Folate

• Background
• Related terms
• Evidence
• Dosing
• Safety
• Methodology
• Selected references

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Folate

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.

Folic acid supplements are effective for increasing folate levels in blood and decreasing symptoms associated with low folate levels. Folic acid supplementation, with and without other B vitamins, reduce levels of homocysteine in blood (a cardiovascular risk factor).

Folic acid supplements are suggested for use in women of childbearing age in order to prevent neural tube defects. Neural tube defect risk appears to have decreased in many countries since folic acid fortification of flour and cereals.

Folic acid is also of interest with respect to cognitive enhancement, cancer, psychiatric illnesses, and cardiovascular conditions, although conclusions may not be drawn for many of these uses at this time. Some concern exists with respect to increased folic acid intake masking symptoms of vitamin B12 deficiency, especially in the elderly population,

Related terms

5-Methyltetrahydrofolate, B complex vitamin, Beyaz, Equaline™, folacin, folate, folic acid, folinic acid, Folvite ^® , heptaglutamyl folic acid, hexaglutamyl folic acid, L-5-methyltetrahydrofolate, leucovorin, methyltetrahydrofolate, monoglutamyl folic acid, Nature Made ^® , Nutri Plus ^® , polyglutamyl folic acid, pteroylglutamic acid, pteroylmonoglutamic acid, pteroylpolyglutamate, Safeway™, Sunmark™, vitamin B9, vitamin M, Your Life ^® .

Evidence

These uses have been tested in humans or animals. Safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider.

Grading rationale

Uses based on tradition or theory

The below uses are based on tradition or scientific theories. They often have not been thoroughly tested in humans, and safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider.

AIDS, anemia (associated with inflammatory bowel disease), anti-aging (preventing signs of aging), aphthous ulcers (canker sore), appetite stimulation, arsenic poisoning, autism, cardiovascular disease risk, celiac disease, colorectal adenoma, critical illness (supplementation due to refusal of blood transfusion), Crohn's disease, dental conditions, fistula (abnormal connection in the blood vessel), fracture (risk reduction), gastritis (atrophic), genetic damage (X-ray-induced chromosomal damage), infertility, inflammatory bowel disease, insomnia, ischemic heart disease, lichen planus (itchy rash in the mouth), liver disease, low birth weight, macular degeneration, memory enhancement, mood, myofascial pain (pain in muscles and fascia), osteoporosis, peripheral neuropathy, restless leg syndrome, retinal vein occlusion (blocked vein in the eye), schizophrenia, sickle cell anemia, spinal cord injury (myelopathy), thrombosis, ulcerative colitis, weight loss.

Dosing

The below doses are based on scientific research, publications, traditional use, or expert opinion. Many herbs and supplements have not been thoroughly tested, and safety and effectiveness may not be proven. Brands may be made differently, with variable ingredients, even within the same brand. The below doses may not apply to all products. You should read product labels, and discuss doses with a qualified healthcare provider before starting therapy.

Adults (over 18 years old)

U.S. Recommended Dietary Allowance (RDA) for adults (oral) : Four hundred micrograms daily for males or females ages 14 years and older; 500 micrograms daily for breastfeeding adult women; 600 micrograms daily for pregnant adult women. Given as dietary folate equivalents (DFE).

Tolerable upper intake levels (UL) daily : The UL is the maximum daily level of intake that is likely not to pose a risk of adverse effects. The UL is 800 micrograms daily for males or females ages 14-18 years-old (including pregnant or breastfeeding women); and 1,000 micrograms daily for males or females ages 19 years and older (including pregnant or breastfeeding women).

Adjunct treatment with conventional antidepressants : Doses of 200 to 500 micrograms daily has been used for enhancing treatment response to antidepressants. Limited clinical research suggests that folic acid is not effective as a replacement for conventional antidepressant therapy.

Anticonvulsant-induced folate deficiency : Fifteen milligrams (15,000 micrograms) daily has been used under the supervision of a qualified healthcare provider.

Cervical cancer : Doses of 0.8 to 10 milligrams (800 to 10,000 micrograms) daily have been used.

Colon cancer : Doses of 400 micrograms daily have been used to reduce the risk of colon cancer occurring, although supplementation has not been proven to be effective.

Depression : Doses of 500 micrograms folic acid or 15-50 milligrams methylenetetrahydrofolate daily, as adjunct treatment with conventional antidepressants.

Drug-induced toxicity : For reduction of toxicity symptoms (nausea and vomiting) associated with methotrexate therapy for rheumatoid arthritis (RA) or psoriasis, 1 milligram daily (1,000 micrograms daily) may be sufficient, but up to 5 milligrams daily (5,000 micrograms daily) may be used.

