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Methylfolate and Depression

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:

January 26, 2025

Table of Contents

    How Methyl-Life Supplements was Formed 🧪 The Origins Behind Methyl-Life Supplements Source: https://www.youtube.com/@MethylLife

    Methylfolate and depression management

    Depression is one of the most common mood disorders in the world, affecting an estimated 350 million individuals.

    While many factors may be involved in the development of depression, one of the predominant theories is an imbalance of “brain chemicals”—i.e. the neurotransmitters that contribute to a healthy mood. These neurotransmitters include serotonin, norepinephrine, and dopamine.1


    L-methylfolate plays a key role in the production of these neurotransmitters. For this reason, L-methylfolate has been prescribed to people suffering from depression for many years. However, research into the efficacy of this treatment is still somewhat limited.

    How does methylfolate work within the body to treat depression?

    Folate is essential for the synthesis of important neurotransmitters in the central nervous system. Folate deficiency is a major risk factor in depression, and also makes it more difficult to treat.


    Folate must be reduced to tetrahydrofolate (THF) within the body before it can become metabolically active with its conversion into 5-Methyltetrahydrofolate (5-MTHF or L-methylfolate). This is the fully-activated folate derivative normally found in healthy circulation of those who do not have MTHFR genetic variants. It’s also the only form of folate that can be absorbed and used to create serotonin, dopamine, and norepinephrine. These are three of the neurotransmitters most important for mood regulation and other nervous system functions. Serotonin plays a particularly crucial role in appetite, sleep, and emotional health. 


    It’s for these reasons, L-methylfolate supplementation has been found to be beneficial for those with depression, especially for those who have not responded adequately to treatment with antidepressant medications.

    Methylfolate dosage for depression treatment and how to take it (morning/evening)

    Every case of depression is different. Your unique body chemistry and health history should be assessed by a qualified health practitioner before you start any supplement regime.


    To date, studies involving patients with depressive disorders who are given the prescription medical food L-methylfolate (Deplin) may have to take anywhere from 7.5 mg to 15 mg to achieve its benefits. 

    A 2012 study showed that supplementary L-methylfolate at 15 mg/day resulted in significant improvement in the response and degree of change in depression scores as compared to continued SSRI therapy plus placebo.2 

    To figure out the right methylfolate dosage for your own needs, your best bet would be to seek out an assessment from a qualified healthcare provider or naturopath.

    Some physicians suggest taking methylfolate 2x a day to keep the serum folate levels in the body more steady over a longer period of time. Learn more about L-methylfolate dosage suggestions.

    How long does it take to see results?

    When taking a high dose of methylfolate, you may notice improvements in your symptoms within a few days or weeks. However, individual responses can vary, and some people may experience relief sooner or later than others.


    It is important to be patient and stick to the dosage as directed by your healthcare practitioner. Monitoring your progress and discussing any concerns with your doctor will help determine what dosage works best for you. Some doctors have found that it may take up to 4 full months of daily methylfolate dosage before results are seen.

    Taking antidepressants and L-methylfolate together

    Numerous studies have shown that L-methylfolate may enhance the response to antidepressants. It’s believed that L-methylfolate’s role in the production of THB (tetrahydrobiopterin or BH4) may increase the availability of neurotransmitters.3


    Other researchers suggest that augmentation of SSRI/SNRI with L-methylfolate may support serotonin levels in depressed patients, helping to sustain the effect of the medication.4


    A 2011 study published in Innovations in Clinical Neuroscience compared the efficacy of treating depressed patients with L-methylfolate and SSRI/SNRIs or an SNRI alone. After 60 days, 18.5% of patients taking L-methylfolate + SSRI/SNRI experienced major improvement, compared to 7% of those taking only SSRI/SNRIs. The authors concluded that L-methylfolate increases central neurotransmitter levels and thereby improves the effectiveness of antidepressant therapy, which makes the combination of L-methylfolate and antidepressants a more therapeutic solution than taking antidepressants alone.5


    Two 2012 clinical trials found that patients receiving 15 mg/day of adjunctive L-methylfolate (LMF) therapy showed significantly greater response rates (more than 50% improvement in depressive symptoms) than those receiving an SSRI with a placebo.6 The researchers concluded that taking 15mg L-methylfolate alongside SSRIs was safe, effective, and well-tolerated in patients with depression who had not responded adequately to SSRIs before.

