MTHFR and Anxiety

MTHFR and Anxiety

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 27, 2025

Table of Contents

    Symptoms of Anxiety

    Everyone experiences anxiety differently. Symptoms range from mild feelings of an upset stomach and fast heartbeat to feeling completely out of control, experiencing nightmares, panic attacks and dark thoughts. A general feeling of fear and worry, troubled sleep, poor concentration and restlessness are also common.


    Anxiety usually comes on gradually, and an anxiety attack typically occurs prior to a stressful situation, experience, or event. An anxiety attack can lead to feeling faint or dizzy, with shortness of breath, dry mouth, sweating and chills. Those affected will feel distressed, severely apprehensive, restless, fearful, and possibly experience numbness or tingling.

    These symptoms can result in avoidance of certain situations, as well as hyperventilation, becoming motionless, and/or difficulty speaking. 3

    Types of anxiety

    There are several types of anxiety disorders. The most common are:


    Generalized anxiety disorder
    People with generalized anxiety disorder feel anxious most of the time. They worry about several things at the same time, such as health, work, relationships, studies, etc.
    Symptoms include: feeling restless or on the edge, fatigue, difficulty concentrating, irritability, muscle tension, sleep problems. 


    Panic disorder
    People with panic disorder experience sudden periods of intense fear that come on quickly and reach their peak within minutes. Attacks can occur unexpectedly or can be brought on by a trigger, such as a feared object or situation. These folks may also worry about the next attack, making them avoid certain places and situations.
    Symptoms include: heart palpitations, sweating, shaking, shortness of breath, and the feeling of being out of control. 


    Phobia-related disorder
    Phobias are intense fears or aversions to specific objects or situations. This fear is often out of proportion to the actual danger. 


    Social anxiety
    People with social anxiety may avoid certain social situations because they fear being judged, and are easily embarrassed. 


    Separation anxiety
    A fear of being separated from people you are attached to.

    Can MTHFR Cause Anxiety?

    With so much evidence linking MTHFR to depression, many are wondering if the MTHFR gene mutation and anxiety are also linked. 

    An MTHFR mutation reduces the function of the MTHFR enzyme, which is required for numerous methylation processes in the body.  Methylation is essential for the production of DNA, metabolism of various hormones, healthy detoxification, and much more. It is also vital for the conversion of homocysteine and production of neurotransmitters that contribute to healthy mood. 4

    First, let’s explain how a MTHFR mutation affects methylation. Each copy of the variant reduces MTHFR enzyme efficiency by approximately 35%. 5 People who are homozygous for the T variant (known as a ‘double mutation’) have about 30% of the normal enzyme activity. Those who are heterozygous (CT - known as a ‘single mutation’) have about 65% of the normal enzyme activity.

    The most studied polymorphisms are C677T and A1298C. These have both been significantly associated with reduced MTHFR enzymatic activity and methylation, which are both factors in various mental health disorders, including schizophrenia, bipolar disorder, and depression. 


    The link between these mental health disorders has largely to do with the accumulation of homocysteine, an amino acid that becomes harmful when elevated. It must be converted to methionine by methylfolate and other B vitamins to keep the body in healthy balance. Our body needs methionine to make a range of brain chemicals that support positive mood, including the neurotransmitters serotonin, dopamine, and norepinephrine. 6

     

    Methionine is also used to make S-adenosylmethionine (SAMe), an important substrate that helps to maintain cell membranes, and produce and regulate hormones. Along with serotonin and dopamine, SAMe is also involved in making GABA (Gamma-aminobutyric acid), an inhibitory neurotransmitter that helps to reduce anxiety and promote feelings of calm. 7

    The link between MTHFR, anxiety, and GABA

    Studies have confirmed that deficiencies in MTHFR result in increased levels of homocysteine, which leads to reduced levels of S-adenosylmethionine (SAMe). In the brain, SAMe donates methyl groups to catechol-O-methyltransferase (COMT), which is involved in neurotransmitter analysis. Increased levels of homocysteine have been linked to impaired monoamine synthesis (i.e., the making of serotonin) due to reduced levels of SAMe.

