Is MTHFR and Low Folate Related to ADHD? | Methyl-Life®

Is MTHFR and Low Folate Related to ADHD? | Methyl-Life®

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:

March 25, 2025

Table of Contents

    Is MTHFR and Low Folate Related to ADHD?

    Attention Deficit Hyperactivity Disorder (ADHD) is a complex neurological disorder with a spectrum of symptoms that vary in severity. The disorder impacts areas of the brain involved in planning, focusing, and executing tasks. Those with ADHD struggle with organization and controlling impulses.


    In the past few decades, rates of ADHD have increased significantly around the world, causing much speculation for its causative factors. It affects an estimated 11% of children and almost 5% of adults in the U.S.


    There appears to be no single cause for ADHD, and its likely caused by a variety of factors. Still, possible risk factors for ADHD may include exposure to environmental toxins, notably lead, the use of drugs or alcohol during pregnancy, and premature birth.


    Recent research suggests that genetic traits may play a part, particularly those involved in the production of neurotransmitters. For this reason, some researchers1 have suggested that the MTHFR gene and a corresponding folate deficiency may be linked to a child’s risk of being born with ADHD.


    This article will discuss the possible role of genetics in ADHD and studies supporting this theory. We will explain how folate, neurotransmitters, and MTHFR are related to ADHD and whether supplementation with methylfolate may be advisable.

    How Does Genetics Play a Role in ADHD?

    Although the exact etiology of ADHD has not been determined, many related factors2 include:

    • Familial or hereditary traits
    • Prenatal or perinatal factors
    • Exposure to chemotoxic factors
    • Socio-psychological stress 
    • Structural and functional abnormalities and/or developmental neurobiological factors in certain regions of the brain


    Studies involving families have provided substantial evidence that ADHD may be an inherited condition, with heritability believed to be about 70%3.


    Gene association studies have provided consistent evidence of an association between ADHD and dopamine receptor genes4 and that the COMT gene influences the behavioral patterns of those with ADHD.


    Methylation is essential for the proper functioning of the Catechol-O-Methyl-Transferase (COMT) enzyme, an enzyme responsible for the breakdown of catecholamines5, including dopamine and norepinephrine. If methylation is impaired, the proper functioning of either Histamine N-Methyltransferase (HNMT) or COMT is affected, and the body is less efficient at removing toxins6.


    For this reason, there may be a link between childhood neuropsychiatric problems, folate metabolism, and the genetic polymorphism MTHFR. MTHFR has been related to neuropsychiatric conditions such as schizophrenia, depression, and bipolar disorder7.


    MTHFR is required for converting folic acid into 5-methyltetrahydro­folate, the predominant circulating form of folate. This reaction is required for the multistep process that converts homocysteine to methionine, which is then used to make proteins and other important compounds. 

    Active Folate, Neurotransmitters, and MTHFR

    The relationship between childhood neuropsychiatric problems, folate metabolism, and MTHFR may be central to ADHD.


    Neurotransmitters are chemicals produced by the brain and nervous system, including serotonin, norepinephrine, epinephrine, dopamine, and melatonin. Each of these is responsible for a range of bodily functions: mood, energy, sleep, digestion, muscle and nerve function, memory, and cognition.


    The methylation process is necessary to create these neurotransmitters. The brain must have access to sufficient folate8 for methylation to occur successfully. However, the processing deficiency caused by MTHFR can mean that folate is not produced.


    Methylation is required for over 200 biochemical reactions in the body9. It occurs billions of times per second in cells, contributing to detoxification, DNA repair, energy production, mood balancing, glutathione production, and control of inflammation.


    Activated folate is also needed for the proper growth and development of cells.


    The MTHF effect on neurotransmitters has already been linked to anxiety and depression. Up to 70% of patients with depression10 test positive for the C677T polymorphism, which is attributed to their inability to process folic acid.


    Methylation is also key to the body’s phase II detoxification pathway, in which toxins are converted into water-soluble compounds11 so they can be excreted. The MTHFR enzyme is also responsible for the downstream effect of generating glutathione, the body’s most potent antioxidant, and detoxifier. Glutathione is the main intracellular antioxidant and is critical for drug and xenobiotic detoxification.


