Folate

Related Terms

• B Complex vitamin, folacin, folate, folic acid, folinic acid, pteroylglutamic acid, pteroylmonoglutamic acid, pteroylpolyglutamate, vitamin B9, vitamin M.

Background

• Folate and folic acid are forms of a water-soluble B vitamin. Folate occurs naturally in food and folic acid is the synthetic form of this vitamin. Folic acid is well-tolerated in amounts found in fortified foods and supplements. Sources include cereals, baked goods, leafy vegetables (spinach, broccoli, lettuce), okra, asparagus, fruits (bananas, melons, lemons), legumes, yeast, mushrooms, organ meat (beef liver, kidney), orange juice, and tomato juice. Folic acid is frequently used in combination with other B vitamins in vitamin B complex formulations.

Evidence

*Key to grades:

A: Strong scientific evidence for this use;
B: Good scientific evidence for this use;
C: Unclear scientific evidence for this use;
D: Fair scientific evidence against this use (it may not work);
F: Strong scientific evidence against this use (it likely does not work).

For full grading rationale, click here.

Safety

The U.S. Food and Drug Administration does not strictly regulate herbs and supplements. There is no guarantee of strength, purity or safety of products, and effects may vary. You should always read product labels. If you have a medical condition, or are taking other drugs, herbs, or supplements, you should speak with a qualified healthcare professional before starting a new therapy. Consult a healthcare professional immediately if you experience side effects.

Allergies

• Avoid folic acid supplements if hypersensitive or allergic to any of the product ingredients.

Side Effects and Warnings

• Folate appears to be well tolerated in recommended doses. Stomatitis, alopecia, myelosupression, and zinc depletion have been reported.
• An intravenous loading dose of folic acid, vitamin B6, and vitamin B12 followed by oral administration of folic acid plus vitamin B6 and vitamin B12, taken daily after coronary stenting, might actually increase restenosis rates. Due to the potential for harm, this combination of vitamins should not be recommended for patients receiving coronary stents.
• Erythema, pruritus, urticaria, skin flushing, rash, and itching have been reported.
• Nausea, bloating, flatulence, cramps, bitter taste, and diarrhea have been reported.
• Color of urine may become more intense.
• Folic acid may mask the symptoms of pernicious, aplastic, or normocytic anemias caused by vitamin B12 deficiency and may lead to neurological damage.
• Irritability, excitability, general malaise, altered sleep patterns, vivid dreaming, overactivity, confusion, impaired judgment, increased seizure frequency, and psychotic behavior have been reported. Very high doses can cause significant central nervous system (CNS) side effects. Supplemental folic acid might increase seizures in people with seizure disorders, particularly in very high doses.
• Anaphylaxis and bronchospasm have also been reported.

Pregnancy and Breastfeeding

• Pregnancy: It is recommended that all women capable of becoming pregnant consume folate in order to reduce the risk of the fetus developing a neural tube defect. Folic acid supplementation in higher than recommended doses is categorized as FDA Pregnancy Category C.
• Breastfeeding: Folic acid is present in the breast milk and is likely safe to use during breastfeeding under the supervision of a qualified healthcare provider.

Interactions

Most herbs and supplements have not been thoroughly tested for interactions with other herbs, supplements, drugs, or foods. The interactions listed below are based on reports in scientific publications, laboratory experiments, or traditional use. You should always read product labels. If you have a medical condition, or are taking other drugs, herbs, or supplements, you should speak with a qualified healthcare professional before starting a new therapy.

