Folic Acid: Everything You Need to Know
What is folic acid?
Folic acid is a synthetic, water-soluble vitamin used in supplements and fortified foods.
It’s a man-made version of folate, a naturally occurring B vitamin found in many foods. Your body can’t make folate, so it must be obtained through dietary intake.
Although the words folate and folic acid are often used interchangeably, these vitamins are distinct. Synthesized folic acid differs structurally from folate and has slightly different biological effects in the body. That said, both are considered to contribute to an adequate dietary intake.
Folate is found in a number of plant and animal foods, including spinach, kale, broccoli, avocado, citrus fruits, eggs, and beef liver.
Folic acid, on the other hand, is added to foods like flour, ready-to-eat breakfast cereals, and bread. Folic acid is also sold in concentrated form in dietary supplements.
Your body uses folate for a wide array of critical functions, including (1Trusted Source, 2Trusted Source, 3Trusted Source, 4Trusted Source):
the synthesis, repair, and methylation — the addition of a methyl group — of DNA
cellular division
the conversion of homocysteine to methionine, an amino acid that’s used for protein synthesis or converted into S-adenosylmethionine (SAMe), a compound that acts as a primary methyl donor in your body and is necessary for numerous cellular reactions
the maturation of red blood cells
Folate is involved in a number of vital metabolic processes, and deficiency leads to an array of negative health outcomes, including megaloblastic anemia, increased risk of heart disease and certain cancers, and birth defects in infants whose mothers were deficient in folate (1Trusted Source).
Folate deficiency has multiple causes, including:
poor dietary intake
diseases or surgeries that affect folate absorption in the digestive system, including celiac disease, gastric bypass, and short bowel syndrome
achlorhydria or hypochlorhydria (absent or low stomach acid)
drugs that affect folate absorption, including methotrexate and sulfasalazine
alcoholism
pregnancy
hemolytic anemia
dialysis
Many countries, including the United States, require grain products to be fortified with folic acid to reduce the incidence of folate deficiency.
This is because folate deficiency is somewhat common, and some populations, including older adults and pregnant women, find it difficult to obtain the recommended dietary intake through diet (2Trusted Source).
Recommended intake levels
Folate stores in the body range between 10–30 mg, most of which is stored in your liver, while the remaining amount is stored in blood and tissues. Normal blood levels of folate range from 5–15 ng/mL. The main form of folate in the blood is called 5-methyltetrahydrofolate (1Trusted Source, 5Trusted Source).
Dietary Folate Equivalents (DFEs) is a unit of measure that accounts for the differences in absorbability of folic acid and folate.
Synthetic folic acid is thought to have 100% absorbability when consumed on an empty stomach, while folic acid found in fortified foods is thought to have only 85% absorbability. Naturally occurring folate has a much lower absorbability of around 50%.
When taken in supplement form, 5-methyltetrahydrofolate has the same — if not slightly higher — bioavailability than folic acid supplements (3Trusted Source).
Because of this variability in absorption, DFEs were developed according to the following equation (4Trusted Source):
1 mcg of DFEs = 1 mcg of naturally occurring food folate = 0.5 mcg of folic acid taken in the form of supplements on an empty stomach = 0.6 mcg of folic acid ingested with foods
Adults need about 400 mcg DFE of folate per day to replenish daily folate losses. Pregnant women and breastfeeding women have increased folate needs and need to take in 600 mcg and 500 mcg DFE of folate per day, respectively (6Trusted Source).
The Recommended Dietary Allowance (RDA) for infants, children, and teens are as follows (7Trusted Source):
Birth to 6 months: 65 mcg DFE
Ages 7–12 months: 80 mcg DFE
Ages 1–3: 150 mcg DFE
Ages 4–8: 200 mcg DFE
Ages 9–13: 300 mcg DFE
Ages 14–18: 400 mcg DFE
Benefits and uses
Both folic acid and folate are commonly used in supplemental form for a variety of reasons.
Although folic acid and folate supplements are typically used to treat the same conditions, they have different effects in the body and, therefore, may affect health in different ways, which will be explained later in this article.
The following are the most common benefits and uses of folic acid and folate supplements.
Prevention of birth defects and pregnancy complications
One of the most common uses of folic acid and folate supplements is the prevention of birth defects, specifically neural tube defects, including spina bifida and anencephaly — when a baby is born without parts of its brain or skull (7Trusted Source).
