MTHFR and Fibromyalgia

MTHFR and Fibromyalgia

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Katie Stone - Naturopath

Written By:

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

Medical Reviewer:

Dr. Nare Simonyan - PhD Pharmaceutical Science
Kari Asadorian - BSN, RN

Edited By:

Kari Asadorian - BSN, RN
Last updated:

What Is Fibromyalgia?

Fibromyalgia (FM) is a chronic musculoskeletal condition characterized by widespread pain. It is also described as a pain processing disorder resulting in hypersensitivity.

FM is often accompanied by other symptoms including fatigue, sleep and mood disorders such as anxiety and depression, cognitive dysfunction, and digestive issues.1 These symptoms can impair the ability to carry out normal daily activities. 

Fibromyalgia affects an estimated 2-8% of the world’s population, and it is three times more common in women than in men.2


The causes of fibromyalgia are still not fully understood, but multiple factors may be involved, including genetic predisposition, immunological and neuroendocrine dysfunctions, and psychological or physical stressors.3

Symptoms of Fibromyalgia

FM is associated with a wide range of symptoms that vary in severity, combinations, and underlying contributing factors.

Pain Symptoms Of Fibromyalgia

  • Chronic widespread pain in at least 4 of 5 body regions (in at least 3 or 4 body quadrants) accompanied by functional symptoms4
  • Aching, dull, sharp, shooting, or burning pain
  • Increased pain in certain areas, such as back, neck, shoulders.
  • Hyperalgesia (increased sensitivity) 
  • Allodynia: pain from stimulus that should not normally cause pain

Common Accompanying Symptoms of Fibromyalgia

  • Sensitivity to environmental factors (smoke, certain foods, bright lights).
  • Stiffness
  • Fatigue
  • Difficulty sleeping or non-restorative sleep
  • Slowed cognitive function including poor memory, reduced concentration (“fibro-fog”)
  • Low mood, depression, anxiety
  • Headaches and/or migraines
  • Irritable bowel syndrome (IBS) or other gastrointestinal symptoms such as bloating, constipation, diarrhea 
  • Interstitial cystitis
  • Dizziness and clumsiness
  • Poor body temperature regulation 
  • Restless legs syndrome
  • Paresthesia (tingling, numbness, prickling or burning sensations in hands and feet)
  • Painful periods

How To Treat Fibromyalgia

Fibromyalgia is highly individualized. Symptoms and causes vary significantly from one person to the next. Each case may be influenced by a range of genetic factors, mental and physical health, environmental contributors, pain threshold, and other medical conditions.5

Patients may respond differently to the same interventions, so treatment should be tailored to the individual. 

Diagnosis should include a comprehensive evaluation of the health history, pain characteristics, sleep patterns, fatigue severity, psychiatric symptoms, and cognitive dysfunction, along with screening for other conditions such as inflammatory arthritis, osteoarthritis, thyroid disease, and specific causes of pain.6

Effective treatment requires a multidisciplinary approach combining patient education, regular physical activity, cognitive behavioral therapy, stress management, pharmacological interventions, lifestyle modifications, and the management of comorbid conditions.

Medications To Treat Fibromyalgia

Medications may be given to patients with moderate-to-severe symptoms or those who do not respond to nonpharmacological interventions. However, research suggests that medications are only moderately effective in around 50% of cases.7

  • Antidepressants may be used to treat related symptoms such as depression, anxiety, sleep disorders, and fatigue. These include selective serotonin reuptake inhibitors (SSRIs) and/or selective serotonin and noradrenaline reuptake inhibitors (SNRIs).
  • Anticonvulsants - drugs to prevent or stop seizures - (pregabalin and gabapentin) may be used but have many side effects, such as dizziness.
  • Nonsteroidal anti-inflammatory drugs, acetaminophen, and opioids are generally not recommended due to their limited effectiveness and potential risks.

Non-Pharmacological Treatments For Fibromyalgia

Sleep hygiene
Sleep hygiene education is shown to be effective in improving sleep quality and alleviating pain and depression in people with fibromyalgia.8 Techniques include setting a regular bedtime, creating a quiet and comfortable bedroom environment, and avoiding caffeine, alcohol, and devices at night.


Physical activity
Aerobic and resistance training consistently reduces pain and improves function and quality of life in people with fibromyalgia. These forms of physical activity help to enhance central pain inhibition, improve mitochondrial efficiency, and reduce inflammatory signaling. Resistance training also helps to improve muscular strength and confidence in movement, while aerobic programs improve cardiorespiratory fitness and resilience to fatigue.9

Mind-body and aquatic programs are also found to be effective and often well tolerated, especially when programs are combined.


