When to Choose Methylfolate Versus SAM-e | Methyl-Life®

When to Choose Methylfolate Versus SAM-e | Methyl-Life®

Katie Stone - Naturopath

Written By:

Katie Stone - Naturopath
Dr. Nare Simonyan - PhD Pharmaceutical Science

Medical Reviewer:

Dr. Nare Simonyan - PhD Pharmaceutical Science
Kari Asadorian - Bachelor of Science in Nursing

Edited By:

Kari Asadorian - Bachelor of Science in Nursing

Updated On:

March 23, 2025

Table of Contents

    When to Choose Methylfolate Versus SAM-e

    Those affected by depression may be curious about the benefits of using methylfolate and/or SAM-e (S-adenosylmethionine) to assist in treating their symptoms.


    L-Methylfolate has been shown in numerous studies to enhance the response to antidepressants. SAM-e has been on the US market for only two decades but is now a prescription drug in several European countries, primarily for major depression.


    This article will explain what SAM-e is, how it works, and how it compares with methylfolate to treat depression. We will compare each supplement and their efficacy in improving depressive symptoms and whether patients can choose between the two.


    We will then suggest how best to supplement with methylfolate and/or SAM-e. 

    What is SAM-e?

    S-Adenosylmethionine (SAMe) is an essential compound that plays a major role in the central nervous system function through the body’s transmethylation pathways, including the methylation of DNA, histones, and several neurotransmitters and hormones. SAM-e is almost as valuable as adenosine triphosphate1 when serving as a cofactor in biochemical methylation reactions.


    SAMe is found throughout the body, but its highest concentrations are in the liver, brain, adrenal glands, and pineal gland. It functions as the major donor of methyl groups2 required to create neurotransmitters and phospholipids, DNA, ribonucleic acid, and proteins.


    SAM-e is produced in the body from two other compounds: methionine, a sulfur-containing amino acid, and adenosine triphosphate, an energy-carrying molecule found in the cells of all living things.


    The process of generating SAMe involves both the folate and methionine cycles, which both belong to the one-carbon cycle. Folate or folic acid is converted into SAMe via L-methylfolate.


    SAM-e then functions in the transmethylation pathway as it produces the neurotransmitters serotonin, dopamine, and norepinephrine. For this reason, numerous studies have demonstrated that SAMe may be useful in treating depression3 or major depressive disorder.

    Methylfolate, SAM-e, and Depression

    Both L-methylfolate and SAMe are shown to be effective and well-tolerated4 in treating depression and may be especially useful as a means of improving the response to antidepressants.


    The pathway to neurotransmitter synthesis requires enzymes and cofactors, including both SAMe and folate. Impairment in the functioning of these enzymes or cofactors will impair neurotransmitter generation, which is crucial for healthy mood and cognitive function. Learn more here about how MTHFR and low methylfolate are linked to anxiety/depression.


    Folate deficiency has been causatively linked to depression5 because folate is required in the synthesis of neurotransmitters in the central nervous system. Depressed people with low folate are significantly less likely to respond to antidepressants and more likely to relapse during treatment.


    Folate deficiency can also lead to elevated homocysteine levels, which in turn cause oxidative stress, resulting in cerebral, vascular, and neurological damage as well as neurotransmitter deficiency6.


    SAMe deficiency has been reported in patients with folate and methionine metabolism defects and depression. Deficiencies of folate and vitamin B127 may account for decreased SAMe levels as they are necessary co-factors in the synthesis of SAMe.


    Researchers suggest that the correlation between low folate levels and low SAMe levels may result in decreased monoamine synthesis8, increasing the risk of depression or treatment resistance.


    Preliminary studies suggest that taking SAMe may help treat chronic liver disease caused by medications or alcoholism.


    A 2013 study9 in which 33 depressed patients supplemented with SAMe for 8 weeks found that 60% of those patients showed improvement in their symptoms. The researchers concluded that SAMe might improve depression by enhancing the methylation of catecholamines and increasing serotonin turnover. It also appeared to enhance dopamine activity and the reuptake inhibition of norepinephrine and increase the conversion of phosphatidylcholine.

    Does Methylfolate Increase SAM-e?

    Folate acts as a coenzyme required10 to convert homocysteine to methionine, and methionine is required for the synthesis of SAM-e.


    Folic acid and dihydrofolate undergo enzymatic transformation to become L-methylfolate, the only form that can be used by cells and can cross the blood–brain barrier for use in the central nervous system. L-methylfolate supplement then joins with homocysteine to form methionine, which is then metabolized by methionine adenosyltransferase and vitamin B12 to form SAMe. SAM-e can then be used for methylation reactions11 and neurotransmitter synthesis, among many other functions.

    Can You Take Them Together?

    SAMe and folate are needed as cofactors and methyl donors in the one-carbon metabolism cycle to generate neurotransmitters.


    In clinical trials, supplementation of SAMe and folate12 has been shown to improve symptoms of depression. The mechanism of action of both of these compounds is to provide donor methyl groups to support the one-carbon cycle and the production of monoamine neurotransmitters.


    L-methylfolate supplementation is preferable13 over other folates as it has greater bioavailability in patients with a genetic polymorphism, and none of the side effects associated with folic acid supplements.


     

    One study involving 554 patients14 with depression showed that taking L-methylfolate significantly improved symptoms and functioning. Over 12 weeks, 67.9% of patients responded to the L-methylfolate, and 45.7% achieved remission.


    Although studies on SAMe are limited, it is also found to be an effective and well-tolerated form of adjunctive treatment15 for depressed patients who have not responded to SSRIs (Selective serotonin reuptake inhibitors).


