What is folic acid?
Folic acid is a synthetic form of the essential B vitamin folate and is widely available as a dietary supplement and in fortified foods. Folic acid is the most widely available form of supplemental folate due to its high stability and bioavailability. Folate, or vitamin B9, is required for many vital biological pathways, including DNA synthesis, repair, and methylation; neurotransmitter synthesis; and the metabolism of homocysteine and other amino acids.[8][9] Accordingly, a folate deficiency may increase the risk of various diseases and can negatively affect fetal development during pregnancy.
The human body can’t make folate (apart from small amounts produced by the intestinal microbiome), so folate must be consumed in the diet or through supplementation.[2] Folate occurs naturally in a variety of foods, including green leafy vegetables, legumes, citrus fruit, eggs, and liver.[10] Additionally, some countries have mandated the fortification of certain cereal grains with folic acid (e.g., wheat, corn, rice), resulting in widespread exposure to folic acid through foods like bread and cereal.
While folic acid can serve a therapeutic role in certain contexts, supplementation in excess may have risks.
What are folic acid’s main benefits?
Folic acid is an effective treatment for megaloblastic anemia and for the prevention of neural tube defects (NTDs) when taken during early pregnancy or before conception.[11][12] Folic acid is also routinely recommended for people taking low-dose methotrexate (as used for some autoimmune conditions) and sulfasalazine, to reduce medication side effects and prevent deficiency, respectively.[6][13]
Folic acid supplementation reliably reduces plasma homocysteine concentrations, most notably in people with elevated homocysteine and low folate levels at baseline.[3] These reductions in homocysteine may have beneficial cardiovascular effects, including a reduction in the risk of stroke (particularly in regions without folate fortification),[14][15][16] improved endothelial function,[17][18][19] and reduced atherosclerosis progression.[20]
Does folic acid impact autism spectrum disorder?
Does folic acid improve depression?
Does folic acid improve blood sugar regulation?
Does folic acid improve inflammation?
Does folic acid improve cognitive function?
Does folic acid improve male infertility or erectile dysfunction?
Are there any additional benefits of folic acid supplementation during pregnancy?
Is folic acid still effective if you have a MTHFR polymorphism?
What are folic acid’s main drawbacks?
Folic acid is generally considered safe and well-tolerated when taken at appropriate dosages, but some people may experience gastrointestinal side effects such as diarrhea or nausea.[21]
When taken during pregnancy, observational studies suggest higher doses of folic acid may be associated with an increased risk of gestational diabetes,[22][23] childhood asthma,[24] and impaired psychomotor and neurological development.[25][26]
Folic acid can mask the signs of vitamin B12 deficiency. Left untreated, a vitamin B12 deficiency can lead to irreversible cognitive impairment and neuropathy (a type of nerve damage). This could be avoided by supplementing with vitamin B12 at the same time or having your blood levels of vitamin B12 checked to ensure they are normal. Importantly, natural folates found in food and supplemental L-methylfolate don’t carry this risk.[27]
Folic acid might lower the effectiveness of some medications, including anti-epileptic medications (e.g., phenytoin), which could increase the risk of seizures, and high-dose methotrexate used for cancer treatment.[28][29]
How does folic acid work?
