Folate and Methylfolate Deficiency Symptoms, Causes, & Treatment

Written By:

Katie Stone - Naturopath

Medical Reviewer:

Kari Asadorian - Bachelor of Science in Nursing

Edited By:

Jamie Hope - Founder of Methyl-Life

Updated On:

January 20, 2025

What is folate deficiency?

Folate deficiency occurs when you have insufficient amounts of folate (vitamin B9) in your blood. Folate cannot be made by the body, so you must obtain it through food or supplements.

Folate plays a major role in many bodily processes involved with growth and development, which means it’s especially critical during pregnancy.

Folate deficiency has been associated with various health issues, such as megaloblastic anemia and cardiovascular disease, as well as neural tube defects in children.

Difference between folate and methylfolate deficiency

Folate is a B vitamin naturally present in foods such as leafy green vegetables and legumes.

Methylfolate is the biologically active form of folate found in your blood. It’s the only form the body can actually use, and it must be created by converting dietary folate or folic acid (the synthetic form of folate).

However, not everyone can properly convert the folate or folic acid they ingest. This is because the conversion process requires an enzyme called MTHFR, and for people who have a very common genetic mutation on the MTHFR gene, this enzyme does not function properly.

Around 60–70% of people have some form of mutation on the MTHFR gene which impacts their ability to obtain methylfolate from food and folic acid.¹ This can lead to folate deficiencies and symptoms even when the dietary intake of folate or supplementation through folic acid is sufficient.

Simply put, it’s possible to have a methylfolate deficiency even when you’re eating plenty of folate-rich foods and/or taking folic acid.

Symptoms of folate deficiency

Folate deficiency symptoms may occur alongside symptoms of anemia, including:

Tiredness or fatigue, even after you have slept
Muscle weakness
Tingling, burning, or numbness in hands or feet
Palpitations
Shortness of breath
Pale skin
Headaches or feeling dizzy
Difficulty concentrating

Other symptoms of folate deficiency may include:

Struggling with depression, unusually poor judgment, or other cognitive and memory problems
Soreness in the mouth and tongue, and/or tongue ulcers
Changes in skin, hair, or fingernail pigmentation
Elevated homocysteine levels
Abdominal pain and gastrointestinal symptoms like nausea, vomiting, and diarrhea
Irritability

Who is at Risk for Folate or Methylfolate Deficiency?

A wide variety of people can suffer from a folate or methylfolate deficiency. You may have increased risk if you fall into one or more of the categories listed below.

People with Alcoholism or Alcohol Use Disorders

Alcohol can speed up the breakdown and excretion of folate in your body, which means you aren't able to absorb what you need. This can happen even though you may seem to be getting enough folate in your diet or through supplementation.

One study found that men who drank moderate amounts of alcohol consistently for two weeks ended up with lower serum concentrations of folate and B12.²

Women of Childbearing Age

Women in their early 20s to mid-40s (reproductive age) are more likely than men to have deficiencies of folate and other B vitamins, especially B12. Women with these vitamin deficiencies are at a higher risk of giving birth to a child with neural tube defects, or malformations in the brain and spine.

Women in this age group are encouraged to supplement with at least 400 micrograms of folate daily. However, it’s important to remember that they may still not get sufficient amounts of folate even when taking folic acid, as folic acid must undergo a lengthy conversion process in the body before it becomes ‘active’ and usable.³

If you are planning to become pregnant, and are experiencing any symptoms of folate or methylfolate deficiency, it’s highly recommended that you have your folate levels tested.

Pregnant Women

Women who are pregnant have much higher demands for folate as it is one of the key nutrients for fetal development. Folate-deficiency anemia is most common in pregnant women, and can lead to serious neurodevelopmental and congenital defects in the child.

The American College of Obstetricians and Gynecologists recommends taking a daily prenatal supplement with at least 600 micrograms of folate. Methylfolate’s major advantage over folic acid is that it is an active form of folate.⁴

People with Malabsorptive Disorders

Vitamin and iron deficiencies are common in patients with inflammatory bowel disease (IBD) as a result of chronic intestinal inflammation, increase in demand, or dietary restrictions.⁵ Gastrointestinal disorders such as Celiac disease, Crohn’s disease, and other inflammatory bowel conditions that impact the absorption of nutrients can lead to folate deficiency.
Folate deficiency is especially common in patients with Crohn's disease.⁶

People with the MTHFR Mutation

The MTHFR mutation affects the body’s ability to convert folate and folic acid into methylfolate.

A homozygous C677T mutation typically results in decreased MTHFR enzyme function, as does the A1298C together with C677T.

Causes of Folate or Methylfolate Deficiency

Diet

A lack of folate-rich foods in the diet may lead to folate deficiency. Folate-rich foods include leafy green vegetables, legumes, animal products, nuts, seeds, and citrus fruits.

