Folate is a generic term that typically refers to a group of water-soluble compounds that play an essential role in deoxyribonucleic acid (DNA) biosynthesis.[1] It is also known as vitamin B9 and is different from folinic acid, or leucovorin, which is more technically known as 5-formyltetrahydrofolate (5-FTHF). Folic acid is the synthetic form of folate. Folate converts into tetrahydrofolic acid (THF), a compound that undergoes several transfer/methylation reactions that are important for the synthesis of nitrogenous bases in DNA and ribonucleic acid (RNA) and are necessary for maturation of red blood cells (RBCs). There are small reserve pools in the liver and kidney. A deficiency of folic acid can result in macrocytic megaloblastic anemia and usually results from chronic alcoholism, malabsorption disorders, hemolytic anemia, or increased requirement during pregnancy. Folate appears naturally in some food sources and must be ingested regularly since humans, and all other animals, cannot synthesize it. Sources of folate in the diet include leafy green vegetables, like spinach, broccoli, and lettuce; meats, such as liver; and milk and eggs. Despite the need for regular amounts of folate, however, daily intake levels are frequently lower than the recommended dosage given by national health authorities.[2]

One of the most important indications for folate use is when considering the development of the central nervous system. Women planning on getting pregnant should take folic acid supplements to reduce the risk of neural tube defects (NTDs), such as spina bifida, arising in the developing fetus. Some have proposed that the mechanism by which NTDs form in the absence of folate involves the increased ubiquitination of neural tube closure–related genes, thereby affecting their expression.[3] One of the beneficial roles of folate appears to be its ability to reduce homocysteine levels in NTDs.[4] The period of greatest vulnerability is during the fourth week of development, when a woman may be unaware that she is pregnant. For this reason, it is advisable for women of childbearing age to be taking folic acid supplements if they are sexually active, especially when they are planning to conceive. If the expectant mother were to take 4mg of folic acid daily, it could take 20 weeks for her body to reach folate levels that are optimal for reducing the risk of a neural tube defect. Because of this, supplementation should be initiated 5 to 6 months before conception.[5] Folic acid is also associated with a decreased risk of preterm birth.[6]

Many other therapeutic uses of folic acid exist, though these uses are less impactful than those already mentioned. Folic acid can help to protect against neoplasia in ulcerative colitis, prevent cervical dysplasia, treat vitiligo, restore hematopoiesis in macrocytic anemia due to a folate deficiency, and increase gingival resistance to local irritants, thereby reducing inflammation.[4][7] Of these uses, treatment of megaloblastic anemia is the only indication recognized by the FDA, including the prevention of NTDs. Folic acid is also used as an alternative to leucovorin calcium and serves as adjunctive therapy in methanol toxicity. When homocysteine levels increase above baseline, they can reduce global cognition, especially in the elderly. [8] Because of the role of homocysteine in this pathogenesis and folate’s ability to reduce homocysteine levels, some research has shown that a combination of vitamin B12 and folate can significantly improve cognitive performance, and the two of them together is superior to either folate or B12 administration alone.[9] The toxicity of hyperhomocysteinemia also has detrimental cardiovascular effects and is a complication of chronic kidney disease (CKD). While there is currently a lack of definitive proof that folic acid or vitamin B12 administration in these situations is directly beneficial, it would be reasonable to consider them as appropriate adjunctive therapy.[10]

Folate mainly concentrates in the liver.[11] The synthetic form, folic acid, is given as dihydrofolate (DHF) and is converted to THF by the action of the dihydrofolate reductase enzyme, which is dependent on nicotinamide adenine dinucleotide phosphate hydrogen (NADPH). THF then converts to 5-10-methylenetetrahydrofolate (5-10-MTHF), which can diverge down different paths: toward DNA synthesis via dTMP or toward methionine synthesis.[12]

For DNA synthesis, deoxyuridine monophosphate (dUMP) accepts one methyl group from 5-10-MTHF—via thymidylate synthase, which accepts the other—to become deoxythymidine monophosphate (dTMP) and allows the cell cycle to continue while simultaneously regenerating DHF. Drugs used in cancer chemotherapy disrupt this process by inhibiting vital enzymes necessary for cell cycle progression. Methotrexate, for example, inhibits dihydrofolate reductase. By reducing available THF and its downstream components, methotrexate indirectly deprives thymidylate synthase of its substrates.[13] Humans are unable to create dTMP in the presence of methotrexate, and the DNA pool becomes unbalanced, resulting in cell death.

Methionine is a byproduct synthesized as folate reduces homocysteine levels in the blood; 5-10-MTHF donates a methyl group to an enzyme, methyl-tetrahydrofolate reductase (MTHFR), and then becomes 5-methyl THF.[13] 5-methyl THF donates its remaining methyl group to homocysteine via methionine synthase, converting homocysteine to methionine. This transfer of both methyl groups from the original 5-10-MTHF regenerates THF, which can then re-enter the cycle. Vitamin B12 is a crucial cofactor for methionine synthase, and B12 deficiency can lead to macrocytic megaloblastic anemia, similar to that of folate deficiency but with additional clinical symptoms that are beyond the scope of this article.[14]

Folic acid is often administered as an oral supplement. Dosing is usually dependent on the disorder the physician is attempting to treat. The recommended daily requirement of folate for an adult is 240 mcg.[7] For preventing neural tube defects in pregnancy, the World Health Organization recommends a daily dose of 400 to 800 mcg. Clinicians generally prescribe iron-folic acid supplements as prenatal vitamins during and before pregnancy.[15][16] Most of these include 1 mg of folate, which is more than enough to meet this criterion.[17] Again, for maximum effect, this supplementation must begin in the earliest stages of pregnancy, if not months before conception. 

For macrocytic anemia, folic acid may be given orally, intravenously, or subcutaneously. Oral recommendations are 1 to 5 mg once daily, but doses up to 15 mg once daily have been recommended as well. 

For intravenous administration, 5 mg or less of undiluted folic acid may be infused over at least 1 minute, or 5 mg or less of folic acid may be combined with 50 mL of either normal saline (NS) or dextrose 5% in water (D5W) and infused over 30 minutes. Folic acid may also be given as an infusion when added to other IV maintenance solutions. To avoid folic acid deficiency in patients on hemodialysis, the recommended dose is estimated to be in the range of 1 to 5 mg daily.[18]

For the general population, a diet that contains a daily amount of folic acid below the established upper intake level of 1000 mcg has not demonstrated to result conclusively in any adverse health outcomes. The U.S. National Toxicology Program (NTP) examined areas of previous concern, including cognition (relating to vitamin B12 deficiency), cancer, diabetes- and thyroid-related disorders, and hypersensitivity-related outcomes. Researchers identified these areas from previous reports of patients that received more than 400 mcg per day. Overall, the NTP report concluded that, for the areas considered, no definitive evidence exists for adverse effects due to folic acid.[19][20] However, reports exist of rare instances of GI upset.[21]

This report, as well as other literature reviews performed since, draw their conclusions while still emphasizing the need for further investigation. Overall, the benefits that stand to be gained from folic acid intake justify any potential risk that might be encountered. Furthermore, the mandatory folic acid fortification program guidelines in countries across the world have yielded no established risks for adverse effects.

Hypersensitivity to folic acid or its formulation is a potential contraindication to its administration. One must recall that research has yet to establish hypersensitivity reactions to folic acid, but a history of an anaphylactic reaction from any substance must deter the administration of the offending agent.