The effects of folic acid are primarily due to the role that folate plays as a coenzyme in one-carbon metabolism — a series of metabolic pathways that are vital for normal cellular functioning. As a coenzyme, folate carries and donates one-carbon units that are required for processes like nucleic acid (DNA and RNA) synthesis and repair, amino acid metabolism (most notably the conversion of homocysteine to methionine), and cell division.[30] During pregnancy, folate is especially important to support the rapidly growing fetus and the increased blood volume of the mother.[2]
Folic acid supplementation can effectively reduce homocysteine levels by increasing the metabolism of homocysteine to methionine, which is proposed to be the mechanism by which folic acid can reduce inflammation and positively affect some aspects of cardiovascular health (e.g., stroke risk, endothelial function).[14] By increasing the production of methionine, folate increases levels of S-adenosylmethionine (SAMe), which is involved in the synthesis of neurotransmitters like serotonin and dopamine and regulates gene expression through DNA methylation.[31][32]
What are other names for Folic Acid (Vitamin B9)
- Folate
- Pteroylgutamic acid
- Vitamin B9
- Folacin
- Methylfolate
- L-Methylfolate
- L-5-Methylfolate
- Levomefolic acid
- 5-Methyltetrahydrofolate (5-MTHF)
Dosage information
Folic acid is most often taken at a dosage of 400 to 800 micrograms (μg), i.e., 0.4 to 0.8 mg, daily. The tolerable upper intake level (UL) of folic acid is 1,000 μg (1 mg) daily. This represents the maximum daily dose unlikely to cause adverse effects and was set based on the concern of folic acid masking vitamin B12 deficiency.[1] In some circumstances, a higher dosage may be warranted.
For the prevention of NTDs during pregnancy, folic acid can be dosed at 400 μg (0.4 mg) daily, ideally starting a minimum of 4 weeks before conception and continuing until at least the end of the first trimester. In women with a previous pregnancy affected by NTDs, the recommended dose may be much higher (4 to 5 mg daily).[2]
For reducing homocysteine levels, the maximum benefit can be achieved with folic acid 800 μg (0.8 mg) daily.[3]
When used for depression in addition to antidepressant medication, the best evidence currently suggests a dose of L-methylfolate 15 mg daily.[4][5]
For reducing the side effects of low-dose methotrexate (as used for some autoimmune conditions), a dosage of 500 to 1000 μg (0.5 to 1 mg) daily appears to be effective.[6]
The recommended daily allowance (RDA) of folate for adults is 400 μg dietary folate equivalents (DFEs) daily, as per the Institute of Medicine. This represents the average amount of folate that is thought to meet the nutritional requirements of most healthy people. Natural dietary folate has a lower bioavailability than folic acid, so DFEs are used to convert between the two. For example, 1 μg of dietary folate (1 DFE) is approximately equal to 0.6 μg (taken with food) or 0.5 μg (taken without food) of folic acid. So, to get 400 μg DFEs entirely from supplementation, you would need to take approximately 200 to 240 μg of folic acid.[7]
Examine Database: Folic Acid (Vitamin B9)
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In this meta-analysis of observational studies, participants with Parkinson’s disease had higher levels of homocysteine and lower levels of both vitamin B12 and folate in comparison with healthy controls.
Frequently asked questions
Folic acid is a synthetic form of the essential B vitamin folate and is widely available as a dietary supplement and in fortified foods. Folic acid is the most widely available form of supplemental folate due to its high stability and bioavailability. Folate, or vitamin B9, is required for many vital biological pathways, including DNA synthesis, repair, and methylation; neurotransmitter synthesis; and the metabolism of homocysteine and other amino acids.[8][9] Accordingly, a folate deficiency may increase the risk of various diseases and can negatively affect fetal development during pregnancy.
The human body can’t make folate (apart from small amounts produced by the intestinal microbiome), so folate must be consumed in the diet or through supplementation.[2] Folate occurs naturally in a variety of foods, including green leafy vegetables, legumes, citrus fruit, eggs, and liver.[10] Additionally, some countries have mandated the fortification of certain cereal grains with folic acid (e.g., wheat, corn, rice), resulting in widespread exposure to folic acid through foods like bread and cereal.
While folic acid can serve a therapeutic role in certain contexts, supplementation in excess may have risks.
