Are Methylfolate Supplements and Insomnia Linked? | Methyl-Life®

Are Methylfolate Supplements and Insomnia Linked? | Methyl-Life®

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    Are Methylfolate Supplements and Insomnia Linked?

    Methylfolate is an essential nutrient required for numerous biochemical processes in the body, namely those related to methylation. The nutrient itself is usually obtained from food or supplements containing folate or folic acid and then converted to methylfolate in the body.


    However, an MTHFR polymorphism can prevent the conversion of folic acid, resulting in negative health issues caused by low folate levels. Remedying these levels will usually require supplementation with a bioavailable form of folate called methylfolate. This is the form that can bypass an MTHFR polymorphism and enter the central nervous system.


    Although studies evaluating the safe upper limits of folate intake have found methylfolate to be a safe and beneficial nutrient, concerns have been raised regarding excessive intake and a possible link between methylfolate supplements and insomnia.


    There is no clinical evidence to support the claim that methylfolate supplements and insomnia are linked. However, some reports show that high doses of methylfolate may increase agitation and potentially lead to mania1


    This article will discuss whether methylfolate and insomnia are linked and other possible side effects from taking too large a dose of methylfolate.

    Possible Side Effects of Taking Too Much Methylfolate

    Research suggests that methylfolate is generally a safe nutrient2. The most commonly reported side-effects3 of taking methylfolate range from digestive complaints to headaches.


    More severe side effects are usually linked to age. Older people appear to be more susceptible to unwanted reactions4 from many medications (not just methylfolate) due to reduced liver function or interactions with other medications.


    The most common side-effects of methylfolate include:

    • Irritability
    • Sleeplessness and insomnia
    • Sore muscles
    • Joint pain
    • Skin irritations (acne, rash)
    • Severe anxiety
    • Palpitations
    • Nausea
    • Headaches or migraines
    • Burning or tingling nerves
    • Runny nose
    • Bronchospasms
    • Difficulty concentrating
    • Confusion
    • Excitability
    • Depression, malaise
    • Taste impairment
    • Reduced appetite
    • Digestive issues: nausea, gas, abdominal bloating


    Although the current data are limited, some research suggests that L-methylfolate may increase agitation5 or contribute to the onset of hypomania/mania. This may affect sleep patterns.

    Methylfolate and Detoxification

    Methylation is required for numerous biochemical reactions in the body that regulate the activity of the cardiovascular, neurological, reproductive, and elimination systems. It is especially crucial for healthy liver function and detoxification.


    Methylfolate plays an important role in phase II liver detoxification of estrogen. Phase II methylation of estrogen requires the COMT enzyme6 (catechol oxygen methyltransferase), which in turn requires a methyl group supplied by SAMe, the body’s methyl donor.


    This process depends on the availability of the universal methyl donor SAMe7 (S-adenosylmethionine).  However, the system that produces SAMe also depends on the availability of methylfolate. The methylation cycle - and the detoxification process - will only work efficiently if adequate methylfolate and SAMe8 are present.


    Low methylfolate caused by a mutation of the MTHFR gene can reduce your ability to methylate catechol estrogens. Poor methylation of these potentially genotoxic catechols is associated with a higher risk of postmenopausal breast cancer9.


    If you have been prescribed methylfolate or diagnosed with an MTHFR polymorphism, it is important that you do not stop taking it without first consulting your health professional. L-methylfolate has no known severe, serious, moderate, or mild interactions with other drugs.


    Sudden discontinuation of your methylfolate supplement may cause withdrawal symptoms or a return of previous health issues such as depression or elevated homocysteine.


    It is generally recommended to reduce your dose slowly until you find the dosage that suits you. This should be done over several weeks or months and only with the guidance of your medical professional. 

    How to Avoid Side Effects

    Reducing the risk of potential side effects when taking methylfolate is relatively simple.

    • Always take the dosage prescribed by your doctor or as stated on the supplement itself. A quality supplement designed by experts will be formulated in a way that provides a specific dosage.
    • Try to limit your intake of folic acid by avoiding foods such as fortified cereals, flours, and other products. The MTHFR mutation impairs the proper conversion of this substance in the body, which can lead to a buildup of unmetabolized folic acid.
    • Supplement your diet with foods rich in vitamin B6 and B12. Both of these nutrients work alongside methylfolate in the methylation cycle. Deficiency in either nutrient can increase the risk of many adverse health issues.
    • Advise your doctor if you are taking methotrexate, which is prescribed for psoriasis. Methylfolate appears to cause a flare-up of psoriasis10 symptoms when taken alongside methotrexate.
    • Folate may trigger episodes of mania in those with bipolar disorder because it enhances the effect of certain antidepressant drugs. Screening for bipolar disorder is highly recommended before taking methylfolate.
    • Methylfolate can interact with a range of drugs, albeit mildly. Discuss all your other medication and supplements with your medical practitioner before taking methylfolate and the possibility of any interactions.

    Why Should You Take a Methylfolate Supplement?

    Methylfolate is absolutely essential for normal bodily function due to its involvement in an enormous range of processes - the most important being methylation.


    Low levels of methylfolate can lead to a variety of health concerns, including elevated homocysteine, depression, and dementia11. In turn, poor DNA methylation has been linked to many diseases12, cancers, and health conditions.


