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Methylfolate 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

    Managing Anxiety with Methyl-Life Supplements 💥 The Link between MTHFR and Anxious Thoughts Source: https://www.youtube.com/@MethylLife

    Methylfolate and Anxiety

    More than one-third of the US population is affected by an anxiety disorder during their lifetime. Unfortunately, anxiety is often under-recognized and undertreated.

    Anxiety can have a significant effect on daily life, often causing the sufferer to avoid certain situations. Mild anxiety is fairly common and may only affect someone from time to time. Severe anxiety, however, can be so overwhelming that life is very much disrupted. The mental and physical symptoms that accompany anxiety may occur without warning and feel impossible to control.

    If you’re looking for ways to treat your anxiety, your health professional may offer a range of options including psychological treatment, medication, or a combination of both. This is where your personal preference and individual needs will play a big role. The right kind of psychological treatment can be very effective in helping you to overcome your anxiety.

    Treating MTHFR-related anxiety

    MTHFR gene mutations can increase your risk of developing mental health conditions, including depression and anxiety.
    For those with a MTHFR genetic mutation and anxiety and/or depression, antidepressant medication is often ineffective. This is because the lack of the MTHFR enzyme results in impaired methylfolate metabolism, which means the brain cannot produce the neurotransmitters required for antidepressant medication to function.4
    Supplementing with B vitamins has shown promise in improving the symptoms of anxiety and other issues associated with MTHFR.5

    Can anxiety be treated with methylfolate?

    At present, there are limited studies on treating anxiety with folate, folic acid, or methylfolate supplements. However, there is substantial evidence that depression can be treated with methylfolate, and the World Health Organization has shown that anxiety and depression are the most common coexisting psychological problems in primary care.6

    One study found that rats with depression and anxiety-like behavior were successfully treated with folic acid supplements. The folic acid improved neuro-oxidative damage and neuro-inflammation caused by nicotine withdrawal, which then helped to reduce their anxiety.7

    Folic acid and antipsychotics have also been successfully used to treat negative symptoms in schizophrenia patients.8 Anxiety symptoms can occur in up to 65% of patients with schizophrenia, which may mean that methylfolate would also be helpful. 9

    It’s also worth noting that many patients with depression have self-reported improvement in their anxiety symptoms after taking Deplin®, a prescription methylfolate product.10

    For those who cannot obtain Deplin®, over-the-counter methylfolate supplements are available from Methyl-Life®.

    How does methylfolate help anxiety?

    Methylfolate is the active form of folate, one of the key nutrients necessary for the production of neurotransmitters such as serotonin and dopamine. These ‘brain chemicals’ are involved in supporting healthy mood, cognition, and normal stress response.11

    Methylfolate is required for the methylation of homocysteine, which forms methionine and S-adenosylmethionine (SAMe). SAMe plays an essential role in neurotransmitter synthesis.12

    Methylfolate and other B vitamins are also involved in the conversion of alpha-linolenic acid to Omega 3 fatty acids. Sufficient levels of omega 3 fatty acids are associated with a lower risk of anxiety.13 

    Dosage of methylfolate for anxiety

    At present, there is no specific dosage recommendation for treating anxiety with methylfolate. However, as anxiety often coexists with depression, it may be helpful to consider the methylfolate dosage guidelines recommended for depressive symptoms.
     

    Studies have shown that methylfolate dosages of 15mg are effective in improving symptoms of depression and anxiety.14
     

    Always consult with your healthcare professional before starting any new supplement, including methylfolate, especially if you're currently on other medications or have a medical condition.

    Follow the recommended dosage provided by your healthcare provider, as excessive intake without professional guidance may lead to adverse effects.

    Taking vitamin B12 and/or vitamin D is effective in improving the symptoms of depression and anxiety, especially in patients who are low in these nutrients.15 Vitamin B12 is another crucial nutrient involved in the production of neurotransmitters.

    GABA for MTHFR anxiety

    Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. It works alongside the excitatory neurotransmitter glutamate to control many processes, including anxiety and stress regulation, sleep patterns, memory, mood, and even the perception of pain.

    Research suggests that the MTHFR mutation can affect levels of glutamate and GABA, possibly due to the brain trying to counter the excitatory effects of homocysteine.18 Too much glutamate and too little GABA can result in anxiety, restlessness, brain fog, insomnia, mental exhaustion, and other symptoms. 

    Studies have shown that people who have very little MTHFR activity tend to have higher levels of glutamate and reduced levels of GABA, which could explain anxiety symptoms.17

    It is for this reason that some pharmacological treatments of anxiety disorders and insomnia usually involve benzodiazepines, which help to increase GABA.

    Recent studies have shown that GABA from supplements, probiotics, and GABA-rich fermented foods may increase GABA levels in the brain. One clinical trial found that GABA not only induces relaxation but also reduces anxiety.18

    CALMING is a supplement from Methyl-Life® specifically formulated to reduce anxiety and support the nervous system. CALMING contains GABA, Saffron, and N-acetyl cysteine (NAC), which work together to improve neurotransmitter activity in the brain and soothe feelings of anxiety.