Maternal folate status is a predictor of neural tube defect risk, which has led to national public health policies regarding folic acid supplementation for women who are or may become pregnant.
For example, the U.S. Preventive Services Task Force, an independent panel of national disease-prevention experts, recommends that all women who are planning to become pregnant or capable of becoming pregnant supplement daily with 400–800 mcg of folic acid starting at least 1 month before becoming pregnant and continuing through the first 2–3 months of pregnancy (7Trusted Source).
Folic acid supplements are prescribed to pregnant women to prevent fetal birth defects and may also help prevent pregnancy-related complications, including preeclampsia (8Trusted Source).
Treatment of folate deficiency
Folate deficiency can occur due to a variety of causes, including inadequate dietary intake, surgery, pregnancy, alcoholism, and malabsorptive diseases (6Trusted Source).
Deficiency can result in serious side effects, including megaloblastic anemia, birth defects, mental impairment, impaired immune function, and depression (9Trusted Source, 10Trusted Source).
Both folic acid and folate supplements are used to treat folate deficiency.
Promotion of brain health
Research has shown that low blood folate levels are associated with poor brain function and an increased risk of dementia. Even normal but low folate levels are associated with an increased risk of mental impairment in older adults (11, 12Trusted Source).
Studies have demonstrated that folic acid supplements may improve brain function in those with mental impairment and help treat Alzheimer’s disease.
A 2019 study in 180 adults with mild cognitive impairment (MCI) demonstrated that supplementing with 400 mcg of folic acid per day for 2 years significantly improved measures of brain function, including verbal IQ and reduced blood levels of certain proteins involved in the development and progression of Alzheimer’s disease, compared with a control group (13Trusted Source).
Another study in 121 people with newly diagnosed Alzheimer’s disease who were being treated with the medication donepezil found that those who took 1,250 mcg of folic acid per day for 6 months had improved cognition and reduced markers of inflammation, compared with those who took donepezil alone (14Trusted Source).
Adjunctive treatment of mental health disorders
People with depression have been shown to have lower blood levels of folate than people without depression (15Trusted Source).
Studies show that folic acid and folate supplements may reduce depressive symptoms when used in conjunction with antidepressant medications.
A systematic review demonstrated that, when used alongside antidepressant medication, treatment with folate-based supplements, including folic acid and methylfolate, were associated with significantly greater reductions in depressive symptoms, compared with antidepressant medication treatment alone (16).
What’s more, a review of 7 studies found that treatment with folate-based supplements alongside antipsychotic medication resulted in reduced negative symptoms in people with schizophrenia, compared with antipsychotic medication alone (17Trusted Source).
Reduction of heart disease risk factors
Supplementing with folate-based supplements, including folic acid, may help improve heart health and reduce your risk of heart disease risk factors.
Having elevated levels of the amino acid homocysteine is associated with an increased risk of developing heart disease. Blood levels of homocysteine are determined by both nutritional and genetic factors.
Folate plays a major role in the metabolism of homocysteine, and low folate levels can contribute to high homocysteine levels, known as hyperhomocysteinemia (18Trusted Source).
Research has shown that supplementing with folic acid may reduce homocysteine levels and heart disease risk.
For example, a review that included 30 studies and over 80,000 people demonstrated that supplementing with folic acid led to a 4% reduction in overall heart disease risk and a 10% reduction in stroke risk (19Trusted Source).
What’s more, folic acid supplements may help reduce high blood pressure, a known heart disease risk factor (20Trusted Source).
Additionally, folic acid supplements have been shown to improve blood flow, which may help improve cardiovascular function (21Trusted Source).
Other potential benefits
Supplementing with folic acid has also been associated with the following benefits:
Diabetes. Folate-based supplements may help improve blood sugar control, reduce insulin resistance, and enhance cardiovascular function in those with diabetes. These supplements may also help reduce diabetic complications, including neuropathy (22Trusted Source, 23Trusted Source, 24Trusted Source).
Fertility. Higher intake of supplemental folate (more than 800 mcg per day) is associated with higher rates of live births in women undergoing assisted reproductive technology. Adequate folate is also essential for oocyte (egg) quality, implantation, and maturation (25Trusted Source).
Inflammation. Folic acid and folate supplements have been shown to reduce inflammatory markers, including C-reactive protein (CRP), in different populations, including women with polycystic ovary syndrome (PCOS) and children with epilepsy (26Trusted Source, 27Trusted Source).
