The Benefits of L-Methylfolate

The Benefits of L-Methylfolate

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:

April 22, 2025

Table of Contents

    The Benefits of L-Methylfolate

    Methylfolate supplements have only been available to consumers since 2001, when Metafolin (a prescription medical food) was released by Merck. Now that the benefits of methylfolate have been published in dozens of studies and numerous brands are available over the counter, methylfolate is among the most sought-after nutritional supplements on the market.

    What is methylfolate?

    Methylfolate is the active form of folate (vitamin B9) and the primary form used by the body. It is not the same as folic acid, which is a synthetic version of folate that must be activated by specific enzymes in the body before it can be used. Folic acid is problematic for people with certain genetic mutations - such as MTHFR, DHFR and SHMT - because they lack the enzyme required for this conversion process. Only methylfolate can be instantly absorbed and utilized without further processing.1

    Benefits of methylfolate for hair

    While studies on methylfolate's direct impact on hair health are limited, folate itself is essential for hair cell division and growth. Some studies have revealed a high prevalence of folate deficiency in people with hair loss and thinning hair.2 Folate deficiency has also been linked to genomic instability in keratinocytes (the cells that produce the structural protein in hair) in which cells are at increased risk of DNA mutations or damage.3 Previous studies have also shown that folate deficiency can lead to changes in the hair, skin and nails.4

    One study found that people with premature greying were deficient in vitamin B12 and folate, and had lower levels of biotin.5

    Benefits of methylfolate for the skin

    The skin has high demands for folate as it is constantly renewing and regenerating. Folate is essential as it is a critical component of DNA repair and skin cell proliferation.6 Both synthetic folic acid and methylfolate are degraded by ultraviolet light.7


    Low folate can then lead to DNA damage, increasing the risk of errors when cells divide. This can also increase the vulnerability of skin cells to UV damage and reduce their ability to repair damage from oxidative stress. Over time, this can lead to serious skin conditions including a higher risk of skin cancer. However, research has shown that these negative effects can be reversed by restoring folate levels through supplementation.8

    These are the benefits of methylfolate

    Benefits of methylfolate for women’s health and pregnancy

    Methylfolate supplementation is critical for women who are pregnant or planning to conceive. Women have higher requirements for folate during pregnancy, and it is essential to have optimal folate levels before conception and in the first trimester when the neural tube closes.9


    Low folate levels can lead to neural tube defects, anemia, depression, and other pregnancy complications. Many of these issues can be prevented by supplementing with methylfolate in preconception and pregnancy, especially in women with MTHFR gene mutations that impair folate metabolism.10


    While women are often prescribed folic acid during pregnancy, methylfolate is considered a superior form of supplementation as it is readily absorbed by the body.11 Unlike folic acid, methylfolate has no tolerable upper intake level and does not mask vitamin B12 deficiency. A 2024 study showed that supplementation with methylfolate may reduce unmetabolized folic acid by around 50%.12


    Methylfolate is also effective in reducing homocysteine levels. Healthy blood vessels and folate levels are essential for fertility and pregnancy, and high homocysteine can make it difficult to conceive and maintain a pregnancy.13


    Supplementation with a prenatal medical food containing L-methylfolate and high-dose vitamin B12 was found to maintain hemoglobin levels and decrease anemia in pregnancy more effectively than standard prenatal vitamins containing folic acid.14


    Methylfolate is effective in the treatment and prevention of depression in women trying to conceive and during pregnancy.15 It is also helpful in treating post-partum depression in women with folate deficiency and/or MTHFR.16

    Benefits of methylfolate for men’s health

    Folate is essential for normal DNA methylation in sperm development. Low folate levels disrupt one-carbon metabolism, reducing methyl groups and DNA building blocks needed for healthy sperm and stable genes. Adequate folate levels, on the other hand, are shown to serve as protection against DNA damage.17


    The C677T MTHFR mutation is associated with low folate and an increased risk of male infertility.18 Folic acid may not be suitable, with studies showing that high-dose folic acid supplementation in men with MTHFR mutations resulted in significant loss of DNA methylation in sperm.19


    However, a 2020 study involving infertile males who supplemented with folate, B vitamins, zinc, and cysteines reported an increase in DNA methylation levels, resulting in improved sperm nuclear maturation and antioxidant defenses, potentially improving their reproductive function.20

