Folic acid is one of the B vitamins and is also known as vitamin B9. It is found in various forms in common foods, especially green, leafy vegetables.
The vitamin is readily destroyed by air and heat, and appreciable amounts are lost when foods are improperly stored, overcooked, or reheated.
Folic acid and folate are both terms used to describe this vitamin. Folic acid describes the chemical compound, pteroylmono glutamic acid, which is commonly used as a vitamin supplement. Folate is the general term used to refer to any of the protein-bound or other conjugated forms of folic acid, which are forms generally found in foods.
The body readily absorbs up to 90 percent of folic acid (the form found in supplements). Folate or protein-bound folic acid compounds cannot be absorbed until they are modified by enzymes in the body. As little as 50 percent of folate can be absorbed.
Folic deficiency results in megaloblastic anemia.
Since January 1998, the FDA has required fortification of cereal grain products such as bread and cold cereals with folic acid (140 mcg/100 g product).The intent is to reduce the likelihood of deficiency during the initial months of pregnancy, as this deficiency increases the risk of children being born with neural tube birth defects.
The biological functions of folate all stem from the roles of folate coenzymes in one-carbon metabolism. Folate coenzymes mediate transfer of one carbon units (methyl or methylene groups) in biochemical reactions.
Folate coenzymes are essential for nucleic acid metabolism in two ways: synthesis of DNA and synthesis of methionine.
DNA is synthesized from thymidine and purine precursors; these reactions are dependent on folate coenzymes.
Methionine is required for the synthesis of S-adenosylmethionine (SAMe), a methyl group donor used in methylation reactions including methylation of DNA and RNA. Methylation of DNA is essential for normal development and may impact transcription of genes. A folate coenzyme is required for the biosynthesis of methionine.
Folic acid plays a role in the biosynthesis of heme and hemoglobin.
Folate coenzymes are required for the conversion of histidine to glutamic acid and serine to glycine.
Folate is essential for formation of red and white blood cells from stem cells in bone marrow and for their maturation.
Male 9 to 13 years 14 to 18 years 19+ years Female 13 to 19 years 14 to 18 years 19+ years
300 400 400
300 400 400
600 800 1000
600 800 1000
Pregnancy < = 18 years 19 to 50 years
Lactation < = 18 years 19 to 50 years
* Values for infants are Adequate Intake (AI), others are RDA. ND=Not determinable due to lack of data concerning
adverse effects in this age group and concern with regard to lack of ability to
handles excess amounts.
Folic acid deficiency may occur because of a lack of dietary intake or because of a failure to absorb the vitamin from the intestines. Failure to absorb folic acid can result from interactions with drugs (such as cholestyramine) or diseases such as ulcerative colitis or Crohn's disease.
Poor dietary intake of folic acid results in growth retardation, macrocytic anemia, glossitis, GI disorders.
Neural tube defects (NTDs) affect nearly 4,000 pregnancies in the United States each year. The Center for Disease Control (CDC) and the United States Public Health Service (USPHS) estimate that 400 mcg of folic acid per day could help to prevent nearly 70 percent of birth defects. Since NTDs occur very early in pregnancy (before the sixth week of gestation), folic acid supplements are recommended for any woman of child bearing age. Women at particular risk are those who have had a previous NTD-affected pregnancy and those who have a close relative affected by such a pregnancy (such as a sibling). Research is now focusing on how folic acid protects against NTDs.12
Homocysteine is the product of demethylation of methionine. It is also an intermediate in the synthesis of L-cysteine from L-methionine (building blocks for proteins). When folic acid concentrations are inadequate, these reactions slow and homocysteine concentrations may accumulate in the bloodstream. Studies have linked high homocysteine levels to coronary heart disease, cerebral vascular disease (including strokes), and peripheral vascular disease.3 Studies have shown that folic acid, along with other B vitamins, lower homocysteine levels but these studies have not shown that lowering homocysteine improves disease outcome or prevents disease development.