    As every patient’s needs are different, consulting with a medical professional regarding supplementation with L-methylfolate, SAM-e, or both, is strongly recommended.

    Final Considerations

    Both L-methylfolate and SAM-e are available as OTC supplements in-store and online. As mentioned above, it is important to first discuss with your doctor before starting any new supplement regime, especially if you are already taking other medication.


    When choosing an L-methylfolate supplement, be sure to look for a product that contains the highly bioavailable Calcium salt form of (6S)-5-methyltetrahydrofolic acid. It has been shown to increase plasma folate more effectively than folic acid, irrespective of whether a patient has genetic defects that affect uptake.


     

    Methyl-Life’s® Methylfolate range is made with the internationally-patented Magnafolate® PRO, the most active folate form in plasma circulation. Compared with ordinary folate, Magnafolate® PRO was absorbed faster and utilized more quickly in the body. This can help provide the folate required for the one-carbon metabolic cycle and the subsequent synthesis of SAM-e.

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    References

    1. G L Cantoni; "Biological Methylation: Selected Aspects"; Annual Review of Biochemistry Vol. 44; 1975

      https://www.annualreviews.org/doi/10.1146/annurev.bi.44.070175.002251

    2. George I Papakostas, Clair F Cassiello, Nadia Iovieno; "Folates and S-Adenosylmethionine for Major Depressive Disorder"; CanJPsychiatry; 2012

      https://journals.sagepub.com/doi/pdf/10.1177/070674371205700703

    3. Domenico De Berardi, Laura Orsolini, Nicola Serroni, Gabriella Girinelli, Felice Iasevoli, Carmine Tomasetti, Andrea de Bartolomeis, Monica Mazza, Alessandro Valchera, Michele Fornaro, Giampaolo Perna, Monica Piersanti, Marco Di Nicola, Marilde Cavuto, Giovanni Martinotti, Massimo Di Giannantonio; "A comprehensive review on the efficacy of S-Adenosyl-L-methionine in Major Depressive Disorder"; CNS & neurological disorders drug targets; 2016

      https://pubmed.ncbi.nlm.nih.gov/26295824/

    4. George I Papakostas, Clair F Cassiello, Nadia Iovieno; "Folates and S-Adenosylmethionine for Major Depressive Disorder"; CanJPsychiatry; 2012

      https://journals.sagepub.com/doi/pdf/10.1177/070674371205700703

    5. 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/

    6. T Bottiglieri, M Laundy, R Crellin, B K Toone, M W Carney, E H Reynolds; "Homocysteine, folate, methylation, and monoamine metabolism in depression"; Journal of neurology, neurosurgery, and psychiatry.; 2000 Aug

      https://pubmed.ncbi.nlm.nih.gov/10896698/

    7. Anup Sharma, Patricia Gerbarg, Teodoro Bottiglieri, Lila Massoumi, Linda L Carpenter, Helen Lavretsky, Philip R Muskin, Richard P Brown, David Mischoulon; "S-Adenosylmethionine (SAMe) for Neuropsychiatric Disorders: A Clinician-Oriented Review of Research"; The Journal of clinical psychiatry; 2017 Dec

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501081/

    8. George I Papakostas, Clair F Cassiello, Nadia Iovieno; "Folates and S-Adenosylmethionine for Major Depressive Disorder"; CanJPsychiatry; 2012

      https://journals.sagepub.com/doi/pdf/10.1177/070674371205700703

    9. Domenico De Berardis, Stefano Marini, Nicola Serroni, Gabriella Rapini, Felice Iasevoli, Alessandro Valchera, Maria Signorelli, Eugenio Aguglia, Giampaolo Perna, Anatolia Salone, Giuseppe Di Iorio, Giovanni Martinotti, Massimo Di Giannantonio; "S-Adenosyl-L-Methionine Augmentation in Patients with Stage II Treatment-Resistant Major Depressive Disorder: An Open Label, Fixed Dose, Single-Blind Study"; The Scientific World Journal; 2013 May

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666233/

    10. Oregan State University; "Folate"; Micronutrient Information Center; 2025

      https://lpi.oregonstate.edu/mic/vitamins/folate

    11. G Bistulfi, P Diegelman, B A Foster, D L Kramer, C W Porter, D J Smiraglia; "Polyamine biosynthesis impacts cellular folate requirements necessary to maintain S-adenosylmethionine and nucleotide pools"; FASEB journal : official publication of the Federation of American Societies for Experimental Biology.; 2009

      https://pubmed.ncbi.nlm.nih.gov/19417083/

    12. George I Papakostas, Clair F Cassiello, Nadia Iovieno; "Folates and S-Adenosylmethionine for Major Depressive Disorder"; The Canadian Journal of Psychiatry; 2012

      https://journals.sagepub.com/doi/10.1177/070674371205700703

    13. George I Papakostas, Clair F Cassiello, Nadia Iovieno; "Folates and S-Adenosylmethionine for Major Depressive Disorder"; The Canadian Journal of Psychiatry; 2012

      https://pubmed.ncbi.nlm.nih.gov/22762295/

    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. George I. Papakostas, David Mischoulon, Irene Shyu, Jonathan E. Alpert, Maurizio Fava; "S-Adenosyl Methionine (SAMe) Augmentation of Serotonin Reuptake Inhibitors for Antidepressant Nonresponders With Major Depressive Disorder: A Double-Blind, Randomized Clinical Trial"; The American Journal of Psychiatry; 2010 Aug

      https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2009.09081198

    16. 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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