For Patients & Caregivers
Bottom Line: Folate is used to prevent certain types of anemia and birth defects. It may also reduce the risk of certain cancers.
Folate is a vitamin of the vitamin B complex. The main food sources of folate include fortified breakfast cereals and breads, liver, Brussels sprouts, potatoes, spinach, chickpeas and brewer’s yeast. It is also available in supplemental form as folic acid. Folate deficiency can result in the reduction of essential cell division and can lead to anemia. The vitamin has been shown to reduce the risk of neural tube defects and is vital for pregnant women.
Higher levels of folate have been shown to reduce the risk for breast cancer, pancreatic cancer and colon cancer.
- To treat Alzheimer’s disease
Studies have linked low folate levels with Alzheimer’s disease. Research also shows a possible link between the intake of folate and decreased risk of Alzheimer’s.
- To prevent cancer
Clinical studies have shown that higher levels of folate reduce the risk for breast, pancreatic and colon cancers. Folic acid supplementation does not appear to affect the risk of prostate cancer.
- To prevent heart disease
- Low folic acid levels have been linked to higher homocysteine levels, a risk factor for death caused by diseases of the heart and blood vessels. However, further studies are needed to understand this association.
- To treat chronic fatigue syndrome
Folic acid was ineffective in treating chronic fatigue syndrome.
- To prevent neural tube birth defects
Studies have shown a significant decrease in the risk of neural tube (tissue in the embryo that develops into the brain and the spinal cord) defects as a result of increased dietary folate.
Cardiovascular Disease & Stroke
A study of 3,680 patients with cerebral infarction (blockage of blood supply to the brain) examined the effect of folic acid, vitamin B6 and vitamin B12 on stroke. Participants were randomly assigned to receive either high or low doses of the studied vitamins once a day for two years. The high-dose group had a greater reduction in total homocysteine, but neither group experienced a decreased risk of stroke, coronary heart disease events or death. A randomized controlled trial of seventy-five subjects with coronary artery disease divided subjects into three groups: placebo, folic acid alone, or folic acid plus vitamins C and E. After four months, subjects who received folic acid supplements were found to have significant increases in plasma folate and improvement in blood flow. However, it is unclear whether these changes reduced cardiovascular events.
Five hundred fifty-three subjects were examined in a randomized controlled trial of a homocysteine-lowering therapy regimen containing folic acid. The subjects had all previously undergone angioplasty (a procedure to unblock blood vessels) and were assigned to receive either placebo or a combination of folate, vitamin B12 and vitamin B6 for six months. Subjects in the treatment arm had significantly lower homocysteine levels and few major adverse effects.
A population-based case-control study observed 1,321 cases of breast cancer and 1,382 control cases to examine the relationship between dietary folate intake and breast cancer risk. High folate intake was found to reduce breast cancer risk, and the reduction was even more pronounced in women who also consumed high levels of methionine, vitamin B12 and vitamin B6. A 20-year study of 14,407 subjects examining the association between folate intake and colon cancer risk found higher folate intake to reduce colon cancer risk in men, especially in non-drinkers. A prospective analysis of 27,101 healthy male smokers between the ages of 50 and 69 found that dietary folate can reduce pancreatic cancer risk. One study of 88,756 women found that long-term (more than 15 years) supplementation of folic acid significantly lowered the risk of colon cancer risk.
This study was done to determine the effects of folic acid in reducing neural-tube defects in babies in China. A daily dose of 400 micrograms of folic acid was suggested to women starting from their premarital exam to the end of the first trimester. Researchers report a reduction in risk of neural tube defects in fetuses or infants of women who took the folic acid supplement compared to those who did not take it. This effect was seen both in women from areas with high neural-tube defects and in areas with low rates.
For Healthcare Professionals
Folate and folic acid are water-soluble vitamins of the vitamin B complex. Folate is naturally available in green leafy vegetables, whereas folic acid is the synthetic supplemental form and has higher bioavailability than folate (1).
Folate is essential during pregnancy and has been shown to reduce the risk of neural tube defects (10). Data also suggest a nearly 50% reduction in risk of medulloblastoma in children born to women who took folic acid supplements during pregnancy (11). Folate supplementation may benefit women with polycystic ovary syndrome (PCOS) (42). High folate intake was also found to reduce chromosomal aberrations in sperm of healthy men (12).
In other studies, folic acid has been shown effective in decreasing levels of homocysteine, a risk factor for cardiovascular disease mortality (13)(14)(15), and reducing blood pressure in smokers (5)(16). However, trials on the risk of stroke yielded mix results (17)(18)(19)(20). Folic acid supplementation was ineffective in the treatment of chronic fatigue syndrome (21). 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).
Folic acid supplementation improved cognitive function in older adults (26) and response to cholinesterase inhibitors in patients with putative Alzheimer’s disease (27).
In individuals chronically exposed to arsenic, folic acid supplementation lowers blood arsenic concentrations by facilitating urinary excretion (28).
