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Folate

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Principal Proposed UsesOther Proposed Uses


Folate

Supplement Forms / Alternate Names

  • Folic Acid
  • Folacin
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

Requirements

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

Food Sources

The National Institutes of Health's Office of Dietary Supplements offers this list of foods that are high in folate:149
Food Serving size Folate content
(milligrams [mg]) 		% Daily Value
100% fortified breakfast cereal ¾ cup 400 mg 100
Beef liver, cooked, braised 3 ounces 215 54
Lentils, cooked ½ cup 179 45
Spinach, frozen, cooked, boiled ½ cup 155 29
Enriched egg noodles, cooked ½ cup 110 28
25% fortified breakfast cereal ¾ cup 100 23
Great Northern beans, boiled ½ cup 90 23
Asparagus, boiled 4 spears 89 22
Enriched macaroni, cooked ½ cup 84 21
Enriched white, long-grain rice ½ cup 77 19
Avocado, raw ½ cup 59 15
Spinach, raw 1 cup 58 15
Papaya, raw 1 cup 52 13
Corn, canned ½ cup 52 13
Frozen broccoli, chopped ½ cup 51 13
Tomato juice, canned 1 cup 49 12
Green peas, frozen, boiled ½ cup 47 12
Orange juice 1 cup 47 12
Bread 1 slice 43 11
Peanuts, dry roasted 1 ounce 41 10

Folate Deficiency

Until recently, folate deficiency was fairly common in the developed world, causing thousands of children to be born with preventable birth defects. 1-3 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. 114 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. 134

Folate Absorption

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 . 4-30,120,130 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. 31Oral contraceptives may also affect folate slightly, but there doesn't appear to be a need for supplementation. 32-34

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. 35 You can get around this by taking the two supplements at different times of day.

Therapeutic Uses

The use of folate supplements by pregnant women dramatically decreases the risk that their children will be born with a serious birth defect called neural tube defect. 36,37 This congenital problem consists of problems with the brain or spinal cord.
Folate supplements may also help prevent other types of birth defects, such as defects of the heart, palate, and urinary tract; conversely, drugs that impair folate action may increase risk of birth defects. (See Requirements/Sources for a list of the drugs involved.) An observational study suggests that folate supplements may reduce this risk in pregnant women taking such drugs. 38
Folate also lowers blood levels of homocysteine, which in turn has been hypothesized to reduce the risk of heart disease and other conditions. Studies conflict on the optimum dose of folate for this purpose; 100 to 400 mcg may produce some homocysteine-lowering effects, while 800 mcg daily may lead to maximum effects. 46,115,121,131,135 Note however, that there is as yet no meaningful evidence that reducing homocysteine is beneficial, and considerable evidence that it is not. Overall, studies of folate supplementation for reducing cardiovascular risk have failed to show benefit. 136,145 On a more positive note, a double-blind, placebo-controlled study of 728 Danish seniors with high homocysteine and relatively low folate intake found that use of folate supplements slowed the progression of age-related hearing loss. 137 See the full Homocysteine article for additional information. Folate supplementation might also improve mental function in seniors with high homocysteine levels. 138
Based on preliminary evidence, folate has been suggested as a treatment for depression . 48-54,124,141,146 One double-blind, placebo-controlled trial found that folate supplements at a dose of 500 mcg daily may help antidepressants work more effectively in women, but perhaps not in men. 55 However, another study randomized 909 older adults with mild depression to different treatment groups, which included a group that took folate (400 mcg) and vitamin B 12 (100 mcg) daily for 2 years. 146 Folate and vitamin B 12 were no better than placebo at improving their depressive symptoms.
Observational studies hint that a deficiency in folate might predispose people to develop cancer of the cervix, 56 colon, 57 lung, 58 breast, 59 pancreas, 60 and mouth, 61 and that folate supplements may help prevent colon cancer, especially when taken for many years or by people with ulcerative colitis . 62-64,125 However, observational studies are notoriously unreliable; large double-blind, placebo-controlled studies are needed to prove a treatment effective. One such study performed on folate for cancer prevention among 1,000 people over a 5-year period found folate ineffective for preventing early colon cancer. 140 However, a much smaller study involving 94 individuals with colon polyps (a precancerous condition) found that folate may reduce the risk of recurrent polyps over a 3-year period. 144
High-dose folate (10 mg daily) might be helpful for normalizing abnormalities in the appearance of the cervix (as seen under a microscope) in women taking oral contraceptives, but it does not appear to reverse actual cervical dysplasia . 65,66
Some evidence suggests that folate supplements might reduce risk of stroke . 139
Folate deficiency may also increase the risk of Alzheimer's disease , although this has not yet been proven. 67
Folate supplements may reduce drug side effects in individuals taking the drug methotrexate for certain conditions. 68-72,126 Folate may also reduce side effects of the antiseizure drug carbamazepine . 132
Folate supplements may help medications in the nitroglycerin family remain effective. 73
Folate supplementation may reduce blood arsenic levels in people who have been exposed to this toxic substance. 142
Very high dosages of folate may be helpful for gout , 74 although some authorities suggest that it was actually a contaminant of folate that caused the benefit seen in some studies. 75 Furthermore, other studies have found no benefit at all. 76,77
Based on intriguing but not yet definitive evidence, folate in various dosages has been suggested as a treatment for bipolar disorder , osteoarthritis (in combination with vitamin B 12 ), osteoporosis , restless legs syndrome , rheumatoid arthritis , seborrheic dermatitis , and vitiligo (splotchy loss of skin pigmentation). 78-87 Other conditions for which it has been suggested include migraine headaches and periodontal disease .
Folate does not appear to be helpful for enhancing mental function in seniors. 133

