The terms folic acid and folate are often used interchangeably for this water-soluble B-complex vitamin. Folic acid, the more stable form, occurs rarely in foods or the human body but is the form most often used in vitamin supplements and fortified foods. Naturally occurring folates exist in many chemical forms. Folates are found in foods as well as in metabolically active forms in the human body (1). In the following discussion forms found in food or the body will be referred to as "folates", while the form found in supplements or fortified foods will be referred to as "folic acid".
The only function of folate coenzymes in the body appears to be in mediating the transfer of one-carbon units (2). Folate coenzymes act as acceptors and donors of one-carbon units in a variety of reactions critical to the metabolism of nucleic acids and amino acids (3).
Nucleic acid metabolism
Folate coenzymes play a vital role in DNA metabolism through two different pathways. 1) The synthesis of DNA from its precursors (thymidine and purines) is dependent on folate coenzymes. 2) A folate coenzyme is required for the synthesis of methionine, and methionine is required for the synthesis of S-adenosylmethionine (SAM). SAM is a methyl group (one-carbon unit) donor used in many biological methylation reactions, including the methylation of a number of sites within DNA and RNA. Methylation of DNA may be important in cancer prevention (see Disease Prevention).
Amino acid metabolism
Folate coenzymes are required for the metabolism of several important amino acids. The synthesis of methionine from homocysteine requires a folate coenzyme as well as a vitamin B12-dependent enzyme. Thus, folate deficiency can result in decreased synthesis of methionine and a buildup of homocysteine. Increased levels of homocysteine may be a risk factor for heart disease as well as several other chronic diseases (see Disease Prevention).
Vitamin B12 and vitamin B6
The metabolism of homocysteine, an intermediate in the metabolism of sulfur-containing amino acids, provides an example of the interrelationships among nutrients necessary for optimium physiological function and health. Healthy individuals utilize two different pathways to metabolize homocysteine (see diagram). One pathway (methionine synthase) synthesizes methionine from homocysteine and is dependent on a folate coenzyme and a vitamin B12-dependent enzyme. The other pathway converts homocysteine to another amino acid, cysteine, and requires two vitamin B6-dependent enzymes. Thus, the amount of homocysteine in the blood is regulated by three vitamins: folate, vitamin B12, and vitamin B6 (4).
Folate deficiency is most often caused by a dietary insufficiency; however, folate deficiency can occur in a number of other situations. For example, alcoholism is associated with low dietary intake and diminished absorption of folate, which can lead to folate deficiency. Additionally, certain conditions such as pregnancy or cancer result in increased rates of cell division and metabolism, causing an increase in the body's demand for folate (5). Several medications may also contribute to deficiency (see Drug interactions).
Individuals in the early stages of folate deficiency may not show obvious symptoms, but blood levels of homocysteine may increase (see Prevention). Rapidly dividing cells are most vulnerable to the effects of folate deficiency; thus, when the folate supply to the rapidly dividing cells of the bone marrow is inadequate, blood cell division becomes abnormal resulting in fewer but larger red blood cells. This type of anemia is called megaloblastic or macrocytic anemia, referring to the enlarged, immature red blood cells. Neutrophils, a type of white blood cell, become hypersegmented, a change which can be found by examining a blood sample microscopically. Because normal red blood cells have a lifetime in the circulation of approximately four months, it can take months for folate deficient individuals to develop the characteristic megaloblastic anemia. Progression of such an anemia leads to a decreased oxygen carrying capacity of the blood and may ultimately result in symptoms of fatigue, weakness, and shortness of breath (1). It is important to point out that megaloblastic anemia resulting from folate deficiency is identical to the megaloblastic anemia resulting from vitamin B12 deficiency, and further clinical testing is required to diagnose the true cause of megaloblastic anemia.
