[3] Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and storage.

[1] Symptoms may include feeling tired, heart palpitations, shortness of breath, open sores on the tongue, and changes in the color of the skin or hair.

A pterin (2-amino-4-hydroxy-pteridine) heterocyclic ring is linked by a methylene bridge to a p-aminobenzoyl group that in turn is bonded through an amide linkage to either glutamic acid or poly-glutamate.

Deficiency of folate in pregnant women has been implicated in neural tube defects (NTDs), with an estimate of 300,000 cases worldwide prior to the implementation in many countries of mandatory food fortification.

[31] Many women take this medication less than the CDC recommends, especially in cases where the pregnancy was unplanned, or in countries that lack healthcare resources and education.

Some countries have implemented either mandatory or voluntary food fortification of wheat flour and other grains,[32] but many others rely on public health education and one-on-one healthcare practitioner advice.

[36][37] One systematic review indicated no effect of folic acid on mortality, growth, body composition, respiratory, or cognitive outcomes of children from birth to 9 years old.

[40] One meta-analysis reported that multi-year folic acid supplementation, in amounts in most of the included clinical trials at higher than the upper limit of 1,000 μg/day, reduced the relative risk of cardiovascular disease by a modest 4%.

[43][44] Chronically insufficient intake of folate may increase the risk of colorectal, breast, ovarian, pancreatic, brain, lung, cervical, and prostate cancers.

[50][51] A review of trials that involved folic acid dietary supplements reported a statistically significant 24% increase in prostate cancer risk.

Folinic acid, under the drug name leucovorin, a form of folate (formyl-THF), can help "rescue" or reverse the toxic effects of methotrexate.

[64][63][65] Relative risk of autism spectrum disorders (ASDs) was reported reduced by 23% when the maternal diet was supplemented with folic acid during pregnancy.

[68] Limited evidence from randomized controlled trials showed using folic acid in addition to selective serotonin reuptake inhibitors (SSRIs) may have benefits.

[70][71] The exact mechanisms involved in the development of schizophrenia and depression are not entirely clear, but the bioactive folate, methyltetrahydrofolate (5-MTHF), a direct target of methyl donors such as S-adenosyl methionine (SAMe), recycles the inactive dihydrobiopterin (BH2) into tetrahydrobiopterin (BH4), the necessary cofactor in various steps of monoamine synthesis, including that of dopamine and serotonin.

[78] In addition to a role in intestinal absorption, RFC is expressed in virtually all tissues and is the major route of delivery of folate to cells within the systemic circulation under physiological conditions.

This action is rate-limiting in humans leading to elevated blood concentrations of unmetabolized folic acid when consumption from dietary supplements and fortified foods nears or exceeds the U.S. Tolerable Upper Intake Level of 1,000 μg per day.

The liver produces folate-containing bile, which if not all absorbed in the small intestine, contributes to fecal folate, intact and as cleavage products, which under normal dietary intake has been estimated to be similar in amount to urinary excretion.

Pterin is in turn derived in a series of enzymatically catalyzed steps from guanosine triphosphate (GTP), while PABA is a product of the shikimate pathway.

[82] This series of reactions using the β-carbon atom of serine as the carbon source provide the largest part of the one-carbon units available to the cell.

[99] The United Kingdom's Dietary Reference Value for folate, set by the Committee on Medical Aspects of Food and Nutrition Policy in 1991, is 200 μg/day for adults.

[114] Both adults and children need folate to make normal red and white blood cells and prevent anemia, which causes fatigue, weakness, and inability to concentrate.

In the US, mandatory fortification of enriched breads, cereals, flours, corn meal, pastas, rice, and other grain products began in January 1998.

Because the neural tube closes in the first four weeks of gestation, often before many women even know they are pregnant, many countries in time decided to implement mandatory food fortification programs.

[125][126] Food Safety Minister Kate Wilkinson reviewed the decision to fortify in July 2009, citing as reasons to oppose claims for links between over consumption of folate with increased risk of cancer.

A 2018 review by authors based in the United Kingdom strongly recommended that mandatory fortification be reconsidered as a means of reducing the risk of neural tube defects.

[135] In 1996, the United States Food and Drug Administration (FDA) published regulations requiring the addition of folic acid to enriched breads, cereals, flours, corn meals, pastas, rice, and other grain products.

This means that fortification led to a bigger increase in folic acid intake than first projected, and that more than half the adults are consuming more than the RDA of 400 μg (as DFEs).

The Centers for Disease Control and Prevention reported in 2015 that since the addition of folic acid in grain-based foods as mandated by the FDA, the rate of neural tube defects dropped by 35%.

[144] In 1931, researcher Lucy Wills made a key observation that led to the identification of folate as the nutrient required to prevent anemia during pregnancy.

[2] Bob Stokstad isolated the pure crystalline form in 1943, and was able to determine its chemical structure while working at the Lederle Laboratories of the American Cyanamid Company.