Folate and Folic Acid: Health Benefits and Common Uses

Folate is essential for our health. Learn about the many health benefits of folate and folic acid and find out how they are used for treating different medical conditions.

What are Folate and Folic Acid

Folate is a form of water soluble B vitamin, called vitamin B9. The term encompasses different forms of folate – both natural as well as synthetic folates.

Our body uses folate for making our DNA and other genetic material.  Folate also plays an important role in the divison of cells. It is essential for our health and can be taken for preventing or alleviating a range of medical conditions.

Folate naturally occurs in many foods, such as green leafy vegetables, legumes, and some fruits.  It is also sold in different forms in dietary supplements and added to certain fortified foods (such as cereals).  

Many people, even doctors and nutritionists, use the terms folate and folic acid interchangeably, so we often assume that they are the same. However, there are important differences between them.

In our article, we use the word ‘folate’ for the naturally occurring forms of folate. The term ‘folic acid’ is used for the synthetic, oxidized form of folate.

Natural Folates

Natural folates are found in different chemical forms in food sources and metabolically active forms in our body.  

Maintaining sufficient folate levels has been shown to have important health benefits. Natural folates support the health of our nervous system, decrease the risk of heart disease and stroke, prevent folate deficiency anemia and help prevent cancer development.

The main form of folate found in our body is called tetrahydrofolate. 

Folic Acid

Folic acid is the synthetic form of folate, which is prevalent in nutritional supplements and fortified foods. 

Folic acid was first synthesized in 1943. Before that it was nonexistent in human body. Later on, researchers discovered that folic acid helps prevent neural tube defects in infants by raising the levels of folate in the blood.

For that reason, folic acid was included into food fortification program in 1998 and can now be found in many store-bought foods.

However, our body can’t use folic acid directly. Once ingested, it must first be converted into the biologically active form - tetrahydrofolate. This process requires the help of a certain enzyme dihydrofolate reductase.

When a person has low activity of this enzyme, supplementing with folic acid can lead to high levels of unmetabolized folic acid in the blood (1). This may lead to several consequences.

Dangers of Excessive Blood Levels of Folic Acid

Folic Acid Intake May Hide B12 Deficiency

Regularly taking supplements or fortified foods with folic acid may mask the symptoms of B12 deficiency. If left untreated, the deficiency in B12 vitamin detrimentally affects the nervous system and causes symptoms, such as tingling, difficulty walking, depression, memory problems and in most severe cases dementia. It may also lead to pernicious anemia in which the body is unable to make enough healthy blood cells (2).

Folic Acid Supplements Have Been Linked to Cancer Growth

Having adequate level of natural, biologically active folate in blood has been proven to help prevent cancer.

The relation between folic acid and the risk of cancer is not so clear, though.

Some studies have shown that supplementing with folic acid may trigger existing pre-cancerous growths and lesions to turn into cancer (3).  Most of these studies have dealt with colorectal cancer and colon polyps (4, 5).

There have been other studies, though, showing that folic acid supplements don’t lead to higher cancer rates (6, 7, 8).

Some researchers say that taking very high amounts of folic acid may be problematic (upper daily intake recommendation for adults is 1.000 mcg per day) - and that taking the typically recommended daily amount (400mcg) shouldn’t be a concern.

But still, it is always best to err on the side of caution. And since it is uncertain whether or not folic acid supplementation may increase your cancer risk, it would be prudent to stay away from these supplements for the time being.

Why Should You Take Natural Form of Folate (5-MTHF) Instead of Folic Acid

The naturally occurring form of folate - 5-MTHF has several advantages over synthetically made folic acid.

Unlike Folic Acid, 5-MTHF Reliably Raises the Blood Folate Levels

The conversion of folic acid into the form of folate that our body uses, called tetrahydrofolate, requires several steps. Some people have metabolic defect that prevents the folic acid to be converted effectively.

This may lead to low levels of folate in the blood even if they take a dietary supplement with recommended daily amount of folic acid.  A well known case where this happens is the MTHFR gene mutation. This mutation leads to low activity of the enzyme called methylenetetrahydrofolate reductase and affects the body’s ability to use folic acid.

Taking 5-MTHF Instead of Folic Acid Reduces the Risk of Undiagnosed B12 deficiency

For many people, the first sign of B12 deficiency is anemia. Taking folic acid masks the hematological symptoms of vitamin B12 deficiency. This means that deficiency doesn’t show on the blood, but at the same time neurological damage continues unchecked.

On the other hand, 5-MTHF doesn't mask the anemia, which means that B12 deficiency can be recognized and treated without delay.