    Benefits of methylfolate for cardiovascular health

    High levels of homocysteine can damage the blood vessels, increasing the risk of blood clots and cardiovascular disease, including atherosclerosis. Elevated homocysteine is also associated with a higher risk of stroke and neuronal disorders such as Alzheimer’s and Parkinson’s disease.21


    Taking methylfolate with vitamins B6 and B12 has been shown to lower homocysteine levels more effectively than conventional vitamin supplementation with high-dose folic acid.22

    Benefits of methylfolate for childrens’ health

    While studies involving children and methylfolate supplementation are currently limited, there is some evidence that L-methylfolate supplementation can improve symptoms of aggression and disruptive behavior in children with the MTHFR C677TT mutation.23


    Animal studies suggest that folate deficiency during pregnancy is associated with poorer cognitive and behavioural outcomes in children, and that supplementation with bioavailable folate may contribute to healthy cognitive and behavioural development.24

    Benefits of methylfolate after alcohol consumption

    Alcohol can deplete folate levels, leading to deficiencies that affect mood and cognitive function. Supplementation with methylfolate can help restore these levels, potentially alleviating some of the negative effects associated with alcohol use.25

    Benefits of methylfolate for depression and anxiety

    Methylfolate plays a key role in production of neurotransmitters including serotonin and dopamine. Deficiency in methylfolate results in poor neurotransmitter production, which may then lead to symptoms of depression and/or anxiety. Antidepressants are also unhelpful as these medications require neurotransmitter availability to be effective.


    However, taking methylfolate can improve the efficacy of antidepressants. Methylfolate increases the availability of serotonin, while antidepressants allow the serotonin to remain in the brain.26 There is substantial clinical evidence that methylfolate can reduce symptoms of depression, including treatment-resistant depression. A 2022 meta-analysis involving 6,707 patients concluded that taking L-methylfolate alongside antidepressants was more effective than taking antidepressants alone. 27


    Other studies have demonstrated the efficacy of taking methylfolate alone in reducing depressive symptoms and improving cognitive function in people with both normal and low folate levels.28

    Case studies have also suggested that supplementing with B vitamins and SAMe can help with symptoms of anxiety. Methylfolate is a key component in the body’s production of SAMe.29

    Limitations of methylfolate

    As research into methylfolate supplementation is still evolving, evidence of its benefits is still limited. Talk to your doctor before taking methylfolate supplements.


    It should also be noted that while no major adverse reactions have been reported, some people have experienced side effects such as sexual dysfunction, drowsiness, nausea, dizziness, insomnia, agitation, constipation, and fatigue after supplementing with methylfolate.30

    A word from Methyl-Life®’s founder Jamie Hope:

    As the founder of Methyl-Life®, my personal journey began with a genetic condition that requires lifelong methylfolate supplementation. Determined to ensure I was taking the highest quality product, I dedicated extensive time to researching and testing various brands before discovering the purest methylfolate we now use in our formulas, Cerebrofolate™. My goal has been to share these findings with others facing similar genetic challenges, so they too can experience the transformative health benefits I have.


    Methyl-Life® is a family-owned business built on the principle of “taking our own medicine” — we use the very products we offer. Our supplements feature the purest and most potent form of L-methylfolate available, Cerebrofolate™. We rigorously test for purity, potency, and stability. Our products are manufactured in FDA-registered, cGMP and NSF-certified facilities which use third party testing labs. We are committed to supporting individuals with MTHFR and related genetic conditions by providing science-backed, high-quality supplements and educational resources that help improve quality of life.

    Product Recommendations

    L Methylfolate 15 mg - A Mood-Boosting Supplement - Methyl-Life® Supplements

    L Methylfolate 15 mg - A Mood-Boosting Supplement
    (156)

    $76.00

    • Professional Strength - Ask Your Doctor
    • High-Dose L Methylfolate 15 Mg for Natural Mood Support2
    • 3rd-Party Tested for Purity, Potency & Safety
    • 90 Vegan, Non-GMO, Chewable Mint Tablets

    How to find the best methylfolate supplement

    Does methylfolate have to be patented?