Folic acid fortification refers to the addition of folic acid to the food supply — most commonly through the enrichment of wheat, rice, and corn — in an attempt to reduce the potential consequences of folate deficiency. Fortification became mandatory in the United States and Canada in 1998, and today over 80 countries follow similar practices.[33][34]
The rationale for fortification was to prevent NTDs — a group of potentially fatal birth defects that can occur within the first four weeks of pregnancy, particularly in the context of folate deficiency. To reap the benefits, a woman ideally needs to start supplementing at least 4 weeks before conception, and because many pregnancies are unplanned, fortification ensures that women are universally exposed to folic acid. Observational research suggests that countries that introduced mandatory fortification have seen 30 to 60% reductions in the rates of NTDs.[33][35][36][37] Compared to regions without fortification, rates of NTDs are generally observed to be lower in countries with fortification; however, differences in monitoring strategies between countries make it difficult to draw accurate conclusions.[35]
Fortification may have had other positive consequences, including reductions in rates of anemia and reduced levels of homocysteine, which may have translated to a small reduction in the rate of strokes.[38][37][39][40][41]
Alternatively, fortification may have led to some unintended negative health consequences. Folic acid fortification has been associated with an increased risk of cognitive impairment in older adults with concurrent low vitamin B12 levels.[42][43] This could be because folic acid can mask the clinical signs of a vitamin B12 deficiency, meaning the deficiency may go untreated, potentially leading to irreversible cognitive impairment in the long term.[42]
Additionally, when folic acid fortification was being implemented in North America between 1996 and 1998, a short-term increase in the rate of colorectal cancer was observed (approximately 4 to 6 additional cases per 100,000 people).[44] While research has generally found folic acid intake to have a neutral or beneficial effect on colorectal cancer risk,[45][46][47] there is evidence that high intakes of folate might exacerbate preexisting precancerous lesions.[48][49] However, colorectal cancer rates returned to normal after 1998, which calls into question whether fortification was truly the factor driving the short-term increase.[50]
Lastly, there is concern that increased exposure to unmetabolized folic acid (UMFA) at a population level may have negative health consequences. UMFA occurs when the amount of folic acid ingested exceeds the body's ability to convert it to a usable form of folate, and UMFA has been found in the serum of nearly all Americans post-fortification.[51] Currently, there is very little evidence for or against the safety of UMFA and further research is needed.
Folate deficiency can occur for several reasons, including:[27][2][95][17]
- Insufficient dietary intake
- Certain medications (e.g., methotrexate, antiepileptics, oral contraceptives)
- Impaired absorption (e.g., celiac disease, gastric bypass, alcohol use disorder)
- Pregnancy (due to an increased biological demand for folate)
- Genetic polymorphisms (e.g., MTHFR, DHFR)
A folate deficiency can be diagnosed by doing a blood test, as the primary clinical sign is a type of anemia characterized by abnormally large and underdeveloped red blood cells (megaloblastic anemia).[17] Symptoms of deficiency can include fatigue, poor concentration, increased heart rate (tachycardia), irritability, dizziness, pale skin, and a painful red tongue.[2]
L-methylfolate, also known as methylfolate or 5-methyltetrahydrofolate (5-MTHF), is the primary active form of folate found in the body, and it directly participates as a coenzyme in metabolic pathways. Since L-methylfolate does not require enzymes like DHFR and MTHFR for activation (unlike folic acid), it has been suggested as an alternative way to supplement folate, particularly in people with genetic mutations that reduce the effectiveness of these enzymes.[34]
Research suggests that L-methylfolate supplementation can increase plasma and red blood cell folate levels to a similar or greater extent than folic acid when given at equivalent doses and can comparably reduce plasma homocysteine levels.[103][104][105] Additionally, unlike folic acid supplementation, L-methylfolate is both less likely to mask a vitamin B12 deficiency and avoids the unknown potential consequences of unmetabolized folic acid in the body.[106]
Despite the promising features of L-methylfolate, folic acid has been used in the vast majority of clinical trials, and it hasn’t been established that L-methylfolate provides the same benefits as folic acid — including for the prevention of NTDs. An exception to this is folate supplementation for depression: there is evidence to suggest that L-methylfolate may be more effective than folic acid.[4][5]
Folic acid is an effective treatment for megaloblastic anemia and for the prevention of neural tube defects (NTDs) when taken during early pregnancy or before conception.[11][12] Folic acid is also routinely recommended for people taking low-dose methotrexate (as used for some autoimmune conditions) and sulfasalazine, to reduce medication side effects and prevent deficiency, respectively.[6][13]
Folic acid supplementation reliably reduces plasma homocysteine concentrations, most notably in people with elevated homocysteine and low folate levels at baseline.[3] These reductions in homocysteine may have beneficial cardiovascular effects, including a reduction in the risk of stroke (particularly in regions without folate fortification),[14][15][16] improved endothelial function,[17][18][19] and reduced atherosclerosis progression.[20]
It has been hypothesized that autism spectrum disorder (ASD) may have a connection with folate insufficiency or excess, but the evidence is mixed and largely inconclusive.