    Adequate folate intake, on the other hand, is associated with numerous health benefits, including the reduction of neural tube defects13, lower risk of cardiovascular disease14, and prevention of certain cancers15.


    Methylfolate may be prescribed by doctors or natural health practitioners when required to correct a deficiency. Side effects of methylfolate supplementation are generally rare and can be avoided by checking whether there may be any interactions with your current medication or health conditions.


    A quality methylfolate supplement with an appropriate dosing schedule will also help to minimize the risk of side effects. Methylfolate supplements are often known or 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 range, which includes a variety of dosage level options: Methylfolate 7.5+, Methylfolate 10, and Methylfolate 15.


    Each of the methylfolate products in the Methyl-Life® range contains the internationally-patented Magnafolate® PRO [(L)-5-methyltetrahydrofolate, Calcium, which is carried on an ultra-stable Type C Crystalline molecule (L-Methylfolate) for superior absorption].


    This type is approximately three times more pure than other L-Methylfolate forms available on the health supplement market today. These top-rated products are formulated especially for people with a heightened need for bioavailable folate due to MTHFR defects, dietary deficiencies (such as vegans or vegetarians), or other conditions in which nutritional absorption is impaired.  

    Product Recommendations

    Methylated Multivitamin 3-Product Pack - MTHFR Folate, Sublingual B12 + Cofactors

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    • Bioactive MTHFR Folate, Methylfolate, for Max Absorption
    • Sublingual B12 to Aid B12 Sufficiency via Active Hydroxy Form
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    References

    1. Sara Robinson, John J. Miller; "L-Methylfolate: Augmenting Agent May Contribute to Agitation and Mania"; Psychiatric Times; 2020 Mar

      https://www.psychiatrictimes.com/view/l-methylfolate-augmenting-agent-may-contribute-agitation-and-mania

    2. K.E. Niederberger, I. Dahms, T.H. Broschard, R. Boehni, R. Moser; "Safety evaluation of calcium L-methylfolate"; Toxicology Reports Vol. 6, Pg. 1018-1030; 2019

      https://www.sciencedirect.com/science/article/pii/S221475001930232X

    3. John P. Cunha; "L-methylfolate"; RxList.com; 2025

      https://www.rxlist.com/consumer_deplin_l-methylfolate/drugs-condition.htm#what_are_side_effects_associated_with_using_l-methylfolate

    4. Ginger Skinner; "Risk of Drug Side Effects Rises as You Age"; Consumer Reports; 2017 Oct

      https://www.consumerreports.org/drug-safety/risk-of-drug-side-effects-rises-as-you-age/

    5. Sara Robinson, John J. Miller; "L-Methylfolate: Augmenting Agent May Contribute to Agitation and Mania"; Psychiatric Times; 2020 Mar

      https://www.psychiatrictimes.com/view/l-methylfolate-augmenting-agent-may-contribute-agitation-and-mania

    6. ScienceDirect®; "Catechol Estrogen"; Encyclopedia of Toxicology (Second Edition); 2005

      https://www.sciencedirect.com/topics/medicine-and-dentistry/catechol-estrogen

    7. ScienceDirect®; "S Adenosylmethionine"; Medical Epigenetics; 2016

      https://www.sciencedirect.com/topics/neuroscience/s-adenosylmethionine

    8. ​Mahmoud AM, Ali MM. "Methyl Donor Micronutrients that Modify DNA Methylation and Cancer Outcome." Nutrients; 2019 Mar

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

    9. ​Fuhrman BJ, Schairer C, Gail MH, Boyd-Morin J, Xu X, Sue LY, Buys SS, Isaacs C, Keefer LK, Veenstra TD, Berg CD, Hoover RN, Ziegler RG; "Estrogen metabolism and risk of breast cancer in postmenopausal women"; Journal of the National Cancer Institute; 2012 Feb

      https://pubmed.ncbi.nlm.nih.gov/22232133/

    10. Roya S Nazarian, Angela J Lamb; "Psoriatic flare after the concomitant administration of L-methylfolate and methotrexate"; JAAD Case Reports; 2016 Dec

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5192351/

    11. Teodoro Bottiglieri, Malcolm Laundy, Richard Crellin, Brian K Toone, Michael W P Carney, Edward H Reynolds; "Homocysteine, folate, methylation, and monoamine metabolism in depression"; BMJ Journals;

      https://jnnp.bmj.com/content/69/2/228

    12. Zelin Jin, Yun Liu; "DNA methylation in human diseases"; KeAi, Genes & Diseases; 2018 Jan

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147084/

    13. Apolline Imbard, Jean-François Benoist, Henk J Blom; "Neural Tube Defects, Folic Acid and Methylation"; International Journal of Environmental Research and Public Health; 2013 Sep

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799525/

    14. M.C. Verhaar, E. Stroes, T.J. Rabelink; "Folates and Cardiovascular Disease"; Arterioscler Thromb Vasc Biol.; 2002 Jan

      https://www.ahajournals.org/doi/pdf/10.1161/hq0102.102190

    15. Y I Kim; "Folate and cancer prevention: a new medical application of folate beyond hyperhomocysteinemia and neural tube defects"; Nutrition reviews.; 1999 Oct

      https://pubmed.ncbi.nlm.nih.gov/10575908/

    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!