What Is the Scientific Evidence for Folate?

Prevention of Birth Defects and Other Benefits

Very strong evidence tells us that regular use of folate by pregnant women can reduce the risk of neural tube defect (NTD) by 50% to 80%. 88,89 NTDs include conditions like spina bifida, when the baby's spine does not completely close during early pregnancy, and anencephaly, when the upper section (head and skull) of the neural tube does not develop. To reduce the chance of NTDs, women of reproductive age are encouraged to take daily folate supplements.
A systematic review of 5 trials involving 6,105 women reinforced the evidence that folate supplementation can prevent NTDs in both women who have had a baby with an NTD and those who have not. 147 Participants took daily doses between 360 mcg to 4 mg with or without additional supplements. There was not enough information, though, to say whether folate can reduce the risk of developing other conditions, like cleft lip or cleft palate.
Less direct evidence suggests that folate can help prevent other kinds of birth defects, especially among women using medications that interfere with folate. 90
A study involving 38,954 children found that the use of folate supplementation during early pregnancy reduced the children’s chance of having a severe language delay at 3 years of age. 148

Depression

One study found that people with depression who do not respond well to antidepressants are likely to be low in folate. 127
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. 101 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. 105,106,116,126 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. 102 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 103,104,116 and in those with psoriasis. 106
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. 117-118
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.

Safety Issues

Folate at nutritional doses is extremely safe. The only serious potential problem is that folate supplementation can mask the early symptoms of vitamin B 12 deficiency (a special type of anemia), potentially allowing more irreversible symptoms of nerve damage to develop. For this reason, when taking more than 400 mcg daily, it is important to get your B 12 level checked. See the article on Vitamin B 12 for more information.
Very high dosages of folate, greater than 5 mg (5,000 mcg) daily, can cause digestive upset. The maximum recommended dosage of folate for pregnant or nursing women is 1,000 mcg daily (800 mcg if under 19 years old). 113
Media reports that use of folate by pregnant women may increase their risk of breast cancer are based on a single study of highly questionable validity. 128 At present, this is not considered a significant concern, but further research will follow.
As mentioned previously, the antiseizure drug phenytoin may interfere with folate absorption. However, folate may reduce the effectiveness of phenytoin. 107-112 If you are taking phenytoin, you should consult with a physician about the proper dosage of folate for you.
Also, as noted above, individuals who are taking the drug methotrexate for rheumatoid arthritis, juvenile rheumatoid arthritis, or psoriasis can safely take folate supplements at the same time. However, if you are taking methotrexate for any other purpose, do not take folate except on the advice of a physician.

Interactions You Should Know About

If you are taking

References

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36 Werler MM, Shapiro S, Mitchell AA. Periconceptional folic acid exposure and risk of occurrent neural tube defects. JAMA . 1993;269:1257-1261.

37 Milunsky A, Jick H, Jick SS, et al. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA. 1989;262:2847-2852.

38 Hernandez-Diaz S, Werler MM, Walker AM, et al. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med . 2000;343:1608-1614.

39 Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B 6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA . 1998;279:359-364.

40 Moghadasian MH, McManus BM, Frolich JJ. Homocyst(e)ine and coronary artery disease. Arch Intern Med . 1997;157:2299-2308.

41 Ubbink JB, van der Merwe A, Vermaak WJH, et al. Hyperhomocysteinemia and the response to vitamin supplementation. Clin Investig . 1993;71:993-998.

42 den Heijer M, Brouwer IA, Bos GMJ, et al. Vitamin supplementation reduces blood homocysteine levels: a controlled trial in patients with venous thrombosis and healthy volunteers. Arterioscler Thromb Vasc Biol . 1998;18:356-361.

43 Ward M, McNulty H, McPartlin J, et al. Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid. QJM . 1997;90:519-524.

44 Graham IM, Daly LE, Refsum HM, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA . 1997;277:1775-1781.

45 Wald NJ, Watt HC, Law MR, et al. Homocysteine and ischemic heart disease: results of a prospective study with implications regarding prevention. Arch Intern Med. 1998;158:862-867.

46 Wald DS, Bishop L, Wald NJ, et al. Randomized trial of folic acid supplementation and serum homocysteine levels. Arch Intern Med. 2001;161:695-700.