Folate is undoubtedly crucial for fetal neurodevelopment during early pregnancy. Folic acid supplementation during pregnancy, often in the form of a multivitamin, has generally been associated with neutral to beneficial effects on ASD risk.[63][64] However, both high and low levels of maternal serum folate during pregnancy have been associated with an increased risk of ASD.[65][66]
Lending support to the theory of a connection between folate and ASD, a 2021 meta-analysis of observational studies found that children with ASD were 19 times more likely to have cerebral folate receptor autoantibodies, which could indicate a reduced capacity to transport folate into the brain.[67] Additionally, autism is associated with an increased likelihood of MTHFR polymorphism, suggesting impaired folate metabolism.[68]
While further research is needed to understand the relationship between folate and autism, it seems fair to suggest that folic acid supplementation at appropriate doses during pregnancy may have a neutral to beneficial effect on the risk of ASD.
Folic acid may have a role in managing depression for some people when taken along with prescription antidepressants. Still, more research is needed to understand this effect and what form of supplemental folate may be most effective.
Mechanistically, folate is involved in the generation of S-adenosylmethionine (SAMe), a compound that is important for synthesizing neurotransmitters like dopamine, norepinephrine, and serotonin. Additionally, low folate levels may lead to high homocysteine, which has been positively correlated with depression symptom severity.[31] Although research has generally been mixed regarding whether depression is associated with reduced folate status,[69][70][31] folate deficiency has been associated with an increased risk of depression and longer, more severe episodes of depression.[31]
Folic acid taken along with antidepressant medications, specifically selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs), may reduce depression symptoms and increase rates of remission compared to antidepressants alone.[71][9][72] However, supplementing with L-methylfolate (an active form of folate that can cross the blood-brain barrier) may be more effective than folic acid.[4][5]
Importantly, there is insufficient research to suggest that folic acid or L-methylfolate taken alone is effective for depression or to determine whether folic acid or L-methylfolate are effective when taken with other types of antidepressants (e.g., tricyclic antidepressants).
Folic acid supplementation may have minor benefits on blood glucose regulation, but these effects are probably not clinically relevant. Research suggests that folic acid may slightly reduce fasting blood glucose, fasting insulin, and HOMA-IR (a marker of insulin resistance), but not in people with type 2 diabetes. Additionally, folic acid does not appear to affect hemoglobin A1c.[73][74][75]
Folic acid does seem to have anti-inflammatory effects, likely by reducing levels of homocysteine. Research suggests that folic acid supplementation may reduce C-reactive protein and TNF-alpha in a variety of populations including people with metabolic syndrome and type 2 diabetes.[76][77][78] However, most studies have been small and the clinical relevance of this effect isn’t clear.[77]
Although it’s mechanistically plausible that folic acid supplementation could improve cognitive function, in clinical trials it does not seem to have a significant effect.
High levels of homocysteine and low levels of folate have been associated with an increased risk of dementia and Alzheimer’s disease.[79][80] While this doesn’t prove that high homocysteine and low folate can cause cognitive decline, mechanistically such an effect could make sense.
