How Long Does L-Methylfolate Take to Work?

How Long Does L-Methylfolate Take to Work?

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 18, 2025

Table of Contents

    How Long Does L-Methylfolate Take to Work?

    The time it takes for methylfolate to work varies from patient to patient. It can take between 1 to 4 weeks1 for L-methylfolate to begin working; however, this depends on many factors such as metabolic function, age, symptom severity, and more. It could take several months for it to become fully effective.


    L-methylfolate is a folate vitamin required for numerous biochemical functions in the body. It plays a key role in the methylation cycle, which is responsible for the growth and development of all cells and the control of everything from DNA replication to digestive function. Without L-methylfolate, the  production and the recycling of many important proteins, hormones, and neurotransmitters would not occur.


    As a medical food and supplement, L-methylfolate is prescribed to treat conditions related to low folate or folate deficiency. It may be used in patients with major depressive disorder and/or anxiety who have not had satisfactory results from antidepressant medication.


    This article will discuss the use of L-methylfolate in depression and anxiety and how long it takes to work. We will also explain why the brand of L-methylfolate matters and what to look for when choosing a supplement.

    How Long Will it Take L-Methylfolate to Help Depression?

    L-methylfolate is not an antidepressant. It is a form of folate—the only form that can cross the blood-brain barrier. It plays an essential role in the one-carbon cycle metabolic pathway required to produce neurotransmitters2 (serotonin, dopamine, and norepinephrine).

     

    Up to 70% of patients with depression3 (self reported depression symptoms) have a genetic variant of the methylenetetrahydrofolate reductase enzyme that compromises their ability to convert dietary folate or synthetic folic acid to L-methylfolate.


    Supplementation with L-methylfolate has been shown to improve response to antidepressants4 such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) in people who do not otherwise respond adequately.


    Prescription L methylfolate supplements such as Deplin have been used successfully to treat many forms of treatment-resistant depression by acting as an adjunct to other antidepressant medications.


    The time it takes for L-methylfolate to work varies from patient to patient. In clinical trials, DEPLIN® is expected to start working within 1 to 2 weeks5 for those already on an antidepressant. Other sources say that the benefits of L-methylfolate usually take effect within 2-4 weeks6.


    One study showed that patients with depression taking 7.5 mg or 15 mg L-methylfolate reported significant improvements in depressive symptoms7 and functioning, with 67.9% of patients responding and 45.7% achieving remission over 12 weeks. Compliance was high, with over 90% of patients reporting nearly every dose.

     

    Some practitioners recommend that patients take L-methylfolate every day for at least four months to gauge its effectiveness. Anecdotal evidence is generally mixed: some patients may see results within days, weeks, and or others might need the entire four months.

    How Long Will it Take L-Methylfolate to Help Anxiety?

    Anxiety is one of the many common symptoms of depression. An analysis of 702 patients8 with treatment-resistant depression (TRD) found that comorbid anxiety disorder was the most powerful variable associated with TRD. Antidepressants and/or L-methylfolate may be prescribed to relieve symptoms such as restlessness, anxiety, and insomnia.


    As with depression, the benefits of L-methylfolate supplement may take anywhere from 2-4 weeks to four months.

    What Factors Determine How Long it Takes L-Methylfolate to Have an Effect?

    It is difficult to gauge how long methylfolate will take to work for each patient, as the expected effect of any medication varies from person to person depending on age, weight, genetics, concomitant health issues, and more.

    Factors that influence how long it takes methylfolate to work may include.

    • Metabolic function
    • Other illnesses (diabetes, atrophic gastritis, Crohn’s disease, ulcerative colitis, kidney disorders, hypothyroidism)
    • Other medications (for example, some seizure medications may lower the effectiveness of L-methylfolate)
    • Age
    • Symptom severity
    • Presence/type of MTHFR genetic polymorphism
    • Serum folate levels
    • L-methylfolate form and dosage
    • Patient compliance


    For best results, L-methylfolate supplement should be taken exactly as prescribed by your health provider or as per directions on the supplement.

    Why Does Brand Matter?

    L-methyl folate is available both as a prescription and as an over-the-counter supplement. However, some brands are better than others.


    The most biologically active L-methylfolate supplements are the “L” or “6(S)” form. This includes the identical form labeled as (6S)-5-methyltetrahydrofolate or (6S)-5-MTHF.


    The calcium salt of L-5-methyltetrahydrofolic acid is a pure, stable crystalline form9 of the naturally-occurring predominant form of folate. Also known as [6S]-5-MTHF10 (Metafolin: calcium salt of [6S]-5-MTHF), it has been shown to increase plasma folate more effectively than folic acid, irrespective of whether a patient has a C677T mutation.


    A crossover comparative study11 involving human volunteers concluded that folate from 5MTHF-glucosamine exhibited a similar bioavailability to folate from 5MTHF-Calcium.


    A study involving healthy females12 found that the calcium-salt form of methylfolate ([6S]-5-methyltetrahydrofolate) increased plasma folate more effectively than folic acid with the homozygous C677T polymorphism.