    Connection between folate levels and depression

    Several key enzymes involved in one-carbon metabolism depend on folate to function properly, including those that create serotonin, norepinephrine, and dopamine. This has led researchers to form a biologically plausible link between folate and mood.


    A 2017 meta-analysis reported that individuals with depression tend to have lower folate levels and consume less folate than non-depressed individuals.7 Another systematic review of observational studies showed that low folate levels are prevalent in people with depression.8 The Medscape Psychiatry & Mental Health eJournal has also suggested that depression is one of the most common neuropsychiatric outcomes of folate deficiency.9


    Numerous studies have shown that low folate may result in poor response to antidepressants and/or relapse of depressive symptoms, and also longer duration of depressive episodes.10,11


    MTHFR gene mutations are associated with an increased risk of a variety of common mental health conditions, including depression. This may be due to the body’s inability to metabolize folic acid efficiently, leading to lower levels of L-methylfolate and, subsequently, poor neurotransmitter production. 

    Up to 70% of depressed patients have the MTHFR genetic mutation that compromises their ability to convert folate from food or from synthetic folic acid (used in some supplements) to L-methylfolate.12


    A 2019 study investigated the efficacy of using L-methylfolate in depressed patients who also had the MTHFR variants C677T and A1298C.13 Patients with the C677T genotype who were treated with L-methylfolate showed significant improvement in their depressive symptoms, which supported previous studies that associated the C677T genotype with L-methylfolate deficiency and depression. However, they added that further studies were needed to confirm the efficacy of L-methylfolate treatment for depression.

    L-Methylfolate and Treatment-Resistant Depression

    MTHFR is one of the known associations in treatment-resistant depression due to causing lower levels of L-methylfolate and monoamines.14 However, the use of L-methylfolate in adults with TRD (Treatment-Resistant Depression) has had some positive results.


    A 12-month study involving patients with treatment-resistant depression (who had already participated in two similar trials) evaluated their response to taking 15mg L-methylfolate calcium alongside antidepressants. Of 68 subjects, 38% achieved full recovery, and none experienced a recurrence of their depression.15

    In a 2019 study involving adolescents with treatment-resistant depression who were prescribed adjunctive L-methylfolate, 80% demonstrated improvement in their depression, anxiety, and irritability. The majority (also 80%) of the patients had an MTHFR gene variant.16

    Can methylfolate cause depression?

    No, methylfolate won’t make you depressed. The majority of studies show methylfolate has only positive effects on people with depression symptoms.

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    Frequently Asked Questions about Methylfolate and Depression

    Is L-methylfolate good for depression?

    Numerous studies show that L-methylfolate can improve depression symptoms, whether taken alone or in combination with antidepressants. This is because L-methylfolate assists with the production of neurotransmitters required for normal mood.

    How long does it take for methylfolate to help depression?

    Everyone experiences depression differently, and everyone will respond to L-methylfolate differently. Some people may see results within a few weeks, some months, while others may have to alter their dosage to see their symptoms improve.

    Does L-methylfolate increase dopamine?

    Studies suggest that methylfolate improves the production of neurotransmitters including dopamine, serotonin, and norepinephrine.

    How does L-methylfolate make you feel?

    Everyone responds to methylfolate differently. However, the majority of people who take methylfolate consistently report that their symptoms of depression improve, along with their cognitive function and energy levels.

    References

    1. National Institutes of Health (US), Biological Sciences Curriculum Study; "Information about Mental Illness and the Brain"; NIH Curriculum Supplement Series [Internet]; 2007

      https://www.ncbi.nlm.nih.gov/books/NBK20369/

    2. George I Papakostas, Richard C Shelton, John M Zajecka, Bijan Etemad, Karl Rickels, Alisabet Clain, Lee Baer, Elizabeth D Dalton, Garret R Sacco, David Schoenfeld, Michael Pencina, Allison Meisner, Teodoro Bottiglieri, Erik Nelson, David Mischoulon, Jonathan E Alpert, James G Barbee, Sidney Zisook, Maurizio Fava; "L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials"; The American Journal of Psychiatry; Dec 2012

      https://pubmed.ncbi.nlm.nih.gov/23212058/

    3. Matthew Macaluso, "L-Methylfolate in Antidepressant Non-responders: The Impact of Body Weight and Inflammation"; Frontiers in Psychiatry; 2022 Mar

      https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2022.840116/full

    4. Samet Kose, Kemal Sayar; "L-methylfolate in patients with treatment resistant depression: fulfilling the goals of personalized psychopharmacological therapy"; Psychiatry and Clinical Psychopharmacology Vol. 28 Iss. 4; 2018 Dec

      https://www.tandfonline.com/doi/full/10.1080/24750573.2018.1552401

    5. 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://www.ncbi.nlm.nih.gov/pmc/articles/PMC3036555/

