MTHFR and Fibromyalgia: Is There a Connection | Methyl-Life®

MTHFR and Fibromyalgia: Is There a Connection | Methyl-Life®

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Dr. Nare Simonyan - PhD Pharmaceutical Science

Medical Reviewer:

Dr. Nare Simonyan - PhD Pharmaceutical Science
Kari Asadorian - Bachelor of Science in Nursing

Edited By:

Kari Asadorian - Bachelor of Science in Nursing

Updated On:

March 26, 2025

Table of Contents

    MTHFR and Fibromyalgia

    Chronic health issues such as fatigue, migraines, depression, cardiovascular disease, and fibromyalgia are now more common than ever. In some cases, these conditions can be related to nutritional status, psychological stress, genetic traits, or a combination of these factors. Most conditions are treated with medication or lifestyle intervention.


    In recent decades, connections have been made between the above conditions and specific genetic variants, namely the MTHFR gene.


    The methylenetetrahydrofolate reductase gene controls the enzyme that metabolizes folate and its biochemical pathway, methylation.


    The methylation process occurs billions of times every second within cells and plays a crucial role in many bodily functions, including detoxification, energy production, and neurotransmitter production. Methylation is also involved in repairing DNA, regulating inflammation, and controlling levels of homocysteine - a harmful amino acid that can damage blood vessels and increase the risk of chronic inflammation.


    Various studies indicate that a mutation on the MTHFR gene may play a part in the pathophysiology of fibromyalgia.


    This article will explain fibromyalgia and its symptoms as well as its etiology. We will discuss the possible links to MTHFR, particularly regarding research into its impact on glutathione and how those with fibromyalgia may find relief through supplementation with methylated folate. 

    What is Fibromyalgia?

    Fibromyalgia is a chronic condition characterized by chronic widespread musculoskeletal pain1 and tenderness without any obvious origins. It affects around 2% of the general population, mainly women. Although often compared to arthritis, fibromyalgia doesn’t cause joint or muscle inflammation or damage but soft tissue pain or myofascial pain.


    Symptoms of fibromyalgia include: 

    • Pain throughout the body
    • Pain and stiffness in the facial muscles and jaw
    • Tingling or numbness in extremities
    • Restless leg syndrome (RLS)
    • Joint and muscle stiffness upon rising in the morning 
    • Headaches
    • Insomnia or irregular sleep patterns
    • Digestive issues such as irritable bowel syndrome (IBS)
    • Menstrual pain
    • Sensitivity to cold or heat
    • Brain fog
    • Poor memory or concentration


    The specific cause of fibromyalgia is yet to be determined. Instead, it appears to be triggered or aggravated by a range of physical and emotional factors. These include psychological stressors, trauma, infections, bodily injury.


    For this reason, fibromyalgia is considered to stem from alterations in pain and sensory processing of the central nervous system. This seems to cause a disorder of pain regulation.


    Patients become hypersensitive to pain perception, which is often related to psychological issues. There is also evidence that fibromyalgia patients have elevated levels of excitatory neurotransmitters and reduced levels of serotonin, norepinephrine, and dopamine2. This may contribute to the prolonged perception of pain.


    Anxiety and depression3 are commonly associated with fibromyalgia, and some studies suggest a major role in the stress response and neuroendocrine abnormalities.


    Some studies have shown a genetic predisposition for fibromyalgia4 though there is no evidence of a definitive gene. However, fibromyalgia appears to be characterized by a hypomethylated DNA pattern5, specifically in genes involved in the stress response, DNA repair, autonomic system response, and subcortical neuronal abnormalities.


    It has also been found that genetic variants and inheritance mechanisms in pain-related genes contribute to 50% in the development of chronic pain6, which indicates a correlation between genetic variants and pain response.

    Is There a Connection Between MTHFR and Fibromyalgia?

    Although classified as a rheumatic disease, fibromyalgia is treated more like a neurological problem than a rheumatic problem. The MTHFR connection partly explains this.


    The strong association of genetic variants with chronic pain disorders has led researchers to conclude that pain-related gene polymorphisms are involved in the pathogenesis of fibromyalgia.


    The MTHFR polymorphism impairs the methylation process, which in turn impairs the production of numerous neurotransmitters, particularly those that affect mood, motivation, sleep, and pain regulation.


    MTHFR affects the body’s ability to create methylfolate. Methylfolate is essential for producing neurotransmitters such as serotonin, dopamine, and norepinephrine, which help regulate mood and pain perception.


    Low serotonin has been linked to chronic pain7 disorders such as fibromyalgia. There is also a significant association between COMT (catecholaminergic enzyme) and regulation of serotonin8).


