Folate as a dietary supplement

Definition: Essential natural substance used as a dietary supplement for specific health benefits.

Principal proposed uses: Cancer prevention, depression, heart disease prevention, prevention of birth defects and disorders, reduction of methotrexate side effects

Other proposed uses: Bipolar disorder, enhancing memory and mental function, hearing loss, gout, improving action of drugs in the nitroglycerin family, migraine headaches, nutritional support for cigarette smokers, osteoarthritis, osteoporosis, periodontal disease, restless legs syndrome, rheumatoid arthritis, seborrheic dermatitis, stroke prevention, vitiligo

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 US 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 among Blacks, Hispanics, Asians, and Pacific Islanders, as well as young or overweight people.

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. Some of these drugs may put pregnant women at higher risk of giving birth to children with various kinds of birth defects, and 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 four hundred mcg daily for adults. However, higher dosages, up to ten milligrams (mg) daily, have been used to treat specific diseases. Before taking more than four hundred 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. One hundred to four hundred mcg may produce some homocysteine-lowering effects, while eight hundred 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 older Danish 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 older adults 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 five hundred 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 (four hundred mcg) and vitamin B₁₂ (one hundred 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 (ten 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 the 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 the 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.

High doses of folate may help gout, but some authorities suggest it was a contaminant of folate that caused the benefit seen in some studies. Furthermore, other studies have found little 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 older adults.

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 five hundred 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 several severe side effects. These include liver toxicity and gastrointestinal distress. The use of methotrexate is thought to raise levels of homocysteine, potentially increasing the risk of heart disease. Folate supplementation 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 a folate deficiency, but taking extra folate may 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, but its usual side effects may decrease, too. For example, in a forty-eight-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. 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 to check one’s B₁₂ level.

Doses of folate greater than five mg (five thousand mcg) daily can cause digestive upset. The maximum recommended dosage of folate for pregnant or nursing women is 1,000 mcg daily (eight hundred mcg if eighteen years of age or younger).

As mentioned, phenytoin may interfere with folate absorption, and folate may reduce the effectiveness of phenytoin. Individuals taking phenytoin should consult with a physician about the proper dosage of folate.

People taking the drug methotrexate for rheumatoid arthritis, juvenile rheumatoid arthritis, or psoriasis can safely take folate supplements. Conversely, 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.

Those taking phenytoin may need more folate, but 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 people taking pancreatin (a proteolytic enzyme), it is advisable to separate the dose of pancreatin from the dose of folate by a minimum of two hours to avoid absorption problems.

For individuals 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 people taking methotrexate for other conditions, folate might decrease the drug’s effectiveness. Finally, green and black tea may decrease the absorption of folic acid into the bloodstream.

Bibliography

"Folate." National Institutes of Health, 30 Nov. 2022, ods.od.nih.gov/factsheets/Folate-HealthProfessional. Accessed 29 Aug. 2023.

"Folate (Folic Acid)." Mayo Clinic, 10 Aug. 2023, www.mayoclinic.org/drugs-supplements-folate/art-20364625. Accessed 29 Aug. 2023.

Gamble, M. V., et al. “Folic Acid Supplementation Lowers Blood Arsenic.” American Journal of Clinical Nutrition, vol. 86, 2007, pp. 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, vol. 61, 2007, pp. 631-637.

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, vol. 197,2010, pp. 45-54.

Wang, X., et al. “Efficacy of Folic Acid Supplementation in Stroke Prevention.” The Lancet, vol. 369, 2007, pp. 1876-1882.