
  14. Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. JAMA 2002;288:973-9.
  15. Wald DS, Bishop L, Wald NJ, Law M, Hennessy E, Weir D et al. Randomized trial of folic acid supplementation and serum homocysteine levels. Arch.Intern.Med 2001;161:695-700.
  16. Mangoni AA, Sherwood RA, Swift CG, Jackson SH. Folic acid enhances endothelial function and reduces blood pressure in smokers: a randomized controlled trial. J Intern Med 2002;252:497-503.
  17. Al-Delaimy Wael K, et al. Folate intake and risk of stroke among women. Stroke. 2004 Jun;35(6):1259-63.
  18. Bazzano LA, He J, Ogden LG, Loria C, Vupputuri S, Myers L et al. Dietary intake of folate and risk of stroke in US men and women: NHANES I Epidemiologic Follow-up Study. National Health and Nutrition Examination Survey. Stroke 2002;33:1183-8.
  19. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-75.
  20. Larsson SC, Mannisto S, Virtanen MJ, et al. Folate, vitamin B6, vitamin B12, and methionine intakes and risk of stroke subtypes in male smokers. Am J Epidemiol. 2008;167(8):954-61. Epub 2008 Feb 12.
  21. Kaslow JE, Rucker L, Onishi R. Liver extract-folic acid-cyanocobalamin vs placebo for chronic fatigue syndrome. Arch.Intern.Med 1989;149:2501-3.
  22. Griffith SM, Fisher J, Clarke S, Montgomery B, Jones PW, Saklatvala J et al. Do patients with rheumatoid arthritis established on methotrexate and folic acid 5 mg daily need to continue folic acid supplements long term? Rheumatology.(Oxford) 2000;39:1102-9.
  23. Shiroky JB. The use of folates concomitantly with low-dose pulse methotrexate. Rheum.Dis.Clin North Am 1997;23:969-80.
  24. Schroder H, Clausen N, Ostergard E, Pressler T. Folic acid supplements in vitamin tablets: a determinant of hematological drug tolerance in maintenance therapy of childhood acute lymphoblastic leukemia. Pediatr.Hematol.Oncol 1986;3:241-7.
  25. Chládek J, Simková M, Vanecková J, et al. The effect of folic acid supplementation on the pharmacokinetics and pharmacodynamics of oral methotrexate during the remission-induction period of treatment for moderate-to-severe plaque psoriasis. Eur J Clin Pharmacol. 2008;64(4):347-55. Epub 2007 Dec 29.
  26. Durga J, van Boxtel MP, Schouten EG, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial.Lancet. 2007;369(9557):208-16.
  27. Connelly PJ, Prentice NP, Cousland G, Bonham J. A randomised double-blind placebo-controlled trial of folic acid supplementation of cholinesterase inhibitors in Alzheimer's disease. Int J Geriatr Psychiatry 2008;23(2):155-60.
  28. Gamble MV, Liu X, Slavkovich V, et al. Folic acid supplementation lowers blood arsenic. Am J Clin Nutr. 2007;86(4):1202-9.
  29. Froscher W, Maier V, Laage M, Wolfersdorf M, Straub R, Rothmeier J et al. Folate deficiency, anticonvulsant drugs, and psychiatric morbidity. Clin Neuropharmacol. 1995;18:165-82.
  30. Mason P. Dietary Supplements. London: Pharmaceutical Press; 2001.
  31. Title LM, Cummings PM, Giddens K, Genest JJ, Jr., Nassar BA. Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll.Cardiol. 2000;36:758-65.
  32. Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C, Rosner BA et al. Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Annals of Internal Medicine 1998;129:517-24.
  33. Zhang SM, Cook NR, Albert CM, et al. Effect of combined folic acid, vitamin B6, and vitamin B12 on cancer risk in women: a randomized trial. JAMA. 2008 Nov 5;300(17):2012-21.
  34. Ebbing M, Bonaa KH, Nygard O, et al. Cancer Incidence and Mortality After Treatment With Folic Acid and Vitamin B12. JAMA. 2009;302(19):2119-2126.
  35. Stevens VL, McCullough ML, Sun J, et al. High Levels of Folate From Supplements and Fortification Are Not Associated With Increased Risk of Colorectal Cancer. Gastroenterology. 2011 Jul;141(1):98-105, 105.e1.

