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MTHFR and Mental Health

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Dr. Conor Sheehy - PharmD, BCPS

Medical Reviewer:

Dr. Conor Sheehy - PharmD, BCPS
Kari Asadorian - Bachelor of Science in Nursing

Edited By:

Kari Asadorian - Bachelor of Science in Nursing

Updated On:

January 26, 2025

Table of Contents

    What are Mood Disorders?

    The clinical definition of a mood disorder is a “pervasive and sustained feeling that is endured internally, and that impacts nearly all aspects of a person’s thoughts, feelings, and actions.”1 Those affected by mood disorders frequently experience extreme disruptions to their emotions, including severe lows (such as depression) or highs (mania).2 These episodes can cause severe functional impairment and reduced quality of life.

    The broad categories of mood disorders include bipolar disorders and depressive disorders.

    Some common types of mood disorders include:3

    • Major depression: Reduced interest in usual activities, feelings of sadness or hopelessness, decreased energy levels, concentration, appetite and other symptoms for at least two weeks.
    • Dysthymia: Chronic, low-grade, depressed, or irritable mood persisting over at least two years.
    • Bipolar disorder: Periods of depression alternating with periods of mania or elevated mood.
    • Illness-related mood disorder: Depression caused by serious injuries or chronic medical illnesses.

    Folate Deficiency and Mental Health

    Folate plays a key role in mental health, and folate deficiency is a factor in several mood disorders, including anxiety, depression, postpartum depression, bipolar disorder, and schizophrenia.4 


    Folate is an important component of the one-carbon cycle, a biochemical pathway that leads to the methylation of compounds in the body which fundamentally impacts health and wellbeing. Folate works alongside vitamins B12 and B6 in converting the amino acid homocysteine to methionine. This process is critical to healthy mood and overall wellbeing.
    Methionine is a precursor for S-adenosylmethionine (SAMe), a compound also involved in producing and regulating chemicals including serotonin and dopamine that affect our mood.5 Dopamine provides a sense of temporary pleasure, while serotonin contributes to long-lasting feelings of happiness or well-being. Low levels of methionine are prevalent in depression, likely due to low neurotransmitter production. 6 


    Folate deficiency has also been shown to be a risk factor in developing more severe depressive symptoms, longer episodes of depression, and symptom relapse.7 Elevated levels of homocysteine have also been linked to both depression and anxiety.8 

    People with lower levels of folate are less likely to respond to antidepressants, while those with higher levels tend to have better response rates.9


    Other symptoms of folate deficiency may include sleeplessness, irritability, poor cognitive function, and fatigue, which also impact mood.

    What Are Gene Mutations and How Do They Affect Mental Health?

    A gene mutation is a change in a person's DNA. This change can be inherited or it can happen due to mistakes in DNA replication during cell division. Gene mutations can also be caused by exposure to mutagens like radioactive substances, ultraviolet radiation, certain chemicals, or viral infections.10

    Previous studies have found genetic links to mental health. A 2016 study found that people with the genetic mutation DISC1 had changes in the structure of their brain linked with the severity of their symptoms. The researchers explained that similar genetic effects can increase the risk of major mental illnesses.11

    One mutation that has been linked to mental health is the MTHFR gene mutation. The MTHFR gene provides the body with instructions for making the enzyme methylenetetrahydrofolate reductase (MTHFR). The MTHFR enzyme is needed for the one-carbon metabolism of folic acid into methylfolate. However, the enzyme is affected by the C677T polymorphism, a genetic variation that can impair the conversion to L-methylfolate.12

    The MTHFR Gene and Mental Health

    MTHFR mutations have been associated with an increased risk of depression (including treatment-resistant depression), bipolar disorder, schizophrenia, and some behavioral disorders such as attention-deficit hyperactivity disorder (ADHD) and autism. While these are not technically genetic mental disorders, it does appear that genes are involved.

