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How Long Does L-Methylfolate Take to Work?

How Long Does L-Methylfolate Take to Work?

How Long Does L-Methylfolate Take to Work? 

The time it takes for methylfolate to work varies from patient to patient. It can take between 1 to 4 weeks for L-methylfolate to begin working; however, this depends on many factors such as metabolic function, age, symptom severity, and more. It could take several months for it to become fully effective. 

L-methylfolate is a folate vitamin required for numerous biochemical functions in the body. It plays a key role in the methylation cycle, which is responsible for the growth and development of all cells and the control of everything from DNA replication to digestive function. Without L-methylfolate, the  production and the recycling of many important proteins, hormones, and neurotransmitters would not occur.

As a medical food and supplement, L-methylfolate is prescribed to treat conditions related to low folate or folate deficiency. It may be used in patients with major depressive disorder and/or anxiety who have not had satisfactory results from antidepressant medication.

This article will discuss the use of L-methylfolate in depression and anxiety and how long it takes to work. We will also explain why the brand of L-methylfolate matters and what to look for when choosing a supplement.

How Long Will it Take L-Methylfolate to Help Depression?

L-methylfolate is not an antidepressant. It is a form of folate—the only form that can cross the blood-brain barrier. It plays an essential role in the one-carbon cycle metabolic pathway required to produce neurotransmitters (serotonin, dopamine, and norepinephrine).


Up to 70% of patients with depression (self reported depression symptoms) have a genetic variant of the methylenetetrahydrofolate reductase enzyme that compromises their ability to convert dietary folate or synthetic folic acid to L-methylfolate. 

Supplementation with L-methylfolate has been shown to improve response to antidepressants such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) in people who do not otherwise respond adequately.

Prescription L methylfolate supplements such as Deplin have been used successfully to treat many forms of treatment-resistant depression by acting as an adjunct to other antidepressant medications.

The time it takes for L-methylfolate to work varies from patient to patient. In clinical trials, DEPLIN® is expected to start working within 1 to 2 weeks for those already on an antidepressant. Other sources say that the benefits of L-methylfolate usually take effect within 2-4 weeks.

One study showed that patients with depression taking 7.5 mg or 15 mg L-methylfolate reported significant improvements in depressive symptoms and functioning, with 67.9% of patients responding and 45.7% achieving remission over 12 weeks. Compliance was high, with over 90% of patients reporting nearly every dose.


Some practitioners recommend that patients take L-methylfolate every day for at least four months to gauge its effectiveness. Anecdotal evidence is generally mixed: some patients may see results within days, weeks, and or others might need the entire four months.

How Long Will it Take L-Methylfolate to Help Anxiety?

Anxiety is one of the many common symptoms of depression. An analysis of 702 patients with treatment-resistant depression (TRD) found that comorbid anxiety disorder was the most powerful variable associated with TRD. Antidepressants and/or L-methylfolate may be prescribed to relieve symptoms such as restlessness, anxiety, and insomnia.  

As with depression, the benefits of L-methylfolate supplement may take anywhere from 2-4 weeks to four months.

What Factors Determine How Long it Takes L-Methylfolate to Have an Effect?

What Factors Determine How Long it Takes L-Methylfolate to Have an Effect

It is difficult to gauge how long methylfolate will take to work for each patient, as the expected effect of any medication varies from person to person depending on age, weight, genetics, concomitant health issues, and more.

Factors that influence how long it takes methylfolate to work may include:

  • Metabolic function

  • Other illnesses (diabetes, atrophic gastritis, Crohn’s disease, ulcerative colitis, kidney disorders, hypothyroidism)

  • Other medications (for example, some seizure medications may lower the effectiveness of L-methylfolate)

  • Age

  • Symptom severity

  • Presence/type of MTHFR genetic polymorphism

  • Serum folate levels

  • L-methylfolate form and dosage

  • Patient compliance

For best results, L methylfolate supplement should be taken exactly as prescribed by your health provider or as per directions on the supplement.

Why Does Brand Matter?

L-methyl folate is available both as a prescription and as an over-the-counter supplement. However, some brands are better than others. 

The most biologically active L-methylfolate supplements are the “L” or “6(S)” form. This includes the identical form labeled as (6S)-5-methyltetrahydrofolate or (6S)-5-MTHF. 

The calcium salt of L-5-methyltetrahydrofolic acid is a pure, stable crystalline form of the naturally-occurring predominant form of folate. Also known as [6S]-5-MTHF (Metafolin: calcium salt of [6S]-5-MTHF), it has been shown to increase plasma folate more effectively than folic acid, irrespective of whether a patient has a C677T mutation.

A crossover comparative study involving human volunteers concluded that folate from 5MTHF-glucosamine exhibited a similar bioavailability to folate from 5MTHF-Calcium.

A study involving healthy females found that the calcium-salt form of methylfolate ([6S]-5-methyltetrahydrofolate) increased plasma folate more effectively than folic acid with the homozygous C677T polymorphism. 

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How to Choose the Best Supplement for You

How to Choose the Best Supplement for You

When choosing the best supplement for you, be sure to check the form of L-methylfolate used in the product. Any forms of methylfolate that don’t specify the L form (or 6S form) of methylfolate (such as methyl folate L-5-MTHF) may not be 99% pure biologically active methylfolate

These less bioavailable forms include 5-MTHF, 5-Methylfolate, and 5-Methyltetrahydrofolate.

Methyl-Life’s® Methylfolate 15mg is made with the internationally-patented Magnafolate® PRO, clinically tested as the purest methylfolate.

Magnafolate® is the L-5-MTHF form, the most active folate form in plasma circulation. Compared with ordinary folate, Magnafolate® PRO was absorbed faster and utilized more quickly in the body.

Methyl-Life’s® product range is formulated especially for people with a heightened need for bioavailable folate due to depressive disorders, anxiety, MTHFR/MTR/MTRR defects, nutritional deficiencies, vegans, vegetarians, or those with conditions in which nutritional absorption is impaired. 

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