Folate
What is it? Overview Usage Side Effects and Warnings
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Folate Overview

Written by FoundHealth, sshowalter.

Folate, a B vitamin, plays a critical role in many biological processes. It participates in the crucial biological process known as methylation and plays an important role in cell division: without sufficient amounts of folate, cells cannot divide properly. Adequate folate intake can reduce the risk of heart disease and prevent serious birth defects, and it may lessen the risk of developing certain forms of cancer.

Requirements/Sources

Folate requirements rise with age. The official US and Canadian recommendations for daily intake are as follows:

  • Infants
  • 0-6 months: 65 mcg
  • 7-12 months: 80 mcg
  • Children
  • 1-3 years: 150 mcg
  • 4-8 years: 200 mcg
  • Males
  • 9-13 years: 300 mcg
  • 14 years and older: 400 mcg
  • Females
  • 9-13 years: 300 mcg
  • 14 years and older: 400 mcg
  • Pregnant women: 600 mcg
  • Nursing women: 500 mcg

Until recently, folate deficiency was fairly common in the developed world, causing thousands of children to be born with preventable birth defects. 1 2 However, in 1998, widespread fortification of cereal products began in the US. and Canada. As a result, the prevalence of folate deficiency has begun to decrease in these countries. 3 Deficiency appears to be most common today among individuals who are African-American, Hispanic, or of Asian/Pacific Islander race/ethnicity, as well as younger people and those who are overweight. 4 Various drugs may impair your body's ability to absorb or utilize folate, including antacids , bile acid sequestrants (such as cholestyramine and colestipol), H 2 blockers , methotrexate , oral medications used for diabetes, various antiseizure medications ( carbamazepine , phenobarbital , phenytoin , primidone , and valproate), sulfasalazine and possibly other certain NSAID-type drugs , high-dose triamterene , nitrous oxide , and the antibiotic trimethoprim-sulfamethoxazole . 5 In addition, some of these drugs might put pregnant women at higher risk of giving birth to children with various kinds of birth defects; taking folate supplements may help reduce this risk. 6 Oral contraceptives may also affect folate slightly, but there doesn't appear to be a need for supplementation. 7 8 Good sources of folate include dark green leafy vegetables, oranges, other fruits, rice, brewer's yeast, beef liver, beans, asparagus, kelp, soybeans, and soy flour.

Therapeutic Dosages

For most uses, folate should be taken at nutritional doses, about 400 mcg daily for adults. However, higher dosages—up to 10 mg daily—have been used to treat specific diseases. Before taking more than 400 mcg daily, it is important to make sure that you don't have a vitamin B 12 deficiency (see Safety Issues).

A particular kind of digestive enzyme taken as a supplement, pancreatin , may interfere with the absorption of folate. 9 You can get around this by taking the two supplements at different times of day.

What Is the Scientific Evidence for Folate?

Birth Defects

Very strong evidence tells us that regular use of folate by pregnant women can reduce the risk of neural tube defect by 50% to 80%. 10 Less direct evidence suggests that folate can help prevent other kinds of birth defects, especially among women using medications that interfere with folate. 11

Depression

One study found that people with depression who do not respond well to antidepressants are likely to be low in folate. 12 A 10-week, double-blind, placebo-controlled trial of 127 individuals with severe major depression found that folate supplements at a dose of 500 mcg daily significantly improved the effectiveness of fluoxetine (Prozac) in female participants. 13 Improvement in male participants was not significant, but blood tests taken during the study suggested that higher intake of folate might be necessary for men.

Methotrexate Side Effects

Methotrexate is used in cancer chemotherapy as well as for treating inflammatory diseases such as rheumatoid arthritis and psoriasis . While often highly effective, it can produce a number of severe side effects. These include liver toxicity as well as gastrointestinal distress. In addition, use of methotrexate is thought to raise levels of homocysteine, potentially increasing risk of heart disease.

Supplementation with folate may help. Methotrexate is called a "folate antagonist" because it prevents the body from converting folate to its active form. In fact, this inactivation of folate plays a role in methotrexate's therapeutic effects. This leads to an interesting Catch-22: Methotrexate use can lead to folate deficiency, but taking extra folate could theoretically prevent methotrexate from working properly.

However, evidence suggests that individuals who take methotrexate for rheumatoid arthritis, juvenile rheumatoid arthritis, or psoriasis can safely use folate supplements. 14 Not only does the methotrexate continue to work properly, but its usual side effects may decrease as well.