5-MTHF Doesn't Build Up to Excessive Levels in the Body

5-MTHF is tetrahydrofolate, which is the biologically active form of folate. There is no conversion needed – the body simply uses the amount that it needs and the rest is excreted in urine. Taking 5-MTHF instead of folic acid effectively eliminates the possible risks of having unconverted folic acid in blood stream (9). 

Other commonly used names for folate/folic acid: folic acid, 5-methyltetrahydrofolate, 5-MTHF, L-methylfolate, methylfolate, vitamin B9, folinic acid, folacine

Folate deficiency

Most people have sufficient levels of folate in their blood. However, some simply don’t get enough folate from their diet or they have troubles absorbing it from food. This may lead to low blood levels of folate or the so called folate deficiency.

Causes of Low Folate Levels

Certain people are more likely to suffer from folate deficiency. Risk factors include:

  • Diet low in folate rich foods, such as green leafy vegetables and legumes
  • Alcoholism
  • Kidney and liver diseases
  • Conditions that affect intestinal absorption, such as inflammatory bowel disease or celiac disease
  • Sickle cell disease
  • Smoking (some studies show that smokers have 15% lower folate in their blood than non smokers)
  • Taking certain medications for seizures, cancer or arthritis
  • Pregnancy (pregnant women need higher levels of folate to support the healthy development of the baby’s nervous system)

Symptoms of Folate Deficiency

Having too little folate may eventually lead to a range of problems.

Folate deficiency can cause megaloblastic anemia, which is a condition where your body can't make enough healthy red blood cells.  Blood cells become larger and there are fewer of them. This makes you feel weak, fatigued and short of breath. Other symptoms of anemia include troubles concentrating, irritability and memory problems.

Low folate levels also contribute to stomach and gum inflammation (gingivitis). The tongue may feel smooth and tender and there may be open sores on the tongue and lining of the mouth.

Typically, people with folate deficiency also have pale skin, brittle fingernails and suffer from hair loss.

Folate deficiency in pregnancy is especially important as it may cause neural tube defects in the baby, premature birth or low birth weight.

What Does Folate Do in the Body

Folate Helps Create the Body’s Genetic Material

Folate is essential for the creation of our DNA and RNA and production of new cells. Sufficient folate levels are especially important at times when cells are dividing rapidly, such as pregnancy and early infancy.

Folate also prevents the changes to DNA, which in turn decreases the risk of cancer.

Folate is Involved in Metabolism of Different Amino Acids

Folate participates in metabolism of several amino acids, including cysteine, serine, methionine, glycine and histidine.

Folate Deficiency Raises Blood Levels of Homocysteine

Low folate levels may lead to accumulation of a certain amino acid, called homocysteine.

High concentrations of homocysteine in the body have been linked to an increased risk of heart disease and stroke. There is also some evidence that people with increased homocysteine are more likely to develop Alzheimer’s disease.

 It helps Create Healthy Red Blood Cells

We need folate to make both red as well as white blood cells. Folate deficiency leads to the creation of abnormal blood cells, called megaloblastic anemia.

Folate is Vital for Nervous System Health

Folate is important for the functioning of the nervous system and supports our mental and emotional well-being. Insufficient levels of folate have been linked to conditions, such as depression, anxiety, dementia, and Alzheimer’s disease.

Common Medical Uses of Folate and Folic Acid

People take folate supplements for many different reasons. Most nutritional supplements on the market contain folate in the form of synthetic folic acid, since it is more easily synthesized and stable than other forms of folate.

That is why a large majority of studies presented below include the use of folic acid.

However, you can also find supplements with folate in the form of 5-MTHF (sometimes the label also says l-methylfolate or simply methylfolate). For many reasons, these supplements are a better choice. They are becoming more and more used by general population as well as studied by researchers as new understanding emerges of the important differences between methylfolate and folic acid.

Folate For Preventing Neural Tube Defects in Pregnancy

Most well-known use of folate supplements is for preventing neural tube defects in pregnancy. This defect occurs when the neural tube doesn’t close properly and affects the baby’s brain, spine or spinal cord. Neural tube defect happens in the first month of pregnancy, when many women aren’t even aware that they are pregnant. For that reason, experts suggest that all women of childbearing years take a folate supplement as a precaution.

Studies show that folic acid/folate supplementation reduces the rate of all types of neural tube defects (anencephaly, spina bifida, encephalocele) by 57% to 83% - depending on the type of defect (10, 11).  

For Reducing the Risk of Other Birth Defects, Miscarriage and Autism

There is also evidence that folate prevents other birth defects, such as cleft lip and cleft palate (12, 13).  

Studies have mixed results about whether or not folate supplementation during pregnancy may alleviate the risk of autism in children.

In 2013, a population based study in Norway, which included 109.000 children, showed that taking folic acid during pregnancy may be beneficial for the neurological development of the children and decrease the rate of autism (14). However, a few years later another multi-center study (13) hasn’t been able to replicate the results (15). 