    It’s also been found that elevated homocysteine results in stimulation of glutamate, the most abundant excitatory neurotransmitter in the nervous system. In cases of severe MTHFR deficiency, glutamate is increased in the amygdala and GABA is decreased in the thalamus. 8

    Higher levels of glutamate have been detected in people affected by anxiety. Patients with social anxiety were found to have 13.2% higher glutamate levels than controls, which was correlated with their social anxiety symptoms. 9

    Those with impaired methylation usually have excess levels of glutamate: an excitatory neurotransmitter that can promote increased feelings of stress and anxiety. As the MTHFR deficiency typically results in low levels of SAMe - and subsequently low levels of neurotransmitters - it may also result in low levels of GABA, an inhibitory neurotransmitter that balances the effects of glutamate and helps to reduce symptoms of anxiety. Excess glutamate in the brain is known to increase feelings of anxiety, fear, nervousness, restlessness and/or insomnia. 10 Studies on MTHFR association with anxiety and depression have shown that MTHFR mutations and high homocysteine have been linked to depression without comorbid anxiety disorder. 


    People with MTHFR mutations and high homocysteine also appear to have lower vitamin D concentrations, which can affect mood as well. 11

    Is the relationship between MTHFR and anxiety different for adults and children?

    Adults and children may experience anxiety differently. While adults can explain their experiences and compare their symptoms to what might be considered anxiety-related, children don’t have the cognitive awareness to do so. Anxiety in children can also appear similar to normal developmental stages which cause insecurity and fear. However, high rates of ADHD and anxiety symptoms have been documented in autism, which has also been associated with MTHFR. 12


    Signs of anxiety in children may include:

    • Behavioral issues at school
    • Difficulty concentrating 
    • Not sleeping or frequently waking with bad dreams 
    • Eating more or less than usual 
    • Uncontrollable outbursts, anger, or irritation
    • Constantly worrying 
    • Clinginess 
    • Tension or fidgeting 
    • Often complaining of tummy aches or feeling sick

    Can MTHFR Cause Other Mental Health Issues?

    Poor MTHFR activity or folate deficiency have been associated with the onset of several psychiatric and cognitive conditions, including schizophrenia, bipolar disorder, depression, autism, dementia, and ADHD (Attention Deficit Hyperactivity Disorder).

     

    A meta-analysis of seven studies found that people with TT homozygotes (double mutation) had the greatest risk of schizophrenia, compared to people with no mutation or a single mutation. 16

     

    Another study reported that those with the homozygous TT genotype were also more likely to develop schizophrenia along with a higher risk of bipolar disorder. 17
    Interestingly, this association between homozygous 677TT genotypes and bipolar disorder appears to be even stronger in males than females. 18

    ADHD and Anxiety

    Anxiety disorders are also common in adults who have ADHD, with some research showing that more than half of people with ADHD also have anxiety. 13
    Anxiety symptoms generally do not worsen on stimulant medication. A large meta-analysis found that treating ADHD individuals with psychostimulants significantly reduced their risk of developing anxiety. 14
    However,  it has also been found that those with ADHD are at risk for substance abuse, partly due to their symptoms and associated medication. 15
    Stimulants are therefore considered only as a second-line option for adolescents and adults with ADHD and substance use disorders.

    The takeaway about MTHFR and Anxiety

    Those suffering from anxiety are often at a loss as to why they feel the way they do. Their lives are significantly impacted by their disorder, and yet they often find no relief from medication.

     

    The good news is that scientists now understand more about the MTHFR mutation and anxiety, particularly in terms of the impact that MTHFR has on biochemical processes within the body. The many requirements of folate are also better understood, particularly with regards to its role in creating chemicals involved in mood and brain function.

     

    As you will have learned in this article, methylfolate is one of the most important nutrients for everyday function. It is necessary not only for healthy methylation but also reducing harmful homocysteine levels and the manufacturing of important neurotransmitters. The depletion of these nutrients has a detrimental effect on our ability to feel calm, positive, and motivated.


    Anxiety can be managed with the right nutrients and lifestyle changes. This begins with taking a quality methylfolate supplement. Methylfolate bypasses the MTHFR mutation, providing your body with an active form of the folate it needs to carry out methylation and many other biochemical pathways. It’s the most effective way to optimize your body’s methylation processes and support a healthy mood.

    MTHFR and Anxiety

    Key Takeaways

    Anxiety affects almost one-third of the US population. It may be triggered by any number of factors, such as medications, substance abuse, trauma, stress, hormone fluctuations, poor sleep, diet, injuries, digestive issues (such as leaky gut) and more.1


    More recently, research has highlighted the link between anxiety and the common genetic mutation that affects methylenetetrahydrofolate reductase (MTHFR). 


    The MTHFR mutation impairs the body’s ability to convert folate (vitamin B9) into methylfolate. Low levels of methylfolate in the brain can directly impact the processes required for supporting healthy mood, which can increase the risk of developing disorders such as anxiety and depression.2

    This article will explain how the MTHFR mutation can affect the biochemical pathways involved in mental health, and how this can lead to anxiety. We’ll also cover how to manage the symptoms of anxiety by taking the right supplements.