Cognitive therapy
Cognitive-behavioral therapy and/or mindfulness-based stress reduction, or meditation and relaxation techniques have been shown to reduce pain, sleep disturbances, and symptoms of depression and anxiety, especially when combined with patient education.10

What To Avoid When You Have Fibromyalgia

  • High intake of caffeine and alcohol can affect sleep quality, so limitation is advised.  
  • Strenuous exercise (such as intense cardiovascular activity and weight training) should be avoided to reduce strain on the body.
  • Being sedentary is also unhelpful
  • Foods high in saturated fat, sugar, and artificial additives can increase oxidative stress and inflammation in the body. Some individuals may find that avoiding gluten, dairy, and high-FODMAP foods is beneficial. 

The Connection Between Fibromyalgia And MTHFR

Some studies have suggested a link between fibromyalgia and the MTHFR genetic mutation. 

MTHFR variants such as C677T reduce the function of the MTHFR enzyme, leading to reduced folate and increased homocysteine. Low folate is a common contributor to mood disorders such as depression and anxiety.

Folate metabolism is essential for the production of several neurotransmitters, including serotonin and dopamine, which are linked to mood and feelings of fatigue. Previous research has shown a higher prevalence of the MTHFR mutation and fatigue in people with migraine.11

People with the MTHFR mutation are also found to have higher rates of depression and anxiety, and to respond less effectively to antidepressants and pain medications.12

Fibromyalgia is closely associated with impaired neurotransmitter pathways, particularly serotonin. Serotonin and norepinephrine dysfunctions are often associated with mood and pain disorders. While research regarding MTHFR and fibromyalgia is limited, genetic variants that affect serotonin are known to increase susceptibility to fibromyalgia, depression, and pain perception.13

Treating Fibromyalgia And MTHFR At The Same Time

Supporting folate and B12 pathways may be beneficial in both MTHFR and fibromyalgia, as symptoms of deficiency can overlap.


Vitamin B9 (folate/methylfolate)
Folate plays a key role in homocysteine metabolism and neurotransmitter production. 

Research has suggested a link between MTHFR 677TT and 1298CC genotypes and an increased risk of treatment-resistant depression, which results in lower L-methylfolate and subsequently lower neurotransmitter levels.14

Multiple studies and systematic reviews have investigated the use of L-methylfolate as stand-alone or adjunctive treatment for depression. Methylfolate crosses the blood-brain barrier and is a cofactor required for the synthesis of serotonin, norepinephrine, and dopamine in the brain. Supplementation with L-methylfolate alongside antidepressants or alone has been effective in reducing symptoms of depression.15

A 2019 animal study found that a combination of melatonin and folic acid supplementation helped to reduce increased pain sensitivity and depression in fibromyalgia more effectively than supplementing either nutrient alone. The researchers concluded that melatonin plus folic acid helped to improve behavioral defects, oxidative and nitrosative stress, inflammation, and microglial activation.16


Vitamin B12
Folate and B12 are both required for homocysteine metabolism and for neurotransmitter function. Vitamin B12 deficiency has similar symptoms to fibromyalgia, such as pain, fatigue, sleepiness, paresthesia, or sensory disturbances, especially in patients who are vegan and/or have malabsorption disorders. 

B12 functions alongside folate in homocysteine metabolism and neurotransmitter synthesis, and also plays an important role in the regeneration of injured nerves and reducing neurotoxicity. A 2022 study involving female patients with fibromyalgia found that daily supplementation with 1,000 mcg of sublingual vitamin B12 significantly improved the severity of fibromyalgia symptoms and anxiety.17 Other studies have suggested that B12 may play a role in pain relief in various neuropathic pain conditions such as diabetic neuropathy.18

MTHFR and Fibromyalgia

Key Takeaways

  • Icon Fibromyalgia is a chronic pain disorder that affects at least 4 of 5 body regions and usually occurs alongside fatigue, cognitive dysfunction, mood disorders, and sleeplessness.
  • Icon MTHFR gene variants have been linked to higher rates of depression, anxiety, fatigue, and pain sensitivity, including overlap with fibromyalgia.
  • Icon Supplementation with active folate and active B12 is often recommended for those with MTHFR, and may be beneficial for pain conditions such as fibromyalgia.

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  • 3rd-Party Tested for Purity, Potency & Safety
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Frequently Asked Questions about Fibromyalgia and MTHFR

Is fibromyalgia an autoimmune disease?

