Unmetabolized Folic Acid

Unmetabolized Folic Acid

Updated On:

May 02, 2025

Table of Contents

    What is unmetabolized folic acid syndrome?

    Unmetabolized folic acid (UMFA) syndrome occurs when the synthetic form of folate (folic acid) is not broken down (metabolized) properly in the body, so it remains in the bloodstream.1 UMFA can be a result of supplementing with high doses of folic acid. It does not occur when supplementing with natural and active forms of folate. This is because folic acid must be converted into its active form, methylfolate  (5-MTHF), through a two-step process involving an enzyme called dihydrofolate reductase (DHFR). However, DHFR is often inefficient and can quickly reach its maximum capacity, which means it doesn’t process folic acid properly. When this happens, any excess folic acid remains unmetabolized and accumulates in the bloodstream as unmetabolized folic acid (UMFA).2


    In people with functioning MTHFR and DHFR enzymes, low doses of folic acid are usually metabolized and methylated in the gut or liver. However, doses over 200 μg (a single serve of breakfast cereals can contain up to 400 μg) can lead to UMFA in blood and cord blood.3


    Researchers have noted that the extremely low conversion rate of folic acid means that any benefits will be limited by saturation of DHFR, especially in people who have lower than average DHFR activity.4


    Circulating levels of UMFA in the general population have been increasing since 1998, when folic acid was first added to fortified foods. Folic acid is also used in over 50 other countries. While numerous studies support the benefits of folic acid, recent research has highlighted concerns regarding potential unintended adverse consequences due to high circulating UMFA.


    Studies show that even low doses of folic acid (0.2–0.4 mg) can lead to detectable UMFA levels, and trace amounts have been found even in those not taking supplements.5 It is estimated that over a third of the US population is exposed to high levels of dietary folic acid from both supplements and fortified foods.6


    People with MTHFR mutations are at higher risk of UMFA as they are unable to process even low doses of folic acid.

    Symptoms of unmetabolized folic acid

    UMFA does not cause specific symptoms, so you may not be immediately aware if you are affected. However, some health concerns have been noted.

    Masking B12 deficiency

    One of the most common side effects of unmetabolized folic acid is that it can hide the signs of a vitamin B12 deficiency. This is called ‘masking’. Normally, low B12 causes anemia (low red blood cell count), which can be an early warning sign. Folic acid can correct the anemia without correcting the underlying B12 deficiency because both folate and B12 are required for red blood cell production. High doses of folic acid can normalize red blood cell production even if B12 levels are insufficient. This improves blood count, but the underlying B12 deficiency remains untreated and possibly unnoticed. This is dangerous because, unlike folate, B12 is required for maintaining the myelin sheath that protects nerves. Chronically low B12 levels can then lead to irreversible nerve damage, including numbness, cognitive decline, and motor issues.7

    Gestational diabetes

    Some research has linked high folic acid concentration to an increased risk of gestational diabetes mellitus (GDM), especially when combined with an imbalance in vitamin B12 levels.8

    Modulation of genes

    Excess folic acid supplementation may affect how genes are turned on or off, potentially leading to abnormal genetic regulation in future generations. This happens through epigenetic modifications - chemical changes that influence gene activity without altering DNA itself. Since folate plays a key role in these processes, imbalances in parents' folate levels could impact their children’s long-term health, possibly contributing to diseases later in life.9

    Impact on neurodevelopment

    Folic acid doses exceeding the upper limit during the time before and shortly after conception (the periconceptual phase) have been linked to impaired neurocognitive development in children.10 Doses of more than 5mg folic acid per day in pregnant mothers has been shown to lead to poor psychomotor development in their children compared with those receiving 0.4–1 mg/day.11

    Possible cancer risk

    High concentrations of UMFA in plasma have been found to decrease cytotoxicity of natural killer cells (the ability to kill other cells). This is an immune response which may promote carcinogenesis.12 In addition, women with a mutation on the DHFR gene were found to have an increased risk of breast cancer due to decreased functionality of the enzyme and higher levels of UMFA.13

    Pseudo MTHFR

    High doses of folic acid can lead to a “pseudo-MTHFR” syndrome in people who do not have the MTHFR genetic mutation. Pseudo-MTHFR means the folic acid accumulation mimics the effects of MTHFR deficiency.

    This is because the folic acid interferes with the body’s natural methylfolate levels by competing for transport into cells. This can create a "false" folate deficiency, affecting important metabolic processes in the body. One case report found that a patient with normal MTHFR function developed persistently high homocysteine levels after taking too much folic acid.14

    How to get rid of unmetabolized folic acid

    The first step in reducing unmetabolized folic acid is to stop taking folic acid supplements. You should also avoid fortified foods that contain folic acid.

