MTHFR and Migraines

MTHFR and Migraines

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Kari Asadorian - Bachelor of Science in Nursing

Medical Reviewer:

Kari Asadorian - Bachelor of Science in Nursing
Jamie Hope - Founder of Methyl-Life

Edited By:

Jamie Hope - Founder of Methyl-Life

Updated On:

February 10, 2025

Table of Contents

  1. MTHFR and Migraines
    1. Does MTHFR cause migraines?
      1. How is MTHFR related to migraines?
        1. How does MTHFR relate to homocysteine levels?
          1. Relation to magnesium
            1. How does methylfolate help with migraines?

              Does MTHFR cause migraines?

              Yes, research suggests that MTHFR gene mutations may be linked to migraine. MTHFR is the most investigated genetic risk factor in migraine, especially migraine with aura. People with the MTHFR C677T mutation have a significantly higher risk of experiencing migraine with aura as well as with increased homocysteine concentrations, which is also linked to migraine.3

              A mutation on the MTHFR gene impairs the body’s ability to convert folic acid to methylfolate, and methylfolate is a key component of the process required for metabolizing homocysteine for promoting SAMe and utilizing intracellular glutathione. If folate levels are low - which is common in people with MTHFR mutations - homocysteine levels may increase significantly. 

              Deficiency in B6, B12 and folate, coupled with a MTHFR mutation, results in a significant DNA hypomethylation, which in turn plays a significant role in triggering migraine attacks.4

              How does MTHFR relate to homocysteine levels?

              Homocysteine is an amino acid naturally produced by the body which can lead to significant health issues if levels are too high. Normally, homocysteine is recycled into methionine (another amino acid), which is then used to create important neurotransmitters. This recycling process requires vitamins B12, B6, and folate. However, a lack of these vitamins means the body cannot properly convert homocysteine to methionine. Instead, homocysteine builds up in the blood, where it can cause serious damage to blood vessels as well as impairing neurotransmitter production.
               

              People with a MTHFR mutation are at higher risk of elevated homocysteine as they are more likely to be low in folate, B12, and B6.5

              Elevated homocysteine can lead to inflammation in the central nervous system (CNS) as well as causing cerebral vessels to dilate. This is thought to cause the pain associated with migraine.6

              Oxidative damage to the lining of the blood vessels may also increase the likelihood of migraine.7

              Relation to magnesium

              Magnesium deficiency is a known risk factor for migraine. A lack of magnesium can lead to cortical spreading depression (CSD): a wave of brain cell depolarization in the cerebral cortex and other areas of the brain. When CSD occurs, nerve cells in the cortex become highly active then their activity is reduced. This process is thought to be linked to the aura phase that occurs before a migraine.8

              Imbalances in magnesium and calcium levels can also disrupt NMDA receptor function, potentially triggering cortical depression. The NMDA receptor, which regulates glutamate release, depends on a precise balance of these ions. Magnesium blocks the receptor's calcium channel, preventing an excessive influx of calcium ions and protecting cells from damage. When magnesium levels are low, this regulation weakens, leading to increased glutamate activity, excitotoxicity, and oxidative stress. These effects are all linked to migraine onset.9
               

              Magnesium supplementation has been shown to help prevent and alleviate migraine by improving mitochondrial function and energy production in the brain as well as reducing oxidative stress, which is a major cause of migraine.10

              How does methylfolate help with migraines?

              Methylfolate is the active form of folate, one of the nutrients involved in reducing homocysteine levels in the blood. Methylfolate works alongside vitamins B6 and B12 to convert homocysteine to methionine. A lack of methylfolate and/or reduced MTHFR enzymatic activity can result in increased homocysteine levels, and an increased risk of migraine.11


              Studies show that supplementation with folate, vitamin B6 and vitamin B12 can decrease homocysteine concentrations, and may also reduce the frequency of headache as well as the impact of migraine on a person’s quality of life.12


              Taking methylfolate has also been shown to decrease the severity of migraines with aura.13


              One study found that supplementing with 2 mg folic acid, 25 mg vitamin B6 and 400 μg vitamin B12 significantly reduced homocysteine levels and migraine symptoms in people affected by migraine with aura. This study also showed that the MTHFR C677T genotype is a major factor in migraine, as people with the CC allele (which represents ‘no mutation’ have greater MTHFR enzyme activity) experienced a better response to folic acid supplementation than those with the TT allele (which represents a ‘double mutation’), who have much lower MTHFR enzyme activity and therefore cannot metabolize folic acid properly.14

              MTHFR and Migraines

              A migraine is a type of headache that causes moderate to severe throbbing pain on one side of the head.1 This pain may be accompanied by nausea, vomiting, sensitivity to light and/or loud noises, and sometimes also double vision or aura. Aura refers to the bright lights, lines, and shapes that appear in front of the eyes, and/or tinnitus or sounds in the ears.2


              Around 25% of people who get migraines experience aura, which can occur before or during the headache. Auras develop gradually and typically last up to 60 minutes.


              Recent research has shown that the MTHFR gene mutation may play a part in causing migraine, particularly migraine with aura.

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              Frequently Asked Questions about MTHFR and migraines

              Does the MTHFR gene cause migraines?

              Several studies have shown that the MTHFR C677T mutation is a common cause of migraines, especially migraine with aura. People with MTHFR mutations are unable to metabolize folic acid properly, which can lead to low folate levels in the body. Folate is essential for the breakdown of homocysteine, and low folate can lead to a buildup of homocysteine, which is a major factor in migraines.

              Can methylated vitamins cause migraines?