Although many breads, cereals, and grain-based products are fortified with folic acid, not everyone can process folic acid properly (or chooses to eat these foods).

Pregnancy and nursing

Folate needs increase during pregnancy to support the growth and development of the fetus as well as the mother’s tissue growth. Lactation also requires greater amounts of folate to accommodate milk folate levels, which can increase the risk of deficiency.⁷

Age

Folate deficiency is common in older individuals due to intestinal malabsorption. Medications and poor diet can also contribute to low folate levels.⁸

MTHFR mutation

A MTHFR genetic mutation can mean your body is unable to process folate properly, even if you are eating foods that contain folate or folic acid. This can lead to low levels of active folate in your blood.

Malabsorption

Digestive disorders or intestinal diseases can impair the absorption of many nutrients, including folate. Your diet may be good, but your body may not be processing and absorbing the vitamins and minerals within the food you eat. This is especially common in inflammatory bowel conditions such as Crohn’s disease.

Medications

Certain medications can prevent or limit folate absorption. Drugs like phenytoin (Dilantin), trimethoprim-sulfamethoxazole, methotrexate, metformin, warfarin, sulfasalazine, and others can alter your body's ability to take in B vitamins, including folate.

Alcohol intake

Drinking at least a moderate amount of alcohol on a regular basis can affect absorption of folate and many other nutrients. Studies suggest that 8 ounces of wine (240 ml) or 2.7 fluid oz of vodka (80ml) per day each day can impair your ability to process folate.

Treating a Methylfolate Deficiency

In most cases, a folate deficiency can be restored with regular supplementation of methylfolate, the active form of folate. Methylfolate is the only form that can bypass the MTHFR mutation and digestive disorders because it is absorbed directly into the bloodstream without any need for further conversion.

Studies have shown that methylfolate is the most effective form of folate supplementation for those with MTHFR or malabsorption disorders.⁹

The most important thing is to consider the causes of your folate deficiency. If you are eating a healthy diet and you are not affected by malabsorption disorders or taking medication, it may be a good idea to get tested for a MTHFR mutation.

Health problems related to folate deficiency

Untreated folate deficiency can lead to a range of health issues, including megaloblastic anemia, cardiovascular disease due to elevated homocysteine levels or cognitive disorders (such as dementia).

Deficiency during pregnancy can result in neural tube birth defects, congenital disabilities and autism.

Low folate or folate deficiency has been associated with increased risk of many cancers. However, it should also be noted that folic acid supplementation and high levels of unmetabolized folic acid are also associated with increased risk of prostate cancer, possibly due to MTHFR gene mutations.¹⁰

B12 deficiency vs. folate deficiency

B12 deficiency is more common than folate deficiency. Vitamin B12 works alongside folate in many processes, including in making red blood cells and in producing neurotransmitters.

B12 is only available in animal foods, which means that those who are vegetarian or vegan are at high risk of B12 deficiency. Absorption of B12 requires intrinsic factor, which is made by the stomach. Production of intrinsic factor decreases with age and is often compromised by gastrointestinal disorders.

Treating B12 deficiency is critical for preventing health problems such as anemia, cognitive disorders, and depression. As with folate deficiency, B12 deficiency can be treated by supplementing with active forms of the vitamin.

Folate Deficiency

Key Takeaways

Folate deficiency is too little folate in your blood, which can cause health issues such as anemia, cardiovascular problems, and depression. Deficiency during pregnancy can lead to neural tube defects.
Causes of folate deficiency include diet, malabsorption disorders, age, pregnancy, and the MTHFR genetic mutation.
Symptoms are similar to B12 deficiency, but B12 must be restored first.
Methylfolate is the active form of folate and supplementation is the most effective way to restore folate deficiency.

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Frequently Asked Questions About Folate Deficiency

What happens if your folate is low?

Low folate can lead to health issues such as low red blood cell count (anemia), low energy, muscle weakness, shortness of breath, mood disorders (such as depression), difficulty concentrating, and gastrointestinal problems. Low folate can also cause high homocysteine levels, which can then lead to cardiovascular problems.¹¹
During pregnancy, low folate can result in neural tube defects such as spina bifida or even behavioral disorders such as autism.¹²

What are the first two symptoms of folate deficiency?

The most obvious symptoms of folate deficiency are extreme fatigue or tiredness, along with a sore red tongue and/or mouth sores.

Do you replace B12 or folate first?

B12 and folate levels should always be tested together, as “normal” folate levels can mask an underlying B12 deficiency. If someone is deficient in both vitamin B12 and folate, vitamin B12 should be replaced first.¹³

How long does it take to correct folate deficiency?