Interactions with Drugs

• Excessive use of alcohol increases the requirement for folic acid.
• Aminosalicylic acid can reduce dietary folate absorption, worsening the folate deficiency often seen with active tuberculosis, or preventing its reversal during treatment. Megaloblastic anemia occurs rarely and usually when there are other contributing factors, such as concurrent vitamin B12 malabsorption. Patients being treated for tuberculosis may be advised to take folic acid supplements if their dietary folate intake is low.
• Chronic use of large doses of antacids can reduce folic acid absorption, but this is likely only significant if dietary folate intake is very low. Maintenance of the recommended daily intake of folic acid in the diet is recommended.
• Antibiotic therapy can disrupt the normal gastrointestinal (GI) flora, interfering with the absorption of folic acid. Folate supplements are not considered necessary.
• Aspirin may decrease serum folate levels, especially with chronic large doses. It is suggested that folate is just being redistributed in the body rather than an actual folate deficiency; therefore folate supplementation is not considered necessary.
• Oral contraceptives (birth control pills) may impair folate metabolism producing depletion, but the effect is unlikely to cause anemia or megaloblastic changes.
• Carbamazepine (Tegretol®) can reduce serum folate levels, but megaloblastic anemia has not been reported. Pregnant women taking carbamazepine may be especially at risk from reduced folate levels.
• Chloramphenicol may antagonize some effects of folic acid on the blood (hematopoietic system).
• Cholestyramine reduces folic acid absorption. It can lower serum and red blood cell folate levels in children taking large doses for several months. Maintenance of dietary folate intake is recommended.
• Colestipol (Colestid®) can interfere with absorption of folic acid, and reduced serum folate levels may occur. Maintenance of dietary folate intake is recommended.
• Cycloserine can reduce serum folate levels, and rare cases of megaloblastic anemia have occurred. Maintenance of dietary folate intake is recommended.
• Limited data suggests that diuretics ("water pills") may increase excretion of folic acid. Reduced red blood cell folate levels, possibly contributing to increased homocysteine levels, a risk factor for cardiovascular disease, were found in one group of people taking diuretics for six months or longer. The need for folic acid supplementation during diuretic therapy requires further study before a firm recommendation can be made. Currently, maintenance of dietary folate intake is recommended.
• Reduced serum and red blood cell folate levels can occur in some women taking conjugated estrogens (Premarin®), but this is unlikely in women with adequate dietary folate intake. Supplements are recommended only for those women with inadequate dietary intake or other conditions that contribute to folate deficiency, and for those diagnosed with, or at increased risk for, cervical dysplasia (due to family history for example).
• Folic acid absorption from the small intestine is optimal at pH 5.5 to 6. The increased pH associated with the use of H2 blockers (such as cimetidine (Tagamet®), famotidine (Pepcid®), nizatidine (Axid®), and ranitidine (Zantac®)) may therefore reduce folic acid absorption, but this is probably only significant if dietary folate intake is very low. Another class of prescription drugs that may affect folic acid absorption is proton pump inhibitors (PPIs). These are used for reflux disease and ulcers and include esomeprazole (Nexium®), lansoprazole (Prevacid®), omeprazole (Prilosec®), pantoprazole (Protonix®), and rabeprazole (Aciphex®). Maintenance of dietary folate intake is recommended.
• Reduced vitamin B12 and, to a lesser extent, folate levels occur in some people with diabetes and can contribute to hyperhomocysteinemia, which adds to their already increased risk of cardiovascular disease. The reduced folate levels seen in diabetics have been linked to metformin use in some cases, possibly as a result of reduced folic acid absorption. Symptomatic folate deficiency is unlikely to occur with metformin, but people with diabetes may need folic acid supplements to reduce hyperhomocysteinemia. Diabetes should be treated by a qualified healthcare provider.
• Methotrexate is a folate antagonist that prevents the conversion of folic acid to its active form, and lowers plasma and red blood cell folate levels. Folic acid supplements reduce side effects without reducing the efficacy of methotrexate in treating rheumatoid arthritis or psoriasis. Patients being treated with methotrexate for cancer should avoid folic acid supplements, unless recommended by their oncologist. Folic acid could interfere with the anticancer effects of methotrexate.
• Reduced serum folate levels have been noted in people with multiple sclerosis (MS) after treatment with methylprednisolone sodium succinate (Solu-Medrol®). Clinical significance is unknown.
• Chronic cigarette smoking is associated with diminished folate status.
• Folate-dependent enzymes have been inhibited in laboratory experiments by certain NSAIDs (ibuprofen (Advil®, Motrin®, Nuprin®), naproxen (Anaprox®, Aleve®), indomethacin (Indocin®), and sulindac (Clinoril®). Clinical significance is unknown.
• Reduced folate levels can occur in some people taking pancreatic extracts (such as Pancrease®, Cotazym®, Viokase®, Creon®, Ultrase®) possibly due to reduced absorption. Folate levels should be checked in patients taking pancreatic enzymes for prolonged periods.
• Pentamidine is a prescription drug used to treat Pneumocystis carinii pneumonia (PCP). Decreased serum folate levels and megaloblastic bone marrow changes can occur rarely with prolonged intravenous pentamidine (Pentacarinat®, Pentam 300®) therapy. Most patients are unlikely to need folic acid supplements.
• Phenobarbital (Luminal®) and primidone (Mysoline®) can reduce serum folate levels, occasionally leading to megaloblastic anemia (usually in people with low dietary folate intake), and possibly contributing to neurological side effects, mental changes, and cerebral atrophy. Pregnant women taking phenobarbital or primidone may be especially at risk from reduced folate levels. Folic acid can have direct convulsant activity in some people, reversing the effects of phenobarbital or primidone and worsening seizure control. Folic acid may increase metabolism of phenobarbital. Seizure activity should be monitored closely.
• Pyrimethamine (Daraprim®) is a folate antagonist that prevents conversion of folic acid to its active form. Patients taking pyrimethamine should avoid folic acid supplements since they can antagonize the therapeutic effects against Toxoplasmosis and Pneumocystis carinii pneumonia. Patients taking lower doses of pyrimethamine for prolonged periods should maintain the recommended dietary folate intake and monitored for folate deficiency. Folic acid does not antagonize the effects of pyrimethamine in the treatment of malaria. Folinic acid may be used as an alternative to folic acid when indicated. Pyrimethamine also reduces serum folate levels.
• One study found that administration of folic acid to pregnant women might not interfere with the protective effect of sulfadoxine/pyrimethamine combination when used for intermittent preventative treatment of malaria.
• Sulfasalazine inhibits absorption and metabolism of folic acid. Patients on chronic sulfasalazine therapy may be advised to increase their dietary folate intake, and to take a supplement if they have any other condition, which could also contribute to deficiency.
• Triamterene (Dyrenium®) is a folate antagonist that prevents conversion of folic acid to its active form, and also reduces folate absorption. Reduced serum and red blood cell folate levels have occurred, and occasional cases of megaloblastic anemia, usually in people with other conditions contributing to folate deficiency. Patients on chronic triamterene therapy should to maintain the recommended dietary folate intake, or take a supplement if advised by their physician.
• There is a general belief that folic/folinic acid supplements do not interfere with the therapeutic effects of trimethoprim. However, this view has been challenged, and failure of trimethoprim therapy has occurred rarely when folinic acid is given concurrently.