    Support your body’s detoxification pathways by drinking at least 2-3 litres of water a day and eating a wholesome diet.

    You can also support your body’s folate needs by supplementing with the active form, methylfolate. Unlike folic acid, methylfolate is already in its ready-to-use form, so it does not need to be metabolized and does not build up in the bloodstream.

    Methylfolate has even been found to have a protective effect against breast cancer risk when compared to folic acid.15

    Methylfolate supplementation has also been recommended over folic acid for reducing the risk of neural tube defects.16

    Unmetabolized Folic Acid

    Key takeaways:

    • Icon Folic acid that is not broken down in the body can accumulate in the bloodstream, causing UMFA (unmetabolized folic acid syndrome).
    • Icon UMFA occurs when certain enzymes do not function properly, including DHFR and MTHFR.
    • Icon UMFA may increase the risk of certain health concerns including cancer, epigenetic changes, and neurodevelopmental issues (during pregnancy). It can also mask B12 deficiency.

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    Frequently Asked Questions about unmetabolized folic acid

    What causes unmetabolized folic acid?

    Unmetabolized folic acid can build up in the bloodstream when the body is unable to keep up with the breakdown and conversion process. This can occur following high doses of folic acid, causing the DHFR enzyme to reach its maximum capacity. When this happens, any excess folic acid remains unmetabolized and accumulates in the bloodstream.
    UMFA may also occur in people with MTHFR mutations, as they lack another enzyme required to break down folic acid.
    Folic acid is added to many foods (such as breads, cereals, snacks, and some milks) and is also often used in cheap multivitamin supplements, so there is a high risk of taking excess amounts.

    What happens if you can't metabolize folic acid?

    If your body cannot break down the folic acid you consume from synthetic sources (specifically supplements and foods fortified with folic acid), it may build up in the bloodstream. High levels of unmetabolized folic acid have been linked to some long-term health concerns, including cancer and some neurodevelopmental problems in children.17
    A lack of usable folate in the blood can also mean that homocysteine accumulates, which can cause serious damage to blood vessels as well as a higher risk of blood clots.18

    What is unmetabolized folic acid MTHFR?

    Unmetabolized folic acid is any excess folic acid that the body has not broken down into a usable form. Instead, it builds up in the bloodstream, and may increase the risk of certain health conditions. Those with MTHFR are at higher risk of unmetabolized folic acid because they lack the enzyme required to break it down. Anyone with a MTHFR genetic mutation should avoid foods or supplements containing folic acid and instead take methylfolate, the active form of folate that does not need to be metabolized.

    References

    1. Ping Chen, Linlin Tang, Yun Song, Binyan Wang, Xianhui Qin, Nan Zhang, Yaping Wei, Xiping Xu, Ziyi Zhou, Qiangqiang He, Lishun Liu, Sultan Mehmood Siddiqi, Xiao Huang, Xiaoshu Cheng, Genfu Tang, Yong Duan, Houqing Zhou, Jie Jiang, Sha Li; "Association of folic acid dosage with circulating unmetabolized folic acid in Chinese adults with H-type hypertension: a multicenter, double-blind, randomized controlled trial"; Frontiers in nutrition.; 2023 Sep

      https://pmc.ncbi.nlm.nih.gov/articles/PMC10538967/

    2. Steven W Bailey, June E Ayling; "The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake"; Proceedings of the National Academy of Sciences of the United States of America; 2009 Sep

      https://pubmed.ncbi.nlm.nih.gov/19706381/

    3. Mary Rose Sweeney, Joseph McPartlin, John Scott; "Folic acid fortification and public health: report on threshold doses above which unmetabolised folic acid appear in serum"; BMC public health; 2007 Mar

      https://pubmed.ncbi.nlm.nih.gov/17378936/

    4. Steven W Bailey, June E Ayling; "The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake"; Proceedings of the National Academy of Sciences of the United States of America; 2009 Sep

      https://pubmed.ncbi.nlm.nih.gov/19706381/

    5. Imran Patanwala, Maria J King, David A Barrett, John Rose, Ralph Jackson, Mark Hudson, Mark Philo, Jack R Dainty, Anthony J A Wright, Paul M Finglas, David E Jones; "Folic acid handling by the human gut: implications for food fortification and supplementation"; The American journal of clinical nutrition; 2014 Aug

      https://pubmed.ncbi.nlm.nih.gov/24944062/

    6. 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/

    7. P Kelly, J McPartlin, M Goggins, D G Weir, J M Scott; "Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements"; The American journal of clinical nutrition; 1997 Jun