    A mutation in the MTHFR gene can reduce the enzyme's activity to metabolize folate by 20-40%, making it harder for the body to convert folic acid into L-methylfolate.13  Since MTHFR is crucial for one-carbon metabolism, this mutation can impact the production of neurotransmitters linked to psychiatric disorders.14

    This level of enzyme function reflects how much methylfolate may or may not be available to convert homocysteine to methionine. For example, people with a heterozygous MTHFR C677T mutation (a single mutation) have only 65% of normal MTHFR enzymatic function, while those who are homozygous for MTHFR C677T (a double mutation) have only 30% function.15

    A 2022 meta-analysis of 81 published studies assessed the association between MTHFR mutations and susceptibility to psychiatric disorders. The researchers found a significant link between both major depression and one of the most common MTHFR mutations, MTHFR C677T. This particular mutation was also linked to a higher risk of bipolar disorder. The other common MTHFR mutation, MTHFR A1298C, had only a minor link to major depression.16

    A 2024 study reviewed 186 patients who were tested for an MTHFR deficiency and compared their psychiatric diagnoses and the number of failed medication attempts. Of those 186 patients, 77 had normal MTHFR enzyme function, 85 were found to have a moderate MTHFR deficiency, and 24 had a severe MTHFR deficiency.17

    The takeaway

    Folate has powerful implications for mental health. Numerous studies have confirmed that folate is a vital component of neurotransmitter synthesis, and also that folate deficiency increases the risk of depression and other mental illnesses. 

    Those who cannot metabolize the synthetic form of folate - folic acid - due to the MTHFR genetic mutation are advised to take the active form - L-methylfolate - instead. L-methylfolate supplementation is shown to be significantly more effective in improving symptoms of depression due to its ability to bypass the MTHFR mutation.

    MTHFR and Mental Health

    Key Takeaways

    MTHFR genetic mutations and/or folate deficiency have been associated with many psychiatric disorders, including schizophrenia, bipolar disorder, depression, autism, and ADHD. This appears to be due to the role of folate in the production of neurotransmitters, which are essential for maintaining normal mood and overall mental health.

    This article will cover the relationship between MTHFR and mental health, and current insights into how MTHFR mutations may contribute to mood disorders.

    • Icon MTHFR genetic mutations can lead to folate deficiency due to poor folate metabolism
    • Icon A lack of folate in the brain impairs the production of neurotransmitters that are required for healthy mood and cognitive function
    • Icon Folate deficiency has been associated with a higher risk of developing psychiatric disorders such as depression, schizophrenia, bipolar disorder, and others

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    Frequently Asked Questions about MTHFR and mood disorders

    How does MTHFR affect the brain?

    The MTHFR mutation increases the risk of developing cerebral folate deficiency, which in turn can impair the production of vital neurotransmitters that support normal mood. Low folate is associated with mood disorders such as depression, anxiety, bipolar disorder, and even severe psychiatric illnesses such as schizophrenia. Cerebral folate deficiency is also linked to autism spectrum disorders.18

    What psychiatric disorder is associated with MTHFR mutations?

    The MTHFR C677T mutation is significantly associated with depression, bipolar disorder, and schizophrenia, particularly in people who also have severe folate deficiency.

    How does MTHFR affect mood?

    The MTHFR mutation affects the metabolism of folate in the body, which means that important neurotransmitters are not produced. Neurotransmitters are vital for healthy mood and cognitive function, and studies show that those with an MTHFR mutation may be at greater risk of developing mood disorders.

    Does folate help with mental health?

    Folate plays a crucial role in many central nervous system functions. It is required for the conversion of homocysteine to methionine, a vital step in the synthesis of S-adenosyl-methionine (SAMe), a crucial methyl donor involved in the production of neurotransmitters that support normal mood. Taking active folate (L-methylfolate) has been shown to improve symptoms of depression and other mood disorders.19

    What are the mental symptoms of folate deficiency?

    Folate deficiency can lead to depression, irritability, insomnia, cognitive decline, fatigue, and certain mood disorders.20

    Can low folate cause mood swings?

    Yes, low folate and/or folate deficiency may affect levels of serotonin in the brain, which can lead to mood disorders such as depression or bipolar disorder.

    Does folate increase dopamine?

    Folate is a nutrient required for the production of serotonin, dopamine, and norepinephrine. Taking folate as a supplement can support the body’s ability to create these neurotransmitters.

    References

    1. Sandeep Sekhon, Vikas Gupta; "Mood Disorder"; StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan

      https://pubmed.ncbi.nlm.nih.gov/32644337/

    2. Sandeep Sekhon, Vikas Gupta; "Mood Disorder"; StatPearls [Internet].; 2023 May

      https://www.ncbi.nlm.nih.gov/books/NBK558911/

    3. Sandeep Sekhon, Vikas Gupta; "Mood Disorder"; StatPearls [Internet].; 2023 May

      https://www.ncbi.nlm.nih.gov/books/NBK558911/

    4. Nelson Siu Kei Lam, Xin Xin Long, Xuegang Li e, Mirette Saad, Florence Lim, James CG Doery, Robert C. Griffin, Cherrie Galletly; "The potential use of folate and its derivatives in treating psychiatric disorders: A systematic review"; Biomedicine & Pharmacotherapy Vol. 146; 2022 Feb

      https://www.sciencedirect.com/science/article/pii/S0753332221013287

    5. H Fanet, L Capuron, N Castanon, F Calon, S Vancassel; "Tetrahydrobioterin (BH4) Pathway: From Metabolism to Neuropsychiatry"; Current Neuropharmacology; 2021 Apr