Fortified foods such as breads and cereals are good dietary sources of folic acid. Good sources of folate are dark green leafy vegetables (such as asparagus and broccoli), Brewer’s (nutritional) yeast, liver, orange juice, beets, dates, and avocados. Poor sources of folate are chicken, milk, most fruits and meats. Supplements generally contain folic acid but folate supplements (L-methyl folate) are now available, especially in prenatal vitamins. Green and black tea reduce the bioavailability of folic acid supplements; they should not be taken at the same time. 20
Anticonvulsant drug therapy in pregnant women has been associated with a higher risk of birth defects in their babies. Folic acid supplementation with 8400 mcg per day in pregnant women greatly reduces the risk of neural tube defects.
People with arthritis who regularly take aspirin may experience an increased loss of folic acid in the urine. In patients with rheumatoid arthritis, supplementation of 400 mcg folic acid per day is sometimes recommended by physicians.
Smoking and chewing tobacco have been shown to deplete folic acid concentrations. Folic acid supplements are recommended for smokers to help increase plasma and red blood cell folate concentrations.
Intake of large quantities of alcoholic beverages can deplete stores of folic acid by interfering with absorption and increasing excretion. Anyone who consumes excessive alcohol may benefit from supplementation with folic acid. Physicians may want to include supplements of folic acid for their alcoholic patients.
A number of conditions can lead to folate deficiency: malabsorption syndromes, including Crohn's disease, lymphoma or amyloidosis of the small intestine, diabetic enteropathy, tropical and non-tropical sprue can result in folate deficiency due to inadequate absorption. Other conditions such as chronic hemolytic anemias, chronic hemodialysis or peritoneal dialysis, and chronic exfoliative skin disorders increase the demand for folate.
Since homocysteine, one of the factors which may affect cardiovascular disease and cognitive function, increases with age, folic acid supplementation or multivitamins are recommended for the elderly.
Increased blood homocysteine concentrations are associated with increased risk of cardiovascular disease incidence and mortality in the general population and with even greater risk in persons with diabetes mellitus. Hyperhomocysteinemia in macrovascular and microvascular diabetes complications could be of importance in their prevention through dietary (folic acid and vitamin B12 supplements) and pharmacological modifications of blood homocysteine concentrations.
Anticonvulsant such as carbamazepine (Tegretol), valproic acid (Depakene), and phenytoin (Dilantin) have been reported to reduce folate levels in humans. Partial depletion of folate may actually contribute to the anticonvulsant action of these drugs.
Antibiotics such as isoniazid, tetracycline, cycloserine and erythromycin therapy longer than 2 weeks may interfere with absorption and/or activity of folic acid.
Oral contraceptives use can cause folic acid depletion.
Acid-suppressing drugs such as PPIs and H2 blockers may reduce dietary folate absorption. It is unlikely that these drugs will cause a deficiency unless dietary folate intake is very low. Supplemental folic acid absorption is not affected.
Folate antagonists such as Methotrexate (anticancer and antiarthritis agent) and Pyrimethiamine (antimalaria agent) interfere with folic acid metabolism. People taking these drugs should follow the instructions of their pharmacist or physician regarding supplements.
Long-term sulfonamide therapy (Sulfamethoxazole and Sulasalzine), of more than two weeks can interfere with the activity of folic acid.
Metformin, used to lower blood sugar concentrations in individuals with Type 2 diabetes, can lead to low serum folic acid and vitamin B12 concentrations in some patients.
Information on the relationship between substances and disease is provided for general information, in order to convey a balanced review of the scientific literature. In many cases the relationship between a substance and a disease is tentative and additional research is needed to confirm such a relationship.
Supplementation with a multivitamin containing 800 microg of folic acid shortens the time to reach the preventive red blood cell folate concentration in healthy women.
