L-Methylfolate and Depression: Dosage and how it works

L-Methylfolate and Depression: Dosage and how it works

Methylfolate and Depression


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Methylfolate and depression management

Written By:
Katie Stone - Naturopath

Medical Reviewer:
Dr. Conor Sheehy - PharmD, BCPS

Edited By:
Kari Asadorian - RN

Updated On:

Sep 1, 2024

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 1.

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.


How does methylfolate work within the body to treat depression?

Folate is essential for the synthesis of important neurotransmitters in the central nervous system. Folate deficiency is a major risk factor in depression, and also makes it more difficult to treat.

Folate must be reduced to tetrahydrofolate (THF) within the body before it can become metabolically active with its conversion into 5-Methyltetrahydrofolate (5-MTHF or L-methylfolate). This is the fully-activated folate derivative normally found in healthy circulation of those who do not have MTHFR genetic variants. It’s also the only form of folate that can be absorbed and used to create serotonin, dopamine, and norepinephrine. These are three of the neurotransmitters most important for mood regulation and other nervous system functions. Serotonin plays a particularly crucial role in appetite, sleep, and emotional health.

It’s for these reasons, L-methylfolate supplementation has been found to be beneficial for those with depression, especially for those who have not responded adequately to treatment with antidepressant medications.


Methylfolate dosage for depression treatment and how to take it (morning/evening)

Every case of depression is different. Your unique body chemistry and health history should be assessed by a qualified health practitioner before you start any supplement regime.


To date, studies involving patients with depressive disorders who are given the prescription medical food L-methylfolate (Deplin) may have to take anywhere from 7.5 mg to 15 mg to achieve its benefits.


A 2012 study showed that supplementary L-methylfolate at 15 mg/day resulted in significant improvement in the response and degree of change in depression scores as compared to continued SSRI therapy plus placebo 2.


To figure out the right methylfolate dosage for your own needs, your best bet would be to seek out an assessment from a qualified healthcare provider or naturopath.


Some physicians suggest taking methylfolate 2x a day to keep the serum folate levels in the body more steady over a longer period of time. Learn more about L-methylfolate dosage suggestions.

How long does it take to see results?

When taking a high dose of methylfolate, you may notice improvements in your symptoms within a few days or weeks. However, individual responses can vary, and some people may experience relief sooner or later than others.

It is important to be patient and stick to the dosage as directed by your healthcare practitioner. Monitoring your progress and discussing any concerns with your doctor will help determine what dosage works best for you. Some doctors have found that it may take up to 4 full months of daily methylfolate dosage before results are seen.


Taking antidepressants and L-methylfolate together

Numerous studies have shown that L-methylfolate may enhance the response to antidepressants. It’s believed that L-methylfolate’s role in the production of THB (tetrahydrobiopterin or BH4) may increase the availability of neurotransmitters 3.

Other researchers suggest that augmentation of SSRI/SNRI with L-methylfolate may support serotonin levels in depressed patients, helping to sustain the effect of the medication.

A 2011 study published in Innovations in Clinical Neuroscience compared the efficacy of treating depressed patients with L-methylfolate and SSRI/SNRIs or an SNRI alone. After 60 days, 18.5% of patients taking L-methylfolate + SSRI/SNRI experienced major improvement, compared to 7% of those taking only SSRI/SNRIs. The authors concluded that L-methylfolate increases central neurotransmitter levels and thereby improves the effectiveness of antidepressant therapy, which makes the combination of L-methylfolate and antidepressants a more therapeutic solution than taking antidepressants alone 5.

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.

Connection between folate levels and depression

Several key enzymes involved in one-carbon metabolism depend on folate to function properly, including those that create serotonin, norepinephrine, and dopamine. This has led researchers to form a biologically plausible link between folate and mood. 3.

A 2017 meta-analysis reported that individuals with depression tend to have lower folate levels and consume less folate than non-depressed individuals 7. Another systematic review of observational studies showed that low folate levels are prevalent in people with depression 8.

