Could a Simple Supplement Help Ease Depression?

For certain people, a form of folic acid may help with depression and improve the effectiveness of antidepressants.

closeup of a white man's hands as he pours a tablet out of a supplement bottle

Updated on October 27, 2023.

I see a lot of people with depression in my practice. My experience treating it has been similar to what is discussed in medical literature. In about 70 percent of patients there has been some improvement with antidepressants, but a full remission has occurred in only 40 to 50 percent. In the interest of boosting this disappointing remission rate, I have been searching for something that will either augment antidepressants or that could be used alone.

I have found a supplement considered to be medicinal food. It is safe, and it really does work. It is a vitamin that is a form of folic acid known as L-methylfolate.

Folic acid is an essential B vitamin. It is found in green leafy vegetables, eggs, cereals, and fortified foods, to name a few. (When it appears in whole foods it’s known as folate.) When you take in folate or folic acid in your diet, it is absorbed by the small intestine, where it is converted by an enzyme into L-methylfolate. This metabolite is used to make serotonin, norepinephrine, and dopamine, which are all important brain chemicals for mood regulation.

Scientists have identified 40 mutations on the gene responsible for making the enzyme that converts folic acid into L-methylfolate. If there is one mutation on this gene—known as MTHFR—your ability to convert folic acid is reduced by a sizable amount. If you have two mutations, it is reduced even further.

If you have a defective enzyme, you cannot convert folic acid to L-methylfolate properly. This can potentially lead to lower levels of serotonin, norepinephrine, and dopamine. As it turns out, these gene mutations are quite common.

The treatment is simple: a prescription of L-methylfolate. If given in the proper amounts (7.5 to 15 milligrams) it can improve mild depression relatively quickly. One 2011 study of people with major depression found that adding L-methylfolate improved depression symptoms over a period of 60 days from 7 percent for those taking an antidepressant alone to 18.5 percent with the addition of L-methylfolate.

A 2013 study published in The Primary Care Companion for CNS Disorders reported on the results of a survey conducted among patients with major depression disorder who were treated with L-methylfolate as an addition to their ongoing antidepressant. The participants reported significant improvements in their depressive symptoms and functioning, with 45.7 percent of patients achieving remission from their symptoms over 12 weeks.

Other published case studies have shown similarly promising results. Interestingly, some research has shown that patients with depression who also have elevated levels of inflammation and/or obesity show an even greater response to L-methylfolate.

L-methylfolate is generally well-tolerated with no more side effects than placebo. It tends not to interact with other medications. In my experience, if an antidepressant has produced a positive response but the patient is still somewhat depressed, L-methylfolate can help.

The results I have seen are impressive. When I treat people with MTHFR mutations (with or without mild depression) with L-methylfolate, their mood improves and often they sleep better. Related problems such as irritable bowel syndrome will often get better as well. If you are depressed and/or on medication for depression, consider asking your healthcare provider for more information about MTHFR genetic mutations.

Taking L-methylfolate to help with depression may not work for everyone. But if your serotonin levels are genetically low, it may be a healthy way to boost them.

Article sources open article sources

Kim HY, Lee HJ, Jhon M, et al. Predictors of Remission in Acute and Continuation Treatment of Depressive Disorders. Clin Psychopharmacol Neurosci. 2021;19(3):490-497.
Macaluso M. L-Methylfolate in Antidepressant Non-responders: The Impact of Body Weight and Inflammation. Front Psychiatry. 2022;13:840116. Published 2022 Mar 17.
Jain R, Manning S, Cutler AJ. Good, better, best: clinical scenarios for the use of L-methylfolate in patients with MDD. CNS Spectrums. 2020;25(6):750-764. 
MedlinePlus. MTHFR gene (methylenetetrahydrofolate reductase). Last updated October 1, 2019.
Samarasinghe N, Mahaliyanage D, De Silva S, Jasinge E, Punyasiri N, Dilanthi HW. Association of selected genetic variants in CBS and MTHFR genes in a cohort of children with homocystinuria in Sri Lanka. J Genet Eng Biotechnol. 2022;20(1):164. Published 2022 Dec 13.
Maletic V, Shelton R, Holmes V. A Review of l-Methylfolate as Adjunctive Therapy in the Treatment of Major Depressive Disorder. Prim Care Companion CNS Disord. 2023;25(3):22nr03361. Published 2023 May 9.
Guaraldi GP, Fava M, Mazzi F, la Greca P. An open trial of methyltetrahydrofolate in elderly depressed patients. Ann Clin Psychiatry. 1993;5(2):101-105.
Ginsberg LD, Oubre AY, Daoud YA. L-methylfolate Plus SSRI or SNRI from Treatment Initiation Compared to SSRI or SNRI Monotherapy in a Major Depressive Episode. Innov Clin Neurosci. 2011;8(1):19-28.
Shelton RC, Sloan Manning J, Barrentine LW, Tipa EV. Assessing Effects of l-Methylfolate in Depression Management: Results of a Real-World Patient Experience Trial. Prim Care Companion CNS Disord. 2013;15(4):PCC.13m01520.
Hardin A, Baldwin-Sayre C. L-Methylfolate as a Monotherapy for Treatment-Resistant Depression: A Case Study. Integr Med (Encinitas). 2020;19(4):14-18.
Rainka, M, Meaney, J, Westphal, E, et al. Effect of L-methylfolate on Depressive Symptoms in Patients with MTHFR Mutations. Neurology. Apr 2019, 92 (15 Supplement) P3.9-057.
Miller, John, MD; Robinson, Sara, DNP, RN, PMHNP-BC. L-Methylfolate: Augmenting Agent May Contribute to Agitation and Mania. Psychiatric Times. March 17, 2020.

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