Recent research has suggested that fibromyalgia and other chronic pain conditions may be linked to autoantibody-mediated autoimmunity. Individuals with fibromyalgia have been found to have elevated levels of certain antibodies in both serum and plasma, and higher antibody levels appear to lead to greater severity of self-reported pain.19

How is fibromyalgia diagnosed?

In the US, fibromyalgia is clinically diagnosed when widespread pain occurs in at least 4 of 5 body regions for at least 3 months, alongside a Widespread Pain Index and Symptom Severity Scale (which includes fatigue, non-restorative sleep, and cognitive symptoms). The presence of another disease does not exclude a diagnosis of FM.20

What causes fibromyalgia?

The causes of fibromyalgia are still not fully understood, but multiple factors may be involved, including genetics, immunological and neuroendocrine dysfunctions, and psychological or physical stressors.21

What autoimmune diseases are linked to MTHFR?

Some research has suggested that the MTHFR C677T variant may increase the risk of rheumatoid arthritis.22 Other studies have suggested MTHFR gene variants may also be linked to Behcet's disease, multiple sclerosis, and ankylosing spondylitis.23

References

  1. Tamara Filipovic, Aleksandar Filipović, Dejan Nikolic, Francesca Gimigliano, Jelena Stevanov, Marija Hrkovic, Ivana Bosanac, Masahiro Kohzuki; "Fibromyalgia: Understanding, Diagnosis and Modern Approaches to Treatment"; Journal of clinical medicine; 2025 Feb

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11818761/

  2. Serge Perrot; "Fibromyalgia: A misconnection in a multiconnected world?"; Eur J Pain; 2019 May

    https://pubmed.ncbi.nlm.nih.gov/30663833/

  3. Tamara Filipovic, Aleksandar Filipović, Dejan Nikolic, Francesca Gimigliano, Jelena Stevanov, Marija Hrkovic, Ivana Bosanac, Masahiro Kohzuki; "Fibromyalgia: Understanding, Diagnosis and Modern Approaches to Treatment"; Journal of clinical medicine; 2025 Feb

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11818761

  4. Michael Nicholas, Johan W S Vlaeyen, Winfried Rief, Antonia Barke, Qasim Aziz, Rafael Benoliel, Milton Cohen, Stefan Evers, Maria Adele Giamberardino, Andreas Goebel, Beatrice Korwisi, Serge Perrot, Peter Svensson, Shuu-Jiun Wang, Rolf-Detlef Treede, IASP Taskforce for the Classification of Chronic Pain; "The IASP classification of chronic pain for ICD-11: chronic primary pain"; Pain; 2019 Jan

    https://pubmed.ncbi.nlm.nih.gov/30586068/

  5. Tamara Filipovic, Aleksandar Filipović, Dejan Nikolic, Francesca Gimigliano, Jelena Stevanov, Marija Hrkovic, Ivana Bosanac, Masahiro Kohzuki; "Fibromyalgia: Understanding, Diagnosis and Modern Approaches to Treatment"; Journal of clinical medicine; 2025 Feb

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11818761/

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

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

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

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

  8. Emine Başar Okul, Tülay Kars Fertelli; "The Effects of Sleep Hygiene Education on Sleep Quality, Pain, and Depression in Individuals With Fibromyalgia"; Pain management nursing; 2025 Jun

    https://pubmed.ncbi.nlm.nih.gov/39732519/

  9. Alexander Mazzorana, Laith Fada, John Wahidy, Greg Jacobs; "Role of Exercise in Fibromyalgia Management: A Narrative Review of Mechanisms, Modalities, and Clinical Evidence"; Cureus; 2026 Jan

    https://pmc.ncbi.nlm.nih.gov/articles/PMC12890375/#sec3

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

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

  11. Anzel Bahadir, Recep Eroz, Suber Dikici; "Investigation of MTHFR C677T gene polymorphism, biochemical and clinical parameters in Turkish migraine patients: association with allodynia and fatigue"; Cell Mol Neurobiol.; 2013 Nov

    https://pubmed.ncbi.nlm.nih.gov/23975093/

  12. Lisa Lynn Dragic, Erica L Wegrzyn, Michael E Schatman, Jeffrey Fudin; "Pharmacogenetic guidance: individualized medicine promotes enhanced pain outcomes"; Journal of pain research; 2017 Dec

    https://pmc.ncbi.nlm.nih.gov/articles/PMC5743122/

  13. Alfonso Alfaro-Rodríguez, Samuel Reyes-Long, Ernesto Roldan-Valadez, Maykel González-Torres, Herlinda Bonilla-Jaime, Cindy Bandala, Alberto Avila-Luna, Antonio Bueno-Nava, Elizabeth Cabrera-Ruiz, Pedro Sanchez-Aparicio, Angélica González Maciel, Ana Lilia Dotor-Llerena, José Luis Cortes-Altamirano; "Association of the Serotonin and Kynurenine Pathways as Possible Therapeutic Targets to Modulate Pain in Patients with Fibromyalgia"; Pharmaceuticals (Basel); 2024 Sep