The Medscape Psychiatry & Mental Health eJournal has also suggested that depression is one of the most common neuropsychiatric outcomes of folate deficiency 9.

Numerous studies have shown that low folate may result in poor response to antidepressants and/or relapse of depressive symptoms, and also longer duration of depressive episodes 10,11.


MTHFR gene mutations are associated with an increased risk of a variety of common mental health conditions, including depression. 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.


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 12.


A 2019 study investigated the efficacy of using L-methylfolate in depressed patients who also had the MTHFR variants C677T and A1298C. 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.

Product Recommendation

Sale Off
L Methylfolate 15 mg - A Mood-Boosting Supplement - Methyl-Life® Supplements
$76.00

  • PROFESSIONAL STRENGTH - ASK YOUR DOCTOR
  • High-dose L Methylfolate 15 mg for natural mood support2
  • 3rd-party tested for Purity, Potency & Safety
  • 90 Vegan, Non-GMO, Chewable mint tablets

Outcomes for Depression Patients Using L-Methylfolate

"I have been selling methylfolate since 2012, long before most people had ever heard of it. I learned about it through a doctor who was able to save his son’s life using the nutrient. I was convinced not only by the science I learned from Dr. Neil Rawlins, but also by my own personal journey as well as the responses my customers had with the nutrient. Many have sent testimonials telling us how powerful this specific form of folate has been for their mood levels and some have even spoken of being off of depression drugs for the first time in their lives, taking only the methylfolate to help with their formerly-incapacitating symptoms.

I will stop and caveat right now, that I don’t advocate anyone take action without their doctor’s knowledge and consent, especially in the case of depression, which can be so isolating and debilitating. So talk to your doctor if you’re looking at methylfolate as a real option to fight your depression symptoms. I will also say that I had my serotonin levels tested before I started taking methylfolate in 2011 and they were at 85, normal range for my test was 125-185. Then about 3 months after taking methylfolate every day and feeling so much better, I had my levels tested again – sure enough, my serotonin level came back in-range at 136. I take approximately 6 mg of methylfolate a day. It changed my life and that’s why I became a methylfolate expert and am obsessed with ensuring the methylfolate I take every day has the best chemistry, highest quality and is the purest on the planet."

Methyl-Life® Founder, Jamie Hope

L-Methylfolate and Treatment-Resistant Depression

MTHFR is one of the known associations in treatment-resistant depression due to causing lower levels of L-methylfolate and monoamines. However, the use of L-methylfolate in adults with TRD (Treatment-Resistant Depression) has had some positive results.

A 12-month study 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, 38% achieved full recovery, and none experienced a recurrence of their depression 15.

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 16.

Can methylfolate cause depression?


No, methylfolate won’t make you depressed. The majority of studies show methylfolate has only positive effects on people with depression symptoms.

Frequently Asked Questions about Methylfolate and Depression


Is L-methylfolate good for depression?
Numerous studies show that L-methylfolate can improve depression symptoms, whether taken alone or in combination with antidepressants. This is because L-methylfolate assists with the production of neurotransmitters required for normal mood.

How long does it take for methylfolate to help depression?
Everyone experiences depression differently, and everyone will respond to L-methylfolate differently. Some people may see results within a few weeks, some months, while others may have to alter their dosage to see their symptoms improve.

Does L-methylfolate increase dopamine?
Studies suggest that methylfolate improves the production of neurotransmitters including dopamine, serotonin, and norepinephrine.

How does L-methylfolate make you feel?
Everyone responds to methylfolate differently. However, the majority of people who take methylfolate consistently report that their symptoms of depression improve, along with their cognitive function and energy levels.


About the Author

Katie is a qualified naturopath (BNatMed) and freelance writer from New Zealand. She specializes in all things health and wellness, particularly dietary supplements and nutrition. Katie is also a dedicated runner and has completed more half-marathons than she can count!

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