End stage renal disease (ESRD) : Doses of 0.8 to 15 milligrams (800 to 15,000 micrograms) folic acid daily are generally used, but the degree of homocysteine reduction is very variable (between 12%-50%), and normal homocysteine levels (<12 micromoles per liter) may not always be achieved. Folic acid 2.5 to 5 milligrams (2,500 to 5,000 micrograms) three times weekly also reduces homocysteine levels in ESRD patients on dialysis. Doses greater than 15 milligrams (15,000 micrograms) daily do not provide additional benefit. Doses of 30 to 60 milligrams (30,000 to 60,000 micrograms) seem to cause a rebound in homocysteine levels when treatment is stopped.

Folate deficiency : The typical dose is 250 to 1,000 micrograms daily. For severe folate deficiency, such as in cases of megaloblastic anemia and malabsorption disorders, 1-5 milligrams (1,000 to 5,000 micrograms) daily is often used until corrected blood tests are documented by a qualified healthcare professional.

Hyperhomocysteinemia : Doses of 0.2 to 5 milligrams daily (500 to 15,000 micrograms) have been used, although 0.8 to 1 milligrams daily (800 to 1,000 micrograms) appears to provide maximal reduction of homocysteine levels. Doses greater than 1 milligram daily (1,000 micrograms) do not seem to produce any greater benefit except in some people with certain gene mutations that cause homocysteine levels of 20 micromoles per liter or higher. However, initial data suggest that the U.S. government-mandated fortification of cereals and flour with 140 micrograms folic acid per 100 grams is reducing the mean homocysteine level in the general population by about 7%. Consumption of at least 300 micrograms daily of dietary folate seems to be associated with a 20% lower risk of stroke and a 13% lower risk of cardiovascular disease when compared with consumption of less than 136 micrograms of folate daily. Doses of 10 milligrams (10,000 micrograms) daily of folic acid have been used to improve coagulation status, oxidative stress, and endothelial dysfunction.

Hypertension : Doses of 5-10 milligrams daily folic acid.

Megaloblastic anemia : In cases of megaloblastic anemia resulting from folate deficiency or malabsorption disorders such as sprue, oral doses of 1 to 5 milligrams (1,000 to 5,000 micrograms) daily may be used until hematologic recovery is documented by a qualified healthcare provider.

Methotrexate toxicity : Doses of 1-27.5 milligrams weekly folic acid or 1-20 milligrams weekly folinic acid.

Neural tube defects (prevention) : Doses of at least 400 micrograms of folic acid daily from supplements or fortified food should be taken by women capable of becoming pregnant and continued through the first month of pregnancy. Women with a history of previous pregnancy complicated by such neural tube defects usually take 4 milligrams (4,000 micrograms) daily beginning one month before and continuing for three months after conception under the guidance of a qualified healthcare professional. Doses of 0.36-5 milligrams daily folic acid.

Pancreatic cancer : Consuming greater than 280 micrograms daily of dietary folate is associated with a decreased risk of exocrine pancreatic cancer. Further research is needed to confirm these results.

Phenytoin-induced gingival hyperplasia : Applying folic acid topically may inhibit gingival hyperplasia secondary to phenytoin therapy. However, taking folic acid by mouth does not seem to be beneficial for this indication.

Pregnancy-related gingivitis : Applying folic acid topically may improve gingivitis in pregnancy.

Preventing increases in homocysteine levels after nitrous oxide anesthesia : Folate 2.5 milligrams (2,500 micrograms) in combination with pyridoxine 25 milligrams (25,000 micrograms) and vitamin B12 500 micrograms have been used daily for one week before surgery under the supervision of a qualified healthcare provider.

Stroke : Doses of 0.5-15 milligrams folic acid daily.

Vitiligo : Doses of 5 milligrams (5,000 micrograms) have been taken twice daily.

Children (under 18 years old)

U.S. RDA or Adequate Intake (AI) for children (oral) : For infants 0-6 months-old, the AI is 65 micrograms daily; for infants 7-12 months-old, the AI is 80 micrograms daily; for children 1-3 years-old, the RDA is 150 micrograms daily; for children 4-8 years-old, the RDA is 200 micrograms daily; for children 9-13 years-old, the RDA is 300 micrograms daily. Given as dietary folate equivalents (DFE).

Tolerable (UL) daily : The UL is the maximum daily level of intake that is likely not to pose a risk of adverse effects. For children 1-3 years-old, the UL is 300 micrograms; for children 4-8 years-old, the UL is 400 micrograms; for children 9-13 years-old, the UL is 600 micrograms; for adolescents 14-18 years-old, the UL is 800 micrograms.

Caution : Folic acid injection contains benzyl alcohol (1.5%) as a preservative, and extreme care should be used in administration to neonates. Folic acid injections should be administered by a qualified healthcare provider.

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 provider before starting a new therapy. Consult a healthcare provider 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 may cause low blood pressure. Caution is advised in patients taking herbs or supplements that lower blood pressure.

Folate may lower blood sugar levels. Caution is advised in patients with diabetes or hypoglycemia and in those taking drugs, herbs, or supplements that affect blood sugar. Blood glucose levels may need to be monitored by a qualified healthcare professional, including a pharmacist, and medication adjustments may be necessary.

Folate appears to be well-tolerated in suggested doses. Stomatitis, alopecia, myelosupression, and zinc depletion have been reported.