A randomized, placebo-controlled study investigated the amount of time required to reach the neural tube defect (NTD) preventive concentration of folate in red blood cells in healthy women. Forty-six women participated in the 16 week trial. Participants consumed a daily folic acid supplement (800 mcg) or a placebo. Plasma and red blood cell folate were determined from blood samples collected every four weeks. Mean (+/-SED) RBC folate increased during the 16 week trial to 1430 +/- 53 nmol/L, but did not plateau. The target concentration (906 nmol/L) was reached after 4.2 +/- 3.5 weeks. These results suggest that the necessary folic acid supplement for women of child bearing age might be higher than the standard 400 mcg daily and that the time needed to reach safe levels might be longer than previously thought. 17
Vitamin Intervention for Stroke Prevention Trial: An Efficacy Analysis
In an efficacy analysis of the Vitamin Intervention for Stroke Prevention trial (VISP), the researchers found a subgroup of approximately 2,100 participants who were more likely to benefit from vitamin therapy. A 21% reduction in risk for events (ischemic stroke, coronary disease, or death) was observed in the high-dose vitamin group (25 mg vitamin B6, 0.4 mg vitamin B12, 2.5 mg folic acid), compared to the low-dose vitamin group (20 mcg folic acid, 200 mcg vitamin B6, 6 mcg vitamin B12).25
Homocysteine-lowering treatment with folic acid, cobalamin, and pyridoxine does not reduce blood markers of inflammation, endothelial dysfunction, or hypercoagulability in patients with previous TIA.
In a randomized substudy of the Vitamins to Prevent Stroke (VITATOPS) trial, effect of B vitamin therapy vs. placebo on lowering total homocysteine (tHcy) was examined in 285 patients with recent transient ischemic attack (TIA) or stroke. Folic acid based multivitamin therapy (2mg folic acid, 0.5mg vitamin B12, 25mg vitamin B6) did reduce tHcy, however, there was no significant difference in blood concentrations of markers of vascular inflammation (hs-CRP), endothelial dysfunction and hypercoagulability in patients receiving vitamin therapy.24,26
Randomized trial of folic acid supplementation and serum homocysteine levels.
A study determined the effect of of folic acid supplementation on serum homocysteine concentration with 151 people with ischemic heart disease. Participants consumed0.2, 0.4, 0.6, 0.8, or 1.0 mg folic acid or a placebo daily during a 3 month trial. Serum homocysteine and folate were determined at baseline, after three months of supplementation, and three months after supplements were discontinued. Serum homocysteine level was decreased with folic acid supplements. The greatest homocysteine reduction (placebo adjusted) was found for 0.8 mg folic acid daily: 2.7 micromol/L (23%). These results suggest that folic acid supplements may reduce serum homocysteine concentrations for ischemic heart disease patients.11
Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomized, placebo-controlled trial.
A randomized, placebo-controlled trial investigated the efficacy of high dose folic acid plus vitamin B6 for lowering homocysteine for people with subclinical atherosclerosis. One-hundred-sixty-seven people with premature atherothrombotic disease and 158 healthy siblings consumed either 5 mg folic acid plus 250 mg vitamin B6 or a placebo daily for 2 years. B vitamin supplementation was found to decrease fasting homocysteine concentration (from 14.7 to 7.4 umol/L vs from 14.7 to 12.0 umol/L) and postmethionine homocysteine concentration (from 64.9 to 34.9 umol/L vs from 64.8 to 50.3 umol/L). Vitamin supplements were also associated with a decreased rate of abnormal exercise electrocardiography tests (odds ratio 0.40 [0.17-0.93]; p=0.035). The data suggest that vitamin supplementation aimed at lowering concentrations of total blood homocysteine may favorably influence the course of atherosclerotic disease.12
Homocysteine lowering and cardiovascular events after acute myocardial infarction.
The Norwegian Vitamin Trial (NORVIT) evaluated the efficacy of homocysteine-lowering treatment with B vitamins for secondary prevention in patients who had had an acute myocardial infarction (MI). Participants included 3,749 men and women randomly assigned to receive folic acid (0.8 mg), vitamin B12 (0.4 mg), and vitamin B6 (40 mg); folic acid and vitamin B12; vitamin B6 alone; or a placebo daily. Patients were seen at a 2 month follow-up visit and at a final visit after 2 to 3.5 years. Despite a substantial reduction in plasma total homocysteine, interevention with B vitamins did not lower the risk of recurrent cardiovascular disease or death after an acute MI. In the group receiving B vitamins, there was a trend toward an increased rate of events. Researchers concluded that B vitamin intervention not be recommended after acute MI.9
Homocysteine lowering with folic acid and B vitamins in vascular disease.