    How to Choose the Best Supplement for You

    When choosing the best supplement for you, be sure to check the form of L-methylfolate used in the product. Any forms of methylfolate that don’t specify the L form (or 6S form) of methylfolate (such as methyl folate L-5-MTHF) may not be 99% pure biologically active methylfolate.


    These less bioavailable forms include 5-MTHF, 5-Methylfolate, and 5-Methyltetrahydrofolate.


    Methyl-Life’s® Methylfolate 15mg is made with the internationally-patented Magnafolate® PRO, clinically tested as the purest methylfolate13.

    Magnafolate® is the L-5-MTHF form, the most active folate form14 in plasma circulation. Compared with ordinary folate, Magnafolate® PRO was absorbed faster and utilized more quickly15 in the body.


    Methyl-Life’s® product range is formulated especially for people with a heightened need for bioavailable folate due to depressive disorders, anxiety, MTHFR/MTR/MTRR defects, nutritional deficiencies, vegans, vegetarians, or those with conditions in which nutritional absorption is impaired. 

    Product Recommendations

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

    L Methylfolate 15 mg - A Mood-Boosting Supplement
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    • Professional Strength - Ask Your Doctor
    • High-Dose L Methylfolate 15 Mg for Natural Mood Support2
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    References

    1. How You May Benefit From DEPLIN® | Deplin.com

      https://www.deplin.com/is-deplin-right-for-you

    2. Stephen M Stahl; "Novel therapeutics for depression: L-methylfolate as a trimonoamine modulator and antidepressant-augmenting agent"; CNS spectrums; 2007

      https://pubmed.ncbi.nlm.nih.gov/17934378/

    3. 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/

    4. 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"; Prim Care Companion CNS Disord; 2013

      https://www.psychiatrist.com/pcc/depression/assessing-effects-l-methylfolate-depression-management/

    5. How You May Benefit From DEPLIN® | Deplin.com

      https://www.deplin.com/is-deplin-right-for-you

    6. Chris Aiken; "L-Methylfolate"; www.moodtreatmentcenter.com; 2021 Feb

      https://www.moodtreatmentcenter.com/wp-content/uploads/2021/03/methylfolate.pdf

    7. 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"; Prim Care Companion CNS Disord; 2013

      https://www.psychiatrist.com/pcc/depression/assessing-effects-l-methylfolate-depression-management/

    8. Daniel Souery, Pierre Oswald, Isabelle Massat, Ursula Bailer, Joseph Bollen, Koen Demyttenaere, Siegfried Kasper, Yves Lecrubier, Stuart Montgomery, Alessandro Serretti, Joseph Zohar, Julien Mendlewicz, Group for the Study of Resistant Depression; "Clinical factors associated with treatment resistance in major depressive disorder: results from a European multicenter study"; The Journal of clinical psychiatry; 2007 Jul

      https://pubmed.ncbi.nlm.nih.gov/17685743/

    9. Harriet Wallin, Paul M Kuznesof; "CALCIUM L-5-METHYLTETRAHYDROFOLATE (L-5-MTHF-Ca)"; Chemical and Technical Assessment 65th JECFA

      https://www.fao.org/fileadmin/templates/agns/pdf/jecfa/cta/65/l-5-mthf.pdf

    10. R Prinz-Langenohl, S Brämswig, O Tobolski, YM Smulders, DEC Smith, PM Finglas, K Pietrzik; "[6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C→T polymorphism of methylenetetrahydrofolate reductase"; British Journal of pharmacology; 2009 Nov

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2807663/

    11. European Food Safety Authority (EFSA), Parma, Italy; "Scientific Opinion on (6S)-5-methyltetrahydrofolic acid, glucosamine salt as a source of folate added for nutritional purposes to food supplements"; EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) | EFSA Journal; 2013

      https://efsa.onlinelibrary.wiley.com/doi/pdf/10.2903/j.efsa.2013.3358

    12. R Prinz-Langenohl, S Brämswig, O Tobolski, YM Smulders, DEC Smith, PM Finglas, K Pietrzik; "[6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C→T polymorphism of methylenetetrahydrofolate reductase"; British Journal of pharmacology; 2009 Nov

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2807663/

    13. XUE Juan, MA Wenbin, TU Hua, LIU Kang, CHENG Yongzhi, LIAN Zenglin; "Research on the enhancement effect of 6S-5-methyltetrahydrofolatecalcium on the immunity of mice"

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

    14. XUE Juan, MA Wenbin, TU Hua, LIU Kang, CHENG Yongzhi, LIAN Zenglin; "Research on the enhancement effect of 6S-5-methyltetrahydrofolatecalcium on the immunity of mice"

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

    15. Agnieszka Seremak-Mrozikiewicz; "[Metafolin--alternative for folate deficiency supplementation in pregnant women]"; Ginekologia polska; 2013 Jul

      https://pubmed.ncbi.nlm.nih.gov/24032278/

    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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