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Folate

Folate

Common Names

  • Folic acid
  • Vitamin B9

For Patients & Caregivers

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Folate is used to prevent certain types of anemia and birth defects. Studies on increased folate intake or supplements to reduce cancer risk are mixed.

Folate is a member of the vitamin B complex that must be obtained from food sources like grains, leafy vegetables, and liver. It is important for cell division, and if not consumed enough from food, can lead to anemia and birth defects. Folic acid is a form of folate used as a supplement to correct deficiencies. It is also added to some processed foods to increase dietary consumption.

Some studies suggest adequate folate intake can help reduce the risk of Alzheimer’s disease, heart disease, and certain types of cancer, but other studies find increased colon and skin cancer risks with higher intake levels. Excess folate or folic acid may mask vitamin B12 deficiency.

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  • To treat Alzheimer’s disease
    Studies have linked low dietary folate and low folate levels in the blood with Alzheimer’s disease.
  • To prevent cancer
    Some studies have shown that higher levels of folate reduce the risk for various cancers, but other studies found it may increase precancerous colon abnormalities or skin cancer risk. Therefore, more research is needed to understand the relationships between folate levels, supplementation, and cancer risks or prevention.
  • To prevent heart disease
    Low folic acid levels have been linked to higher homocysteine levels, a risk factor for heart disease-related death. However, further studies are needed to understand this association.
  • To prevent neural tube birth defects
    Studies have shown a significant decrease in risk of some types of birth defects with increased dietary folate.
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  • You are taking anticonvulsants: Using folic acid may reduce their effectiveness.
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High intake levels of folic acid can lead to excess blood levels of folic acid.

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  • Since many foods are fortified with folic acid, additional supplementation may be harmful to certain groups of people.
  • Taking folic acid with black or green tea may cause a decrease in folic acid absorption.
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For Healthcare Professionals

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Pteroylglutamic acid
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Folate is an essential member of the vitamin B complex family that is naturally available in grains, green leafy vegetables, and liver. Folic acid and the L-methylfolate (5-MTHF) derivative are synthetic supplemental forms that have higher bioavailability (1). Folate is important in cell growth and division and involved in the methylation process and DNA synthesis. Inadequate intake can cause deficiency leading to megaloblastic anemia.

Folate is essential during pregnancy. Supplementation has been shown to reduce risks of neural tube birth defects (10) and medulloblastoma in offspring (11). One study among South American populations suggests the protective effect against neural tube defects may be greater in female than male infants (65). In high doses (5 mg/day), it reduced homocysteine levels at time of delivery and may lessen pregnancy complications (43). Folate supplementation may benefit women with polycystic ovary syndrome (PCOS) (42). High folate intake also reduced chromosomal aberrations in sperm of healthy men (12).

In other studies, folic acid decreased homocysteine levels, a risk factor for cardiovascular disease mortality (13) (14) (15), and reduced blood pressure in smokers (5) (16). Among hypertensive adults, folic acid therapy reduced risk of first stroke (44) (45) (66), but smoking status may affect efficacy (67). Other trials on stroke risk have yielded mixed results (17) (18) (19) (20).

Folic acid supplementation improved cognitive function in older adults (26). In patients with Alzheimer’s disease, it improved response to cholinesterase inhibitors (27), cognition, and inflammatory markers (46). In individuals chronically exposed to arsenic, it lowered blood arsenic concentrations by facilitating urinary excretion (28). There is limited evidence on whether folic acid supplementation can increase serum folate levels, or have an effect on anemia in patients with sickle cell disease (68).

Studies on increased folate intake or supplements to reduce cancer risk are mixed. In young children, folic acid fortification was associated with reduced incidence of Wilms tumor and primitive neuroectodermal tumors (PNET) (36). Folate supplementation also helps cervical intraepithelial neoplasia (CIN 1) regression (47). 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) and pancreatic cancers (3), but not prostate cancer (7). Studies on colorectal cancer risk produced mixed results (4) (5) (32) (35) (48) and some even suggest a negative effect (6) (8) (49). A large population study suggests an association between dietary folate intake and increased risk for overall skin cancer, basal cell carcinoma, and nonmelanoma skin cancer, particularly in women (50).

Overconsumption of folic acid may increase risk of toxicity (51) and some cancers (52). Therefore, more research is needed to examine the relationships between folate levels, supplementation, and cancer risks or prevention.

Studies that evaluate folic acid in combination with other B vitamins are largely negative, with no overall effect on breast or invasive cancers  (33), and the potential for increased cancer incidence and mortality in patients with ischemic heart disease  (34). Such interventions have also produced mixed results in studies for older adults with depression  (53) (54), and did not improve bone mineral density (55) or reduce fracture risk or incidence (56) (69).

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). Excess folate or folic acid may mask vitamin B12 deficiency  (70).