    Studies have shown that single nucleotide polymorphisms9 identified in genes coding for neurotransmitters (such as serotonin and dopamine) may lead to the dysfunction of pain pathways in fibromyalgia patients. These polymorphisms are also identified in other symptoms seen in those patients, especially depression and anxiety.


    It is also known that various mental disorders, especially depression, often accompany10 fibromyalgia. The MTHFR polymorphism is also associated with psychiatric disorders11 such as anxiety, bipolar disorder, and schizophrenia.


    However, a Turkish study that investigated the link between the C677T gene polymorphism found it to be protective against fibromyalgia12. The authors noted that further research would be required to explain this finding.


    Gene polymorphisms have been related to a decreased pain threshold13, higher levels of inflammation, and an increased susceptibility to disorders associated with chronic pain. Some of those genetic variants may trigger the onset of fibromyalgia.


    MTHFR is also the most commonly identified gene in migraine14, which is a known symptom of fibromyalgia.


    While there is some speculation about the link between MTHFR, fibromyalgia, and glutathione, evidence to support this theory is lacking. 

    Can You Boost Serotonin Levels?

    Serotonin may be the key to resolving many symptoms associated with MTHFR and/or fibromyalgia.


    Several studies have identified impairment in the serotonin pathway in fibromyalgia patients, which is also a significant effect of the MTHFR polymorphism.


    Serotonin is central to chronic pain disorders as it both inhibits and promotes pain perception15 by different physiological mechanisms. Studies of antidepressant administration in animal models of pain have shown the role of monoamines in pain modulation.


    Methylfolate acts as an important regulator of cofactors16 involved in the synthesis of neurotransmitters, including serotonin. It is also required for the conversion of homocysteine to methionine, an amino acid that is converted to s-adenyl-methionine (SAMe). SAMe then serves as the methyl donor for all three monoamines serotonin, norepinephrine, and dopamine.


    As an indirect regulator of serotonin, methylfolate supplementation has already been successfully used in the management of treatment-resistant depression.


    Improving levels of serotonin has helped to improve symptoms17 of depression, anxiety, insomnia, and somatic pains in a variety of patients.


    Some studies have investigated the benefits of supplementing with vitamin B12 and folate18 as a means to improve symptoms of chronic fatigue syndrome and fibromyalgia. Researchers have suggested that boosting serotonin may be a therapeutic mechanism19 for the treatment of fibromyalgia.

    Steps to Take with Fibromyalgia

    Addressing chronic pain such as fibromyalgia requires a multifaceted approach. While pharmaceutical drugs are most often used to manage pain, more recent modalities recognize the role of cognitive dysfunction in fibromyalgia.


    Self-management skills and cognitive behavioral approaches20 may be beneficial as a means of managing pain and associated disorders such as depression and anxiety.


    Supporting neurotransmitter production is also crucial. Studies have highlighted the importance of serotonin in the management of fibromyalgia21 and its benefits in modulating or alleviating the symptoms of pain, fatigue, and sleep disturbances.


    Improving serotonin naturally is best done through supplementation of methylfolate. This is especially recommended if the patient also has an MTHFR polymorphism that inhibits their metabolism of folic acid. Methylfolate is an active form of folate that can bypass the MTHFR mutation. It is already in its metabolized form, which means it can be readily absorbed and utilized in the body for many biochemical reactions.


    Some of the most highly recommended methylfolate supplements are in the Methyl-Life® product range. These are formulated especially for people with a heightened need for bioavailable folate due to MTHFR defects, dietary deficiencies, or other conditions in which nutritional absorption is impaired. 

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    References

    1. Juhi Bhargava, Jennifer Goldin; "Fibromyalgia"; StatPearls [Internet]; 2025 Jan

      https://www.ncbi.nlm.nih.gov/books/NBK540974/

    2. Juhi Bhargava, Jennifer Goldin; "Fibromyalgia"; StatPearls [Internet]; 2025 Jan

      https://www.ncbi.nlm.nih.gov/books/NBK540974/

    3. Lesley M. Arnold, James I. Hudson, Paul E. Keck, Jr., Megan B. Auchenbach, Kristin N. Javaras, Evelyn V. Hess; "Comorbidity of Fibromyalgia and Psychiatric Disorders"; The Journal of Clinical Psychiatry; 2006 Aug

      https://www.psychiatrist.com/jcp/medical/comorbidity/comorbidity-fibromyalgia-psychiatric-disorders/

    4. Dan Buskila, Piercarlo Sarzi-Puttini; "Biology and therapy of fibromyalgia. Genetic aspects of fibromyalgia syndrome"; Arthritis Research & Therapy; 2006 Jul

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1779444/

    5. Simona D’Agnelli, Lars Arendt-Nielsen, Maria C Gerra, Katia Zatorri, Lorenzo Boggiani, Marco Baciarello, Elena Bignami; "Fibromyalgia: Genetics and epigenetics insights may provide the basis for the development of diagnostic biomarkers"; Molecular Pain; 2018 Nov

