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?

Folic acid deficiency is actually folate deficiency. Folate (vitamin B9) is the naturally occurring form of vitamin B9 present in foods such as leafy greens, legumes, and citrus fruits. Folic acid is the synthetic form used in supplements and food fortification. Methylfolate is the bioidentical form of folate that is fully converted and bioavailable for immediate use in the body.

Folate is poorly stored in the body, and deficiency can develop within weeks if your diet lacks folate-rich foods. It can also occur if your body is unable to properly metabolize (break down) folic acid in foods or supplements.

Folate deficiency can lead to macrocytic anemia, a condition in which red blood cells are larger than normal and the body also lacks hemoglobin (the protein in red blood cells that carries oxygen).¹ Low red blood cell count can deprive the tissues of the oxygen they need in order to function effectively, which can lead to fatigue and poor cognitive function.

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.² 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 B12.³

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.⁴

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.⁵

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.⁶ 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.⁷

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.

Main Causes of Folate, Methylfolate and Folic Acid Deficiency

Diet

A major cause of folate deficiency is low consumption of animal products and/or fresh fruits and vegetables. Overcooking can also destroy the nutritional content of food.⁸

Genetics

An estimated 60-70% of the population are affected by some form of MTHFR genetic mutation, which impairs their ability to efficiently convert both folic acid and dietary folate to its immediately usable form, methylfolate.⁹

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.¹⁰

Age

Folate deficiency is common in older individuals due to intestinal malabsorption. Medications and poor diet can also contribute to low folate levels.¹¹

Malabsorption

Folate deficiency can also occur as a result of health conditions that affect absorption in the gastrointestinal tract, for example, Celiac disease and Crohn’s disease.¹²

Excess alcohol intake

Alcohol significantly interferes with the absorption of folic acid, and may also increase the excretion of folate through the urine.¹³

Medications

Certain medications - including Metformin, Barbiturates, Methotrexate, Warfarin, sulfasalazine, and trimethoprim-sulfamethoxazole can also impair the uptake of folate, potentially leading to deficiency¹⁴

How to Prevent Folic Acid Deficiency

Eat plenty of folate-rich foods: leafy green vegetables such as spinach and kale; animal products such as beef, liver, and eggs; legumes; nuts and seeds; and citrus fruits.
Research regarding whether food folates can be metabolised by those with MTHFR is limited. Some sources claim that natural folates are unable to be metabolized by those with MTHFR genetic mutations, more research may be needed to verify these claims fully.
Folate-rich foods provide many other nutrients to the body - including coenzymes that assist with the absorption of folate - so they are wholly beneficial.

Seek nutritional advice during pregnancy
Folic acid deficiency during pregnancy increases the risk of miscarriage and neural tube defects. Speak to your healthcare professional about folate supplementation, especially if you have a MTHFR genetic mutation.

Avoid excess alcohol intake
Alcohol interferes with folate metabolism.

Supplement with active bioidentical folate (L-5-MTHF)
The most effective way to prevent and treat a folate deficiency is with methylfolate, the fully activated form of folate. Methylfolate is immediately available for use upon ingestion, unlike folic acid.

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.¹⁵

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.¹⁶

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.¹⁷
During pregnancy, low folate can result in neural tube defects such as spina bifida or even behavioral disorders such as autism.¹⁸

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.¹⁹

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.²⁰

References

Sujatha Baddam, Kashif M. Khan, Ishwarlal Jialal; "Folic Acid Deficiency"; StatPearls [Internet]; 2025 Jun

https://www.ncbi.nlm.nih.gov/books/NBK535377/
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/
Sujatha Baddam, Kashif M. Khan, Ishwarlal Jialal; "Folic Acid Deficiency"; StatPearls [Internet]; 2025 Jun

https://www.ncbi.nlm.nih.gov/books/NBK535377/
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
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
Tyesha Zuvarox, Chris Belletieri; "Malabsorption Syndromes"; StatPearls [Internet]; 2023 Jul

https://www.ncbi.nlm.nih.gov/books/NBK553106/
Valentina Medici, Charles H Halsted; "Folate, Alcohol, and Liver Disease"; Molecular nutrition & food research; 2014 Apr

https://pmc.ncbi.nlm.nih.gov/articles/PMC3736728/
D G Lambie, R H Johnson; "Drugs and folate metabolism"; Drugs; 1985 Aug

https://pubmed.ncbi.nlm.nih.gov/3896745/
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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