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

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  • Alzheimer’s disease
  • Cancer prevention
  • Cardiovascular disease
  • Neural tube birth defect prevention
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The bioactive form of folate is tetrahydrofate, which can be converted from folic acid through the action of the enzyme dihydrofolate reductase. Drugs that inhibit this enzyme can reduce folic acid activity. Folate acts as a co-enzyme in the methylation process. The amino acid serine reacts with tetrahydrofolate, resulting in 5,10- methylenetetrahydrofolate, the derivative involved in nucleotide synthesis. 5-methyltetrahydrofolate transfers a methyl group to cobalamin (vitamin B12) and then to homocysteine, converting it to methionine. Methionine is the precursor of the methyl donor, S-adenosyl-methionine (SAMe), which plays a major role in neurological function and several biochemical pathways (41). Genetic polymorphisms that lowered the production of methylenetetrahydrofolate reductase (MTHFR) can also reduce SAMe and increase homocysteine levels. Supplementation with folic acid can reduce homocysteine levels and DNA oxidative damage (57) (58). This may in turn lower risks for cardiovascular and psychiatric diseases by increasing SAMe (59) (60). Folic acid supplementation also improves endothelial function (16) (31).

Although low folate status is associated with increased risk of cardiovascular disease and some cancers (61), increased intake from fortified foods may actually raise cancer risk (49) (50) (62). There is also evidence that high levels of unmetabolized folic acid in plasma can reduce natural killer cell cytotoxicity (63).

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Increased risk of toxicity with overconsumption  (51)

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  • Anticonvulsants: Concurrent use of folic acid may antagonize the effects of certain anticonvulsants (29).
  • Black or green tea: May cause a decrease in folic acid absorption (64).
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  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. Van Guelpen B, Hultdin J, Johansson I, et al. Low folate levels may protect against colorectal cancer. Gut 2006;55(10):1461-6.

  6. 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.

  7. Cole BF, Baron JA, Sandler RS. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007 ;297(21):2351-9.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. Al-Delaimy Wael K, et al. Folate intake and risk of stroke among women. Stroke. 2004 Jun;35(6):1259-63.

  14. 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.

  15. Kaslow JE, Rucker L, Onishi R. Liver extract-folic acid-cyanocobalamin vs placebo for chronic fatigue syndrome. Arch.Intern.Med 1989;149:2501-3.

  16. 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.

  17. Shiroky JB. The use of folates concomitantly with low-dose pulse methotrexate. Rheum.Dis.Clin North Am 1997;23:969-80.

  18. 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.

  19. Gamble MV, Liu X, Slavkovich V, et al. Folic acid supplementation lowers blood arsenic. Am J Clin Nutr. 2007;86(4):1202-9.

  20. 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.

  21. Mason P. Dietary Supplements. London: Pharmaceutical Press; 2001.

  22. 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.

  23. 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.

  24. 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.

  25. 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.

  26. 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.

  27. 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.

  28. 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.

  29. 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.

  30. 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.

  31. Folic Acid. Alternative Medicine Review. 2005;10(3): 222-229.

  32. Gylling B, Van Guelpen B, Schneede J, et al. Low folate levels are associated with reduced risk of colorectal cancer in a population with low folate status. Cancer Epidemiol Biomarkers Prev. Oct 2014;23(10):2136-2144.

  33. Mudryj AN, de Groh M, Aukema HM, et al. Folate intakes from diet and supplements may place certain Canadians at risk for folic acid toxicity. Br J Nutr. Oct 2016;116(7):1236-1245.

  34. Wallace K, Grau MV, Levine AJ, et al. Association between folate levels and CpG Island hypermethylation in normal colorectal mucosa. Cancer Prev Res (Phila). Dec 2010;3(12):1552-1564.

  35. Gilbody S, Lewis S, Lightfoot T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol. Jan 01 2007;165(1):1-13.

  36. Crider KS, Yang TP, Berry RJ, et al. Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate’s role. Adv Nutr. Jan 2012;3(1):21-38.

  37. Hirsch S, Sanchez H, Albala C, et al. Colon cancer in Chile before and after the start of the flour fortification program with folic acid. Eur J Gastroenterol Hepatol. Apr 2009;21(4):436-439.

  38. Poletta FA, Rittler M, Saleme C, et al. Neural tube defects: Sex ratio changes after fortification with folic acid. PLoS One. 2018;13(3):e0193127.

  39. Dixit R, Nettem S, Madan SS, et al. Folate supplementation in people with sickle cell disease. Cochrane Database Syst Rev. Mar 16 2018;3:Cd011130.

  40. Cuskelly GJ, Mooney KM, Young IS. Folate and vitamin B12: friendly or enemy nutrients for the elderly. Proc Nutr Soc. Nov 2007;66(4):548-558.

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