L-methylfolate vs Deplin® for Depression: Are They the Same? banner

L-methylfolate vs Deplin® for Depression: Are They the Same?

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:

January 30, 2025

Table of Contents

    L-methylfolate vs Deplin® for Depression: Are They the Same?

    Around 8.9 million US adults take medication for depression. Of these, around 2.8 million (30.9%) are affected by treatment-resistant depression (TRD), in which they are unable to find relief with antidepressant medications alone.1 TRD can be extremely distressing for those affected, and can increase the severity of their depressive symptoms.

    Fortunately, L-methylfolate may be a solution. 


    L-methylfolate (vitamin B9) is one of the most important nutrients involved in the production of serotonin, dopamine, and norepinephrine. These neurotransmitters play a vital role in mood management. 

    Studies show that taking L-methylfolate in supplement form can help to restore neurotransmitter levels in the body, which can then make antidepressant medication more effective.2 

    L-methylfolate is available as Deplin®, a prescription ‘medical food’ that contains a high dose of L-methylfolate, or as an over-the-counter supplement. 


    So, how does an L-methylfolate supplement compare to Deplin®? Why would you choose one over the other?

    L-methylfolate vs Deplin®

    L-methylfolate and Deplin® both provide the kind of folate that is readily available for making the chemicals that support healthy, happy mood. As the active form of folate, L-methylfolate doesn’t need to be converted in the body, so it’s immediately available for use.


    Deplin® is a registered L-methylfolate medical food with two dosage options: 7.5mg and 15mg. It is used for the clinical dietary management of depression, schizophrenia, folate deficiency, and hyperhomocysteinemia. Deplin® ingredients include L-methylfolate Calcium (Metafolin®) 7.5 mg and Algae-S powder (Schizochytrium) 90.314 mg. 

     

    Although Deplin® is not an antidepressant or antipsychotic, it is often used as an adjunctive treatment alongside antidepressant medication. Research has shown that Deplin® is particularly effective for those with low levels of L-methylfolate and major depressive disorder or schizophrenia.3

    L-methylfolate dietary supplements are available over the counter (OTC) in a range of brands and dosages. The types of L-methylfolate used in different products can vary significantly, depending on its molecular structure and the type of salt it is bound to. Some of these forms include L-5-MTHF, L-5-Methyltetrahydrofolate, (6S)-L-MTHF, (6S)-L-Methyltetrahydrofolate, D-5-MTHF or D-5-Methyltetrahydrofolate, (6R)-5-MTHF, (6R)-5-Methyltetrahydrofolate.

    What is the difference between D and L forms of Methylfolate?

    The D and L forms of methylfolate (D-MTHF and L-MTHF)  are two forms of the same molecule that differ slightly in structure. In L-MTHF, both chiral centers (specific parts of the molecule) have the natural L-configuration (6S, αS). In D-MTHF, one of these chiral centers is different (6R, αS). When combined, this is called a "racemic mixture" because only one chiral center differs between the two forms.

    The major natural form of the reduced folates is the (6S,αS) diastereoisomer, which has greater biological activity than the (6R,αS) isomer.4 The “D” or “R” forms of methylfolate are not as bioavailable.

    Methyl-Life L-methylfolate vs. Deplin®

    Methyl-Life® is a supplement brand that specializes in products for those with MTHFR, the genetic mutation that results in poor metabolism of folate. 

    Methyl-Life’s range of therapeutic nutraceutical supplements do not require a prescription to purchase, and include L-methylfolate 7.5mg, 10mg, and 15mg products.

    Why is Deplin® prescribed if L-methylfolate is available over the counter?

    Deplin® is prescription-only because it is specially formulated for the management of clinical disorders such as depression, schizophrenia, hyperhomocysteinemia, and other conditions. These disorders can only be diagnosed by a qualified healthcare professional. 