Low levels of folate in the blood are associated with certain forms of cancer (9), whereas higher levels of dietary folate have been shown to reduce the risk of breast (2), pancreatic (3) and colon cancers (4)(5)(6)(32)(35). However, folic acid supplementation does not seem to affect the risk of prostate cancer (7) or colorectal adenoma in patients with a history colorectal adenoma without carcinoma (8). A combination of folic acid, and vitamins B6 and B12 had no effect on overall of invasive cancer or breast cancer (33). Recent data, however, suggest higher cancer incidence and mortality in patients with ischemic heart disease following supplementation with vitamin B12 and folic acid (34).
In children aged 0 — 4 years, folic acid-fortification was associated with a reduction in the incidence of Wilms tumor and primitive neuroectodermal tumors (PNET), but not other childhood cancers (36).
Findings of a meta analysis indicate that folic acid supplementation does not have a significant effect on total cancer incidence, colorectal cancer, prostate cancer, lung cancer, breast cancer, or hematological malignancy, but reduces the risk of melanoma (37).
Clinical studies indicate that folic acid supplementation improves endothelial function in patients with coronary atherosclerosis (31) and in smokers (16). In addition, both oral and intravenous folate administration resulted in comparable homocysteine-lowering effects (13).
Folic acid supplementation has been shown to reduce the risk of colon cancer (32); and dietary folate intake was more strongly associated with reduced breast cancer risk in women who also consumed high levels of folate cofactors (methionine, vitamin B12, and vitamin B6) (2).
Folic acid was shown to have high bioavailability, with large doses of oral folic acid raising the plasma levels significantly in healthy individuals in a time- and dose-dependent manner.
After high-dose oral administration of folic acid (ranging from 25-1,000 mg/day), the red blood cell (RBC) folate levels were found to be elevated for more than 40 days following discontinuation of folic acid use.
It is poorly transported to the brain, and cleared rapidly from the central nervous system.
Elimination of absorbed folic acid was shown to be via feces (through bile) and urine.
Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-75.
3,680 adults with cerebral infarction participated in a study of folic acid, vitamin B6 and vitamin B12 and stroke. Participants received a multivitamin containing the US recommended daily allowance of other vitamins and were randomly assigned to receive once-daily doses of either high-dose or low-dose amounts of the studied vitamins. Subjects were followed for a 2-year period. The high-dose group had a greater reduction in total homocysteine, however neither treatments lowered the risk of stroke, coronary heart disease events or death. Researchers suggest that further studies are necessary to understand the association between total homocysteine levels and vascular risk.
Van Guelpen B, Hultdin J, Johansson I, et al. Low folate levels may protect against colorectal cancer. Gut 2006;55(10):1461-6.
This prospective study was conducted to determine the association between folate levels and the risk of developing colorectal cancer. This is the first study to look at the plasma folate levels unlike the earlier ones that examined the benefits of oral folic acid supplementation. The study involved 226 persons with colorectal cancer and 437 matched controls from the Northersn Sweden Health and Disease Cohort. Researchers observed a bell-shaped association between plasma folate levels and the risk of colorectal cancer. Persons in the highest folate quintile were four times as likely to develop colorectal cancer compared to those in the lowest quintile. These results contradict the data available so far, but the low folate status of the subjects may be the reason. Further studies with long-term follow up are needed to confirm the benefits of folic acid supplementation.
Durga J, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet 2007;369(9557):208-216.
In the Folic Acid and Carotid Intima-media Thickness (FACIT) trial, 818 participants (50-70 years of age) with homocysteine concentrations ranging from 13-26 ìmol/L randomly received placebo or folic acid (800 ìg daily) for 3 years during which cognitive function was assessed by 5 separate tests including memory, word fluency, and sensorimotor, complex, and information processing speeds. Participants that received folic acid experienced benefits in memory, speed of information processing, and sensorimotor speed as compared to those receiving placebo, indicating that folic acid supplementation may improve cognitive function in older adults. Further studies are necessary to determine if individuals with low or high homocysteine levels would also benefit in folic acid supplementation.
Connelly PJ, et al. A randomised double-blind placebo-controlled trial of folic acid supplementation of cholinesterase inhibitors in Alzheimer’s disease. Int J Geriatr Psychiatry 2008;23(2):155-160.A pilot randomized, double-blind, placebo-controlled study of 57 participants with Alzheimer’s disease sought to determine if folic acid supplementation could improve the patients’ response to cholinesterase inhibitors. Consecutive patients were either given placebo or folic acid (1 mg daily) and their Mini-Mental State Examination (MMSE) and Instrumental Activities of Daily Living (IADL) and Social Behavior (SB) scores as well as homocysteine levels were assessed at baseline and 3 and 6 months after treatment initiation. Although MMSE scores were not affected by folic acid supplementation, IADL and IADL/SB scores were. Further studies of larger population sizes will confirm whether folic acid supplementation is beneficial in the treatment of Alzheimer’s disease.