Determination of the RDA
Traditionally, the dietary folate requirement was defined as the amount needed to prevent a deficiency severe enough to cause symptoms like anemia. The most recent RDA (1998) was based primarily on the adequacy of red blood cell folate concentrations at different levels of folate intake, as judged by the absense of abnormal hematological indicators. Red cell folate has been shown to correlate with liver folate stores. Maintenance of normal blood homocysteine levels, an indicator of one-carbon metabolism, was considered only as an ancillary indicator of adequate folate intake. Because pregnancy is associated with a significant increase in cell division and other metabolic processes that require folate coenzymes, the RDA for pregnant women is considerably higher than for women who are not pregnant (3). However, the prevention of neural tube defects (NTD) was not considered when setting the RDA for pregnant women. Rather, reducing the risk of NTD was considered in a separate recommendation for women capable of becoming pregnant (see Prevention), because the crucial events in the development of the neural tube occur before many women are aware that they are pregnant (6).
Dietary Folate Equivalents (DFE)
When the Food and Nutrition Board of the Institute of Medicine set the new dietary recommendation for folate, they introduced a new unit, the Dietary Folate Equivalent (DFE). Use of the DFE reflects the higher bioavailability of synthetic folic acid found in supplements and fortified foods compared to that of naturally occurring food folates (6).
- 1 microgram (mcg) of food folate provides 1 mcg of DFE
- 1 mcg of folic acid taken with meals or as fortified food provides 1.7 mcg of DFE
- 1 mcg of folic acid (supplement) taken on an empty stomach provides 2 mcg of DFE
For example, a serving of food containing 60 mcg of folate would provide 60 mcg of DFE, while a serving of pasta fortified with 60 mcg of folic acid would provide 1.7 x 60 = 102 mcg DFE due to the higher bioavailability of folic acid. A folic acid supplement of 400 mcg taken on an empty stomach would provide 800 mcg of DFE. It should be noted that DFEs were determined in studies with adults and whether folic acid in infant formula is more bioavailable than folates in mother's milk has not been studied. Use of DFEs to determine a folic acid requirement for the infant would not be desirable.Recommended Dietary Allowance for Folate in Dietary Folate Equivalents (DFE) Life Stage Age Males (mcg/day) Females (mcg/day) Infants 0-6 months 65 (AI) 65 (AI) Infants 7-12 months 80 (AI) 80 (AI) Children 1-3 years 150 150 Children 4-8 years 200 200 Children 9-13 years 300 300 Adolescents 14-18 years 400 400 Adults 19-years and older 400 400 Pregnancy all ages - 600 Breast-feeding all ages - 500
A common polymorphism or variation in the gene for the enzyme methylene tetrahydrofolate reductase (MTHFR), known as the C677T MTHFR polymorphism, results in a less stable enzyme (7). Depending on the population, 50% of individuals may have inherited one copy (C/T), and 5% to 25% of individuals may have inherited two copies (T/T) of the abnormal MTHFR gene. MTHFR plays an important role in maintaining the specific folate coenzyme required to form methionine from homocysteine (see diagram). When folate intake is low, individuals who are homozygous (T/T) for the abnormal gene have lower levels of the MTHFR enzyme and thus higher levels of homocysteine in their blood (8). Improved folate nutritional status appears to stabilize the MTHFR enzyme, resulting in improved enzyme levels and lower homocysteine levels. An important unanswered question about folate is whether the present RDA is enough to normalize MTHFR enzyme levels in individuals who are homozygous for the C677T polymorphism, or whether those individuals have a higher folate requirement than the RDA (9).