    Poor methylation may hinder detoxification in the liver and the production of glutathione12.


    Several studies have shown that impaired detoxification may lead to toxic metal accumulation13, which has been linked to autism. This may be due to a combination of genetic susceptibility and exposure to environmental toxins at critical periods during brain development, causing a buildup of neurotoxins and associated inflammation of the brain tissue.


    Research has also suggested that ADHD is related to blood lead level, even at background exposure levels typical in western countries. Children with ADHD are found to have slightly elevated blood lead levels14.

    Can Taking Methylfolate Help with ADHD?

    As MTHFR mutations are genetic, they cannot be ‘cured.’ However, the health conditions associated with MTHFR may be treated or managed with a range of nutrients - particularly methylfolate. This is crucial for supporting the methylation cycle.


    Methylation is necessary for promoting detoxification, producing glutathione and neurotransmitters, controlling inflammation, and balancing hormones.


    The strong association between ADHD and low folate levels has been shown in several studies. Higher hyperactivity and peers relationship problems in children are also associated with low folate in early pregnancy15. Folate deficiency is also associated with aggression, and supplementation has been shown to help manage this.


    Stimulants are often the primary treatment for ADD/ADHD. These drugs usually work by helping to maintain neurotransmitter balance by regulating the availability of dopamine. However, ADHD can be difficult to manage even with these stimulant therapies.


    Folate, specifically L-methylfolate, is an important precursor for dopamine synthesis. Scientists have now found that taking methylfolate may be adjuvant to stimulants16 and can help alleviate the symptoms of ADD/ADHD. L-methylfolate is the naturally occurring metabolite of folate and an important cofactor in the production of neurotransmitters.


    A study in which ADHD patients were treated with a high dose of methylfolate every day for six weeks found that on average, the 32 patients experienced a 27% improvement in their behavior17. Also, 21 of the 32 patients experienced a 53% improvement in their behavior.


    Numerous studies have shown that methylfolate can help to alleviate neuropsychiatric disorders18 such as depression by improving response to antidepressants that affect monoamines.

    Choosing the Right Methylfolate Supplement

    While more research is pending, there are proven benefits in taking methylfolate as a supplement. It should be noted that a methylfolate supplement is not a replacement for ADHD medication but may be used to enhance the benefits of other medications. This should be discussed with a medical practitioner before commencing.


    Methylfolate supplements are now available over-the-counter and online, often labeled as L-MTHF, L-5-Methylfolate, L-5-MTHF, and (6S)-5-Methylfolate.


    Some of the most highly recommended methylfolate supplements are in the Methyl-Life® product suite, which includes a range of dosage levels appropriate for both children and adults.


    These are formulated especially for people with a heightened need for bioavailable folate due to MTHFR defects, medication side effects, dietary deficiencies (such as vegans or vegetarians), or other conditions in which nutritional absorption is impaired.


    Methyl-life’s® Methylfolate is made with the internationally-patented Magnafolate® PRO, clinically tested as the world’s purest methylfolate19.


    Magnafolate® is a methylfolate called L-5-MTHF, which is shown to be the most active form of folate in plasma circulation20. When compared with ordinary folate, Magnafolate® PRO was found to be absorbed faster and utilized more quickly in the body.

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    References

    1. Cem Gokcen, Nadir Kocak, Ahmet Pekgor; "Methylenetetrahydrofolate Reductase Gene Polymorphisms in Children with Attention Deficit Hyperactivity Disorder"; International Journal of Medical Sciences; 2011 Aug

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3167178/

    2. Cem Gokcen, Nadir Kocak, Ahmet Pekgor; "Methylenetetrahydrofolate Reductase Gene Polymorphisms in Children with Attention Deficit Hyperactivity Disorder"; International Journal of Medical

      https://www.medsci.org/v08p0523.htm

    3. Stephen V Faraone, Roy H Perlis, Alysa E Doyle, Jordan W Smoller, Jennifer J Goralnick, Meredith A Holmgren, Pamela Sklar; "Molecular genetics of attention-deficit/hyperactivity disorder"; Biological psychiatry; 2005 Jun

      https://pubmed.ncbi.nlm.nih.gov/15950004/

    4. Xin Li Xue Bao, Anita Thapar, Evangelia Stergiakouli; "An Overview on the Genetics of ADHD"; Europe PMC Funders Group; 2010 Apr