      https://pubmed.ncbi.nlm.nih.gov/9174474/

    8. Beibei Zhu, Xing Ge, Kun Huang, Leijing Mao, Shuangqin Yan, Yeqing Xu, Sanhuan Huang, Jiahu Hao, Peng Zhu, Ying Niu, Shilu Tong, Fangbiao Tao; "Folic Acid Supplement Intake in Early Pregnancy Increases Risk of Gestational Diabetes Mellitus: Evidence From a Prospective Cohort Study"; Diabetes care; 2016 Mar

      https://pubmed.ncbi.nlm.nih.gov/26822325/

    9. Cathrine Hoyo, Amy P Murtha, Joellen M Schildkraut, Randy L Jirtle, Wendy Demark-Wahnefried, Michele R Forman, Edwin S Iversen, Joanne Kurtzberg, Francine Overcash, Zhiqing Huang, Susan K Murphy; "Methylation variation at IGF2 differentially methylated regions and maternal folic acid use before and during pregnancy"; Epigenetics; 2011 Jul

      https://pubmed.ncbi.nlm.nih.gov/21636975/

    10. Laura María Compañ Gabucio, Manuela García de la Hera, Laura Torres Collado, Ana Fernández-Somoano, Adonina Tardón, Mònica Guxens, Martine Vrijheid, Marisa Rebagliato, Mario Murcia, Jesús Ibarluzea, Itxaso Martí, Jesús Vioque; "

      https://pubmed.ncbi.nlm.nih.gov/33498619/

    11. Desirée Valera-Gran, Manuela García de la Hera, Eva María Navarrete-Muñoz, Ana Fernandez-Somoano, Adonina Tardón, Jordi Julvez, Joan Forns, Nerea Lertxundi, Jesús María Ibarluzea, Mario Murcia, Marisa Rebagliato, Jesús Vioque; Infancia y Medio Ambiente (INMA) Project; "Folic acid supplements during pregnancy and child psychomotor development after the first year of life"; JAMA pediatrics; 2014 Nov

      https://pubmed.ncbi.nlm.nih.gov/25365251/

    12. Hathairat Sawaengsri, Junpeng Wang, Christina Reginaldo, Josiane Steluti, Dayong Wu, Simin Nikbin Meydani, Jacob Selhub, Ligi Paul; "High folic acid intake reduces natural killer cell cytotoxicity in aged mice"; The Journal of nutritional biochemistry; 2016 Apr

      https://pubmed.ncbi.nlm.nih.gov/27012626/

    13. Xinran Xu, Marilie D Gammon, James G Wetmur, Manlong Rao, Mia M Gaudet, Susan L Teitelbaum, Julie A Britton, Alfred I Neugut, Regina M Santella, Jia Chen; "A functional 19-base pair deletion polymorphism of dihydrofolate reductase (DHFR) and risk of breast cancer in multivitamin users"; The American journal of clinical nutrition; 2007 Apr

      https://pubmed.ncbi.nlm.nih.gov/17413111/

    14. Dominique Cornet, Arthur Clement, Patrice Clement, Yves Menezo; "High doses of folic acid induce a pseudo-methylenetetrahydrofolate syndrome"; SAGE open medical case reports; 2019 May

      https://pmc.ncbi.nlm.nih.gov/articles/PMC6537060/

    15. Karen L Koenig, Stephanie Scarmo, Yelena Afanasyeva, Tess V Clendenen, Per Magne Ueland, Anne Zeleniuch-Jacquotte; "Circulating unmetabolized folic acid and 5-methyltetrahydrofolate and risk of breast cancer: A nested case-control study"; European journal of clinical nutrition; 2021 Mar

      https://pmc.ncbi.nlm.nih.gov/articles/PMC7508257/

    16. Yves Menezo, Kay Elder, Arthur Clement, Patrice Clement; "Folic Acid, Folinic Acid, 5 Methyl TetraHydroFolate Supplementation for Mutations That Affect Epigenesis through the Folate and One-Carbon Cycles"; Biomolecules; 2022 Jan

      https://pmc.ncbi.nlm.nih.gov/articles/PMC8961567/

    17. Ali M Fardous, Ahmad R Heydari; "Uncovering the Hidden Dangers and Molecular Mechanisms of Excess Folate: A Narrative Review"; Nutrients; 2023 Nov

      https://pmc.ncbi.nlm.nih.gov/articles/PMC10648405/

    18. Laura Tafuri, Edouard J Servy, Yves J R Menezo; "The hazards of excessive folic acid intake in MTHFR gene mutation carriers: An obstetric and gynecological perspective"; Open Access Text; 2017

      https://www.oatext.com/the-hazards-of-excessive-folic-acid-intake-in-mthfr-gene-mutation-carriers-an-obstetric-and-gynecological-perspective.php

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