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Adjunctive L-Methylfolate Offers Benefit in Depression Treatment

January 07, 2020

Supplemental treatment with the medical food L-methylfolate may benefit patients with depression who do not respond to antidepressants, according to a review article published online in CNS Spectrums.

Rakesh Jain, MD, MPH
Rakesh Jain, MD, MPH

“L-methylfolate has been well studied in multiple clinical trials, and findings support its consideration for use as an adjunctive therapy in any depression management program, and especially in patients with characteristics suggestive of potential responsiveness,” wrote lead author and Psych Congress cochair Rakesh Jain, MD, MPH, and colleagues.

Believed to enhance the synthesis of serotonin, norepinephrine, and dopamine as well as to suppress inflammation and promote neural health, L-methylfolate is the biologically active form of folate and is available over-the-counter and in a prescription formulation. Supplemental use of L-methylfolate shows particular promise, the article explained, for improving outcomes in patients with selective serotonin reuptake inhibitor-resistant major depressive disorder and the following characteristics:

• low folate levels;

• mutations in gene-coding enzymes that are involved in the metabolism of folate;

• body mass index greater than 30 kg/m2; and

• elevated markers of inflammation, including C-reactive protein.

Conversely, L-methylfolate should be avoided in patients with hypersensitivity to the nutraceutical. Overall, however, L-methylfolate as adjunctive therapy for major depressive disorder was well tolerated in trials, with a safety profile resembling placebo.

The authors recommended use of L-methylfolate be considered in conjunction with other wellness-promoting interventions, such as diet and exercise.

“Supplementation with L-methylfolate fits well with the changing paradigm of major depressive disorder management,” they wrote, “with the ultimate goal of producing wellness instead of  focusing solely on symptom reduction.”

—Jolynn Tumolo


Jain R, Manning S, Cutler AJ. Good, better, best: clinical scenarios for the use of L-methylfolate in patients with MDD. CNS Spectrums. 2019 December 13;[Epub ahead of print].

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