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11434812/

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

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

  15. Gerald Martone; "Enhancement of recovery from mental illness with l-methylfolate supplementation"; Perspectives in Psychiatric Care; 2017 Jun

    https://onlinelibrary.wiley.com/doi/10.1111/ppc.12227

  16. Roberta Fusco, Rosalba Siracusa, Ramona D’Amico, Alessio Filippo Peritore, Marika Cordaro, Enrico Gugliandolo, Rosalia Crupi, Daniela Impellizzeri, Salvatore Cuzzocrea, Rosanna Di Paola; "Melatonin Plus Folic Acid Treatment Ameliorates Reserpine-Induced Fibromyalgia: An Evaluation of Pain, Oxidative Stress, and Inflammation"; Antioxidants; 2019

    https://www.mdpi.com/2076-3921/8/12/628

  17. Faeze Gharibpoor, Banafsheh Ghavidel-Parsa, Nazila Sattari, Ali Bidari, Fatemeh Nejatifar, Ali Montazeri; "Effect of vitamin B12 on the symptom severity and psychological profile of fibromyalgia patients; a prospective pre-post study"; BMC Rheumatol.; 2022 Sep

    https://pmc.ncbi.nlm.nih.gov/articles/PMC9434892/

  18. Triantafyllos Didangelos, Eleni Karlafti, Evangelia Kotzakioulafi, Eleni Margariti, Parthena Giannoulaki, Georgios Batanis, Solomon Tesfaye, Kοnstantinos Kantartzis; "Vitamin B12 Supplementation in Diabetic Neuropathy: A 1-Year, Randomized, Double-Blind, Placebo-Controlled Trial"; Nutrients; 2021 Jan

    https://pmc.ncbi.nlm.nih.gov/articles/PMC7912007/

  19. Kate Findeisen, Emma Guymer, Geoffrey Littlejohn; "Neuroinflammatory and Immunological Aspects of Fibromyalgia"; Brain Sci.; 2025 Feb

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11852494/

  20. Frederick Wolfe, Daniel J Clauw, Mary-Ann Fitzcharles, Don L Goldenberg, Winfried Häuser, Robert L Katz, Philip J Mease, Anthony S Russell, Irwin Jon Russell, Brian Walitt; "2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria"; Semin Arthritis Rheum.; 2016 Dec

    https://pubmed.ncbi.nlm.nih.gov/27916278/

  21. Tamara Filipovic, Aleksandar Filipović, Dejan Nikolic, Francesca Gimigliano, Jelena Stevanov, Marija Hrkovic, Ivana Bosanac, Masahiro Kohzuki; "Fibromyalgia: Understanding, Diagnosis and Modern Approaches to Treatment"; Journal of clinical medicine; 2025 Feb

    https://pmc.ncbi.nlm.nih.gov/articles/PMC11818761

  22. Pablo Michael Navarro‑Rodríguez, Ramón Francisco Bajeca‑Serrano, Francisco Javier Turrubiates‑Hernández, Hazael Ramiro Ceja‑Gálvez, Jorge Hernández‑Bello, Cristian Oswaldo Hernández‑Ramírez, Saúl Ramírez‑de Los Santos, José Francisco Muñoz‑Valle; "MTHFR‑folate axis as a modulator of the epigenetic landscape in autoimmune diseases (Review)"; International Journal of Molecular Medicine; 2026 Mar

    https://www.spandidos-publications.com/10.3892/ijmm.2026.5741#

  23. Mao Lu, Ke Peng, Li Song, Li Luo, Peng Liang, Yundan Liang; "Association between Genetic Polymorphisms in Methylenetetrahydrofolate Reductase and Risk of Autoimmune Diseases: A Systematic Review and Meta-Analysis"; Disease Markers; 2022 May

    https://pmc.ncbi.nlm.nih.gov/articles/PMC9173919/

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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