    Options for treating anxiety include

    • Psychological therapy
      Cognitive-behavioral therapy (CBT) is a form of ‘talking therapy’ that many people find effective in treating their anxiety disorder. CBT generally involves changing thought patterns that trigger anxiety by learning to identify and assess fears, and applying coping skills.2

    • Medications
      Medications such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly prescribed to treat both anxiety and depression.3

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    References

    1. Borwin Bandelow, Sophie Michaelis; "Epidemiology of anxiety disorders in the 21st century"; Dialogues in Clinical Neuroscience; 2015 Sep

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610617

    2. Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); "Generalized anxiety disorder: Learn More – Treatment options for generalized anxiety disorder"; InformedHealth.org [Internet]; 2024 Apr

      https://www.ncbi.nlm.nih.gov/books/NBK279594/

    3. Andrew J Melaragno; "Pharmacotherapy for Anxiety Disorders: From First-Line Options to Treatment Resistance"; Focus: The Journal Of Lifelong Learning In Psychiatry; 2021 Jun

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475920/

    4. Angelos Halaris, Emilie Sohl, Elizabeth A Whitham; "Treatment-Resistant Depression Revisited: A Glimmer of Hope"; Journal of Personalized Medicine; 2021 Feb

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927134/

    5. R Reilly, H McNulty, K Pentieva, J J Strain, M Ward; "MTHFR 677TT genotype and disease risk: is there a modulating role for B-vitamins?"; The Proceedings Of The Nutrition Society; 2014 Feb

      https://pubmed.ncbi.nlm.nih.gov/24131523/

    6. David S Baldwin, Dwight L Evans, Robert M A Hirschfeld, Siegfried Kasper; "Can we distinguish anxiety from depression?"; Psychopharmacology Bulletin; 2002

      https://pubmed.ncbi.nlm.nih.gov/12490832/

    7. Mikael Rezaei Moghadam, Alireza Khoshrou, Samaneh Kakhki, Seyed Hossein Hosseini, Atefeh Shirinzadeh Feizabadi, Farimah Beheshti; "Folic Acid Ameliorates Anxiety- and Depressive-Like Behavior Induced by Nicotine Withdrawal Through Restoration of Behavioral and Biochemical Alterations in Adolescent Male Rats"; Nicotine & Tobacco: Research on Nicotine and Tobacco; 2024 May

      https://pubmed.ncbi.nlm.nih.gov/37975546/

    8. Kenji Sakuma, Shinji Matsunaga, Ikuo Nomura, Makoto Okuya, Taro Kishi, Nakao Iwata; "Folic acid/methylfolate for the treatment of psychopathology in schizophrenia: a systematic review and meta-analysis"; Psychopharmacology Vol. 235 Pg. 2303-2314; 2018 May

      https://link.springer.com/article/10.1007/s00213-018-4926-4

    9. Henk Temmingh, Dan J Stein; "Anxiety in Patients with Schizophrenia: Epidemiology and Management"; CNS Drugs; 2015

      https://pubmed.ncbi.nlm.nih.gov/26482261

    10. Reviews for Deplin

      https://www.drugs.com/comments/l-methylfolate/deplin.html?search=anxiety#reviews

    11. Penny M Kris-Etherton, Kristina S Petersen, Joseph R Hibbeln, Daniel Hurley, Valerie Kolick, Sevetra Peoples, Nancy Rodriguez, Gail Woodward-Lopez; "Nutrition and behavioral health disorders: depression and anxiety"; Nutrition Reviews Vol. 79 Iss. 3; 2021 Mar

      https://academic.oup.com/nutritionreviews/article/79/3/247/5843529?login=false

    12. 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://www.ncbi.nlm.nih.gov/pmc/articles/PMC9380836/

    13. Kuan-Pin Su, Ping-Tao Tseng, Pao-Yen Lin, Ryo Okubo, Tien-Yu Chen, Yen-Wen Chen, Yutaka J Matsuoka; "Association of Use of Omega-3 Polyunsaturated Fatty Acids With Changes in Severity of Anxiety Symptoms"; Jama network Open; 2018 Sep

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324500

    14. Angela Hardin, Carrie Baldwin-Sayre; "L-Methylfolate as a Monotherapy for Treatment-Resistant Depression: A Case Study"; Integrative Medicine: A Clinician's Journal; 2020 Aug

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572139/

    15. Jaqueline G Borges-Vieira, Camila K Souza Cardoso; "Efficacy of B-vitamins and vitamin D therapy in improving depressive and anxiety disorders: a systematic review of randomized controlled trials"; Nutritional Neuroscience; 2023 Mar

      https://pubmed.ncbi.nlm.nih.gov/35156551/

    16. 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 Report; 2015 Feb

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

    17. 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 Report; 2015 Feb

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

    18. Adham M Abdou, S Higashiguchi, K Horie, Mujo Kim, H Hatta, H Yokogoshi; "Relaxation and immunity enhancement effects of gamma-aminobutyric acid (GABA) administration in humans"; Biofactors (Oxford, England); 2006

      https://pubmed.ncbi.nlm.nih.gov/16971751/

    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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