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®.

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,

Scientific Evidence

Tradition/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 health care professional.

• 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.

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 provider before starting a new therapy.

Interactions with Drugs

• Excessive use of alcohol increases the requirement for folic acid.

• Aminosalicylic acid may 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 may 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 suggested.

• Antibiotic therapy may 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. Based on information from LACT-MED, severe clinical and hematological manifestations of folate deficiency occurred in a previously healthy, fully breastfed, 10 month-old infant whose mother took oral contraceptives.

• Carbamazepine (Tegretol®) may 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 may lower serum and red blood cell folate levels in children taking large doses for several months. Maintenance of dietary folate intake is suggested.

• Colestipol (Colestid®) may interfere with absorption of folic acid, and reduced serum folate levels may occur. Maintenance of dietary folate intake is suggested.

• Cycloserine may reduce serum folate levels, and rare cases of megaloblastic anemia have occurred. Maintenance of dietary folate intake is suggested.

• 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 CVD, 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 conclusion may be made. Currently, maintenance of dietary folate intake is suggested.

• Reduced serum and red blood cell folate levels may occur in some women taking conjugated estrogens (Premarin®), but this is unlikely in women with adequate dietary folate intake. Supplements are suggested 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 6.0. 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 suggested.

• Reduced vitamin B12 and, to a lesser extent, folate levels occur in some people with diabetes and may 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 suggested 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 nonsteroidal anti-inflammatory drugs (NSAIDs) [ibuprofen (Advil®, Motrin®, Nuprin®), naproxen (Anaprox®, Aleve®), indomethacin (Indocin®), and sulindac (Clinoril®)]. Clinical significance is unknown.

• Reduced folate levels may 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 may occur rarely with prolonged intravenous pentamidine (Pentacarinat®, Pentam 300®) therapy. Most patients are unlikely to need folic acid supplements.

• Phenobarbital (Luminal®) and primidone (Mysoline®) may 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 may 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 may antagonize the therapeutic effects against Toxoplasmosis and Pneumocystis carinii pneumonia. Patients taking lower doses of pyrimethamine for prolonged periods should maintain the suggested dietary folate intake and be 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 maintain the suggested 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.

• Folic acid may lower blood sugar levels. Caution is advised when using medications that may also lower blood sugar. Patients taking drugs for diabetes by mouth or insulin should be monitored closely by a qualified healthcare professional, including a pharmacist. Medication adjustments may be necessary.

• Folic acid may cause low blood pressure. Caution is advised in patients taking medications that lower blood pressure.

• Folic acid improved the efficacy of cholinesterase inhibitors in Alzheimer disease.

• Increased dietary folate is associated with decreased risk of certain types of cancers although supplementation with folic acid has no clear role in cancer prevention. Folic acid derivatives (leucovorin) are prescribed along with certain chemotherapeutic agents to increase effectiveness and/or decrease side effects.

• Folate deficiency is associated with depression, although the effect of supplementation is not clear and the interaction with antidepressants is not clear.

• Folic acid reduced the rate of congenital abnormalities in children exposed to anti-epileptic drugs in utero.

• Possible interactions may also occur with antimalarials, cardiovascular agents, homocysteine lowering agents, Parkinson agents, phenytoin, tobacco, vitamin A, warfarin, and folic acid antagonists not listed above.

Interactions with Herbs and Dietary Supplements

• Reduced serum and red blood cell folate levels may 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.

• Folic acid may lower blood sugar levels. Caution is advised when using herbs or supplements that may also lower blood sugar. Blood glucose levels may require monitoring, and doses may need adjustment.

• Folic acid may cause low blood pressure. Caution is advised in patients taking herbs or supplements that lower blood pressure.

• Possible interactions may also occur with aged garlic extract, alcohol, Alzheimer agents, antacids, antibacterials, anticancer agents, anticonvulsants, antidepressants, antimalarials, antioxidants, B vitamins, cardiovascular agents, diuretics, green tea, homocysteine lowering agents, iron, leaf concentrate, omega-3 fatty acids, pancreatic extracts, Parkinson agents, probiotics, and other micronutrients (vitamins and minerals).

Author Information

• This information is based on a systematic review of scientific literature edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

References

Natural Standard developed the above evidence-based information based on a thorough 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.

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