The Heart Outcomes Prevention Evaluation (HOPE) 2 researchers evaluated whether therapy with homocysteine-lowering B vitamins reduced the risk of major vascular events in a high risk population. The investigators randomly assigned 5,522 patients aged 55 years or older with vascular disease or diabetes to a daily B vitamin combination supplement (2.5 mg folic acid, 50 mg vitamin B6, 1 mg vitamin B12) or a placebo for an average of 5 years. Daily administration of the B vitamin combination significantly lowered homocysteine but had no beneficial effects on major vascular events in a high risk population with vascular disease. 10
Dietary intake of folate, but not vitamin B2 or B12, is associated with increased bone mineral density 5 years after the menopause: results from a 10-year follow-up study in early postmenopausal women
Relationships between folate intake and bone mineral density were investigated as a part of the Danish Osteoporosis Prevention Study. Postmenopausal women participated in the ten year study (n=1,869). Folate, vitamin B2, and vitamin B12 intake was assessed from dietary intake questionnaires. After 5 years there were positive correlations between daily intake of folate from diet and from diet plus supplements and BMD at the femoral neck (P < 0.01) but not between intake and changes in BMD. During the trial, 360 participants sustained a fracture; there was no association between folic acid/folate intake and fracture rates. These data suggest that higher intake of folate from diet and supplements may improve BMD after sustained use but may not affect risk of fracture.21
A prospective study of folate intake and the risk of breast cancer.
Data from the Nurses’ Health Study were used to evaluate folic acid, alcohol intake, and breast cancer risk. A total of 88,818 women completed the dietary questionnaire section at the beginning of the study. During the study, 3,483 cases of breast cancer were identified. Overall, total intake of folic acid was not associated with a reduced risk for breast cancer. However, intake of more than 300 mcg folic acid daily reduced breast cancer risk for women who consumed more than 15 g alcohol daily (alcohol intake > or = 15 g/d vs < 15 g/d: < 300 mcg folic acid/d, multivariate RR, 1.32; 95% CI, 1.15-1.50; > 300 mcg folic acid/d, 1.05, 95% CI, 0.92-1.20). No effect on risk was found for women with lower alcohol consumption.14
Multivitamin use, folate and colon cancer in women in the Nurses’ Health Study.
The Nurses’ Health Study included 88,756 women who were free of cancer in 1980. Female nurses completed the dietary assessments and provided updated assessments, including multivitamin supplement use, from 1980 to 1994. During the trial, 442 women with new cases of colon cancer were identified. Higher consumption of folate in 1980 was related to a lower risk for colon cancer (RR, 0.69 [95% CI, 0.52 to 0.93] for intake > 400 mcg/d compared with intake < or = 200 mcg/d) after controlling for age; family history of colorectal cancer; aspirin use; smoking; body mass; physical activity; and intakes of red meat, alcohol, methionine, and fiber. While use of multivitamins for only four years was not associated with reduced risk, use of multivitamins for longer time periods was associated with linearly reduced risk. After 15 years of multivitamin use, relative risk for colon cancer was 0.25 (CI, 0.13 to 0.51). 15
Folate intake, post-folic acid grain fortification, and pancreatic cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.
Data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial were evaluated to determine the relationship between folic acid consumption and pancreatic cancer. At the beginning of the trial, 51,988 men and 57,187 women aged 55 to 74 years completed food frequency questionnaires. During the follow up period (average 6.5 years), 162 men and 104 women were diagnosed with pancreatic cancer. Pancreatic cancer risk was significantly decreased for women in the highest compared with the lowest quartile of food folate (women > or = 253.3 compared with < or = 179.1 mcg/d; hazard ratio = 0.47; 95% CI: 0.23, 0.94; P for trend: 0.09). Food folate but not folic acid supplements were associated with reduced risk for pancreatic cancer. This study suggests that foods high in folate may reduce risk for pancreatic cancer.18
Plasma homocysteine and folate are related to arterial blood pressure in type 2 diabetes mellitus.
