Folate is an essential member of the vitamin B complex family that is naturally present in grains, green leafy vegetables, and liver. Folic acid and the L-methylfolate derivative are synthetic supplemental forms that have higher bioavailability ⁽¹⁾. Folate is important for cell growth and division, and is involved in methylation and DNA synthesis. Inadequate intake can cause deficiency leading to megaloblastic anemia.

Folate is essential during pregnancy, with supplementation shown to reduce risks of neural tube birth defects ⁽¹⁰⁾ and medulloblastoma in offspring ⁽¹¹⁾. A study among South American populations suggests the protective effect against neural tube defects may be greater in female than male infants ⁽⁶⁵⁾. In high doses (5 mg/day), it reduced homocysteine levels at time of delivery and may lessen pregnancy complications ⁽⁴³⁾. Supplementation may also benefit women with polycystic ovary syndrome ⁽⁴²⁾ along with improving BMI ⁽⁸⁹⁾, but supplements taken beyond the first trimester did not prevent pre-eclampsia in women at high risk for this disorder ⁽⁷²⁾. In a large multicenter trial, folic acid and zinc supplementation by male partners of couples seeking infertility treatment did not improve semen quality or live birth rates ⁽⁸¹⁾. In postmenopausal women, folic acid may help improve sexual function ⁽⁹⁵⁾ and reduce hot flushes, but confirmatory data are needed ⁽⁸⁶⁾.

In older adults, folic acid supplementation may improve cognitive function ⁽²⁶⁾. In patients with Alzheimer’s disease, it improved response to cholinesterase inhibitors ⁽²⁷⁾, cognition ⁽⁹⁶⁾, and inflammatory markers ⁽⁴⁶⁾. However, high folate / low vitamin B-12 status has been associated with impaired cognitive function in older adults ⁽⁸²⁾. And although folic acid along with docosahexaenoic acid improved cognitive function and decreased plasma inflammatory cytokines better than each supplement alone in one study ⁽⁸³⁾, other data suggest benefits with folic acid on cognitive function occur in those with a lower, rather than higher, omega-3 fatty acid status ⁽⁸⁴⁾. But a combination of folic acid and vitamin-B12 did not affect the risk of fracture or cardiovascular disease in this population ⁽⁸⁷⁾.

Folic acid decreases homocysteine levels, a risk factor for cardiovascular disease (CVD) mortality ^{(13) (14) (15) (97)}, improves BMI in those with high homocysteine levels  ⁽⁸⁹⁾ along with lowering blood pressure in smokers ^(5) (16) and in patients with CVD and overweight individuals ⁽⁹⁰⁾. A combination of folic acid and vitamin B12 supplements also decreased homocysteine levels and improved anemia in patients with multiple sclerosis ⁽⁷⁴⁾, but evidence is limited on whether supplementation has an effect on anemia in patients with sickle cell disease ⁽⁶⁸⁾. Among hypertensive adults, folic acid therapy reduced risk of first stroke ^{(44) (45) (66)}, but smoking status may affect efficacy ⁽⁶⁷⁾. Other trials on stroke risk have yielded mixed results ^{(17) (18) (19) (20)} with meta-analyses confirming reductions in the risks of cardiovascular disease and stroke ^(73) (91).

In other studies, folate lowered blood arsenic concentrations of chronically exposed individuals by facilitating its urinary excretion ⁽²⁸⁾. It was also associated with lower risk of progression of early-to-late age-related macular degeneration ⁽⁹²⁾ and when added to antipsychotics, may improve symptoms in schizophrenic patients ⁽⁷⁵⁾, but did not have any significant effects on memory ⁽⁹³⁾.

Studies of folate vs cancer risk are mixed. Deficiency has been linked to development of esophageal squamous cell cancer ⁽⁷⁸⁾ and low levels of folate in the blood with certain forms of cancer ⁽⁹⁾, whereas higher levels of dietary folate may reduce the risk of breast ⁽²⁾ and pancreatic cancers ⁽³⁾, but not prostate cancer ⁽⁷⁾. Folate supplementation may help cervical intraepithelial neoplasia regression ^(47) (88), but studies on colorectal cancer risk produced mixed results ^{(4) (5) (32) (35) (48)} and some even suggest a negative effect ^{(6) (8) (49) (71)}. A large population study suggested an association between dietary folate intake and increased risk for overall skin cancer, basal cell carcinoma, and non-melanoma skin cancer, particularly in women ⁽⁵⁰⁾. Over-consumption of folic acid supplements may also increase risk of toxicity and some cancers ^(51) (52). In young children, folic acid fortification was associated with reduced incidence of Wilms tumor and primitive neuroectodermal tumors ⁽³⁶⁾.

Studies of folic acid in combination with other B vitamins reported negative findings, with no overall effect on breast or invasive cancers ⁽³³⁾, along with the potential for increased cancer incidence and mortality in patients with ischemic heart disease ⁽³⁴⁾. Such interventions have also produced mixed results in studies for older adults with depression ^(53) (54), and did not improve bone mineral density ⁽⁵⁵⁾ or reduce fracture risk or incidence ^(56) (69). Further studies are needed for more definitive data.

Due to its antagonistic effects, folic acid can reduce the side effects of methotrexate when used for rheumatoid arthritis  ^(22) (23). However, it may decrease the efficacy of methotrexate in the treatment of acute lymphoblastic leukemia ⁽²⁴⁾ and psoriasis ⁽²⁵⁾. Excess folate or folic acid may mask vitamin B12 deficiency ⁽⁷⁰⁾. More research is needed to address the evidence and knowledge gaps related to the effects of higher intake of folate/folic acid on human health ⁽⁷⁹⁾.