L-Methylfolate and Depression Management

Depression is one of the most common mood disorders in the world, affecting an estimated 350 million individuals.

While many factors may be involved in the development of depression, one of the predominant theories is an imbalance of “brain chemicals”—i.e., the neurotransmitters that contribute to a healthy mood. These neurotransmitters include serotonin, norepinephrine, and dopamine.

L-methylfolate plays a key role in the production of these neurotransmitters. For this reason, L-methylfolate has been prescribed to people suffering from depression for many years. However, research into the efficacy of this treatment is still somewhat limited.

This article will review the current literature regarding the use of methylfolate in treating depression and what the results mean.

Research has suggested that folate levels are involved in the development and course of depression. A 2017 meta-analysis published in the Journal of Psychiatric Research reported that individuals with depression tend to have lower folate levels and consume less folate than non-depressed individuals.

Another systematic review of observational studies showed that low folate levels are prevalent in people with depression, and the Medscape Psychiatry & Mental Health eJournal suggested that depression is one of the most common neuropsychiatric outcomes of folate deficiency.

Numerous researchers have linked folate deficiency with depression, with various studies showing that low folate may result in poor response to antidepressants and/or relapse of depressive symptoms, and also longer duration of depressive episodes.

Folate is a naturally-occurring B vitamin that plays a major role in one-carbon metabolism, a process of biochemical reactions required for daily function and overall health. Several key enzymes involved in one-carbon metabolism depend on folate to function properly, including those that create serotonin, norepinephrine, and dopamine.

These neurotransmitters play vital roles in regulating mood, anxiety, appetite, and sleep cycles. They are also required for antidepressant medication to work properly. This has led researchers to form a biologically plausible link between folate and mood.

MTHFR gene mutations are associated with an increased risk of a variety of common mental health conditions, including depression and anxiety. This may be due to the body’s inability to metabolize folic acid efficiently, leading to lower levels of L-methylfolate and, subsequently, poor neurotransmitter production.

In addition, low folate levels have been associated with a poorer response to antidepressants, more severe symptoms, and overall treatment resistance.

More specifically, those with a polymorphism in the MTHFR gene, leading to decreased conversion to the active form, may benefit from supplemental L-methylfolate therapy. This recommendation is not only supported in multiple meta-analyses but also through the literature; agents of the one-carbon cycle, such as folic acid, L-methylfolate, Vitamin B6, Vitamin B12, and SAMe, are necessary for the methylation of monoamines and, therefore, the synthesis of neurotransmitters that mediate MDD and treatment response.

A study from Northern Ireland found that up to 70% of depressed patients have the MTHFR genetic mutation that compromises their ability to convert folate from food or from synthetic folic acid (used in some supplements) to L-methylfolate.

A 2019 study investigated the efficacy of using L-methylfolate in depressed patients who also had the MTHFR variants C677T and A1298C. The researchers found that patients with the C677T genotype who were treated with L-methylfolate showed significant improvement in their depressive symptoms, which supported previous studies that associated the C677T genotype with L-methylfolate deficiency and depression. However, they added that further studies were needed to confirm the efficacy of L-methylfolate treatment for depression.

The above research has prompted medical professionals to prescribe L-methylfolate to patients who have shown poor response to antidepressant medication, namely selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs).

L-Methylfolate has been shown in retrospective and prospective studies to enhance the response to antidepressants.

A report published in the Journal of Clinical Psychiatry described how L-methylfolate might enhance the response to antidepressant therapy due to its role in the production of THB (tetrahydrobiopterin) (BH4), an essential cofactor for neurotransmitter production. Increasing BH4 may then increase the availability of neurotransmitters.

Other researchers suggest that augmentation of SSRI/SNRI with L-methylfolate may support serotonin levels in certain depressed patients and help sustain treatments’ benefits.

A 2011 study published in Innovations in Clinical Neuroscience compared the efficacy of treating depressed patients with L-methylfolate + SSRI/SNRIs or an SNRI alone.

After 60 days, 18.5 percent of patients taking L-methylfolate + SSRI/SNRI experienced major improvement, compared to 7.04 percent of those taking only SSRI/SNRIs. The authors concluded that L-methylfolate plus an antidepressant in combination therapy led to major symptomatic and functional improvement more rapidly than did antidepressant monotherapy.

Two 2012 clinical trials found that patients receiving 15 mg/day of adjunctive L-methylfolate (LMF) therapy showed significantly greater response rates (more than 50% improvement in depressive symptoms) than those receiving an SSRI with a placebo. The researchers concluded that taking 15mg L-methylfolate alongside SSRIs was safe, effective, and well-tolerated in patients with depression who had not responded adequately to SSRIs before.

In a 2013 real-world patient experience trial involving 554 patients with depression, those taking L-methylfolate reported significant improvements in depressive symptoms and functioning, with 67.9% of patients responding and 45.7% achieving remission over 12 weeks.

A 2020 case study of a 49-year-old Asian American female patient examined the use of L-methylfolate in treating her long-standing fatigue and treatment-resistant depression. She received monotherapy of L-methylfolate at a much higher dosage than the standard RDA (Recommended Dietary Allowance) (400-800 mcg daily). After three months, she reported improvements in both mood and energy levels since initiating the higher dose (higher than 7 mg), and her patient health score for depression was 0.

However, a report published in the Psychiatric Times noted three case studies of patients with unipolar or bipolar depression who displayed agitation and mania shortly after beginning a trial of 15 mg L-methylfolate. In all three cases, the agitation resolved a few days after discontinuing the L-methylfolate.

L-methylfolate is FDA-approved as a medicinal supplement for antidepressant augmentation. Many studies showing positive results for using L-methylfolate have used Deplin®, a prescribed medical food. However, OTC methylfolate supplements are readily available without prescription and functionally equivalent.

Randomized, controlled trials investigating the adjunctive use of L-methylfolate in adults with TRD (Treatment-Resistant Depression) have shown some positive results.

Some researchers have noted that MTHFR is one of the known associations in treatment-resistant depression due to causing lower levels of L-methylfolate and monoamines.

A 12-month study conducted in 2016 involving patients with treatment-resistant depression (who had already participated in two similar trials) evaluated their response to taking 15mg L-methylfolate calcium alongside antidepressants.

Of 68 subjects who met the criteria for the 12-month open-label phase, 38% achieved full recovery, and none experienced a recurrence of their depression. The researchers concluded that adjunctive L-methylfolate 15 mg/day might be useful for patients with treatment-resistant depression.

In a 2019 study involving adolescents with treatment-resistant depression who were prescribed adjunctive L-methylfolate, 80% demonstrated improvement in their depression, anxiety, and irritability. The majority (also 80%) of the patients had an MTHFR gene variant.

The above studies have noted largely positive results in using L-methylfolate to treat depression, particularly in people who have not shown adequate response to antidepressant medication.

There is also some evidence that methylfolate may benefit those with low methylfolate levels due to MTHFR mutations.

However, it is important to note that research is so far limited.

Those who wish to supplement with L-methylfolate are advised to consult their doctor or health professional first. You may also learn more about OTC methylfolate products such as the Methyl-Life® range, which are the functional equivalent of L-methylfolate medical foods such as Deplin®. The Methyl-Life® website also provides a useful guide to dosing.