    6. George I Papakostas, Richard C Shelton, John M Zajecka, Bijan Etemad, Karl Rickels, Alisabet Clain, Lee Baer, Elizabeth D Dalton, Garret R Sacco, David Schoenfeld, Michael Pencina, Allison Meisner, Teodoro Bottiglieri, Erik Nelson, David Mischoulon, Jonathan E Alpert, James G Barbee, Sidney Zisook, Maurizio Fava; "L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials"; The American Journal of Psychiatry; Dec 2012

      https://pubmed.ncbi.nlm.nih.gov/23212058/

    7. Ansley Bender, Kelsey E. Hagan, Neal Kingston; "The association of folate and depression: A meta-analysis"; Journal of Psychiatric Research Vol. 95 Pg. 9-18; 2017 Dec

      https://www.sciencedirect.com/science/article/abs/pii/S0022395617305927

    8. Simon Gilbody, Tracy Lightfoot, Trevor Sheldon; "Is low folate a risk factor for depression? A meta‐analysis and exploration of heterogeneity"; Journal Of Epidemiology & Community Health; 2007 Jul

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2465760/

    9. Jonathan E. Alpert, Maurizio Fava; "Nutrition and Depression: The Role of Folate"; Medscape; 1997 Jan

      https://www.medscape.com/viewarticle/431514

    10. George I Papakostas, Timothy Petersen, David Mischoulon, Julie L Ryan, Andrew A Nierenberg, Teodoro Bottiglieri, Jerrold F Rosenbaum, Jonathan E Alpert, Maurizio Fava; "Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-resistant depression"; The Journal of Clinical Psychiatry; 2004 Aug

      https://pubmed.ncbi.nlm.nih.gov/15323594/

    11. A J Levitt, R T Joffe; "Folate, B12, and life course of depressive illness"; Biological Psychiatry; 1989 Apr

      https://pubmed.ncbi.nlm.nih.gov/2720001/

    12. 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 CNS Disorders; 2013 Aug

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

    13. Michelle Rainka, Jacqueline Meaney, Erica S. Westphal, Traci Aladeen, Kaitlin Landolf, Sarah Stanford, Patrick Galdun, Natalie Asbach, Francis Gengo, Horacio Capote; "Effect of L-methylfolate on Depressive Symptoms in Patients with MTHFR Mutations (P3.9-057)"; General Neurology: Neurotherapeutics, Treatments, and Clinical Trials; 2019 Apr

      https://n.neurology.org/content/92/15_Supplement/P3.9-057

    14. Samet Kose, Kemal Sayar; "L-methylfolate in patients with treatment resistant depression: fulfilling the goals of personalized psychopharmacological therapy", Psychiatry and Clinical Psychopharmacology Vol. 28 Iss. 4, 2018 Dec

      https://www.tandfonline.com/doi/full/10.1080/24750573.2018.1552401

    15. John M Zajecka, Maurizio Fava, Richard C Shelton, Lori W Barrentine, Page Young, George I Papakostas; "Long-term efficacy, safety, and tolerability of L-methylfolate calcium 15 mg as adjunctive therapy with selective serotonin reuptake inhibitors: a 12-month, open-label study following a placebo-controlled acute study"; The Journal of Clinical Psychiatry; 2016 May

      https://pubmed.ncbi.nlm.nih.gov/27035404/

    16. Lauren L Dartois, Danielle L Stutzman, MaryAnn Morrow; "L-methylfolate Augmentation to Antidepressants for Adolescents with Treatment-Resistant Depression: A Case Series"; Journal Of Child Adolescent Psychopharmacology; 2019 Jun

      https://pubmed.ncbi.nlm.nih.gov/31058543/

    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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