Interactions with Herbs and Dietary Supplements

• Reduced serum and red blood cell folate levels can occur in some women taking conjugated estrogens (Premarin®) or birth control pills, but this is unlikely in women with adequate dietary folate intake. Theoretically this interaction may occur with estrogenic herbs and supplements as well.
• Taking folic acid along with vitamin B12 may increase the risk of vitamin B12 deficiency. Caution is advised when taking both of these vitamins together.
• Normal supplemental doses of folic acid are unlikely to have an adverse effect on zinc balance in people with adequate dietary zinc intake. The data on the effects of supplemental folic acid on dietary zinc absorption are conflicting.

Authors

• This information is based on a professional level monograph edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Selected References

Natural Standard developed the above evidence-based information based on a systematic review of the available scientific articles. For comprehensive information about alternative and complementary therapies on the professional level, go to www.naturalstandard.com. Selected references are listed below.

1. Bazzano LA, He J, Ogden LG, et al. Dietary intake of folate and risk of stroke in US men and women: NHANES I Epidemiologic Follow-up Study. National Health and Nutrition Examination Survey. Stroke 2002;33(5):1183-1188.
2. Brown RS, Di Stanislao PT, Beaver WT, et al. The administration of folic acid to institutionalized epileptic adults with phenytoin-induced gingival hyperplasia. A double-blind, randomized, placebo-controlled, parallel study. Oral Surg Oral Med Oral Pathol 1991;71(5):565-568.
3. Bygbjerg IC, Lund JT, Hording M. Effect of folic and folinic acid on cytopenia occurring during co-trimoxazole treatment of Pneumocystis carinii pneumonia. Scand J Infect Dis 1988;20(6):685-686.
4. Chia S, Wilson R, Ludlam CA, et al. Endothelial dysfunction in patients with recent myocardial infarction and hyperhomocysteinaemia: effects of vitamin supplementation. Clin Sci (Lond) 2005;108(1):65-72.
5. Fransen J, Laan RF, Van Der Laar MA, et al. Influence of guideline adherence on outcome in a randomised controlled trial on the efficacy of methotrexate with folate supplementation in rheumatoid arthritis. Ann Rheum Dis 2004;63(10):1222-1226.
6. Mbaye A, Richardson K, Balajo B, et al. Lack of inhibition of the anti-malarial action of sulfadoxine-pyrimethamine by folic acid supplementation when used for intermittent preventive treatment in Gambian primigravidae. Am J Trop Med Hyg. 2006 Jun;74(6):960-4.
7. McMahon JA, Green TJ, Skeaff CM, et al. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med 2006 Jun 29;354(26):2764-72.
8. 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 metaanalysis of randomized controlled trials. J Rheumatol 1998;25(1):36-43.
9. Sato Y, Honda Y, Iwamoto J, et al. Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial. JAMA 2005;293(9):1082-1088.
10. Smolders RG, De Meer K, Kenemans P, et al. Hormone replacement influences homocysteine levels in the methionine-loading test: a randomized placebo controlled trial in postmenopausal women. Eur J Obstet Gynecol Reprod Biol 2004;117(1):55-59.
11. Taylor MJ, Carney SM, Goodwin GM, et al. Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials. J Psychopharmacol 2004;18(2):251-256.
12. Tucker KL, Olson B, Bakun P, et al. Breakfast cereal fortified with folic acid, vitamin B-6, and vitamin B-12 increases vitamin concentrations and reduces homocysteine concentrations: a randomized trial. Am J Clin Nutr 2004;79(5):805-811.
13. Ullegaddi R, Powers HJ, Gariballa SE. B-group vitamin supplementation mitigates oxidative damage after acute ischaemic stroke. Clin Sci (Lond) 2004;107(5):477-484.
14. Vermeulen EG, Stehouwer CD, Twisk JW, et al. Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebo-controlled trial. Lancet 2000;355(9203):517-522.
15. Zesiewicz TA, Wecker L, Sullivan KL, et al. The controversy concerning plasma homocysteine in Parkinson disease patients treated with levodopa alone or with entacapone: effects of vitamin status. Clin Neuropharmacol 2006 May-Jun;29(3):106-11.

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