For example, in a 48-week, double-blind, placebo-controlled trial of 434 individuals with active rheumatoid arthritis, use of folate helped prevent liver inflammation caused by methotrexate. 15 This effect allowed more participants to continue methotrexate therapy; the development of liver inflammation often requires people to stop using the drug. A slightly higher dose of methotrexate was needed to reach the same level of benefit as taking methotrexate alone, but researchers felt this was worth it.

In the study just described, folate supplements did not reduce the incidence of mouth sores and nausea. However, in other studies, folate supplements did reduce these side effects, both in individuals receiving methotrexate for rheumatoid arthritis 16 and in those with psoriasis. 17 In addition, two studies of individuals with rheumatoid arthritis found that use of folate supplements corrected the methotrexate-induced rise in homocysteine without affecting disease control. 18

Note: Folate supplements have been found safe only as supportive treatment in the specific conditions noted above. It is not known, for example, whether folate supplements are safe for use by individuals taking methotrexate for cancer treatment.

References

  1. Oakley GP Jr, Adams MJ, Dickinson CM. More folic acid for everyone, now. J Nutr. 126(3):751S-755S.
  2. Wald NJ, Law MR, Morris JK, Wald DS. Quantifying the effect of folic acid. Lancet. 358(9298):2069-73.
  3. Cembrowski GS, Zhang MM, Prosser CI, Higgins T. Folate is not what it is cracked up to be. Arch Intern Med. 1999;159:2747-2748.
  4. Lawrence JM, Watkins ML, Chiu V, Erickson JD, Petitti DB. Do racial and ethnic differences in serum folate values exist after food fortification with folic acid? Am J Obstet Gynecol. 194(2):520-6.
  5. Hoppner K, Lampi B. Bioavailability of folate following ingestion of cholestyramine in the rat. Int J Vitam Nutr Res. 61(2):130-4.
  6. Hernández-Díaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med. 343(22):1608-14.
  7. Steegers-Theunissen RPM, Van Rossum JM, Steegers EAP, et al. Sub-50 oral contraceptives affect folate kinetics. Gynecol Obstet Invest. 1993;36:230-233.
  8. Mooij PNM, Thomas CMG, Doesburg WH, et al. Multivitamin supplementation in oral contraceptive users. Contraception. 1991;44:277-288.
  9. Russell RM, Dutta SK, Oaks EV, Rosenberg IH, Giovetti AC. Impairment of folic acid absorption by oral pancreatic extracts. Dig Dis Sci. 25(5):369-73.
  10. Werler MM, Shapiro S, Mitchell AA. Periconceptional folic acid exposure and risk of occurrent neural tube defects. JAMA. 269(10):1257-61.
  11. Hernández-Díaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med. 343(22):1608-14.
  12. Papakostas GI, Petersen T, Mischoulon D, Ryan JL, Nierenberg AA, Bottiglieri T, Rosenbaum JF, Alpert JE, Fava M. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-resistant depression. J Clin Psychiatry. 65(8):1090-5.
  13. Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord. 60(2):121-30.
  14. Hunt PG, Rose CD, McIlvain-Simpson G, Tejani S. The effects of daily intake of folic acid on the efficacy of methotrexate therapy in children with juvenile rheumatoid arthritis. A controlled study. J Rheumatol. 24(11):2230-2.
  15. van Ede AE, Laan RF, Rood MJ, Huizinga TW, van de Laar MA, van Denderen CJ, Westgeest TA, Romme TC, de Rooij DJ, Jacobs MJ, de Boo TM, van der Wilt GJ, Severens JL, Hartman M, Krabbe PF, Dijkmans BA, Breedveld FC, van de Putte LB. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 44(7):1515-24.
  16. Morgan SL, Baggott JE, Vaughn WH, Austin JS, Veitch TA, Lee JY, Koopman WJ, Krumdieck CL, Alarcón GS. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med. 121(11):833-41.
  17. Duhra P. Treatment of gastrointestinal symptoms associated with methotrexate therapy for psoriasis. J Am Acad Dermatol. 28(3):466-9.
  18. van Ede AE, Laan RF, Blom HJ, Boers GH, Haagsma CJ, Thomas CM, De Boo TM, van de Putte LB. Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis. Rheumatology (Oxford). 41(6):658-65.
 
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