Folate deficiency can lead to high levels of homocysteine which in turn can result in oxidative stress and stimulation of N-methyl-D-aspartate (NMDA) receptors, both of which could have toxic effects on neurons.[79] Additionally, folate is involved in the development and repair of nerve cells.[81] Despite this, clinical trials have generally been anticlimactic, and folic acid supplementation has demonstrated little to no benefit on various measures of cognitive function, including memory, in older adults with or without dementia.[82][83]
In fact, folic acid fortification in North America has been associated with an increased risk of cognitive impairment in older adults.[42][43] This may be because folic acid can mask the hematological signs of a vitamin B12 deficiency, potentially leading to an undiagnosed deficiency which may result in irreversible cognitive decline in the long term.[42]
Observational studies have found that men with erectile dysfunction (ED) tend to have lower levels of plasma folate compared to men without ED, and folate level seems to negatively correlate with the severity of ED.[84][85] While research is still preliminary, folic acid supplementation may improve symptoms of ED for some men, including when used in addition to the ED medication tadalafil.[85]
As it relates to male infertility, limited research suggests that folic acid supplementation may increase sperm motility in infertile men, but does not seem to affect sperm concentration or morphology. It’s currently unknown if this benefit leads to increased rates of pregnancy.[86] Interestingly, genetic polymorphisms in methionine synthase (MTR) — an enzyme involved in folate metabolism — have been strongly associated with male infertility, most notably in Asian populations.[8] It’s been suggested that folic acid may improve male fertility through antioxidant mechanisms or by promoting DNA methylation during sperm production.[86]
Ensuring a mother has adequate amounts of folate during pregnancy is clearly beneficial for fetal development, although there may be adverse effects if taken beyond recommended dosages. Additionally, folate exposure during pregnancy may impact the infants' epigenome (gene expression), potentially influencing health in the long term.[87]
In the 1990s several large randomized controlled trials (RCTs) conducted in various countries found that folic acid supplementation was effective at lowering the risk of fetal NTDs when taken before conception.[88][89][90] In response, folic acid supplementation is now routinely recommended to women who are pregnant or trying to conceive. Because of the clear benefits of folic acid supplementation, it’s no longer ethical to perform RCTs where one group of pregnant women is given folic acid and the other is not. As a result, much of the research we have today is from decades-old RCTs or observational studies, providing an overall weaker evidence base.
Limited data from RCTs suggests that folic acid supplementation likely reduces the rate of pregnancy termination due to NTDs and may increase birth weight, although research is mixed on the latter.[91][92][12] Unfortunately, folic acid has not been found to protect against other types of congenital disorders, such as cleft lip, cleft palate, or congenital heart defects.[12].
Observational research suggests that folic acid supplementation during pregnancy may be associated with a reduced risk of certain types of childhood cancers,[93][94] and a reduced risk of autism and attention deficit hyperactivity disorder (ADHD) traits.[26]
Folic acid at a sufficient dose should still increase folate levels regardless of a methylenetetrahydrofolate reductase (MTHFR) polymorphism, although the response may be slightly less than in someone without an MTHFR polymorphism.[99]
MTHFR is the key rate-limiting enzyme required for the conversion of folic acid into L-methylfolate, the main active form of folate in the body. MTHFR is prone to genetic mutations called single-nucleotide polymorphisms (SNPs) which can reduce the functioning of the enzyme, leading to impaired production of L-methylfolate and lower overall folate levels.[30][100] Accordingly, people with MTHFR polymorphisms have an increased need for folate.
Approximately 25% of the global population has an MTHFR polymorphism, and these polymorphisms are associated with an increased risk of various medical conditions including heart and blood vessel disease, infertility, certain types of cancer, and NTDs.[101][99] However, there’s evidence that when folate levels are adequate, disease risk may be the same as for those without MTHFR mutations.[102] When comparing how people with and without MTHFR polymorphisms respond to folic acid supplementation, people with polymorphisms do see a slightly lower increase in plasma folate levels. Still, folate increases to an adequate level regardless.[99]
Supplementing with L-methylfolate bypasses MTHFR and may be more efficient at raising folate levels in people with MTHFR polymorphisms, but this supplemental form of folate is much less researched than folic acid.
