Updated March 7, 2025
Original article: January 6, 2008
I do a lot of psychopharmacology research — more than most people would consider normal. I try to share only the most interesting and relevant findings while sparing you the more technical details. But today, you’re in for a deeper dive.
This topic is too important to ignore, especially if you’re struggling with treatment-resistant depression.
What Is L-Methylfolate (MTHF)?
L-methylfolate (MTHF) is the biologically active form of folate, a B vitamin crucial for brain function and neurotransmitter production. Your body converts dietary folate into MTHF, but this process requires specific enzymes — and not everyone produces enough of them efficiently.
You’ve probably heard of folic acid, the synthetic version of folate commonly found in supplements and prenatal vitamins. While folic acid can increase MTHF levels, the conversion process isn’t always effective, particularly for people with certain genetic variations.
Why Does L-Methylfolate Matter for Mental Health?
Low levels of MTHF are linked to depression, and some people don’t synthesize enough of it, even with a folate-rich diet or supplements. This is where things get interesting:
- MTHF is necessary for producing serotonin, dopamine, and norepinephrine, the brain chemicals most antidepressants target.
- Some research suggests MTHF can enhance the effectiveness of antidepressants, even in people without a deficiency.
- Certain medications, including anticonvulsants (mood stabilizers like lamotrigine [Lamictal]), may be able to deplete MTHF levels, potentially reducing the effectiveness of antidepressants over time.
Can L-Methylfolate Help When Antidepressants Aren’t Working?
Emerging research indicates that L-methylfolate supplementation may improve antidepressant response (see below) in people with depression. Unlike standard antidepressants, which directly influence neurotransmitters, MTHF works by supporting their natural production. (Note: The research below suggests that it might work even better for those with inflammation or a higher body mass index [BMI], obesity.) L-methylfolate has even been shown to help those with treatment-resistant depression.
The Food and Drug Administration (FDA) regulates L-methylfolate as a medical food, meaning it requires a prescription but is not classified as a drug. This means it’s unlikely to contribute to your side effect load.
My Experience with L-Methylfolate
My doctor — who is about as no-nonsense as they come — introduced me to L-methylfolate. She respects the researchers studying it and felt it was worth trying. After being on anticonvulsants for years (eight, to be exact), it’s not shocking that I might be low on key nutrients.
Could this explain why antidepressants sometimes stop working? Could MTHF be the missing piece for some people? Possibly.
Final Thoughts: Should You Try L-Methylfolate?
L-methylfolate isn’t a miracle cure, and the research is still evolving. But if antidepressants aren’t working — or if they’ve stopped working — it might be worth discussing with your doctor. Since it’s relatively low-risk compared to other psychiatric treatments, it could be an option worth exploring.
As always, don’t start any new supplement without medical supervision, especially if you’re on other medications.
Recent L-Methylfolate Research
Here are some recent studies that show that L-methylfolate may benefit those taking an antidepressant for depression:
- Maruf, A. A., Poweleit, E. A., Brown, L. C., Strawn, J. R., & Bousman, C. A. (2021). Systematic Review and Meta-Analysis of L-Methylfolate augmentation in depressive Disorders. Pharmacopsychiatry, 55(03), 139–147. https://doi.org/10.1055/a-1681-2047
- Maletic, V., Shelton, R., & Holmes, V. (2023). A review of L-Methylfolate as adjunctive therapy in the treatment of major depressive disorder. The Primary Care Companion for CNS Disorders, 25(3). https://doi.org/10.4088/pcc.22nr03361
- Macaluso, M. (2022). L-Methylfolate in antidepressant non-responders: the impact of body weight and inflammation. Frontiers in Psychiatry, 13. https://doi.org/10.3389/fpsyt.2022.840116
Other Posts You Might Enjoy