Reduction of medication side effects. Folate-based supplements may help reduce the incidence of side effects related to the use of certain medications, including methotrexate, an immunosuppressant drug used to treat rheumatoid arthritis, psoriasis, and certain cancers (28Trusted Source).
Kidney disease. Due to impaired kidney function, hyperhomocysteinemia occurs in over 80% of people with chronic kidney disease. Supplementing with folic acid may help reduce homocysteine levels and heart disease risk in this population (29Trusted Source).
This list is not exhaustive, and there are many other reasons why people use folate-based supplements.
Genetic polymorphisms that affect folate status
Some people have genetic variations that affect how they metabolize folate. Genetic polymorphisms in folate metabolizing enzymes, such as methylenetetrahydrofolate reductase (MTHFR), can affect health by interfering with folate levels in the body.
One of the most common variants is C677T. People with the C677T variant have lower enzyme activity. As such, they may have elevated levels of homocysteine, which may increase heart disease risk.
People with severe MTHFR deficiency can’t make 5-methyltetrahydrofolate, the biologically active form of folate, and may have extremely low folate levels (30Trusted Source).
In addition to C677T, there are many other variants related to folate metabolism, including MTRR A66G, MTHFR A1298C, MTR A2756G, and FOLH1 T484C, that affect folate metabolism.
These variants may also increase the risk of birth defects, migraine, depression, pregnancy loss, anxiety, and certain cancers (30Trusted Source, 31Trusted Source).
The incidence of genetic variants that influence folate metabolism varies depending on ethnicity and geographical location. For example, the C677T mutation is more common in American Indian, Mexican Mestizo, and Chinese Han populations (30Trusted Source).
Recommended treatment typically involves supplementing with biologically active 5-methyltetrahydrofolate and other B vitamins. However, individualized treatment is often necessary (32Trusted Source).
If you’re interested in getting tested for genetic mutations that affect folate metabolism, including MTHFR, consult your medical provider for advice.
Folic acid for pregnancy
Folate plays essential roles in fetal growth and development. For example, it’s needed for cellular division and tissue growth. This is why having optimal folate levels is important both before and during pregnancy.
Since the 1990s, flour and other food staples have been fortified with folic acid based on study results linking low folate status in women with a significantly increased risk of neural tube defects in their children.
It has been proven that both food fortification programs and folic acid supplementation before and during pregnancy significantly reduces the risk of neural tube defects, including spina bifida and anencephaly (33Trusted Source).
Beyond its protective effect against birth defects, supplementing with folic acid during pregnancy may improve neurodevelopment and brain function in children, as well as protect against autism spectrum disorders (34Trusted Source, 35Trusted Source).
However, other studies have concluded that high folic acid intake and high levels of unmetabolized folic acid in the bloodstream may have a negative effect on neurocognitive development and increase autism risk, which will be discussed in the next section (36Trusted Source).
Folate is also important for maternal health, and supplementing with folic acid has been shown to reduce the risk of pregnancy-related complications, including preeclampsia. Additionally, high maternal folate levels have been associated with a significantly reduced risk of preterm birth (37Trusted Source, 38Trusted Source).
The RDA for folate during pregnancy is 600 mcg DFE (7Trusted Source).
Given folate’s importance for maternal and fetal health and the difficulty many women have meeting their needs through diet alone, it’s recommended that all women who are planning to become pregnant or capable of becoming pregnant supplement daily with 400–800 mcg of folic acid starting at least 1 month before becoming pregnant and continuing through the first 2–3 months of pregnancy (7Trusted Source).
Although folic acid supplements are most important during the first few months of pregnancy, some research shows that continuing to take folic acid throughout pregnancy may help boost folate levels in both maternal and umbilical cord blood (39Trusted Source).
It may also prevent the rise in homocysteine levels that usually occurs in late pregnancy. However, it’s not yet known if this is beneficial for pregnancy outcomes or child health (39Trusted Source).
Because a high intake of folic acid can result in high levels of unmetabolized folic acid in the blood and may be associated with negative health outcomes, many experts suggest that pregnant women take 5-methyltetrahydrofolate, the biologically active form of folate, rather than folic acid (40Trusted Source).
Unlike a high intake of folic acid, a high intake of 5-methyltetrahydrofolate does not lead to unmetabolized folic acid in the blood. Plus, studies have shown that 5-methyltetrahydrofolate is more effective at increasing red blood cell folate concentrations.