    Deplin® is an approved nutritional adjunctive antidepressant therapy that increases central neurotransmitter levels and thereby improves the effectiveness of antidepressant therapy. LMF can increase clinical response when used adjunctively in patients with major depressive disorder (MDD) and who are SSRI-resistant.5

    Is Deplin® Right for You?

    While Deplin has been backed by substantial research, it may not be suitable for everyone. 

    Deplin® may not be right for you if:

    • The cost of a monthly prescription (plus doctor’s visits) is too high
    • You have allergies or sensitivities to the excipient ingredients, such as milk or soy
    • You require a lower dose
    • You are pregnant or breastfeeding (your dosage needs may be different)
    • You require a range of vitamins and minerals rather than a single nutrient 


    Everyone is different, and it may take time to find the right supplement for you. Fortunately, there are some excellent alternatives to Deplin®.

    Deplin® Alternatives

    When seeking a Deplin® alternative, it’s important to check the product label carefully as not all products are the same. Different brands may vary in terms of formulation, strength, dosage, and the type of methylfolate they use. Some brands may also contain fillers, dyes, or other ingredients that may cause allergic reactions or impact the efficacy of the methylfolate. 

    Clinically researched brands such as Methyl-Life may actually be superior to Deplin®. The Methyl-Life range is made with internationally-patented Magnafolate® PRO, an exclusive form of methylfolate with a high level of purity. Methyl-Life products are also free from additives and fillers, and the monthly cost is much lower than Deplin®. Methyl-life products don’t require prescription, and can be purchased online and delivered directly to the consumer. 

    The best-known Deplin® alternative l-methylfolate supplement brands include:

    • Methyl-Life: 15mg (6S)-5-methyltetrahydrofolic acid, Calcium salt, Type C crystalline molecule
    • Denovo™: 15 mg L-methylfolate (L-5-MTHF from L-5-methyltetrahydrofolate calcium salt).
    • EnLyte™: L-methylfolate magnesium, folinic acid, folacin, cofactors of b1, b2, b3, b6, b12, betaine, zinc, magnesium, vitamin c, Omega 3s.
    • Methyl-Pro: L-5-methylfolate calcium salt, glycine

    Details on Methyl-Life® L-methylfolate vs. Deplin®

    Both products are formulated with the same ingredient, L-methylfolate calcium, the bioactive form that is easily absorbed into the bloodstream and quickly transported as 5-methylfolate (5 MTHF) to be readily used by the brain and all of the body's cells and tissues. 

    Doctors and integrated health professionals recommend Methyl-Life's® therapeutic L-methylfolate supplements. This range has been clinically researched to support various health conditions and all products are available without a prescription.

    The Methyl-Life methyl-folate range is available in several dosage options to suit different needs. Each dosage can be taken alone, or alongside antidepressants. 

    • For general health and restoring folate deficiencies: 2.5 mg and 5 mg. 
    • For restoring significant folate deficiencies associated with mood disorders (including depression): 7.5 mg, 10 mg, and 15 mg.

    The Methyl-Life® product range includes:

    Each product is designed to support the body’s requirements for energy production and neurotransmitter synthesis while restoring healthy levels of folate.

     Methyl-Life’s® Methylfolate 15 product contains a high dose (15 mg) of internationally-patented Cerebrofolate [(6S)-5-methyltetrahydrofolic acid, Calcium salt, Type C Crystalline molecule (L-Methylfolate)]. This highly-regarded product is formulated specifically for people with an increased need for bioavailable folate due to genetic (MTHFR) defects. It is also suitable for those with dietary deficiencies or drug-induced needs (i.e. taking warfarin, coumadin, metformin, etc.)

    This unique and internationally-patented L-5-Methylfolate ingredient is crystalline calcium salt-based for superior stability and absorption. It has been shown to have approximately three times the purity of any other competing L-Methylfolate brand, including Deplin®.

    Unlike Deplin®, the Methyl-Life range does not include fillers or additives. 

