Table of Contents Hide
- What is folic acid?
- Recommended intake levels
- Benefits and uses
- Genetic polymorphisms that affect folate status
- Folic acid for pregnancy
- Side effects and precautions
- Dosage and how to take
- Storage and handling
- Use in specific populations
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.
- 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 (
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
- hemolytic anemia
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 (
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 (
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 (
Because of this variability in absorption, DFEs were developed according to the following equation (
- 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 (
The Recommended Dietary Allowance (RDA) for infants, children, and teens are as follows (7):
- 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
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 (7).
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 (7).
Folic acid supplements are prescribed to pregnant women to prevent fetal birth defects and may also help prevent pregnancy-related complications, including preeclampsia (
Treatment of folate deficiency
Folate deficiency can occur due to a variety of causes, including inadequate dietary intake, surgery, pregnancy, alcoholism, and malabsorptive diseases (
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,
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 (
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 (
Adjunctive treatment of mental health disorders
People with depression have been shown to have lower blood levels of folate than people without depression (
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 (
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 (
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 (
What’s more, folic acid supplements may help reduce high blood pressure, a known heart disease risk factor (
Additionally, folic acid supplements have been shown to improve blood flow, which may help improve cardiovascular function (
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 (
22, 23, 24).
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 (
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 (
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 (
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 (
This list is not exhaustive, and there are many other reasons why people use folate-based supplements.
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 (
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.
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 (
Recommended treatment typically involves supplementing with biologically active 5-methyltetrahydrofolate and other B vitamins. However, individualized treatment is often necessary (
If you’re interested in getting tested for genetic mutations that affect folate metabolism, including MTHFR, consult your medical provider for advice.
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 (
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 (
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 (
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 (
The RDA for folate during pregnancy is 600 mcg DFE (7).
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 (7).
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 (
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 (
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 (
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 (
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
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 (
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 (7).
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 (
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 (
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 (
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 (7).
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 (7).
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 (7).
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) (7).
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 (7):
|Children ages 14–18||800 mcg|
|Children ages 9–13||600 mcg|
|Children ages 4–8||400 mcg|
|Children ages 1–3||300 mcg|
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 (7).
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 (7).
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.
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 (
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.
Folate supplements may interact with some commonly prescribed medications, including (7):
- 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 (
Store folate supplements in a cool, dry place. Keep supplements away from humid environments.
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 (
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 (7,
Those who have undergone bowel resections or have conditions that cause nutrient malabsorption are encouraged to supplement with folate to avoid deficiency (
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 (
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 (7).
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 (
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 (
For this reason, many experts recommend supplementing with 5-methyltetrahydrofolate over folic acid.