Fetal growth and development are characterized by widespread cell division. Adequate folate is critical for DNA and RNA synthesis. Neural tube defects (NTD) result in either anencephaly or spina bifida, which are devastating and sometimes fatal birth defects. The defects occur between the 21st and 27th days after conception, a time when many women do not realize they are pregnant (10). The risk of NTD in the United States prior to fortification of foods with folic acid was estimated to be one per 1000 pregnancies (1). Results of randomized trials have demonstrated 60% to 100% reductions in NTD cases when women consumed folic acid supplements in addition to a varied diet during the periconceptional period (about one month before and one month after conception). The results of these and other studies prompted the U.S. Public Health Service to recommend that all women capable of becoming pregnant consume 400 mcg of folic acid daily to prevent NTD. The recommendation was made to all women of childbearing age because adequate folic acid must be available very early in pregnancy, and because many pregnancies in the U.S. are unplanned. Despite the effectiveness of folic acid supplementation, it appears that less than half of women who become pregnant follow the recommendation (11). To decrease the incidence of NTD, the FDA implemented legislation in 1998 requiring the fortification of all enriched grain products with folic acid (see Sources). The required level of folic acid fortification in the U.S. was estimated to provide 100 mcg of additional folic acid in the average person's diet, though it probably provides even more due to overuse of folic acid by food manufacturers (9). The Centers for Disease Control and Prevention reported that the frequency of NTD in the U.S. has decreased 26% since the mandate (12). However, studies in Canada, where fortification is nearly identical to that in the U.S. (1.5 and 1.4 mg of folic acid/kg of grain, respectively), have reported greater reductions in the incidence of NTD. In fact, it was recently proposed that the fortification legislation has prevented approximately 50% of NTD in Canada and the U.S, but improvements in the U.S. have been largely underestimated (13).
Other pregnancy complications
Adequate folate status may also prevent the occurrence of other types of birth defects, including certain heart defects and limb malformations. However, the support for these findings is not as consistent or clear as support for NTD prevention (10). Additionally, low levels of dietary folate during pregnancy have been associated with increased risks of premature delivery and infant low infant birth weights. More recently, elevated blood homocysteine levels, considered an indicator of functional folate deficiency, have been associated with increased incidence of miscarriage as well as pregnancy complications like preeclampsia and placental abruption (14). Thus, it is reasonable to maintain folic acid supplementation throughout pregnancy, even after closure of the neural tube in order to decrease the risk of other problems during pregnancy.
The results of more than 80 studies indicate that even moderately elevated levels of homocysteine in the blood increase the risk of cardiovascular diseases (4). An analysis of the observational studies on blood homocysteine and vascular disease indicated that a prolonged decrease in plasma homocysteine level of only 1 micromole/liter resulted in about a 10% risk reduction (15). The mechanism by which homocysteine increases the risk of vascular disease remains the subject of a great deal of research, but it may involve adverse effects of homocysteine on blood clotting, arterial vasodilation, and thickening of arterial walls (16). Although increased homocysteine levels in the blood have been consistently associated with increased risk of cardiovascular diseases, it is not yet clear whether lowering homocysteine levels will reduce cardiovascular disease risk (see below, Folate and homocysteine). Consequently, the American Heart Association recommends screening for elevated total homocysteine levels only in "high risk" individuals, for example those with personal or family history of premature cardiovascular disease, malnutrition or malabsorption syndromes, hypothyroidism, kidney failure, lupus, or individuals taking certain medications (nicotinic acid, theophylline, bile acid-binding resins, methotrexate, and L-dopa). Most research indicates that a plasma homocysteine level of < 10 micromoles/liter is associated with a lower risk of cardiovascular disease and a reasonable treatment goal for individuals at high risk (17).
Folate-rich diets have been associated with decreased risk of cardiovascular disease. A study that followed 1,980 Finnish men for ten years found that those who consumed the most dietary folate had a 55% lower risk of an acute coronary event when compared with those who consumed the least dietary folate (18). Of the three vitamins that regulate homocysteine levels, folic acid has been shown to have the greatest effect in lowering basal levels of homocysteine in the blood when there is no coexisting deficiency of vitamin B12 or vitamin B6 (see Nutrient interactions). Increasing folate intake through folate-rich foods or supplements has been found to lower homocysteine levels. Moreover, blood homocysteine levels have declined since the FDA mandated folic acid fortification of the grain supply (9). A recent meta-analysis of 25 randomized controlled trials found that supplementation with 0.8 mg folic acid daily maximally reduced plasma homocysteine concentrations; daily doses of 0.2 mg and 0.4 mg of folic acid were associated with 60% and 90% reductions, respectively, in plasma homocysteine (19). A supplement regimen of 400 mcg of folic acid, 2 mg of vitamin B6, and 6 mcg of vitamin B12 has been advocated by the American Heart Association if an initial trial of a folate-rich diet (see Sources) is not successful in adequately lowering homocysteine levels (17). Although increased folic acid intake has been found to decrease homocysteine levels, it is presently not clear whether increasing folic acid intake results in decreased risk of cardiovascular diseases. Several randomized placebo-controlled trials have been conducted or are ongoing to determine whether homocysteine lowering through folic acid and other B vitamin supplementation reduces the incidence of cardiovascular diseases. A preliminary meta-analysis of data from four of the ongoing trials, including about 14,000 subjects, showed that B vitamin supplementation had no significant effect on risk of coronary heart disease or stroke (20). Similarly, another meta-analysis of 12 randomized controlled trials, including data from 16,958 individuals with preexisting cardiovascular or renal disease, found that folic acid supplementation had no effect on coronary heart disease, stroke, or all-cause mortality despite 13%-52% reductions in plasma homocysteine concentrations (21). Consequently, the American Heart Association removed its recommendation for using folic acid to prevent cardiovascular diseases in high-risk women (22). Completion of the ongoing clinical trials should provide a more definitive answer whether folic acid is beneficial for the prevention or treatment of heart disease or stroke.