    • Icon The MTHFR genetic mutation has been linked to an increased risk of developing an anxiety disorder or experiencing symptoms of anxiety
    • Icon The link between MTHFR and anxiety may be explained by reduced production of neurotransmitters that support healthy mood and calm
    • Icon Methylfolate may help relieve anxiety symptoms by assisting with the production of key neurotransmitters including serotonin and GABA.

    Product Recommendations

    CALMING Your Stress Naturally with the Best GABA Supplement - Methyl-Life® Supplements

    CALMING Your Stress Naturally with the Best GABA Supplement
    (156)

    $49.00

    • GABA Provides a Sense of Calm & Helps Manage Cortisol
    • GABA Promotes Restful Sleep & Supports Cognitive Function
    • 3rd-Party Tested For Purity, Potency & Safety
    • 60 Vegan, Non-GMO, Gluten-Free Servings

    Frequently Asked Questions about MTHFR and Anxiety

    Does MTHFR mutation cause anxiety?

    Some research suggests that MTHFR mutations may play a role in several behaviors, including anxiety. This may be because an MTHFR mutation can lead to low production of the neurotransmitters (such as serotonin and dopamine) that support healthy mood and calmness.19

    What mental disorders are associated with the MTHFR gene?

    The MTHFR mutation has also been associated with mental health disorders such as schizophrenia, bipolar disorder, depression, autism, dementia, and ADHD.20 This is linked to low levels of neurotransmitters that can result from folate deficiency.

    Can methylation cause anxiety?

    Anxiety disorders may be linked to different DNA methylation patterns. Hypermethylation has been noted in individuals with anxiety, while lower methylation has been found in patients with depression and bipolar disorder.21

    Is folate linked to anxiety?

    Folate is one of the most important nutrients required for the synthesis of neurotransmitters like serotonin, dopamine, and norepinephrine. These neurotransmitters are involved in regulating mood, appetite, and cognition.
    While some studies have found low folate levels in people with OCD, these results were not found in patients with generalized anxiety disorder or higher anxiety scores. Further studies are needed to clarify the associations between folate and different kinds of anxiety disorders.22

    References

    1. Suma P. Chand, Raman Marwaha; "Anxiety", StatPearls [Internet]., 2023 Apr

      https://www.ncbi.nlm.nih.gov/books/NBK470361/

    2. 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/

    3. Suma P. Chand, Raman Marwaha; "Anxiety", StatPearls [Internet]., 2023 Apr

      https://www.ncbi.nlm.nih.gov/books/NBK470361/

    4. Alan L Miller, "The methylation, neurotransmitter, and antioxidant connections between folate and depression", Alternative Medicine Review: A Journal Of Clinical Therapeutic, 2008 Sep

      https://pubmed.ncbi.nlm.nih.gov/18950248/

    5. Simon Gilbody, Sarah Lewis, Tracy Lightfoot; "Methylenetetrahydrofolate Reductase (MTHFR) Genetic Polymorphisms and Psychiatric Disorders: A HuGE Review", American Journal of Epidemiology Vol. 165 Iss. 1 Pg. 1-13, 2007 Jan

      https://academic.oup.com/aje/article/165/1/1/232658?login=true

    6. David O Kennedy; "B Vitamins and the Brain: Mechanisms, Dose and Efficacy—A Review"; Nutrients; 2016 Jan

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772032/

    7. Richard W Olsen, Timothy M DeLorey; "GABA Synthesis, Uptake and Release"; Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition; 1999

      https://www.ncbi.nlm.nih.gov/books/NBK27979/

    8. N.M. Jadavji, F. Wieske, U. Dirnagl, C. Winter; "Methylenetetrahydrofolate reductase deficiency alters levels of glutamate and γ-aminobutyric acid in brain tissue"; Molecular Genetics and Metabolism Reports Vol. 3 Pg. 1-4; 2015 Jun

      https://www.sciencedirect.com/science/article/pii/S2214426915000087?via%3Dihub

    9. K Luan Phan, Daniel A Fitzgerald, Bernadette M Cortese, Navid Seraji-Bozorgzad, Manuel E Tancer, Gregory J Moore; "Anterior cingulate neurochemistry in social anxiety disorder: 1H-MRS at 4 Tesla"; Neuroreport; 2005 Feb

      https://pubmed.ncbi.nlm.nih.gov/15671874/

    10. Cheng-Ta Li, Kai-Chun Yang, Wei-Chen Lin; "Glutamatergic Dysfunction and Glutamatergic Compounds for Major Psychiatric Disorders: Evidence From Clinical Neuroimaging Studies"; Fronters In Psychiatry; 2019 Jan