The time it takes to correct folate deficiency depends on how low your levels are and the method used to restore your folate. Supplementing with methylfolate (the active form of folate) has been shown to restore folate levels faster than folic acid because methylfolate is absorbed directly into the bloodstream and can be used immediately, while folic acid requires a lengthy conversion process which can be complicated by genetic factors.¹⁴

References

Sarah Long, Jack Goldblatt; "MTHFR genetic testing: Controversy and clinical implications"; MTHFR genetic testing: Controversy and clinical implications, Vol. 45, Iss. 4; 2016 Apr

https://www.racgp.org.au/afp/2016/april/mthfr-genetic-testing-controversy-and-clinical-imp
A Gibson, J V Woodside, I S Young, P C Sharpe, C Mercer, C C Patterson, M C McKinley, L A J Kluijtmans, A S Whitehead, A Evans; "Alcohol increases homocysteine and reduces B vitamin concentration in healthy male volunteers--a randomized, crossover intervention study"; QJM: Monthly Journal Of The Association Of Physicians; 2008 Sep

https://pubmed.ncbi.nlm.nih.gov/18790817/
Regan L Bailey, Kevin W Dodd, Jaime J Gahche, Johanna T Dwyer, Margaret A McDowell, Elizabeth A Yetley, Christopher A Sempos, Vicki L Burt, Kathy L Radimer, Mary Frances Picciano; "Total folate and folic acid intake from foods and dietary supplements in the United States: 2003-2006"; The American Journal Of Clinical Nutrition; 2010 Jan

https://pubmed.ncbi.nlm.nih.gov/19923379/
Enrico Ferrazzi, Giulia Tiso, Daniela Di Martino; "Folic acid versus 5- methyl tetrahydrofolate supplementation in pregnancy"; European Journal Of Obstetrics, Gynecology, And Reproductive Biology; 2020 Oct

https://pubmed.ncbi.nlm.nih.gov/32868164/
Matiar Madanchi, Stefania Fagagnini, Nicolas Fournier, Luc Biedermann, Jonas Zeitz, Edouard Battegay, Lukas Zimmerli, Stephan R Vavricka, Gerhard Rogler, Michael Scharl, Swiss IBD Cohort Study Group; "The Relevance of Vitamin and Iron Deficiency in Patients with Inflammatory Bowel Diseases in Patients of the Swiss IBD Cohort"; Inflammatory Bowel Diseases: 2018 Jul

https://pubmed.ncbi.nlm.nih.gov/29669023/
Shaozhong Huang, Jiayi Ma, Mingming Zhu, Zhihua Ran; "Status of serum vitamin B12 and folate in patients with inflammatory bowel disease in China"; Intestinal Research; 2017 Jan

https://pmc.ncbi.nlm.nih.gov/articles/PMC5323299/
Rosemary A Stamm, Lisa A Houghton; "Nutrient Intake Values for Folate during Pregnancy and Lactation Vary Widely around the World"; Nutrients; 2013 Sep

https://pmc.ncbi.nlm.nih.gov/articles/PMC3820052
João Ricardo Araújo, Fátima Martel, Nuno Borges, João Manuel Araújo, Elisa Keating; "Folates and aging: Role in mild cognitive impairment, dementia and depression"; Ageing Research Reviews Vol. 22 Pg. 9-19; 2015 Jul

https://www.sciencedirect.com/science/article/abs/pii/S1568163715000458
Lorena Carboni; "Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health"; Integrative Medicine: A Clinician's Journal; 2022 Jul

https://pmc.ncbi.nlm.nih.gov/articles/PMC9380836/
Renee Pieroth, Stephanie Paver, Sharon Day, Carolyn Lammersfeld; "Folate and Its Impact on Cancer Risk"; Current Nutrition Reports; 2018 Aug

https://pmc.ncbi.nlm.nih.gov/articles/PMC6132377/
Paul Ganguly, Sreyoshi Fatima Alam; "Role of homocysteine in the development of cardiovascular disease"; Nutrition Journal; 2015 Jan

https://pmc.ncbi.nlm.nih.gov/articles/PMC4326479/
Bianka Hoxha, Malvina Hoxha, Elisa Domi, Jacopo Gervasoni, Silvia Persichilli, Visar Malaj, Bruno Zappacosta; "Folic Acid and Autism: A Systematic Review of the Current State of Knowledge"; Cells; 2021 Aug

https://pmc.ncbi.nlm.nih.gov/articles/PMC8394938
SCI Gateway Haematology; "B12 deficiency"; NHS Lothian; 2025

https://apps.nhslothian.scot/refhelp/guidelines/haematology/b12deficiency
Lorena Carboni; "Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health"; Integrative Medicine: A Clinician's Journal; 2022 Jul

https://pmc.ncbi.nlm.nih.gov/articles/PMC9380836/
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About the Author

Katie is a qualified Naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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