What’s more, women with common genetic polymorphisms that affect folate metabolism respond better to treatment with 5-methyltetrahydrofolate, compared with treatment with folic acid (40Trusted Source).
Side effects and precautions
Unlike with naturally occurring folate in food and biologically active supplemental forms of folate like 5-methyltetrahydrofolate, taking high doses of folic acid may lead to negative side effects.
Unmetabolized folic acid and increased risk of autism and neurocognitive development
As mentioned above, due to differences in metabolism, only a high intake of folic acid through fortified food or supplements may result in high blood levels of unmetabolized folic acid (36Trusted Source, 41Trusted Source.)
Eating folate-rich foods or taking natural forms of folate, such as 5-methyltetrahydrofolate, does not result in excess blood levels of folic acid.
Though some studies have associated high maternal levels of folic acid with a decreased risk of autism and improved mental outcomes in children, others have associated high levels of unmetabolized folic acid in the blood with an increased risk of autism and negative effects on neurocognitive development.
A recent study in 200 mothers found that mothers with higher blood concentrations of folate at the 14th week of gestation were more likely to have children with autism spectrum disorder (ASD) (42).
The researchers detected unmetabolized folic acid in a larger number of women who had children with ASD, compared with women who had children without ASD.
This suggests that supplementing with folic acid around week 14 of pregnancy was more common in women whose children later developed ASD (42).
It should be noted that unmetabolized folic acid is not likely to be found in the blood of people taking less than 400 mcg per day (42).
Other studies have shown that high levels of unmetabolized folic acid during pregnancy may lead to negative effects on neurocognitive development in children.
A study in 1,682 mother-child pairs found that children whose mothers supplemented with over 1,000 mcg of folic acid per day during pregnancy scored lower on a test that assessed the children’s mental abilities, compared with children whose mothers supplemented with 400–999 mcg per day (43Trusted Source).
Although these studies suggest that there may be risks to taking high doses of folic acid during pregnancy, more research is needed to confirm these findings.
High folic acid intake may mask B12 deficiency
Another possible risk of high folic acid intake is that taking high doses of synthetic folic acid may mask a vitamin B12 deficiency.
This is because taking large doses of folic acid can correct megaloblastic anemia, a condition characterized by the production of large, abnormal, underdeveloped red blood cells that’s seen with severe B12 deficiency (7Trusted Source).
However, supplementing with folic acid does not correct the neurological damage that occurs with B12 deficiency. For this reason, B12 deficiency may go unnoticed until potentially irreversible neurological symptoms appear.
Other potential risks of high folic acid intake
Aside from the potential side effects listed above, there are several other risks associated with taking high doses of folic acid:
Cancer risk. A review of 10 studies found a borderline significant increase in prostate cancer incidence in people who took folic acid supplements, compared with control groups (44Trusted Source).
Adult mental decline. Studies have shown that supplementing with high doses of folic acid may lead to accelerated mental decline in older people with low vitamin B12 levels (45Trusted Source, 46).
Immune function. Multiple studies have shown that high dose folic acid supplements may suppress immune function by reducing the activity of protective immune cells, including natural killer (NK) cells, and that presence of unmetabolized folic acid may be associated with reduced natural killer cell activity (47Trusted Source, 48Trusted Source).
It’s important to note that most people in the United States have adequate folate status and taking a supplement may not be appropriate.
For example, on average, adult men consume 602 mcg DFE per day, and adult women consume 455 mcg DFE per day, exceeding the 400 mcg DFE intake requirement through food alone (7Trusted Source).
Most U.S. children and teens exceed daily folate intake recommendations through dietary folate sources as well, with an average daily intake of 417–547 mcg DFE per day for children and adolescents ages 2–19 (7Trusted Source).
Dosage and how to take
As mentioned above, the RDA for folic acid is 400 mcg DFE per day for adults, 600 mcg DFE for pregnant women, and 500 mcg DFE for breastfeeding women (7Trusted Source).
Although these needs can be met through diet, taking a supplement is a convenient way to meet folate needs for many people, especially those at risk of deficiency, including pregnant women and older adults.
Folate and folic acid can be found in many forms and are commonly added to multinutrient supplements, including multivitamins and B-complex vitamins. Dosages vary widely, but most supplements deliver around 680–1,360 mcg DFE (400–800 mcg of folic acid) (7Trusted Source).