A prospective study assessed fasting and postmethionine load plasma homocysteine concentrations, folate, vitamin B12, and urinary albumin excretion concentrations in people with non-insulin dependent diabetes mellitus (NIDDM, n=33) and healthy volunteers(n=16). Inverse associations were found for folate and mean arterial pressure (r = -0.352, P = 0.046), folate and systolic blood pressure (r = -0.437, P = 0.013), tHcy and vitamin B12 (r = -0.348, P = 0.04), ln tHcy and ln folate (r = -0.404, P = 0.01), and between tHcy, either fasting or postload, and urinary albumin excretion for people with NIDDM. Higher folate values were associated with lower systolic blood pressure (P = 0.004) and mean arterial pressure (P = 0.02) for people with NIDDM. Folate and vitamin B12 may help to lower plasma homocysteine. Further studies should address whether lowering plasma homocysteine improves blood pressure and other complications for people with NIDDM.16
Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial.
A multicenter, randomized, double blind, placebo controlled trial investigated the effects of high-dose B vitamin supplementation on progression of diabetic nephropathy. Participants included 238 people with type 1 or type 2 diabetes and a clinical diagnosis of diabetic nephropathy. Participants were randomly assigned to receive folic acid (2.5 mg), vitamin B6 (25 mg), and vitamin B12 (1 mg) daily or a placebo for the 36 month trial. Radionuclide glomerular filtration rate (GFR) decreased by 16.5 (1.7) mL/min/1.73 m2 in the B-vitamin group versus 10.7 (1.7) mL/min/1.73 m2 in the placebo group (mean difference, -5.8; 95% CI, -10.6 to -1.1; P = 0.02). Plasma total homocysteine decreased by 2.2 (0.4) umol/L at 36 months in the B-vitamin group compared with an increase of 2.6 (0.4) umol/L in the placebo group (mean difference, -4.8; 95% CI, -6.1 to -3.7; P < 0.001, in favor of B vitamins). A composite of myocardial infarction, stroke, revascularization, and all-cause mortality occurred more often in the B-vitamin group than placebo (hazard ratio, 2.0; 95% CI, 1.0-4.0; P = 0.04). The results of this study suggest that, while this B vitamin supplement reduced symptoms of diabetic nephropathy, participants were at increased risk for vascular events. Thus, high dose B vitamin supplements such as this are not recommended for people with diabetes.13
Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial.
As a part of the Functional Assessment of Chronic Illness Therapy (FACIT) trial, the relationship between folic acid and cognitive function in adults was investigated. The trial included 818 men and women aged 50 to 70 years. Participants were randomly assigned to receive 800 mcg folic acid or a placebo daily for three years. This was a randomized, double-blind, placebo-controlled trial. As expected, serum folate concentrations increased in the folic acid supplemented group compared to the placebo group (576% increase, 95% CI 539 to 614). In the folic acid supplemented group, plasma total homocysteine concentrations decreased by 26% (24 to 28; compared to placebo). After three years, participants in the folic acid group had significantly better scores in change in memory (difference in Z scores 0.132, 95% CI 0.032 to 0.233), information processing speed (0.087, 0.016 to 0.158) and sensorimotor speed (0.064, -0.001 to 0.129) than the placebo group. The results of this study suggest that folic acid supplements (800 mcg daily) may improve or prevent declines in cognitive function. 22
Depression and folate status in the US Population.
A prospective study investigated the relationship between folate status and depression. Serum concentrations of folate and total homocysteine (tHcy) were measured in the participants. Participants included people with no depression (n = 2,526), major depression (n = 301), or dysthymia (n = 121). Depressed individuals had low folate status in this U.S. population. Supplementation with folic acid may improve folate status for those suffering from depression.23
Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: the Women's Antioxidant and Folic Acid Cardiovascular Study.
A randomized, placebo-controlled, double-blind study investigated the effects of a combined supplement with folic acid, vitamin B6, and vitamin B12 on risk for age-related macular degeneration (AMD) in women with cardiovascular disease. Female health care professionals with existing cardiovascular disease were recruited in the study; 5,205 women completed the study. Participants were randomly assigned to receive either a combined supplement containing folic acid (2.5 mg), vitamin B6 (50 mg), and vitamin B12 (1 mg) or a placebo daily. The trial lasted for an average of 7.3 years including treatment and follow-up. At the end of the trial, 55 women in the supplemented group and 82 women in the placebo group had been diagnosed with AMD (relative risk, 0.66; 95% confidence interval, 0.47-0.93; P = 0.02). These results suggest that high-dose B vitamins may reduce risk of AMD for women with cardiovascular disease. 19
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