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55 Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord . 2000;60:121-130.

56 Butterworth CE Jr. Effect of folate on cervical cancer. Synergism among risk factors. Ann N Y Acad Sci . 1992;669:293-299.

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58 Heimburger DC. Localized deficiencies of folic acid in aerodigestive tissues. Ann N Y Acad Sci . 1992;669:87-96.

59 Zhang S, Hunter DJ, Hankinson SE, et al. A prospective study of folate intake and the risk of breast cancer. JAMA. 1999;281:1632-1637.

60 Stolzenberg-Solomon RZ, Pietinen P, Barrett MJ, et al. Dietary and other methyl-group availability factors and pancreatic cancer risk in a cohort of male smokers. Am J Epidemiol. 2001;153:680-687.

61 Heimburger DC. Localized deficiencies of folic acid in aerodigestive tissues. Ann N Y Acad Sci . 1992;669:87-96.

62 Giovannucci E, Stampfer MJ, Colditz GA, et al. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst; 1993;85:875-884.

63 Giovannucci E, Stampfer MJ, Colditz GA, et al. Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Ann Intern Med. 1998;129:517-524.

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65 Butterworth CE Jr, Hatch KD, Gore H, et al. Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives. Am J Clin Nutr. 1982;35:73-82.

66 Butterworth CE Jr, Hatch KD, Soong SJ, et al. Oral folic acid supplementation for cervical dysplasia: A clinical intervention trial. Am J Obstet Gynecol. 1992;166:803-809.

67 Snowdon DA, Tully CL, Smith CD, et al. Serum folate and the severity of atrophy of the neocortex in Alzheimer disease: findings from the Nun Study. Am J Clin Nutr. 2000;71:993-998.

68 van Ede AE, Laan RF, Rood MJ, et al. 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. 2001;44:1515-1524.

69 Morgan SL, Baggott JE, Vaughn WH, et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med. 1994;121:833-841.

70 Griffith SM, Fisher J, Clarke S, 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;39:1102-1109.

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72 Duhra P. Treatment of gastrointestinal symptoms associated with methotrexate therapy for psoriasis. J Am Acad Dermatol. 1993;28:466-469.

73 Gori T, Burstein JM, Ahmed S, et al. Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study. Circulation. 2001;104:1119-1123.

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82 Montes LF, Diaz ML, Lajous J, et al. Folic acid and vitamin B 12 in vitiligo: a nutritional approach. Cutis . 1992;50:39-42.

83 Coppen A, Abou-Saleh MT. Plasma folate and affective morbidity during long-term lithium therapy. Br J Psychiatry. 1982;141:87-89.

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85 Callaghan TJ. The effect of folic acid on seborrheic dermatitis. Cutis. 1967;3:583-588.

86 Juhlin L, Olsson MJ. Improvement of vitiligo after oral treatment with vitamin B12 and folic acid and the importance of sun exposure. Acta Derm Venereol (Stockh) . 1997;77:460-462.

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88 Werler MM, Shapiro S, Mitchell AA. Periconceptional folic acid exposure and risk of occurrent neural tube defects. JAMA . 1993;269:1257-1261.

89 Milunsky A, Jick H, Jick SS, et al. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA . 1989;262:2847-2852.

90 Hernandez-Diaz S, Werler MM, Walker AM, et al. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med . 2000;343:1608-1614.

91 Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B 6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA . 1998;279:359-364.

92 Graham IM, Daly LE, Refsum HM, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project . JAMA. 1997;277:1775-1781.

93 Wald NJ, Watt HC, Law MR, et al. Homocysteine and ischemic heart disease: results of a prospective study with implications regarding prevention. Arch Intern Med. 1998;158:862-867.

94 Moghadasian MH, McManus BM, Frohlich JJ. Homocysteine and coronary artery disease. Arch Intern Med . 1997;157:2299-2308.

95 Ubbink JB, van der Merwe A, Vermaak WJH, et al. Hyperhomocysteinemia and the response to vitamin supplementation. Clin Investig . 1993;71:993-998.

96 den Heijer M, Brouwer IA, Bos GMJ, et al. Vitamin supplementation reduces blood homocysteine levels: a controlled trial in patients with venous thrombosis and healthy volunteers. Arterioscler Thromb Vasc Biol . 1998;18:356-361.

97 Ward M, McNulty H, McPartlin J, et al. Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid. QJM . 1997;90:519-524.

98 Wald NJ, Watt HC, Law MR, et al. Homocysteine and ischemic heart disease: results of a prospective study with implications regarding prevention. Arch Intern Med. 1998;158:862-867.

99 Wald DS, Bishop L, Wald NJ, et al. Randomized trial of folic acid supplementation and serum homocysteine levels. Arch Intern Med. 2001;161:695-700.

101 Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord . 2000;60:121-130.

102 van Ede AE, Laan RF, Rood MJ, et al. 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. 2001;44:1515-1524.

103 Morgan SL, Baggott JE, Vaughn WH, et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med. 1994;121:833-841.

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