Cancer is thought to arise from DNA damage in excess of ongoing DNA repair and/or the inappropriate expression of critical genes. Because of the important roles played by folate in DNA and RNA synthesis and methylation, it is possible for folate intake to affect both DNA repair and gene expression. The consumption of at least five servings of fruits and vegetables daily has been consistently associated with a decreased incidence of cancer. Fruits and vegetables are excellent sources of folate, which may play a role in their anti-carcinogenic effect. Observational studies have found diminished folate status to be associated with cancers of the cervix, colon and rectum, lung, esophagus, brain, pancreas, and breast. Intervention trials of folic acid supplementation in humans have been conducted mainly with respect to cervical and colorectal (colon and rectal) cancer. While the results in cervical cancer have been inconsistent (2), randomized intervention trials regarding colorectal cancer have been more promising (23, 24).
A recent meta-analysis of seven cohort and nine case-control studies found that folate from foods was inversely associated with colorectal cancer risk; however, total folate from foods and folic acid supplements was not associated with colorectal cancer risk (25). It is important to note that the case-control studies examined in this meta-analysis were highly heterogeneous, and that the authors stated that dietary fiber or other vitamins could have confounded their results. Overall, the role of folate in the possible prevention of colorectal cancer provides an example of the complexity of the interactions between genetics and nutrition. In general, observational studies have found that relatively low folate intake and high alcohol intake are associated with increased incidence of colorectal cancer (1, 26, 27). Alcohol interferes with the absorption and metabolism of folate (5). In a prospective study of more than 45,000 male health professionals, current intake of more than two alcoholic drinks per day doubled the risk of colon cancer. The combination of high alcohol and low folate intake yielded an even greater risk of colon cancer; however, increased alcohol intake in individuals who consumed 650 mcg or more of folate per day was not associated with an increased risk of colon cancer (28). In some studies, individuals who are homozygous for the C677T MTHFR polymorphism (TT) have been found to be at decreased risk for colon cancer when folate intake is adequate. However, when folate intake is low and/or alcohol intake is high, individuals with the (T/T) genotype have been found to be at increased risk of colorectal cancer (29, 30).
While dietary folate may be protective against colorectal cancer, high doses of supplemental folic acid may actually accelerate tumor growth in cancer patients. A recent chemopreventive trial in patients with a history of colorectal adenoma associated supplementation of 1 mg/day of folic acid (more than twice the RDA) with a statistical trend for advanced colorectal lesions as well as with a significantly increased risk (>2-fold) for the presence of three or more colorectal adenomas (31). In this study, folic acid supplementation was also associated with an increased risk for cancers at other sites, primarily the prostate. Human observational studies as well as animal studies on high-dose folate and cancer have reported mixed results. Thus, more research is needed to determine the role of high-dose folate in cancer progression.