An examination of 22 studies on the subject (16) has found 15 studies confirming beneficial effect of folic acid during pregnancy on the rate of autism in children, 6 studies have shown no difference, while one study has indicated that extremely large doses of folic acid during pregnancy might even raise the risk of autism (the dose in this study was more than 5 micrograms daily; typically recommended dose is much smaller).  The reason for the results of the last study might be large amounts of unconverted folic acid in the bloodstream, which could be avoided by taking 5-MTHF supplement instead of folic acid.

Folate during pregnancy also has other benefits for both the mother as well as the child. One of the important actions of folate is decreasing the blood levels of homocysteine. This prevents many pregnancy complications – since high homocysteine concentrations are associated with preeclampsia, placental abruption, low birth weight and even miscarriage (17).

Folate for Protecting the Heart

Folate also offers protection against heart disease. It supports heart health in several different ways.

As mentioned earlier in the article, folate is well known for reducing blood levels of amino acid homocysteine. There is evidence that high homocysteine is associated with increased risk of heart disease.

It is not clear whether high homocysteine directly causes heart disease or if it is just an indicator of heart problems. However, many people still take a folate supplement as a preventive measure. And it has been shown that supplemental folate is able to reduce high homocysteine levels by as much as 20 % to 30%. It works best when taken together with vitamins B12 and B6.

Besides lowering homocysteine levels, folate also slightly decreases high blood pressure, which is a major risk factor for heart disease.

As shown by recent analysis of 12 clinical trials (18), high doses of folate also improve another important factor in heart disease – the endothelial dysfunction (dysfunction in the blood vessel lining). Damages to the blood vessels and changes in endothelial function commonly precede the development of cardiovascular disease. 

Folate Supplements for Reducing the Risk of Stroke

Folate also decreases the risk of stroke.  The mechanisms that enable this effect seem to be the same as those that support heart health. They include reducing homocysteine concentration, decreasing high blood pressure, reducing high cholesterol levels, and improving the function of blood vessel lining (19, 20, 21).

That is why many health professionals encourage people who are at risk of stroke to take a daily supplement that contains B vitamin complex with plenty of folate.

Folate for Age-Related Macular Degeneration (AMD)

Low levels of folate and high levels of amino acid homocysteine have been linked to age related macular degeneration and vision loss (22).  Taking folate supplements along with B6 and B12 lowers high homocysteine levels and reduces the risk of developing AMD.

A 2009 study examined the effect of these 3 supplements on women aged 40 years or more who had several risk factors for AMD. 5442 women were monitored for over 7 years. The researchers found that daily supplementation with folate, B6 and B12 reduced the risk for any AMD by 34% and visually significant AMD by 41% (23). The beneficial effects were first observed after 2 years of supplementation – so it takes a while for the supplementation to make a difference.

Taking Folate for Depression

Research has shown that many people with depression have low folate levels in their blood.  Those people that don' respond well to antidepressants might benefit from taking a folate supplement alongside their medication (SSRIs).

Larger doses of folate seem to work better than smaller doses. One study (24), for example, has shown that 5mg of folic acid per day outperforms 1.5mg per day.

However, another multic center trial has failed to find any benefits of folic acid. Instead, researchers proposed that folate in the form of 5-MTHF may work better for people with depression since it is metabolized differently (25).  

Folate for Decreasing the Risk of Alzheimer's Disease

Folate is essential for normal brain development in early childhood and healthy nervous function throughout life.

Several studies examined the relation between folate and Alzheimers disease. A 2015 meta-analyses of 68 relevant studies (26) found that people with Alzheimer’s disease typically have higher levels of homocysteine and lower levels of folate and vitamin B12 in their blood than healthy control subjects. The differences in these levels tend to increase with age.

The results of the analyses also suggest low levels of folate and high levels of homocysteine in the blood are not merely an indicator of the disease, showing that something is wrong. Instead, they are an independent risk factor, which contributes to the development of the disease.

Folate For Cancer Prevention

Regularly eating foods with plenty of folate seem to protect against several different cancers, including colon cancer, stomach cancer, breast cancer, cervical cancer and pancreatic cancer.  

Many believe that the reason for this is folate's importance in the division of our cells. Folate helps keep our genetic material healthy and prevents the changes in DNA that might lead to the development of cancer.

Folate For Gum Problems

The cells in the lining of the mouth have one of the highest rates of turnover in the body. Due to its role on cell division folate is crucial for gum health.  

Too little folate may cause gum inflammation (gingivitis).  This condition is characterized by swollen, red and irritated gums that bleed easily.

