• Folic Acid, Folacin
• Cancer Prevention, Depression, Heart Disease Prevention, Prevention of Birth Defects, Reduction of Methotrexate Side Effects
• 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, Strokes (Prevention), Vitiligo
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.
Folate requirements rise with age. The official US and Canadian recommendations for daily intake are as follows:
- 0-6 months: 65 mcg
- 7-12 months: 80 mcg
- 1-3 years: 150 mcg
- 4-8 years: 200 mcg
- 9-13 years: 300 mcg
- 14 years and older: 400 mcg
- 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. 1-3 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
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
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.
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.
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 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 very preliminary evidence, folate has been suggested as a treatment for depression . 48-54,124,141 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
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
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 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 .
What Is the Scientific Evidence for Folate?
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%. 88,89 Less direct evidence suggests that folate can help prevent other kinds of birth defects, especially among women using medications that interfere with folate. 90
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.
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.
Interactions You Should Know About
If you are taking
- Aspirin and other anti-inflammatory medications , drugs that reduce stomach acid (such as antacids , H 2 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 : You may need to take extra folate.
- Phenytoin : You may need more folate. However, too much folate can interfere with this medication and cause seizures! Physician supervision is essential.
- Drugs in the nitroglycerin family: Folate may help them remain effective
- Pancreatin (a proteolytic enzyme ): It may be advisable to separate your dose of pancreatin from your dose of folate by at least 2 hours in order to avoid absorption problems.
- 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: If you are taking methotrexate for other conditions, folate might decrease the drug's effectiveness.
- Green tea and black tea may decrease the absorption of folic acid into the blood stream.143
8. Lewis DP, Van Dyke DC, Stumbo PJ, et al. Drug and environmental factors associated with adverse pregnancy outcomes. Part I: Antiepileptic drugs, contraceptives, smoking, and folate. Ann Pharmacother. 1998;32:802-817.
22. Ermens AA, Refsum H, Rupreht J, et al. Monitoring cobalamin inactivation during nitrous oxide anesthesia by determination of homocysteine and folate in plasma and urine. Clin Pharmacol Ther. 1991;49:385-393.
27. Vinnicombe HG, Derrick JP. Dihydropteroate synthase from Streptococcus pneumoniae: characterization of substrate binding order and sulfonamide inhibition. Biochem Biophys Res Commun. 1999;258:752-757.
30. Deleu D, Louon A, Sivagnanam S, et al. Long-term effects of nitrous oxide anaesthesia on laboratory and clinical parameters in elderly Omani patients: a randomized double-blind study. J Clin Pharm Ther. 2000;25:271-277.
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.
51. Passeri M, Cucinotta D, Abate G, et al. Oral 5'-methyltetrahydrofolic acid in senile organic mental disorders with depression: Results of a double-blind multicenter study. Aging (Milano) . 1993;5:63-71.
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.
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.
71. Hunt PG, Rose CD, McIlvain-Simpson G, et al. 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. 1997;24:2230-2232.
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.
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.
104. 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.
105. Hunt PG, Rose CD, McIlvain-Simpson G, et al. 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. 1997;24:2230-2232.
112. Lewis DP, Van Dyke DC, Stumbo PJ, et al. Drug and environmental factors associated with adverse pregnancy outcomes. Part I: Antiepileptic drugs, contraceptives, smoking, and folate. Ann Pharmacother. 1998;32:802-817.
113. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B 6 , folate, vitamin B 12 , pantothenic acid, biotin, and choline. Available at: http://www.nap.edu. Accessed October 4, 2001.
115. Venn BJ, Mann JI, Williams SM, et al. Assessment of three levels of folic acid on serum folate and plasma homocysteine: a randomised placebo-controlled double-blind dietary intervention trial. Eur J Clin Nutr. 2002;56:748-754.
116. Ortiz Z, Shea B, Suarez-Almazor ME, et al. The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis. A meta-analysis of randomized controlled trials. J Rheumatol. 1998;25:36-43.
118. Morgan SL, Baggott JE, Lee JY, Alarcon GS. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: implications for cardiovascular disease prevention. J Rheumatol. 1998;25:441-446.
120. Wulffele MG, Kooy A, Lehert P, et al. Effect of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomised, placebo-controlled trial [abstract]. American Diabetes Association 63rd Annual Scientific Sessions; New Orleans, Louisiana; June 13-17, 2003: 732-P.
124. Papakostas GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B(12), and homocysteine in major depressive disorder, part 1: predictors of clinical response in fluoxetine-resistant depression. J Clin Psychiatry . 2004;65:1090-1095.
125. Diculescu M, Ciocirlan M, Ciocirlan M, et al. Folic acid and sulfasalazine for colorectal carcinoma chemoprevention in patients with ulcerative colitis: the old and new evidence. Rom J Gastroenterol . 2004;12:283-286.
127. Papakostas GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B(12), and homocysteine in major depressive disorder, part 1: predictors of clinical response in fluoxetine-resistant depression. J Clin Psychiatry . 2004;65:1090-1095.
133. Pathansali R, Mangoni AA, Creagh-Brown B, et al. Effects of folic acid supplementation on psychomotor performance and hemorheology in healthy elderly subjects. Arch Gerontol Geriatr . 2005 Dec 13. [Epub ahead of print].
138. Durga J, van Boxtel MP, Schouten EG, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet . 2007;369:208-216.
143. Alemdaroglu NC, Dietz U, Wolffram S, et al. Influence of green and black tea on folic acid pharmacokinetics in healthy volunteers: potential risk of diminished folic acid bioavailability. Biopharm Drug Dispos. 2008 Jun 12.
Last reviewed September 2008 by EBSCO CAM Review Board
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