Studies investigating whether folate intake affects breast cancer risk have reported mixed results (32). The results of two prospective studies suggest that increased folate intake may reduce the risk of breast cancer in women who regularly consume alcohol (33-35); moderate alcohol intake has been associated with increased risk of breast cancer in women in several studies. Interestingly, a very large prospective study in more than 88,000 nurses reported that folic acid intake was not associated with breast cancer in women who consumed less than one alcoholic drink per day. However, in women consuming at least one alcoholic drink per day, folic acid intake of at least 600 mcg daily resulted in about half the risk of breast cancer compared with women who consumed less that 300 mcg of folic acid daily (35).
The role of folate in nucleic acid synthesis and methylation reactions is essential for normal brain function. Over the past decade several investigators have described associations between decreased folate levels and cognitive impairment in the elderly (36). A large cross-sectional study in elderly Canadians found that those individuals with low serum folate levels were more likely to have dementia, be institutionalized, and be depressed. However, these findings could reflect the poorer nutritional status of institutionalized elderly and individuals with dementia. In the same study, low serum folate levels were associated with an increased likelihood of short-term memory problems in elderly individuals who hand no signs of dementia (37). A study in 30 elderly nuns, who lived in the same convent, ate the same diet, and had similar lifestyles, reported a strong association between decreased blood folate levels and the severity of brain atrophy related to Alzheimer's disease (38). More recent studies have reported conflicting results as to whether folate status impacts Alzheimer's disease risk. One study in elderly people of predominantly Hispanic and African-American ethnicity with a high prevalence of vascular risk factors reported that a higher folate intake, from diet and folic acid supplements, was associated with a decreased risk for Alzheimer's disease (39). In contrast, a prospective study in elderly individuals reported that dietary folate is not associated with Alzheimer's disease (40), whereas another prospective study reported that a high folate intake, from foods and from folic acid supplements, was associated with increased rates of cognitive decline in the elderly (41). Moderately increased homocysteine levels, as well as decreased folate and vitamin B12 levels, have been associated with Alzheimer's disease and vascular dementia. One study in 370 elderly men and women, who were followed over three years, associated low serum levels of vitamin B12 (< 150 pmol/L) or folate (< 10 nmol/L) with a doubling of the risk of developing Alzheimer's disease (42). In a sample of 1,092 men and women without dementia followed for an average of ten years, those with higher plasma homocysteine levels at baseline had a significantly higher risk of developing Alzheimer's disease and other types of dementia (43). Those with plasma homocysteine levels greater than 14 micromoles/liter had nearly twice the risk of developing Alzheimer's disease.
Green leafy vegetables (foliage) are rich sources of folate and provide the basis for its name. Citrus fruit juices, legumes, and fortified cereals are also excellent sources of folate (1). A number of folate-rich foods are listed in the table below along with their folate content in micrograms (mcg). For more information on the nutrient content of specific foods, search the USDA food composition database.Food Serving Folate (mcg) Fortified breakfast cereal 1 cup 200-400 Orange juice (from concentrate) 6 ounces 83 Spinach (cooked) 1/2 cup 132 Asparagus (cooked) 1/2 cup (~ 6 spears) 134 Lentils (cooked) 1/2 cup 179 Garbanzo beans (cooked) 1/2 cup 141 Lima beans (cooked) 1/2 cup 78 Bread 1 slice 20 (Folic acid)* Pasta (cooked) 1 cup 60 (Folic acid)* Rice (cooked) 1 cup 60 (Folic acid)*
*To help prevent neural tube defects, the FDA required the addition of 1.4 milligrams (mg) of folic acid per kilogram (kg) of grain to be added to refined grain products, which are already enriched with niacin, thiamin, riboflavin, and iron, as of January 1, 1998. The addition of nutrients to foods in order to prevent a nutritional deficiency or restore nutrients lost in processing is known as fortification. It has been estimated that this level of fortification increases dietary intake by an average of 100 mcg folic acid/day (10). For more information on folic acid fortification, review the FDA fact sheet.
The principal form of supplementary folate is folic acid. It is available in single ingredient and combination products such as B-complex vitamins and multivitamins. Doses equal to or greater than 1 mg require a prescription (44).