Studies have shown that mouthwash with folate is very effective for lowering gum inflammation. On the contrary, folate taken in the form of tablets or capsules doesn't seem to improve the condition of the gums or it has minimal effects on gingivitis (27, 28).

Food Sources of Folate

Foods that are high in folate are primarily green leafy vegetables, such as broccoli, lettuce, spinach, brussels sprouts, turnip greens and parsley. Legumes are also rich in folate (beans, peas, lentils). Other vegetables that contain folate include avocado, okra, asparagus and beets.

Some fruits, but not all, are also a good source of folate (strawberries, bananas, lemons, melons, papayas, oranges).

Folate can also be found in meat and organs. Beef liver is an excellent source of folate.

Natural folate is susceptible to light and high heat, so lots of folate from food is lost with cooking and incorrect storage.

Fortified Foods

Fortified foods contain the synthetic form of folate, folic acid. Folic acid is primarily added to flour and other grain products (for example bread, pasta, cornmeal, cereals, etc). 

You might also be interested in:

  1. Wright AJ, Dainty JR, Finglas PM. Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK. (2007)
  2. P Kelly et al. Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. (1997)
  3. Cornelia M Ulrich. Folate and cancer prevention: a closer look at a complex picture. (2007)
  4. Hirsch S et al. Colon cancer in Chile before and after the start of the flour fortification program with folic acid. (2009)
  5. Joel B. Mason et al. A Temporal Association between Folic Acid Fortification and an Increase in Colorectal Cancer Rates May Be Illuminating Important Biological Principles: A Hypothesis (2007)
  6. Mortensen JH et al. Supplemental folic acid in pregnancy and maternal cancer risk. (2015)
  7. Taylor CM et al. Folic acid in pregnancy and mortality from cancer and cardiovascular disease: further follow-up of the Aberdeen folic acid supplementation trial. (2015) 
  8. Qin X et al. Folic acid supplementation and cancer risk: a meta-analysis of randomized controlled trials. (2013)
  9. Aron M. Troen et al. Unmetabolized Folic Acid in Plasma Is Associated with Reduced Natural Killer Cell Cytotoxicity among Postmenopausal Women. (2006)
  10. Blencowe H et al. Folic acid to reduce neonatal mortality from neural tube disorders. (2010)
  11. Gong R et al. Effects of folic acid supplementation during different pregnancy periods and relationship with the other primary prevention measures to neural tube defects. (2016)
  12. Boyles AL et al. Folate and one-carbon metabolism gene polymorphisms and their associations with oral facial clefts. (2008)
  13. Boyles AL et al. Oral facial clefts and gene polymorphisms in metabolism of folate/one-carbon and vitamin A: a pathway-wide association study. (2009)
  14. Robert J. Berry. Maternal prenatal folic acid supplementation is associated with a reduction in development of autistic disorder (2013)
  15. Virk J et al. Preconceptional and prenatal supplementary folic acid and multivitamin intake and autism spectrum disorders. (2016)
  16. Gao Y et al. New Perspective on Impact of Folic Acid Supplementation during Pregnancy on Neurodevelopment/Autism in the Offspring Children - A Systematic Review. (2016)
  17. Scholl TO and Johnson WG. Folic acid: influence on the outcome of pregnancy. (2010)
  18. Marc P. McRae. High-dose folic acid supplementation effects on endothelial function and blood pressure in hypertensive patients: a meta-analysis of randomized controlled clinical trials. (2009).
  19. Qin X et al. Folic Acid Therapy Reduces the First Stroke Risk Associated With Hypercholesterolemia Among Hypertensive Patients. (2016)
  20. Huo Y et al. Efficacy of folic acid supplementation in stroke prevention: new insight from a meta-analysis. (2012)
  21. Lee M et al. Efficacy of homocysteine-lowering therapy with folic Acid in stroke prevention: a meta-analysis. (2010)
  22. Gopinath B et al. Homocysteine, folate, vitamin B-12, and 10-y incidence of age-related macular degeneration. (2013)
  23. Christen WG et al. Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: the Women's Antioxidant and Folic Acid Cardiovascular Study. (2009)
  24. Venkatasubramanian R et al. A randomized double-blind comparison of fluoxetine augmentation by high and low dosage folic acid in patients with depressive episodes. (2013)
  25. Bedson E et al. Folate Augmentation of Treatment--Evaluation for Depression (FolATED): randomised trial and economic evaluation. (2014)
  26. Shen L and Ji HF. Associations between Homocysteine, Folic Acid, Vitamin B12 and Alzheimer's Disease: Insights from Meta-Analyses. (2015)
  27. Thomson ME and Pack AR. Effects of extended systemic and topical folate supplementation on gingivitis of pregnancy. (1982)
  28. Pack AR. Folate mouthwash: effects on established gingivitis in periodontal patients. (1984)

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