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353824/

    11. Jinyan Zhao, Xianghong Li, Qing Chen; "Effects of MTHFR C677T polymorphism on homocysteine and vitamin D in women with polycystic ovary syndrome"; Gene; 2024 Aug

      https://pubmed.ncbi.nlm.nih.gov/38670392/

    12. Einat Avni, Esther Ben-Itzchak, Ditza A Zachor; "The Presence of Comorbid ADHD and Anxiety Symptoms in Autism Spectrum Disorder: Clinical Presentation and Predictors"; Frontiers In Psychiatry; 2018 Dec

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306461/

    13. Andréanne Filion Quenneville, Eleni Kalogeropoulou, Rosetta Nicastro, Sébastien Weibel, Florence Chanut, Nader Perroud; "Anxiety disorders in adult ADHD: A frequent comorbidity and a risk factor for externalizing problems", Psychiatry Research, 2022 Apr

      https://pubmed.ncbi.nlm.nih.gov/35152068/

    14. Catherine G Coughlin, Stephanie C Cohen, Jilian M Mulqueen, Eduardo Ferracioli-Oda, Zachary D Stuckelman, Michael H Bloch; "Meta-Analysis: Reduced Risk of Anxiety with Psychostimulant Treatment in Children with Attention-Deficit/Hyperactivity Disorder", Journal Of Child Adolescent Psychopharmacology; 2015 Oct

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617411/

    15. Dusan Kolar, Amanda Keller, Maria Golfinopoulos, Lucy Cumyn, Cassidy Syer, Lily Hechtman; "Treatment of adults with attention-deficit/hyperactivity disorder", Neuropsychiatric Disease And Treatment; 2008 Apr

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518387/

    16. J W Muntjewerff, R S Kahn, H J Blom, M den Heijer; "Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis"; Molecular Psychiatry; 2006 Feb

      https://pubmed.ncbi.nlm.nih.gov/16172608/

    17. Błażej Misiak, Filip Stramecki, Łukasz Gawęda, Katarzyna Prochwicz, Maria M. Sąsiadek, Ahmed A. Moustafa, Dorota Frydecka; "Interactions Between Variation in Candidate Genes and Environmental Factors in the Etiology of Schizophrenia and Bipolar Disorder: a Systematic Review"; Molecular Neurobiology 55, 5075–5100; 2018 Jun

      https://link.springer.com/article/10.1007/s12035-017-0708-y

    18. E. Siobhan Mitchell, Nelly Conus, Jim Kaput; "B vitamin polymorphisms and behavior: Evidence of associations with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline"; Neuroscience & Biobehavioral Reviews. Vo.47 Pg. 307-320; 2014 Nov

      https://www.sciencedirect.com/science/article/pii/S0149763414002048

    19. NM Jadavji, F Wieske, U Dirnagl, C Winter; "Methylenetetrahydrofolate reductase deficiency alters levels of glutamate and γ-aminobutyric acid in brain tissue"; Molecular Genetics And Metabolism Reports; 2015 Feb

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4750636/

    20. Samira Khan, Abeera Naeem; "MTHFR Deficiency in Biological Siblings Diagnosed With Autism and Attention-Deficit Hyperactivity Disorder (ADHD): A Report of Two Cases"; Cureus; 2023 Mar

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10106103/

    21. Andressa Bortoluzzi, Giovanni Abrahão Salum, Eduarda Dias da Rosa, Vinicius de Saraiva Chagas, Mauro Antônio Alves Castro, Gisele Gus Manfro; "DNA methylation in adolescents with anxiety disorder: a longitudinal study", Scientific Reports; 2018 Sep

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138655/

    22. Nora Eszlari, Bence Bruncsics, Andras Millinghoffer, Gabor Hullam, Peter Petschner, Xenia Gonda, Gerome Breen, Peter Antal, Gyorgy Bagdy, John Francis William Deakin, Gabriella Juhasz; "Biology of Perseverative Negative Thinking: The Role of Timing and Folate Intake"; Nutrients; 2021 Dec

      https://www.mdpi.com/2072-6643/13/12/4396

    23. Banner Image Designed by Freepik

      https://www.freepik.com/

    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!

    Related Articles

    The connection between Histamine and Anxiety

    The connection between Histamine and Anxiety

    Written By:

    Browse Categories