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854824/

    5. ScienceDirect®; "Catechol-O-Methyltransferase"; Executive Functions in Health and Disease; 2017

      https://www.sciencedirect.com/topics/psychology/catechol-o-methyltransferase

    6. Donald D. Brown, Julius Axelrod, Robert Tomchick; "Enzymatic N-Methylation of Histamine"; Nature; 1959 Mar

      https://www.nature.com/articles/183680a0

    7. Mohamed A. El-Hadidy, Hanaa M. Abdeen, Sherin M. Abd El-Aziz, Mohammad Al-Harrass; "MTHFR Gene Polymorphism and Age of Onset of Schizophrenia and Bipolar Disorder"; BioMed Research International, Vol. 2014, Iss. 1; 2014 Jul

      https://www.hindawi.com/journals/bmri/2014/318483/

    8. ScienceDirect®; "Folate Metabolism"; Critical Reviews in Oncology/Hematology; 2023

      https://www.sciencedirect.com/topics/medicine-and-dentistry/folate-metabolism

    9. Abeer M Mahmoud, Mohamed M Ali; "Methyl Donor Micronutrients that Modify DNA Methylation and Cancer Outcome"; Nutrients; 2019 Mar

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471069/

    10. Richard C Shelton, J Sloan Manning, Lori W Barrentine, Eleanor V Tipa; "Assessing Effects of l-Methylfolate in Depression Management: Results of a Real-World Patient Experience Trial"; The Primary Care Companion for CNS Disorders; 2013 Aug

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869616/

    11. Simone Phang-Lyn, Valerie A. Llerena; "Biochemistry, Biotransformation"; StatPearls [Internet]; 2023 Aug

      https://www.ncbi.nlm.nih.gov/books/NBK544353/

    12. K Lertratanangkoon, C J Wu, N Savaraj, M L Thomas; "Alterations of DNA methylation by glutathione depletion"; Cancer letters; 1997 Dec

      https://pubmed.ncbi.nlm.nih.gov/9461031/

    13. Altaf Alabdali, Laila Al-Ayadhi, Afaf El-Ansary; "A key role for an impaired detoxification mechanism in the etiology and severity of autism spectrum disorders"; Behavioral and Brain Functions; 2014 Apr

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017810/

    14. Joel T Nigg, Molly Nikolas, G Mark Knottnerus, Kevin Cavanagh, Karen Friderici; "Confirmation and extension of association of blood lead with attention-deficit/hyperactivity disorder (ADHD) and ADHD symptom domains at population-typical exposure levels"; Journal of child psychology and psychiatry, and allied disciplines; 2010 Jan

      https://pubmed.ncbi.nlm.nih.gov/19941632/

    15. Wolff Schlotz, Alexander Jones, David IW Phillips, Catharine R Gale, Sian M Robinson, Keith M Godfrey; "Lower maternal folate status in early pregnancy is associated with childhood hyperactivity and peer problems in offspring"; Journal of child psychology and psychiatry, and allied disciplines; 2011 May

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2862762/

    16. Robert L. Quillin; "High Dose L-Methylfolate As Novel Therapy in ADHD"; ResearchGate; 2013 Oct

      https://www.researchgate.net/publication/267913510_High_Dose_L-Methylfolate_As_Novel_Therapy_in_ADHD

    17. --

      https://aap.confex.com/aap/2013/webprogrampress/Paper20581.html

    18. Richard C Shelton, J Sloan Manning, Lori W Barrentine, Eleanor V Tipa; "Assessing Effects of l-Methylfolate in Depression Management: Results of a Real-World Patient Experience Trial"; The Primary Care Companion for CNS Disorders; 2013 Aug

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869616/

    19. Mangafolate®; "Magnafolate® PRO"; 2025

      https://www.magnafolate.com/products/magnafolate-pro.html

    20. --

      https://i.trade-cloud.com.cn/upload/6405/file/20210929/english-version-magnafolate-enhancing-immunity_524485.pdf

    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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