A tolerable upper intake level (UL), meaning the highest daily dose unlikely to cause adverse effects, has been set for synthetic forms of folate, but not for the natural forms found in food.
This is because adverse effects have not been reported from a high intake of folate from foods. For this reason, the UL is in mcg, not mcg DFE.
The UL for synthetic folate in supplements and fortified foods is as follows (7Trusted Source):
Research has shown that most children in the United States have adequate folate intake through diet, and between 33–66% of children ages 1–13 who supplement with folic acid exceed the UL for their age group due to the intake of fortified foods and supplements (7Trusted Source).
It’s important to consult your child’s healthcare provider before giving your child a folic acid supplement to determine appropriateness and safety.
That said, intake under 1,000 mcg per day is safe for the general adult population (7Trusted Source).
Folic acid is nearly 100% bioavailable when taken on an empty stomach and 85% bioavailable when taken with food. 5-methyltetrahydrofolate has similar bioavailability. You can take all forms of folate with or without food.
Overdose
Although there’s no set upper limit for food forms of folate, adverse effects may occur when taking doses of synthetic folate over the set UL of 1,000 mcg.
Your healthcare provider may recommend higher doses in certain circumstances, such as in the case of folate deficiency, but you should not take more than the UL without medical supervision.
One study reported a fatality due to intentional excessive folic acid ingestion (49Trusted Source).
However, toxicity is rare, as folate is water-soluble and readily excreted from the body. Even so, high dose supplementation should be avoided unless under medical supervision.
Interactions
Folate supplements may interact with some commonly prescribed medications, including (7Trusted Source):
Methotrexate. Methotrexate is a medication used to treat certain cancers and autoimmune diseases.
Epilepsy medications. Folic acid may interfere with antiepileptic medications, such as Dilantin, Carbatrol, and Depacon.
Sulfasalazine. Sulfasalazine is used to treat ulcerative colitis.
If you’re taking one of the medications listed above, consult your healthcare provider before taking folic acid supplements.
It should be noted that supplementing with 5-methyltetrahydrofolate rather than folic acid may reduce potential interactions with certain medications, including methotrexate (3Trusted Source).
Storage and handling
Store folate supplements in a cool, dry place. Keep supplements away from humid environments.
Use in specific populations
Folate supplements have been shown to be particularly important for certain populations, including pregnant women, people with genetic polymorphisms affecting folate metabolism, older adults in nursing homes, and people with low socioeconomic status who are more at risk of folate deficiency (6Trusted Source).
Adolescent girls may also be more vulnerable to folate deficiency. In fact, 19% of adolescent girls ages 14–18 don’t meet the estimated average requirement (EAR) for folate. EAR is the average daily intake of a nutrient estimated to meet the requirements of 50% of healthy individuals (7Trusted Source, 6Trusted Source).
Those who have undergone bowel resections or have conditions that cause nutrient malabsorption are encouraged to supplement with folate to avoid deficiency (6Trusted Source).
Additionally, folate supplements may be helpful for those with alcohol use disorders. Alcohol interferes with folate absorption and increases urinary excretion. People who regularly consume large amounts of alcohol may benefit from supplementing with folate (50Trusted Source).
Folate supplements should not be given to infants under 1 year of age. Breastmilk, formula, and food should be the only sources of folate in infant diets. Avoid supplementing infants with folate unless a healthcare provider advises you to do so (7Trusted Source).
Alternatives
There are many derivatives of folate. However, folinic acid, folic acid, and 5-methyltetrahydrofolate are the most widely used in dietary supplements.
Folinic acid is a naturally occurring folate that’s found in foods and commonly known as leucovorin in the clinical setting. Leucovorin is used to prevent toxic side effects of the drug methotrexate, which is used to treat certain types of cancer and megaloblastic anemia caused by folate deficiency.
Folinic acid is superior to folic acid, as it’s more effective at raising blood folate levels (51Trusted Source).
Some studies have shown that 5-methyltetrahydrofolate has superior absorbability over other forms of synthetic folate (3Trusted Source, 52Trusted Source).
Plus, 5-methyltetrahydrofolate is associated with fewer medication interactions, less likely to mask a B12 deficiency, and better tolerated by those with genetic polymorphisms like MTHFR (40Trusted Source).
For this reason, many experts recommend supplementing with 5-methyltetrahydrofolate over folic acid.