              No, studies show that methylated vitamins such as methylfolate (B9) and methylcobalamin (B12) can reduce homocysteine, a major cause of migraine symptoms.15 Although some research has shown that folic acid is effective in reducing migraine, methylfolate is the active form of folate that is absorbed more effectively by the body, especially in people with MTHFR mutations.16

              Can high homocysteine levels cause migraines?

              Yes, high homocysteine is a major factor in migraine risk, especially in migraine with aura (bright lights and shapes alongside the head pain). Homocysteine increases vascular inflammation and oxidative stress, which can then trigger migraine headaches.

              What genetic mutation causes migraines?

              The MTHFR genetic mutation is the most studied genetic risk factor for migraines, especially migraine with aura. People with the MTHFR C677T mutation are typically prone to higher homocysteine levels and also have a much higher risk of experiencing migraine with aura. 17

              References

              1. National Institute of Neurological Disorders and Stroke; "Migraine"; 2025 Jan

                https://www.ninds.nih.gov/health-information/disorders/migraine

              2. Nidhi Shankar Kikkeri, Shivaraj Nagalli; "Migraine With Aura"; StatPearls [Internet].; 2024 Feb

                https://www.ncbi.nlm.nih.gov/books/NBK554611

              3. Innocenzo Rainero, Alessandro Vacca, Fausto Roveta, Flora Govone, Annalisa Gai, Elisa Rubino; "Targeting MTHFR for the treatment of migraines"; Expert Opinion on Therapeutic Targets Vol. 23, Iss. 1; 2019

                https://www.tandfonline.com/doi/full/10.1080/14728222.2019.1549544

              4. Munvar Miya Shaik, Huay Lin Tan, Mohammad A Kamal, Siew Hua Gan; "Do folate, vitamins B₆ and B₁₂ play a role in the pathogenesis of migraine? The role of pharmacoepigenomics"; CNS & neurological disorders drug targets; 2014

                https://pubmed.ncbi.nlm.nih.gov/24040787

              5. Tauheed Hasan, Reetika Arora, Aniket Kumar Bansal, Reshmee Bhattacharya, Gurumayum Suraj Sharma, Laishram Rajendrakumar Singh; "Disturbed homocysteine metabolism is associated with cancer"; Experimental & Molecular Medicine Vol. 51, pg. 1–13; 2019

                https://www.nature.com/articles/s12276-019-0216-4

              6. Shani Stuart, Hannah C. Cox, Rod A. Lea, Lyn R. Griffiths; "The Role of the MTHFR Gene in Migraine"; Headache: The Journal of Head and Face Pain; 2012

                https://sci-hub.se/https://doi.org/10.1111/j.1526-4610.2012.02106.x

              7. Matteo Paolucci, Claudia Altamura, Fabrizio Vernieri; "The Role of Endothelial Dysfunction in the Pathophysiology and Cerebrovascular Effects of Migraine: A Narrative Review"; Journal of Clinical Neurology; 2021 Mar

                https://pmc.ncbi.nlm.nih.gov/articles/PMC8053543/

              8. Lyudmila V. Vinogradova: "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic"; Epilepsy & Behavior; 2017

                https://www.sciencedirect.com/topics/medicine-and-dentistry/cortical-spreading-depression

              9. Izabela Domitrz, Joanna Cegielska; "Magnesium as an Important Factor in the Pathogenesis and Treatment of Migraine—From Theory to Practice"; Nutrients; 2022 Mar

                https://pmc.ncbi.nlm.nih.gov/articles/PMC8912646/

              10. Izabela Domitrz, Joanna Cegielska; "Magnesium as an Important Factor in the Pathogenesis and Treatment of Migraine—From Theory to Practice"; Nutrients; 2022 Mar

                https://pmc.ncbi.nlm.nih.gov/articles/PMC8912646/

              11. Ian M Graham, Patrick O'Callaghan; "Vitamins, homocysteine and cardiovascular risk"; Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy; 2002 Sep

                https://pubmed.ncbi.nlm.nih.gov/12652107/

              12. Innocenzo Rainero, Alessandro Vacca, Fausto Roveta, Flora Govone, Annalisa Gai, Elisa Rubino; "Targeting MTHFR for the treatment of migraines"; Expert Opinion on Therapeutic Targets Vol. 23, Iss. 1; 2019

                https://www.tandfonline.com/doi/full/10.1080/14728222.2019.1549544

              13. Munvar Miya Shaik, Siew Hua Gan; "Vitamin Supplementation as Possible Prophylactic Treatment against Migraine with Aura and Menstrual Migraine"; Biochemistry Research International; 2015 Feb

                https://pmc.ncbi.nlm.nih.gov/articles/PMC4359851/

              14. Saras Menon, Bushra Nasir, Nesli Avgan, Sussan Ghassabian, Christopher Oliver, Rodney Lea, Maree Smith, Lyn Griffiths; "The effect of 1 mg folic acid supplementation on clinical outcomes in female migraine with aura patients"; The Journal of Headache and Pain: 2016 Jun

                https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-016-0652-7

              15. Merrill F Elias, Craig J Brown; "Medical foods for lowering homocysteine in hypertensive patients"; The Journal of Clinical Hypertension; 2022 Dec

                https://pmc.ncbi.nlm.nih.gov/articles/PMC9832224/

              16. 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://pmc.ncbi.nlm.nih.gov/articles/PMC9380836/

              17. Innocenzo Rainero, Alessandro Vacca, Fausto Roveta, Flora Govone, Annalisa Gai, Elisa Rubino; "Targeting MTHFR for the treatment of migraines"; Expert Opinion on Therapeutic Targets Vol. 23, Iss. 1; 2019

                https://www.tandfonline.com/doi/full/10.1080/14728222.2019.1549544

              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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