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322092/

    6. Jeffrey S. Mogil; "Pain genetics: past, present and future"; Trends in Genetics, Vol. 28, Iss. 6, Pg. 258-266

      https://www.sciencedirect.com/science/article/abs/pii/S0168952512000285

    7. Stephania Paredes, Santiago Cantillo, Kenneth D Candido, Nebojsa Nick Knezevic; "An Association of Serotonin with Pain Disorders and Its Modulation by Estrogens"; International Journal of Molecular Sciences; 2019 Nov

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888666/

    8. Anindya Gupta, Alan J Silman; "Psychological stress and fibromyalgia: a review of the evidence suggesting a neuroendocrine link"; Arthritis Research & Therapy; 2004 Apr

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC416451/

    9. Simona D’Agnelli, Lars Arendt-Nielsen, Maria C Gerra, Katia Zatorri, Lorenzo Boggiani, Marco Baciarello, Elena Bignami; "Fibromyalgia: Genetics and epigenetics insights may provide the basis for the development of diagnostic biomarkers"; Molecular Pain; 2018 Nov

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322092/

    10. Carmen M Galvez-Sánchez, Stefan Duschek, Gustavo A Reyes del Paso; "Psychological impact of fibromyalgia: current perspectives"; Psychology Research and Behavior Management; 2019 Feb

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386210/

    11. 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/

    12. ​Emine Dündar Ahi, Sevgi İkbali Afşar, Seyhan Sözay, Yaprak Yalçın, Hatice Pınar Baysan Çebi; "Association between fibromyalgia syndrome and MTHFR C677T genotype in Turkish patients"; Journal of Surgery and Medicine; 2020 Mar

      https://www.researchgate.net/publication/340418695_Association_between_fibromyalgia_syndrome_and_MTHFR_C677T_genotype_in_Turkish_patients

    13. ​Peck MM, Maram R, Mohamed A, Ochoa Crespo D, Kaur G, Ashraf I, Malik BH; "The Influence of Pro-inflammatory Cytokines and Genetic Variants in the Development of Fibromyalgia: A Traditional Review"; Cureus; 2020 Sep

      https://pubmed.ncbi.nlm.nih.gov/33042712/

    14. ​Diatchenko L, Fillingim RB, Smith SB, Maixner W; "Genetic predictors of human chronic pain conditions"; Neuroscience Letters; 2016 Aug

      https://www.sciencedirect.com/science/article/pii/S0306452216301269

    15. David M Marks, Manan J Shah, Ashwin A Patkar, Prakash S Masand, Geun-Young Park, Chi-Un Pae; "Serotonin-Norepinephrine Reuptake Inhibitors for Pain Control: Premise and Promise"; Current neuropharmacology; 2009 Dec

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2811866/

    16. Samet Kose, Kemal Sayar; "L-methylfolate in patients with treatment resistant depression: fulfilling the goals of personalized psychopharmacological therapy"; Psychiatry and Clinical Psychopharmacology, Vol. 28, Iss. 4; 2018 Dec

      https://www.tandfonline.com/doi/full/10.1080/24750573.2018.1552401

    17. J H Juhl; "Fibromyalgia and the serotonin pathway"; Alternative medicine review : a journal of clinical therapeutic; 1998 Oct

      https://pubmed.ncbi.nlm.nih.gov/9802912/

    18. Björn Regland, Sara Forsmark, Lena Halaouate, Michael Matousek, Birgitta Peilot, Olof Zachrisson, Carl-Gerhard Gottfries; "Response to Vitamin B12 and Folic Acid in Myalgic Encephalomyelitis and Fibromyalgia"; PLoS One; 2015 Apr

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406448/

    19. J H Juhl; "Fibromyalgia and the serotonin pathway"; Alternative medicine review : a journal of clinical therapeutic; 1998 Oct

      https://pubmed.ncbi.nlm.nih.gov/9802912/

    20. G J Macfarlane, C Kronisch, L E Dean, F Atzeni, W Häuser, E Fluß, E Choy, E Kosek, K Amris, J Branco, F Dincer, P Leino-Arjas, K Longley, G M McCarthy, S Makri, S Perrot, P Sarzi-Puttini, A Taylor, G T Jones; "EULAR revised recommendations for the management of fibromyalgia"; Annals of the rheumatic diseases.; 2017 Feb

      https://pubmed.ncbi.nlm.nih.gov/27377815/

    21. Brian Walitt, Gerard Urrútia, María Betina Nishishiny, Sarah E Cantrell, Winfried Häuser; "Selective serotonin reuptake inhibitors for fibromyalgia syndrome"; Cochrane Database of Systematic reviews; 2015 Jun

      https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD011735/full

    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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