    If a nutrient is patented, the company that owns it has the exclusive right to stop others from using and selling it commercially. This simply means that the company has invested a lot of time and research into that nutrient - a good sign that it is high quality. However, this doesn't mean that a non-patented nutrient isn't as good.

    Why is Methyl-Life®'s methylfolate the best?

    First of all, the manufacturer of our methylfolate has developed a proprietary process for micronizing the molecule size of this methylfolate by using sonification instead of the typical grinding process. This means that Cerebrofolate has fewer impurities than other methylfolates. The industry USP standard requires no more than 2.5% impurities for methylfolate and many leading brands test at 0.9% impurities when measured. However, our methylfolate averages 0.2-0.3% total impurities, making it three times more pure than the other leading versions available today.
    In addition, Cerebrofolate is biochemically identical to the medical food Metafolin (available only on prescription) and has been tested as more stable than other major methylfolate brands on the market.

    Why is Methyl-Life®'s methylfolate chemically superior?

    Many of the top three patented methylfolates use a version of methylfolate with the 6S isomer. This is also labeled as L or 6S (which is chemically identical). This version should have no inactive 6R isomer in it, but some non-patented versions may actually contain this inactive part of methylfolate. DL-5-methylfolate is the chemical term for a racemic version which is only partially active, but many will not label their methylfolate with these details. You'll need to see a Certificate of Analysis to determine this. Often the raw ingredient is 4+ times less expensive, which could explain why a product is cheaper.

    What about stability and potency?

    Methyl-Life®'s methylfolate is built on a crystalline calcium salt molecule structure which makes it the most stable in the industry. Only two patented methylfolates are built on this same structure. It has excellent stability, with potency loss occurring only 1-2% per year. Amorphous salt versions can lose up to 16% potency per year.

    Does the salt type of methylfolate matter?

    Methylfolate is available as either glucosamine salt, calcium salt, or magnesium salt. Methyl-Life® uses the calcium salt based methylfolate because it’s more stable and identical to the pharmaceutical brand. If you have a negative reaction to your methylfolate, it may be due to the salt type. Try a version built on the calcium salt type to see if your tolerance is better.

    Does a long shelf life mean a better product?

    A long shelf life indicates that a nutrient is stable and potent. When a number of Methyl-Life® products were tested five years after their manufacture date, the products were still fully potent according to the Supplement Facts claims. We compared these results to the five-year-old products of another leading brand and found that they were no longer fully potent.

    How do you know which brand to trust?

    Look for a company's backstory: their 'why'.

    References

    1. Lorena Carboni; "Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health"; Integrative medicine; 2022 Jul

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

    2. Dinesh Gowda, V Premalatha, DB Imtiyaz; "Prevalence of Nutritional Deficiencies in Hair Loss among Indian Participants: Results of a Cross-sectional Study"; International journal of trichology; 2017 Jul-Sep

      https://pmc.ncbi.nlm.nih.gov/articles/PMC5596642/

    3. Joshua D Williams, Myron K Jacobson; "Photobiological implications of folate depletion and repletion in cultured human keratinocytes"; Journal of photochemistry and photobiology. B, Biology; 2010 Apr

      https://pubmed.ncbi.nlm.nih.gov/20211567/

    4. Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline; "Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline"; Washington (DC): National Academies Press (US); 1998

      https://pubmed.ncbi.nlm.nih.gov/23193625/

    5. Deesha D. Desai, Maria Karim, Ambika Nohria, Carli Needle, Anna Brinks, Caitlin A. Kearney, Amy Ridge, Natasha Mesinkovska, Jerry Shapiro, Kristen I. Lo Sicco; "Premature hair graying: a multifaceted phenomenon"; International Journal of Dermatology; 2024 Dec

      https://onlinelibrary.wiley.com/doi/10.1111/ijd.17580

    6. Nina G. Jablonski, George Chaplin; "Human skin pigmentation as an adaptation to UV radiation"; Proc. Natl. Acad. Sci. U.S.A. 107; 2010

      https://www.pnas.org/doi/full/10.1073/pnas.0914628107

    7. Joshua D Williams, Myron K Jacobson; "Photobiological Implications of Folate Depletion and Repletion in Cultured Human Keratinocytes"; Journal of photochemistry and photobiology. B, Biology; 2011 Apr

