- Folic acid
- Vitamin B9
For Patients & Caregivers
Tell your healthcare providers about any dietary supplements you’re taking, such as herbs, vitamins, minerals, and natural or home remedies. This will help them manage your care and keep you safe.
What is it?
Folate is a chemical that you need for healthy cell growth and function. It’s also needed for making red blood cells.
Folate is found in foods such as dark green leafy vegetables, eggs, dairy products, liver, Brussels sprouts, potatoes, chickpeas, nuts, beans, and poultry. It’s also added to some breakfast cereals, flours, and breads.
You can also take folate as a supplement in tablet or capsule form.
What is it used for?
Folate is used to:
- Treat Alzheimer’s disease (disease that affects memory and mental functioning).
- To prevent heart disease.
- To prevent certain birth defects.
Folate also has other uses that haven’t been studied by doctors to see if they work.
Folate that you get from food is safe. Talk with your healthcare provider before taking supplements or higher amounts of folate. Supplements are stronger than folate you get from food. They can also interact with some medications and affect how they work.
For more information, read the “What else do I need to know?” section below.
What are the side effects?
What else do I need to know?
- Talk to your healthcare provider before taking folate supplements if you’re taking methotrexate (such as Rheumatrex® Trexall®) as part of your cancer treatment or treatment for autoimmune diseases. Folate can make this medication less effective.
- Talk to your healthcare provider before taking folate supplements if you’re taking medications such as phenytoin (Dilantin®), carbamazepine (Carbatrol®, Tegretol®, Equetro®, Epitol®), or valproate (Depacon®) to treat epilepsy (seizure disorder). Folate can affect the way these work in the body.
For Healthcare Professionals
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 (5-MTHF) 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 (PCOS) (42), and high folate intake reduced chromosomal aberrations in sperm of healthy men (12). But supplements taken beyond the first trimester did not prevent pre-eclampsia in women at high risk for this disorder (72).
In other studies, folic acid decreased homocysteine levels, a risk factor for cardiovascular disease mortality (13) (14) (15), along with lowering blood pressure in smokers (5) (16). 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 a meta analysis indicating moderate to low evidence for preventive benefits of folic acid for total cardiovascular disease; and folic acid and B-vitamins for stroke (73). Folic acid supplementation has been shown to improve cognitive function in older adults (26). In patients with Alzheimer’s disease, it improved response to cholinesterase inhibitors (27), cognition, and inflammatory markers (46). In individuals chronically exposed to arsenic, it lowered blood arsenic concentrations by facilitating urinary excretion (28). There is limited evidence on whether supplementation can increase serum folate levels, or has an effect on anemia in patients with sickle cell disease (68). But a combination of folic acid and vitamin B12 supplements decreased serum homocysteine levels and improved anemia in patients with multiple sclerosis (74); and folic acid added to antipsychotics may improve symptoms in schizophrenic patients (75).
Studies on increased folate intake or supplements to reduce 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 have been shown to reduce the risk of breast (2) and pancreatic cancers (3), but not prostate cancer (7). Folate supplementation was found to help cervical intraepithelial neoplasia (CIN 1) regression (47), 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 may also increase risk of toxicity (51) and some cancers (52). In young children, folic acid fortification was associated with reduced incidence of Wilms tumor and primitive neuroectodermal tumors (PNET) (36).
Additional studies that evaluated 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).
Mechanism of Action
Folate acts as a co-enzyme during methylation. The bioactive form is tetrahydrofate, which can be converted from folic acid through the action of dihydrofolate reductase. Drugs that inhibit this enzyme can therefore reduce folic acid activity. The amino acid serine reacts with tetrahydrofolate, resulting in 5,10- methylenetetrahydrofolate, the derivative involved in nucleotide synthesis. In addition, 5-methyltetrahydrofolate transfers a methyl group to cobalamin (vitamin B12) and then to homocysteine, converting it to methionine, the precursor of methyl donor, S-adenosyl-methionine (SAMe) that plays a major role in neurological function and several biochemical pathways (41). Genetic polymorphisms that lower the production of methylenetetrahydrofolate reductase (MTHFR) can also reduce SAMe and increase homocysteine levels. Supplementation with folic acid can therefore reduce homocysteine levels and DNA oxidative damage (57) (58). This may in turn lower risk of cardiovascular and psychiatric diseases by increasing SAMe (59) (60). Folic acid supplementation also improves endothelial function (16) (31); and has a protective effect on retinal vascular endothelial cells from high glucose-induced injury via regulating proteins in the Hippo signaling pathway (76).
Although low folate status is associated with increased risk of cardiovascular disease and some cancers (61), increased intake from fortified foods may actually raise cancer risk (49) (50) (62). There is also evidence that high levels of unmetabolized folic acid in plasma can reduce natural killer cell cytotoxicity (63).
- Increased risk of toxicity with overconsumption. (51)
- In a 43-year-old man with low haemoglobin and multiorgan dysfunction syndrome (MODS), folate supplementation was associated with promoting lymphoma progression (77).
- Prenatal use of iron-folate supplements was found to cause constipation, diarrhea, nausea, severe stomach pain and chest pains (80).