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573752/

    6. Md. Rabiul Islam, Samia Ali, James Regun Karmoker, Mohammad Fahim Kadir, Maizbha Uddin Ahmed, Zabun Nahar, Sardar Mohammad Ashraful Islam, Mohammad Safiqul Islam, Abul Hasnat, Md. Saiful Islam; "Evaluation of serum amino acids and non-enzymatic antioxidants in drug-naïve first-episode major depressive disorder"; BMC Psychiatry Vol. 20; 2020 Jun

      https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-020-02738-2

    7. Timur Liwinski, Undine E Lang; "Folate and Its Significance in Depressive Disorders and Suicidality: A Comprehensive Narrative Review"; Nutrients; 2023 Sep

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10490031/

    8. J Douglas Bremner, Jack Goldberg, Viola Vaccarino; "Plasma homocysteine concentrations and depression: A twin study"; Journal of affective disorders reports; 2021 Aug

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372975/

    9. Maurizio Fava, David Mischoulon; "Folate in Depression: Efficacy, Safety, Differences in Formulations, and Clinical Issues"; The Journal Of Clinical Psychiatry; 2009 Nov

      https://www.psychiatrist.com/jcp/folate-depression-efficacy-safety-differences-formulations

    10. Daniel A. Gilchrist; "​Mutation"; National Human Genome Research Institute; 2025 Jan

      https://www.genome.gov/genetics-glossary/Mutation

    11. University of Edinburgh; "Brain study confirms gene mutation link to psychiatric disorders."; ScienceDaily. ScienceDaily; 2016 Aug.

      https://www.sciencedaily.com/releases/2016/08/160815111259.htm

    12. Maurizio Fava, David Mischoulon; "Folate in Depression: Efficacy, Safety, Differences in Formulations, and Clinical Issues"; The Journal Of Clinical Psychiatry; 2009 Nov

      https://www.psychiatrist.com/jcp/folate-depression-efficacy-safety-differences-formulations

    13. Lin Wan, Yuhong Li, Zhengrong Zhang, Zuoli Sun, Yi He, Rena Li; "Methylenetetrahydrofolate reductase and psychiatric diseases"; Translational Psychiatry; 2018 Nov

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218441/

    14. Yu-Xin Zhang, Lu-Ping Yang, Cong Gai, Cui-Cui Cheng, Zhen-yu Guo, Hong-Mei Sun, Die Hu; "Association between variants of MTHFR genes and psychiatric disorders: A meta-analysis"; Frontiers in Psychiatry; 2022 Aug

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9433753/

    15. Stephan Moll, Elizabeth A. Varga; "Homocysteine and MTHFR Mutations"; Circulation Vol. 132, No. 1; 2015 Jul

      https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.114.013311

    16. Yu-Xin Zhang, Lu-Ping Yang, Cong Gai, Cui-Cui Cheng, Zhen-yu Guo, Hong-Mei Sun, Die Hu; "Association between variants of MTHFR genes and psychiatric disorders: A meta-analysis"; Frontiers in Psychiatry; 2022 Aug

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9433753/

    17. Samira Khan, Abeera Naeem, Alexia Fritts, Melissa Cummins, Caroline Kayes, Wei Fang; "Discovery of Methylenetetrahydrofolate Reductase (MTHFR) Deficiency in Individuals With Common Psychiatric Comorbidities: A Retrospective Case Review"; Cureus; 2024 Apr

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11088868/

    18. Daniel A Rossignol, Richard E Frye; "Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis"; Journal of Personalized Medicine; 2021 Nov

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8622150/

    19. Timur Liwinski, Undine E. Lang; "Folate and Its Significance in Depressive Disorders and Suicidality: A Comprehensive Narrative Review"; Nutrients; 2023 Sep

      https://www.mdpi.com/2072-6643/15/17/3859

    20. Kashif M. Khan, Ishwarlal Jialal; "Folic Acid Deficiency"; StatPearls [Internet]; 2023 Jun

      https://www.ncbi.nlm.nih.gov/books/NBK535377/

    Katie Stone - Naturopath

    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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