Definition: Folate is a water-soluble B vitamin, which is also known as vitamin B9 or folacin.

• Folate is a generic term referring to both natural folates in food and folic acid, the synthetic form used in supplements and fortified food. Folate is critical in the metabolism of nucleic acid precursors and several amino acids, as well as in methylation reactions.
• Deficiency symptoms include: Megaloblastic anemia similar to that seen with vitamin B12 deficiency is the best-known sign of folate deficiency. Other manifestations may include various psychiatric symptoms (e.g., depression, anxiety, fatigue, apathy, confusion, or dementia), polyneuropathy, angular cheilosis, glossitis, hypotonia in infants and children, depressed cell-mediated immunity, impaired neutrophil phagocytosis, and brownish pigmentation of the skin.
• Severe folate deficiency has been reported to cause reversible neurological disease that was clinically indistinguishable from subacute combined degeneration of the spinal cord due to vitamin B12 deficiency. Folate deficiency can also lead to malabsorption, resulting in further folate depletion. Folate status is influenced by the presence of genetic variations in folate metabolism, particularly those found in the methylenetetrahydrofolate reductase (MTHFR) gene.
• Inadequate folate status during early pregnancy increases the risk of congenital anomalies. The introduction of mandatory folic acid fortification of refined grain products in the US in 1998 has reduced the prevalence of neural tube defects (NTDs) in newborns. Yet, folate status is considered inadequate in a majority of women of childbearing age worldwide. Moreover, genetic factors might modify the risk of NTDs by increasing the susceptibility to folate deficiency during pregnancy. Several studies are currently investigating the role of folic acid supplementation in the prevention of congenital anomalies other than NTDs.
• Folate deficiency and elevated concentrations of homocysteine in the blood are associated with an increased risk of cardiovascular disease (CVD). Although folic acid supplementation has been proven effective in controlling circulating homocysteine concentrations, the effect of homocysteine lowering on the incidence of CVD is still debated.
• Low folate status has been linked to increased cancer risk. However, intervention trials with high doses of folic acid have not generally shown any benefit on cancer incidence.
• Prospective cohort studies have reported an inverse association between folate status and colorectal cancer (CRC) risk, especially among men. The relationship between folate status and cancer risk is however complex and requires further research.
• Folate is essential for brain development and function. Low folate status and/or high homocysteine concentrations are associated with cognitive dysfunction in aging (from mild impairments to dementia). Whether supplemental B vitamins, including folic acid, will have long-term benefits in maintaining cognitive health is not yet known.
• Several autosomal recessive disorders affecting folate transport and metabolism can be treated with high doses of folinic acid, a folate derivative.

Drug interactions

• Anticonvulsants interfere with folic acid absorption and may cause folate deficiency. While correction of folate deficiency may improve the neurological side effects and some of the other side effects of anticonvulsants, administration of large doses of folic acid may decrease blood levels of phenytoin, phenobarbital, and carbamazepine, potentially interfering with seizure control. Folic acid mouth rinse has been used successfully to treat phenytoin-induced gingival hyperplasia.
• Contraceptives, oral. Folate deficiency, in some cases severe enough to cause megaloblastic anemia, has been reported in oral contraceptive users. Megaloblastic changes in cervical epithelium resembling cervical dysplasia have also been observed in women taking oral contraceptives. These changes were reversed in some, but not all, studies by supplementation with 5–10 mg/day of folic acid.
• Treatment with fenofibrate has been reported to cause hyper-homocysteinemia, which was reversed by supplementation with 10 mg/day of folic acid.
• In a double-blind trial, supplementation with 500 μg/day of folic acid significantly increased the efficacy and decreased the side effects of fluoxetine in women, but not in men.
• Methotrexate is a folate antagonist. Folate deficiency increases susceptibility to the toxic effects of methotrexate. In patients with rheumatoid arthritis, administration of folic acid or folinic acid reduced methotrexate toxicity without decreasing its efficacy. However, folic acid supplementation may interfere with the efficacy of methotrexate in the treatment of cancer.
• In a case report, a woman developed megaloblastic anemia due to folate deficiency after taking 3 courses of nitrofurantoin over a 9-month period.
• Sulfasalazine inhibits the absorption and transport of folic acid. Clinically significant folate deficiency has been reported in association with the use of sulfasalazine, but it appears to be uncommon.
• Trimethoprim may cause folate deficiency by inhibiting folic acid absorption and by inhibiting dihydrofolate reductase (an enzyme involved in the synthesis of the biologically active form of folic acid). Folic acid in typical doses does not appear to interfere with the antibacterial activity of trimethoprim.
• Folate deficiency may increase the hematologic toxicity of zidovudine.

Nutrient interactions

• Vitamin B12: People taking supplemental folic acid or vitamin B12 should in most cases take both of these vitamins. In addition, a case can be made that grains fortified with folic acid should also be fortified with vitamin B12. Practitioners should be alert to the possibility of vitamin B12 deficiency in patients receiving folic acid supplements, even in the absence of anemia or macrocytosis.
• Vitamin B6: people taking supplemental folic acid or vitamin B6 should in most cases take both of these vitamins.
• In patients with pancreatic insufficiency, duodenal pH may be well below 6.0, and zinc-folate complexes formed in the stomach may fail to dissociate in the duodenum. Thus, in patients with pancreatic insufficiency, the absorption of food-derived folate or zinc may be inhibited by supplementation with zinc or folic acid, respectively. Patients with pancreatic insufficiency who are supplementing with zinc or folic acid may benefit from taking the other nutrients at a different time of the day.
• Pancreatic enzymes: It might be worthwhile for people taking pancreatic enzymes to take supplemental folic acid.

Food sources:

• Good sources of folate include leafy green vegetables, legumes, citrus fruits, beets, whole grains, and fortified refined grains. Folate in homogenized raw vegetables is more bioavailable than folate in vegetables that were boiled prior to homogenization.

Preparations

• Nearly all research demonstrating the clinical benefits of folate has used folic acid. Folinic acid (5-formyl tetrahydrofolate) is the form of folate used in combination with the anticancer drugs, 5-fluorouracil, and methotrexate, and has also been used in patients with cerebral folate deficiency who have impaired transport of folic acid across the blood-brain barrier.
• Other commercially available folate supplements are methylfolate and 5-methyltetrahydrofolate. While these compounds have the theoretical advantage of being biologically active forms of folate, they are less stable than folic acid, and there is insufficient data regarding their absorption, uptake into cells and effectiveness in the treatment of folate-responsive conditions.
• Thus, with the exception of the situations mentioned above regarding folinic acid, folic acid appears to be the preferred form of folate for supplementation.

Dosage and administration

The dosage of folic acid in most studies has ranged from 0.5–5.0 mg/day, although larger doses (up to 80 mg/day) have been used in some instances.