Use cautiously in combination with aspirin based on human studies suggesting folic acid reversed the beneficial effects of aspirin on C-reactive protein (CRP) levels.

Use folic acid injections containing benzyl alcohol (1.5%) as a preservative only under the advice of a healthcare provider.

Use folic acid cautiously in individuals living in a high malaria area due to findings that routine prophylactic supplementation with iron and folic acid increased the risk of dying or needing in-patient treatment for an adverse event

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 suggested for patients receiving coronary stents.

Erythema, urticaria (hives), skin flushing, rash, and itching have been reported.

Nausea, bloating, flatulence, cramps, bitter taste, and diarrhea have been reported.

The color of urine may become more "intense" (further details are lacking).

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 may cause significant central nervous system (CNS) side effects. Supplemental folic acid might increase seizures in people with seizure disorders, particularly in very high doses.

Wheeze and asthma incidence may be increased in infants following use in pregnancy. Anaphylaxis and bronchospasm have also been reported.

Other potential adverse effects to folic acid supplementation include increased cancer incidence and mortality and increased restenosis following stenting. The effects of folic acid itself are not clear. Unmetabolized folic acid (not converted to folate) has been found in the blood of supplement users.

Use supplemental levels above 400 micrograms cautiously.

Pregnancy and Breastfeeding

Pregnancy : It is suggested 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 suggested doses is categorized as U.S. Food and Drug Administration (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.

Wheeze and asthma incidence may be increased in infants following use in pregnancy.

Severe clinical and hematological manifestations of folate deficiency occurred in a previously healthy, fully breastfed, 10 month-old infant whose mother took oral contraceptives.

Methodology

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

Monograph methodology

Selected references

1. Aisen PS, Schneider LS, Sano M, et al. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA 2008 Oct 15;300(15):1774-83.
2. Albert CM, Cook NR, Gaziano JM, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA 2008 May 7;299(17):2027-36.
3. Antoniades C, Antonopoulos AS, Tousoulis D, et al. Homocysteine and coronary atherosclerosis: from folate fortification to the recent clinical trials. Eur Heart J 2009 Jan;30(1):6-15.
4. Blencowe H, Cousens S, Modell B, Lawn J. Folic acid to reduce neonatal mortality from neural tube disorders. Int J Epidemiol. 2010 Apr;39 Suppl 1:i110-21.
5. Blom HJ. Folic acid, methylation and neural tube closure in humans. Birth Defects Res A Clin Mol Teratol. 2009 Apr;85(4):295-302.
6. Dangour AD, Whitehouse PJ, Rafferty K, Mitchell SA, Smith L, Hawkesworth S, Vellas B. B-vitamins and fatty acids in the prevention and treatment of Alzheimer's disease and dementia: a systematic review. J Alzheimers Dis. 2010;22(1):205-24.
7. Figueiredo JC, Levine AJ, Grau MV, et al. Colorectal adenomas in a randomized folate trial: the role of baseline dietary and circulating folate levels. Cancer Epidemiol Biomarkers Prev. 2008 Oct;17(10):2625-31.
8. Ford AH, Flicker L, Thomas J, et al. Vitamins B12, B6, and folic acid for onset of depressive symptoms in older men: results from a 2-year placebo-controlled randomized trial. J Clin Psychiatry 2008 Aug;69(8):1203-9.
9. Gibson A, Woodside JV, Young IS, et al. Alcohol increases homocysteine and reduces B vitamin concentration in healthy male volunteers--a randomized, crossover intervention study. QJM 2008 Nov;101(11):881-7.
10. Held C, Sumner G, Sheridan P, et al. Correlations between plasma homocysteine and folate concentrations and carotid atherosclerosis in high-risk individuals: baseline data from the Homocysteine and Atherosclerosis Reduction Trial (HART). Vasc Med 2008 Nov;13(4):245-53.
11. Lee M, Hong KS, Chang SC, Saver JL. Efficacy of homocysteine-lowering therapy with folic Acid in stroke prevention: a meta-analysis. Stroke. 2010 Jun;41(6):1205-12.
12. Malouf R, Grimley Evans J. Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people. Cochrane Database Syst Rev 2008 Oct 8;(4):CD004514.
13. Molloy AM, Kirke PN, Brody LC, et al. Effects of folate and vitamin B12 deficiencies during pregnancy on fetal, infant, and child development. Food Nutr Bull 2008 Jun;29(2 Suppl):S101-11; discussion S112-5.
14. Mosley BS, Cleves MA, Siega-Riz AM, et al. Neural tube defects and maternal folate intake among pregnancies conceived after folic acid fortification in the United States. Am J Epidemiol 2009 Jan 1;169(1):9-17.
15. Qin X, Huo Y, Langman CB, Hou F, Chen Y, Matossian D, Xu X, Wang X. Folic acid therapy and cardiovascular disease in ESRD or advanced chronic kidney disease: a meta-analysis. Clin J Am Soc Nephrol. 2011 Mar;6(3):482-8.

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