    If you’re interested in learning more about Deplin®, L-Methylfolate, or how you can find alternative ways of managing your depression, contact us at Methyl-Life® today. We can help you regain confidence and get back to your better self.  Our team of experts can answer your questions regarding Methyl-Life® products and whether they may be suitable for you.

    To learn more, check out Methyl-Life® Methylfolate Facts.

    The Methyl-Life® Product Range:

    Product Recommendations

    L Methylfolate 15 mg - A Mood-Boosting Supplement

    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
    • 3rd-Party Tested for Purity, Potency & Safety
    • 90 Vegan, Non-GMO, Chewable Mint Tablets

    References

    1. Hunter TS. L-methylfolate in the therapeutic management of major depressive disorder. J Pharm Pract. 2008;21:278-286.

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    2. Papakostas GI, Shelton RC, Zajecka JM, et al. Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial. J Clin Psychiatry. 2014;75(8):855-863.

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    3. Fava M, Shelton RC, Zajecka JM. Evidence for the use of l-methylfolate combined with antidepressants in MDD. J Clin Psychiatry. 2011;72(8):e25.

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    4. Zajecka J, Fava M, Shelton RC, Barrentine LW, Young P. 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. J Clin Psychiatry. 2016;77(5):654-660.

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    5. Martone G. Enhancement of Recovery from Mental Illness with l-methylfolate Supplementation. Perspectives in Psychiatric Care. 2018;54(2):331-334.

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    6. Reynolds EH, Crellin R, Bottiglieri T, Laundy M, Toone BK, et al. Methylfolate as Monotherapy in Depression. A Pilot Randomised Controlled Trial. J Neurol Psychol. 2015;3(1): 5.

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    7. Di Palma C, Urani R, Agricola R, Giorgetti V, Verde GD. Is Methylfolate Effective in Relieving Major Depression in Chronic Alcoholics? A Hypothesis of Treatment. Current Therapeutic Research-Clinical and Experimental. 1994;55(5):559-568.

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    8. Hardin A, Baldwin-Sayre C. L-Methylfolate as a Monotherapy for Treatment-Resistant Depression: A Case Study. Integrative Medicine. 2020;19(4):14-18.

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    9. Freeman MP, Savella GM, Church TR, Góez-Mogollón L, Sosinsky AZ, Noe OB, Kaimal AJ, Cohen LS. A Prenatal Supplement with Methylfolate for the Treatment and Prevention of Depression in Women Trying to Conceive and During Pregnancy. Annals of Clinical Psychiatry. 2019;31(1):4-16.

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    10. Debra J. Brody, Laura A. Pratt, Jeffery P. Hughes; "Prevalence of Depression Among Adults Aged 20 and Over: United States, 2013–2016"; NCHS Data Brief No. 303; 2018 Feb

      https://www.cdc.gov/nchs/products/databriefs/db303.htm

    11. Alan L Miller, "The methylation, neurotransmitter, and antioxidant connections between folate and depression", Alternative Medicine Review: A Journal Of Clinical Therapeutic, 2008 Sep

      https://pubmed.ncbi.nlm.nih.gov/18950248/

    12. 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/

    13. Robert P Duprey, "MTHFR Gene Polymorphism Positive Treatment-Resistant Depression: Prevalence and Treatment Recommendations", Research Article - Neuropsychiatry Vol. 6 Iss. 2, 2016

      https://www.jneuropsychiatry.org/peer-review/mthfr-gene-polymorphism-positive-treatmentresistant-depression-prevalence-and-treatment-recommendations.html

    14. 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/

    15. Stephen M. Stahl, "Novel Therapeutics for Depression: L-methylfolate as a Trimonoamine Modulator and Antidepressant-Augmenting Agent", CNS Spectrums, Vol. 12, Iss. 10; 2014 Nov

      https://www.cambridge.org/core/journals/cns-spectrums/article/abs/novel-therapeutics-for-depression-lmethylfolate-as-a-trimonoamine-modulator-and-antidepressantaugmenting-agent/7611467A3E15799B39B217BF0851EC75

