Overview
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 disorders, and it may lessen the
risk of developing certain forms of cancer.
Requirements and Sources
Folate requirements rise with age. The official U.S. and Canadian recommendations for daily intake of folate (in micrograms) are as follows: infants to six months of age (65) and seven to twelve months of age (80); children age one to three years (150) and four to eight years (200); children age nine to thirteen years (300); children and adults age fourteen and older (400); pregnant females (600); and nursing females (500).
Folate deficiency was fairly common in the developed world, causing thousands of children to be born with preventable birth defects. However, in 1998, widespread fortification of cereal products began in Canada and the United States. As a result, the prevalence of folate deficiency is decreasing in these countries. Deficiency appears to be most common today among African Americans, Hispanics, Asians, and Pacific Islanders, and among younger people and persons who are overweight.
Various drugs may impair the body’s ability to absorb or utilize folate. These
drugs include antacids, bile acid sequestrants (such as
cholestyramine and colestipol), H2 blockers, methotrexate,
oral medications used for diabetes, various antiseizure medications
(carbamazepine, phenobarbital, phenytoin, primidone, and valproate), sulfasalazine
and possibly other nonsteroidal-anti-inflammatory-type
drugs, high-dose triamterene, nitrous oxide, and the
antibiotic trimethoprim-sulfamethoxazole. 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.
Oral contraceptives may also affect folate slightly, but there appears to be no need for supplementation. 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 milligrams (mg) daily, have been used to treat specific diseases. Before taking more than 400 mcg daily, it is important to make sure that one does not have a vitamin B12 deficiency.
A particular kind of digestive enzyme taken as a supplement, pancreatin, may interfere with the absorption of folate. A person can avoid this by taking the two supplements at different times of the day.
Therapeutic Uses
The use of folate supplements by pregnant women dramatically decreases the risk
that their children will be born with a serious condition called neural tube
defect, which consists of problems with the brain or spinal
cord. Folate supplements may also help prevent other types of birth disorders,
such as defects of the heart, palate, and urinary tract; conversely, drugs that
impair folate action may increase the risk of birth defects. An observational
study suggests that folate supplements may reduce this risk in pregnant women
taking such drugs.
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. Note, however, that there is 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. On a more positive note, a double-blind, placebo-controlled study of 728 Danish elderly people with high homocysteine and relatively low folate intake found that the use of folate supplements slowed the progression of age-related hearing loss. Folate supplementation might also improve mental function in elderly persons with high homocysteine levels.
Based on preliminary evidence, folate has been suggested as a treatment for
depression. 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. 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 two years. Folate and vitamin B12 were no better than
placebo at improving depressive symptoms.
Observational studies hint that a deficiency in folate might predispose people
to develop cancer of the cervix, colon, lung, breast, pancreas, and mouth, and
that folate supplements may help prevent colon cancer, especially when taken for
many years or by people with ulcerative colitis. 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 one thousand people for five
years found folate ineffective for preventing early colon cancer. However, a much
smaller study involving ninety-four persons with colon polyps
(a precancerous condition) found that folate may reduce the risk of recurrent
polyps in a three-year period.
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. Also, some evidence suggests that folate supplements might reduce risk of stroke. Folate deficiency may also increase the risk of Alzheimer’s disease, although this has not been proven.
Folate supplements may reduce drug side effects in persons taking the drug methotrexate for certain conditions. Folate may also reduce side effects of the antiseizure drug carbamazepine.
Folate supplements may help medications in the nitroglycerin family remain effective. Folate supplementation may reduce blood arsenic levels in people who have been exposed to this toxic substance.
Very high dosages of folate may be helpful for gout, although some authorities suggest that it was actually a contaminant of folate that caused the benefit seen in some studies. Furthermore, other studies have found no benefit.
Based on intriguing but not definitive evidence, folate in various dosages has been suggested as a treatment for bipolar disorder, osteoarthritis (in combination with vitamin B12), osteoporosis, restless legs syndrome, rheumatoid arthritis, seborrheic dermatitis, and vitiligo (splotchy loss of skin pigmentation). Other conditions for which folate has been suggested include migraine headaches and periodontal disease. Finally, folate does not appear to be helpful for enhancing mental function in the elderly.
Scientific Evidence
Birth defects and disorders. Strong evidence shows that the regular use of folate by pregnant women can reduce the risk of neural tube defect by 50 to 80 percent. Less direct evidence suggests that folate can help prevent other kinds of birth defects and disorders, especially among women using medications that interfere with folate.