Folic acid is generally considered safe and well-tolerated when taken at appropriate dosages, but some people may experience gastrointestinal side effects such as diarrhea or nausea.[21]
When taken during pregnancy, observational studies suggest higher doses of folic acid may be associated with an increased risk of gestational diabetes,[22][23] childhood asthma,[24] and impaired psychomotor and neurological development.[25][26]
Folic acid can mask the signs of vitamin B12 deficiency. Left untreated, a vitamin B12 deficiency can lead to irreversible cognitive impairment and neuropathy (a type of nerve damage). This could be avoided by supplementing with vitamin B12 at the same time or having your blood levels of vitamin B12 checked to ensure they are normal. Importantly, natural folates found in food and supplemental L-methylfolate don’t carry this risk.[27]
Folic acid might lower the effectiveness of some medications, including anti-epileptic medications (e.g., phenytoin), which could increase the risk of seizures, and high-dose methotrexate used for cancer treatment.[28][29]
There is convincing evidence that folate could play a modulatory role in cancer development, which may be positive or negative depending on the context. While adequate folate levels may be protective, too little may encourage cancer development, and too much may exacerbate preexisting cancer. The effect of supplemental folic acid on cancer risk has generally been found to be neutral, although research results have been mixed.
Folate is required for the maintenance, repair, and methylation of DNA, all of which serve preventative roles against cancer. Accordingly, a folate deficiency can lead to increased DNA breaks, mutations, and hypomethylation, which may increase cancer risk.[52][53] Folate is also required for DNA synthesis and cell division, meaning that it could serve as a growth factor for preexisting cancerous or precancerous cells.[52] Indeed, many cancer cells have increased expression of the membrane receptors responsible for folate uptake,[54] and antifolate medications (e.g., methotrexate, pemetrexed), which block folate metabolism, are effective treatments for some cancers.[55]
The vast majority of epidemiological research has shown that higher intakes of folate are associated with a reduced or unchanged risk of various types of cancer compared to lower intakes.[56][57][58][59][60][52][47] Regarding supplemental folic acid, two meta-analyses of randomized controlled trials (RCTs) concluded that supplementation had no impact on the incidence of cancer in general or specific types of cancer.[45][61][50] Contrary to this, another meta-analysis reported an increased risk of prostate cancer with supplementation.[61] In 2023, the European Food Safety Authority (EFSA) expert panel stated that there was insufficient evidence to suggest a causal relationship between folic acid and the risk of prostate cancer or any other type of cancer.[62]
Concern has been raised about the potential negative effects of unmetabolized folic acid (UMFA), but research on the safety of UMFA is lacking.
After consumption, folic acid must be converted into a usable form by the enzyme dihydrofolate reductase (DHFR). However, DHFR can become easily saturated, leading to a build-up of UMFA. The 2007–2008 National Health and Nutrition Examination Survey (NHANES) found that UMFA was detectable in >95% of Americans who provided serum samples.[51]. UMFA doesn’t behave like natural folate in the body and is generally thought to have no biological effects. However, exactly how UMFA interacts with the body is poorly understood, and it’s unclear whether there are any health risks with long-term exposure.[96]
Preliminary research has raised the concern that UMFA might negatively affect immune function and have an inhibitory effect on normal folate metabolism, but further research is needed.[97][1][98]
The effects of folic acid are primarily due to the role that folate plays as a coenzyme in one-carbon metabolism — a series of metabolic pathways that are vital for normal cellular functioning. As a coenzyme, folate carries and donates one-carbon units that are required for processes like nucleic acid (DNA and RNA) synthesis and repair, amino acid metabolism (most notably the conversion of homocysteine to methionine), and cell division.[30] During pregnancy, folate is especially important to support the rapidly growing fetus and the increased blood volume of the mother.[2]
Folic acid supplementation can effectively reduce homocysteine levels by increasing the metabolism of homocysteine to methionine, which is proposed to be the mechanism by which folic acid can reduce inflammation and positively affect some aspects of cardiovascular health (e.g., stroke risk, endothelial function).[14] By increasing the production of methionine, folate increases levels of S-adenosylmethionine (SAMe), which is involved in the synthesis of neurotransmitters like serotonin and dopamine and regulates gene expression through DNA methylation.[31][32]
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References
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