      https://pmc.ncbi.nlm.nih.gov/articles/PMC2862485/

    8. Joshua D Williams, Myron K Jacobson; "Photobiological Implications of Folate Depletion and Repletion in Cultured Human Keratinocytes"; Journal of photochemistry and photobiology. B, Biology; 2011 Apr

      https://pmc.ncbi.nlm.nih.gov/articles/PMC2862485/

    9. Rima Obeid, Wolfgang Holzgreve, Klaus Pietrzik; "Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?"; Journal of perinatal medicine.; 2013 Sep

      https://pubmed.ncbi.nlm.nih.gov/23482308

    10. Rima Obeid, Wolfgang Holzgreve, Klaus Pietrzik; "Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?"; Journal of Perinatal Medicine, vol. 41, no. 5, pp. 469-483; 2013

      https://www.degruyter.com/document/doi/10.1515/jpm-2012-0256/html

    11. Lorena Carboni; "Active Folate Versus Folic Acid: The Role of 5-MTHF (Methylfolate) in Human Health"; Integrative medicine; 2022 Jul

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

    12. Kelsey M Cochrane, Rajavel Elango, Angela M Devlin, Chantal Mayer, Jennifer A Hutcheon, Crystal D Karakochuk; "Supplementation with (6 S)-5-methyltetrahydrofolic acid appears as effective as folic acid in maintaining maternal folate status while reducing unmetabolised folic acid in maternal plasma: a randomised trial of pregnant women in Canada"; The British journal of nutrition; 2024 Jan

      https://pubmed.ncbi.nlm.nih.gov/37649241/

    13. Henk J Blom, Yvo Smulders; "Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects"; Journal of inherited metabolic disease; 2010 Sep

      https://pmc.ncbi.nlm.nih.gov/articles/PMC3026708/

    14. Susan Bentley, Amy Hermes, Diane Phillips, Yahya A Daoud, Sylvia Hanna; "Comparative effectiveness of a prenatal medical food to prenatal vitamins on hemoglobin levels and adverse outcomes: a retrospective analysis"; Clinical therapeutics.; 2011 Feb

      https://pubmed.ncbi.nlm.nih.gov/21440300/

    15. Marlene P Freeman, Gina M Savella, Taylor R Church, Lina Góez-Mogollón, Alexandra Z Sosinsky, Olivia B Noe, Anjali Kaimal, Lee S Cohen; "A prenatal supplement with methylfolate for the treatment and prevention of depression in women trying to conceive and during pregnancy"; Annals of clinical psychiatry : Official Journal of the American Academy of Clinical Psychiatrists.;2019 Feb

      https://pubmed.ncbi.nlm.nih.gov/30699214/

    16. Emily Morris, Catriona Hippman, Arianne Albert, Caitlin Slomp, Angela Inglis, Prescilla Carrion, Rolan Batallones, Heather Andrighetti, Colin Ross, Roger Dyer, William Honer, Jehannine Austin; "A prospective study to explore the relationship between MTHFR C677T genotype, physiological folate levels, and postpartum psychopathology in at-risk women"; PLoS One; 2020 Dec

      https://pmc.ncbi.nlm.nih.gov/articles/PMC7735580/

    17. Jeffrey Hoek, Régine P M Steegers‐Theunissen, Sten P Willemsen, Sam Schoenmakers; "Paternal Folate Status and Sperm Quality, Pregnancy Outcomes, and Epigenetics: A Systematic Review and Meta‐Analysis"; Molecular nutrition & food research; 2020 Feb

      https://pmc.ncbi.nlm.nih.gov/articles/PMC7317557/

    18. Mancheng Gong, Wenjing Dong, Tingyu He, Zhirong Shi, Guiying Huang, Rui Ren, Sichong Huang, Shaopeng Qiu, Runqiang Yuan; "MTHFR 677C>T Polymorphism Increases the Male Infertility Risk: A Meta-Analysis Involving 26 Studies"; PLoS One; 2015 Mar