    16. Khalid Saad Al-Harbi, "Treatment-resistant depression: therapeutic trends, challenges, and future directions", Patient Preference and Adherence, 2012 May

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3363299/

    17. 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/

    18. 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/

    19. Jonathan E. Alpert, Maurizio Fava; "Nutrition and Depression: the Role of Folate", Nutrition Reviews, Volume 55, Issue 5, May 1997, Pages 145–149; 1997 May

      https://academic.oup.com/nutritionreviews/article/55/5/145/1813961

    20. Alec Coppen, Christina Bolander-Gouaille; "Treatment of depression: time to consider folic acid and vitamin B12"; Journal of Psychopharmacology, Vol. 19, Iss. 1; 2005 Jan

      https://journals.sagepub.com/doi/10.1177/0269881105048899

    21. Simon N Young; "Folate and depression—a neglected problem"; Journal of Psychiatry & Neuroscience; 2007 Mar

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810582/

    22. Folate and tryptophan and metabolites pattern [Interpretation] in Cerebral spinal fluid Narrative

      https://loinc.org/79574-0/

    23. L A Ordonez, R J Wurtman; "Folic acid deficiency and methyl group metabolism in rat brain: effects of L-dopa"; Archives Of Biochemistry And Biophysics; 1974 Feb

      https://pubmed.ncbi.nlm.nih.gov/4831621/

    24. Robert P Duprey; "MTHFR Gene Polymorphism Positive Treatment-Resistant Depression: Prevalence and Treatment Recommendations"; Research Article - Neuropsychiatry Vol. 6 Iss. 2; 2016

      https://www.jneuropsychiatry.org/peer-review/mthfr-gene-polymorphism-positive-treatmentresistant-depression-prevalence-and-treatment-recommendations.html#12

    25. 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/

    26. Drugs.com; "Deplin Interactions"; Drugs.com; 2024

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    27. Banner Image Designed by Freepik

      https://www.freepik.com/

    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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    Deplin® Methyl-Life L-methylfolate
    Prescription-only Does not require prescription Can be purchased directly online
    Prescribed for folate deficiency, hyperhomocysteinemia, and depression. Can be taken to support healthy mood, methylation, and homocysteine levels.
    Active ingredients:
    L-methylfolate Calcium (Metafolin®) 7.5 mg Algae-S powder (Schizochytrium) 90.314 mg     		Active ingredient:
    Magnafolate® PRO [(6S)-5-methyltetrahydrofolic acid calcium salt, Type C Crystalline molecule
    Additional ingredients:
    Silicified Microcrystalline Cellulose, Algae-S Powder (Schizochytrium Algal Oil [Vegetable source]), Glucose Syrup Solids, Mannitol, Sodium Caseinate (milk), Soy Protein, High Oleic Sunflower Oil, 2% or less Sodium Ascorbate, Natural Flavors, Tricalcium Phosphate, Tetrasodium Diphosphate, Tocopherols, Soy Lecithin, and Ascorbyl Palmitate [as antioxidants], Hypromellose, L-methylfolate Calcium, Carrageenan, Magnesium Stearate (Vegetable Source), Potassium Acetate, Black Iron Oxide, Propylene Glycol, Hydroxypropyl Cellulose, Hypromellose.
    Contains Milk and Soy     		Additional ingredients:
    Xylitol (Xylisorb®), microcrystalline cellulose (Microcel®), stearic acid, silicon dioxide, natural mint flavor (dextrose, silicon dioxide, natural flavor.
    Does NOT Contain: wheat, gluten, soy, dairy, tree nuts, animal products, GMOs, artificial ingredients or colorings.
    Available in 7.5 mg or 15 mg Available in a variety of strengths (7.5mg, 10mg, 15mg) Available in formulas alongside active B12

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    L Methylfolate 15 mg - A Mood-Boosting Supplement

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    NEW CEREBROFOLATE™ - Improved Purity & Potency