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

FoodServing size Folate content
(milligrams [mg]) 		% Daily Value
100% fortified breakfast cereal¾ cup400 mg100
Beef liver, cooked, braised3 ounces21554
Lentils, cooked½ cup17945
Spinach, frozen, cooked, boiled½ cup15529
Enriched egg noodles, cooked½ cup11028
25% fortified breakfast cereal¾ cup10023
Great Northern beans, boiled½ cup9023
Asparagus, boiled4 spears8922
Enriched macaroni, cooked½ cup8421
Enriched white, long-grain rice½ cup7719
Avocado, raw½ cup5915
Spinach, raw1 cup5815
Papaya, raw1 cup5213
Corn, canned½ cup5213
Frozen broccoli, chopped½ cup5113
Tomato juice, canned1 cup4912
Green peas, frozen, boiled½ cup4712
Orange juice1 cup4712
Bread1 slice4311
Peanuts, dry roasted1 ounce4110
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), H2blockers, 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.31 Oral 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 B12 (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 B12 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.

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