      https://pmc.ncbi.nlm.nih.gov/articles/PMC4368707/

    19. Mahmoud Aarabi, Maria C San Gabriel, Donovan Chan, Nathalie A Behan, Maxime Caron, Tomi Pastinen, Guillaume Bourque, Amanda J MacFarlane, Armand Zini, Jacquetta Trasler; "High-dose folic acid supplementation alters the human sperm methylome and is influenced by the MTHFR C677T polymorphism"; Human molecular genetics.; 2015 Aug

      https://pmc.ncbi.nlm.nih.gov/articles/PMC4614702/

    20. Farzaneh Bassiri, Marziyeh Tavalaee, Maurizio Dattilio; "Micronutrients in Support to The Carbon Cycle Activate Antioxidant Defences and Reduce Sperm DNA Damage in Infertile Men Attending Assisted Reproductive Technology Programs: Clinical Trial Study"; International Journal of Fertility and Sterility; 2020 Apr

      https://www.ijfs.ir/article_45579.html

    21. A David Smith, Helga Refsum, Teodoro Bottiglieri, Michael Fenech, Babak Hooshmand, Andrew McCaddon, Joshua W Miller, Irwin H Rosenberg, Rima Obeid; "Homocysteine and Dementia: An International Consensus Statement"; Journal of Alzheimer's disease; 2018 Feb

      https://pmc.ncbi.nlm.nih.gov/articles/PMC5836397

    22. A Mazza, A F Cicero, E Ramazzina, S Lenti, L Schiavon, E Casiglia, G Gussoni; "Nutraceutical approaches to homocysteine lowering in hypertensive subjects at low cardiovascular risk: a multicenter, randomized clinical trial"; Journal of biological regulators and homeostatic agents; 2016 Jul-Sep

      https://pubmed.ncbi.nlm.nih.gov/27655522/

    23. Kim S Siscoe, W David Lohr; "L-Methylfolate supplementation in a child with autism and methyltetrahydrofolate reductase, enzyme gene C677TT allele"; Psychiatric genetics; 2017 Jun

      https://pubmed.ncbi.nlm.nih.gov/28272116/

    24. Nathalie Irvine, Gillian England-Mason, Catherine J Field, Deborah Dewey, Fariba Aghajafari; "Prenatal Folate and Choline Levels and Brain and Cognitive Development in Children: A Critical Narrative Review"; Nutrients; 2022 Jan

      https://pmc.ncbi.nlm.nih.gov/articles/PMC8778665

    25. C. Di Palma, R. Urani, R. Agricola, V. Giorgetti, G. Dalla Verde; "Is methylfolate effective in relieving major depression in chronic alcoholics? A hypothesis of treatment"; Current Therapeutic Research; 1994 May

      https://www.sciencedirect.com/science/article/abs/pii/S0011393X05801870

    26. 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://pmc.ncbi.nlm.nih.gov/articles/PMC3869616

    27. Abdullah Al Maruf, Ethan A Poweleit, Lisa C Brown, Jeffrey R Strawn, Chad A Bousman; "Systematic Review and Meta-Analysis of L-Methylfolate Augmentation in Depressive Disorders"; Pharmacopsychiatry; 2022 May

      https://pubmed.ncbi.nlm.nih.gov/34794190/

    28. Lawrence D Ginsberg, Alondra Y Oubre, Yahya A DaouD; "L-methylfolate Plus SSRI or SNRI from Treatment Initiation Compared to SSRI or SNRI Monotherapy in a Major Depressive Episode"; Innovations in clinical neuroscience; 2011 Jan

      https://pmc.ncbi.nlm.nih.gov/articles/PMC3036555

    29. Shanna Anderson, Jacob Panka, Robin Rakobitsch, Kaitlin Tyre, Kerry Pulliam; "Anxiety and Methylenetetrahydrofolate Reductase Mutation Treated With S-Adenosyl Methionine and Methylated B Vitamins"; Integrative medicine; 2016 Apr

      https://pmc.ncbi.nlm.nih.gov/articles/PMC4898281/

    30. Cara T Hoepner, Roger S McIntyre, George I Papakostas; "Impact of Supplementation and Nutritional Interventions on Pathogenic Processes of Mood Disorders: A Review of the Evidence"; Nutrients; 2021 Feb

      https://pmc.ncbi.nlm.nih.gov/articles/PMC7996954

    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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