No adverse effects have been associated with the consumption of excess folate from foods. Concerns regarding safety are limited to synthetic folic acid intake. Deficiency of vitamin B12, though often undiagnosed, may affect a significant number of people, especially older adults (see Vitamin B12). One symptom of vitamin B12 deficiency is megaloblastic anemia, which is indistinguishable from that associated with folate deficiency (see Deficiency). Large doses of folic acid given to an individual with an undiagnosed vitamin B12 deficiency could correct megaloblastic anemia without correcting the underlying vitamin B12 deficiency, leaving the individual at risk of developing irreversible neurologic damage. Such cases of neurologic progression in vitamin B12 deficiency have been mostly seen at folic acid doses of 5,000 mcg (5 mg) and above. In order to be very sure of preventing irreversible neurological damage in vitamin B12 deficient individuals, the Food and Nutrition Board of the Institute of Medicine advises that all adults limit their intake of folic acid (supplements and fortification) to 1,000 mcg (1 mg daily). The board also noted that vitamin B12 deficiency is very rare in women in their childbearing years, making the consumption of folic acid at or above 1000 mcg/day unlikely to cause problems (1); however, there are limited data on the effects of large doses.
Tolerable Upper Intake Level (UL) for Folic AcidAge Group UL (mcg/day) Infants 0-12 months Not possible to establish* Children 1-3 years 300 Children 4-8 years 400 Children 9-13 years 600 Adolescents 14-18 years 800 Adults 19 years and older 1,000
*Source of intake should be from food and formula only.
When nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin or ibuprofen, are taken in very large therapeutic dosages (i.e., to treat severe arthritis), they may interfere with folate metabolism. In contrast, routine low dose use of NSAIDs has not been found to adversely affect folate status. The anticonvulsant, phenytoin, has been shown to inhibit the intestinal absorption of folate, and several studies have associated decreased folate status with long-term use of the anticonvulsants, phenytoin, phenobarbital, and primidone (45). However, few studies controlled for differences in dietary folate intake between anticonvulsant users and nonusers. Also, taking folic acid at the same time as the cholesterol-lowering agents, cholestyramine and colestipol, may decrease the absorption of folic acid (44). Methotrexate is a folic acid antagonist used to treat a number of diseases, including rheumatoid arthritis and psoriasis. Some of the side effects of methotrexate are similar to those of severe folate deficiency, and increased dietary folate or supplemental folic acid may decrease side effects without reducing the efficacy of methotrexate. A number of other medications have been shown to have antifolate activity, including trimethoprim (an antibiotic), pyrimethamine (an antimalarial), triamterene (a blood pressure medication), and sulfasalazine (a treatment for ulcerative colitis). Early studies of oral contraceptives (birth control pills) containing high doses of estrogen indicated adverse effects on folate status; however, this finding has not been supported by more recent studies on low dose oral contraceptives that controlled for dietary folate (1).
The available scientific evidence shows that adequate folate intake prevents neural tube defects and other poor outcomes of pregnancy, is helpful in lowering the risk of some forms of cancer, especially in genetically susceptible individuals, and may lower the risk of cardiovascular diseases. The Linus Pauling Institute recommends that adults take a 400 mcg supplement of folic acid daily, in addition to folate and folic acid consumed in the diet. A daily multivitamin-mineral supplement, containing 100% of the Daily Value (DV) for folic acid provides 400 mcg of folic acid. Even with a larger than average intake of folic acid from fortified foods, it is unlikely that an individual's daily folic acid intake would regularly exceed the tolerable upper intake level of 1,000 mcg/day established by the Food and Nutrition Board (see Safety).
Older adults (65 years and older)
The recommendation for 400 mcg/day of supplemental folic acid as part of a daily multivitamin-multimineral supplement, in addition to a folate-rich diet, is especially important for older adults because blood homocysteine levels tend to increase with age (see Disease Prevention).
Written in April 2002 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in September 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University
Reviewed in September 2007 by:
Barry Shane, Ph.D., Professor
Department of Nutritional Sciences and Toxicology
University of California, Berkeley
Copyright 2000-2008 Linus Pauling Institute
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