Depression. One study found that people with depression who do
not respond well to antidepressants are likely to have low
levels of folate. A ten-week, double-blind, placebo-controlled trial of 127
persons 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. 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 and in treating inflammatory diseases such as rheumatoid arthritis and psoriasis. While often highly effective, methotrexate can produce a number of severe side effects. These include liver toxicity and gastrointestinal distress. In addition, the use of methotrexate is thought to raise levels of homocysteine, potentially increasing the 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. This inactivation of folate plays a role in methotrexate’s therapeutic effects. This leads to a dilemma: Methotrexate use can lead to folate deficiency, but taking extra folate could theoretically prevent methotrexate from working properly.
However, evidence suggests that people who take methotrexate for rheumatoid arthritis, juvenile rheumatoid arthritis, or psoriasis can safely use folate supplements. Not only does the methotrexate continue to work properly; its usual side effects may decrease too.
For example, in a 48-week, double-blind, placebo-controlled trial of 434 persons with active rheumatoid arthritis, the use of folate helped prevent liver inflammation caused by methotrexate. 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 doing so was worth it.
In the foregoing study, 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 persons receiving methotrexate for rheumatoid arthritis and in those with psoriasis. In addition, two studies of people with rheumatoid arthritis found that the use of folate supplements corrected the methotrexate-induced rise in homocysteine without affecting disease control.
Folate supplements have been found safe only as supportive treatment in the specific conditions noted. It is not known, for example, whether folate supplements are safe for use by persons 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 B12 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 check one’s B12 level.
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 eighteen years of age or younger).
Media reports that the use of folate by pregnant women may increase their risk of breast cancer are based on a single study of highly questionable validity. This report is not considered a significant concern, but further research is needed.
As mentioned, the antiseizure drug phenytoin may interfere with folate
absorption. However, folate may reduce the effectiveness of phenytoin. Persons
taking phenytoin should consult with a physician about the proper dosage of
folate.
Persons 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 one is taking methotrexate for any other purpose, one should not take folate except on the advice of a physician.
Important Interactions
Persons may need to take extra folate if also using aspirin and other
anti-inflammatory medications, drugs that reduce stomach acid (such as antacids,
H2 blockers, and proton pump inhibitors), bile acid
sequestrants (such as cholestyramine and colestipol), carbamazepine, estrogen
replacement therapy, nitrous oxide, oral contraceptives, oral hypoglycemic drugs,
phenobarbital, primidone, sulfa antibiotics, triamterene, valproic
acid, or the antibiotic trimethoprim-sulfamethoxazole.
Persons taking phenytoin may need more folate. However, too much folate can interfere with this medication and can cause seizures. Physician supervision is essential.
Folate may boost the effectiveness of drugs in the nitroglycerin family. For persons taking pancreatin (a proteolytic enzyme), it may be advisable to separate the dose of pancreatin from the dose of folate by a minimum of two hours to avoid absorption problems.
For persons taking methotrexate for rheumatoid arthritis, juvenile rheumatoid arthritis, or psoriasis: Evidence suggests that folate supplements may reduce side effects of the drug without decreasing its benefits. Nonetheless, physician supervision is highly recommended. Note that for persons taking methotrexate for other conditions, folate might decrease the drug’s effectiveness. Finally, green tea and black tea may decrease the absorption of folic acid into the bloodstream.
Bibliography
Durga, J., M. P. van Boxtel, et al. “Effect of Three-Year Folic Acid Supplementation on Cognitive Function in Older Adults in the FACIT Trial.” The Lancet 369 (2007): 208-216.
Durga, J., P. Verhoef, et al. “Effects of Folic Acid Supplementation on Hearing in Older Adults.” Annals of Internal Medicine 146 (2007): 1-9.
Ebbing, M., et al. “Mortality and Cardiovascular Events in Patients Treated with Homocysteine-Lowering B Vitamins after Coronary Angiography.” Journal of the American Medical Association 300 (2008): 795-804.
Gamble, M. V., et al. “Folic Acid Supplementation Lowers Blood Arsenic.” American Journal of Clinical Nutrition 86 (2007): 1202-1209.
Gilbody, S., T. Lightfoot, and T. Sheldon. “Is Low Folate a Risk Factor for Depression? A Meta-analysis and Exploration of Heterogeneity.” Journal of Epidemiology and Community Health 61 (2007): 631-637.
Lawrence, J. M., et al. “Do Racial and Ethnic Differences in Serum Folate Values Exist After Food Fortification with Folic Acid?” American Journal of Obstetrics and Gynecology 194 (2006): 520-526.
Walker, J. G., et al. “Mental Health Literacy, Folic Acid and Vitamin B12, and Physical Activity for the Prevention of Depression in Older Adults.” British Journal of Psychiatry 197 (2010): 45-54.
Wang, X., et al. “Efficacy of Folic Acid Supplementation in Stroke Prevention.” The Lancet 369 (2007): 1876-1882.
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