  36. Linabery AM, Johnson KJ, Ross JA. Childhood cancer incidence trends in association with US folic acid fortification (1986-2008). Pediatrics. 2012 Jun;129(6):1125-33.
  37. Qin X, Cui Y, Shen L, et al. Folic acid supplementation and cancer risk: A meta-analysis of randomized controlled trials. Int J Cancer. 2013 Sep 1;133(5):1033-41.
  38. Zettner A, Boss GR, Seegmiller JE. A long-term study of the absorption of large oral doses of folic acid. Ann Clin Lab Sci. 1981;11:516-524.
  39. Gregory JF 3d, Bhandari SD, Bailey LB, et al. Relative bioavailability of deuterium-labeled monoglutamyl tetrahydrofolates and folic acid in human subjects. Am J Clin Nutr. 1992;55:1147- 1153.
  40. Levitt M, Nixon PF, Pincus JH, Bertino JR. Transport characteristics of folates in cerebrospinal fluid; a study utilizing doubly labeled 5-methyltetrahydrofolate and 5- formyltetrahydrofolate. J Clin Invest. 1971;50:1301-1308.
  41. Folic Acid. Alternative Medicine Review. 2005;10(3): 222-229.
  42. Asemi Z, Karamali M, Esmaillzadeh A. Metabolic response to folate supplementation in overweight women with polycystic ovary syndrome: A randomized double-blind placebo-controlled clinical trial. Mol Nutr Food Res. 2014 Jul;58(7):1465-73.

Consumer Information

How It Works

Bottom Line: Folate is used to prevent certain types of anemia and birth defects. It may also reduce the risk of certain cancers.

Folate is a vitamin of the vitamin B complex. The main food sources of folate include fortified breakfast cereals and breads, liver, Brussels sprouts, potatoes, spinach, chickpeas and brewer's yeast. It is also available in supplemental form as folic acid. Folate deficiency can result in the reduction of essential cell division and can lead to anemia. The vitamin has been shown to reduce the risk of neural tube defects and is vital for pregnant women.
Higher levels of folate have been shown to reduce the risk for breast cancer, pancreatic cancer and colon cancer.
 

Purported Uses
  • To treat Alzheimer's disease
    Studies have linked low folate levels with Alzheimer's disease. Research also shows a possible link between the intake of folate and decreased risk of Alzheimer's.
  • To prevent cancer
    Clinical studies have shown that higher levels of folate reduce the risk for breast, pancreatic and colon cancers. Folic acid supplementation does not appear to affect the risk of prostate cancer.
  • To prevent heart disease
  • Low folic acid levels have been linked to higher homocysteine levels, a risk factor for death caused by diseases of the heart and blood vessels. However, further studies are needed to understand this association.
  • To treat chronic fatigue syndrome
    Folic acid was ineffective in treating chronic fatigue syndrome.
  • To prevent neural tube birth defects
    Studies have shown a significant decrease in the risk of neural tube (tissue in the embryo that develops into the brain and the spinal cord) defects as a result of increased dietary folate.
Research Evidence

Cardiovascular Disease & Stroke
A study of 3,680 patients with cerebral infarction (blockage of blood supply to the brain) examined the effect of folic acid, vitamin B6 and vitamin B12 on stroke. Participants were randomly assigned to receive either high or low doses of the studied vitamins once a day for two years. The high-dose group had a greater reduction in total homocysteine, but neither group experienced a decreased risk of stroke, coronary heart disease events or death. A randomized controlled trial of seventy-five subjects with coronary artery disease divided subjects into three groups: placebo, folic acid alone, or folic acid plus vitamins C and E. After four months, subjects who received folic acid supplements were found to have significant increases in plasma folate and improvement in blood flow. However, it is unclear whether these changes reduced cardiovascular events.
Five hundred fifty-three subjects were examined in a randomized controlled trial of a homocysteine-lowering therapy regimen containing folic acid. The subjects had all previously undergone angioplasty (a procedure to unblock blood vessels) and were assigned to receive either placebo or a combination of folate, vitamin B12 and vitamin B6 for six months. Subjects in the treatment arm had significantly lower homocysteine levels and few major adverse effects.

Cancer
A population-based case-control study observed 1,321 cases of breast cancer and 1,382 control cases to examine the relationship between dietary folate intake and breast cancer risk. High folate intake was found to reduce breast cancer risk, and the reduction was even more pronounced in women who also consumed high levels of methionine, vitamin B12 and vitamin B6. A 20-year study of 14,407 subjects examining the association between folate intake and colon cancer risk found higher folate intake to reduce colon cancer risk in men, especially in non-drinkers. A prospective analysis of 27,101 healthy male smokers between the ages of 50 and 69 found that dietary folate can reduce pancreatic cancer risk. One study of 88,756 women found that long-term (more than 15 years) supplementation of folic acid significantly lowered the risk of colon cancer risk.

Neural-tube defects
This study was done to determine the effects of folic acid in reducing neural-tube defects in babies in China. A daily dose of 400 micrograms of folic acid was suggested to women starting from their premarital exam to the end of the first trimester. Researchers report a reduction in risk of neural tube defects in fetuses or infants of women who took the folic acid supplement compared to those who did not take it. This effect was seen both in women from areas with high neural-tube defects and in areas with low rates.

Do Not Take If
  • You are taking Anticonvulsants (Concurrent use of folic acid may antagonize the effects of certain anticonvulsants).
  • You are taking Colestyramine, Sulfasalazine and Salicylazosulfapyridine (May reduce the absorption of folic acid).

 

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