The Methylfolate and Depression Relationship: What You Need To Know

The Methylfolate and Depression Relationship: What You Need To Know

An overwhelming proportion of people today live with depression. Recent statistics suggest that depression affects between 5% and 10% of individuals, including 7.1% of US adults. Depression is the third most common reason for consultation in primary care, making it one of the most common mental disorders of our time. Some researchers predict it will become the second leading cause of disability worldwide.

One in six people (16.6%) will experience depression at some time in their life. It can strike at any time, but most commonly during the late teens to mid-20s. In fact, the age group with the highest rate of depression is those aged 18.25 (13.1%). Women are more likely than men to experience depression; one-third will experience a major depressive episode in their lifetime. 

We here at Methyl-Life™ are experts in the value of methylfolate and its intricate relationship with depression. This article will discuss exactly what you need to know to improve your own folate levels and overcome ‘the black dog’. 

What is depression?

Depression is a complex disorder that comes in many forms, and each person’s experience may be slightly different from someone else’s.

The American Psychiatric Association’s Diagnostic Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) classifies the most common depressive disorders as:

  • Disruptive mood dysregulation disorder
  • Major depressive disorder
  • Persistent depressive disorder (dysthymia)
  • Premenstrual dysphoric disorder
  • Depressive disorder due to another medical condition

Signs and symptoms of depression

While it’s normal to feel a little down from time to time, prolonged feelings of hopelessness and sadness are definitely not. 

Clinical depression affects nearly every aspect of daily life: how you think, feel, and go about your normal activities. Sleeping, eating, working, and relationships all seem more difficult.

In short, depression can severely impair your ability to carry out tasks or function properly.

Diagnosis of clinical depression is usually on the basis of suffering some of these signs and symptoms most of the day, nearly every day, for at least two weeks.

  • Feeling persistently sad, anxious, hopeless
  • Constant pessimism
  • Irritability
  • Feelings of guilt or worthlessness
  • Loss of interest in former hobbies and activities
  • Lack of energy or fatigue
  • Moving or talking more slowly
  • Restlessness
  • Difficulty concentrating, remembering, or making decisions
  • Sleeping problems
  • Appetite and/or weight changes
  • Thoughts of death or suicide
  • Unexplained aches or pains, headaches, cramps, or digestive problems

The severity and frequency of these symptoms and how long they last will vary from person to person.

What causes depression?

The onset of any particular depressive episode may have several causes. Events in your life can play a part, as can chemical changes in your brain.

The most common risk factors include:

  • Biochemistry
    Chemical imbalances of certain neurotransmitters in the brain are usually the predominant factors in the development of depression.
  • Genetics
    A history of mental illness often runs in families. If one identical twin suffers from depression, the other has a 70 percent chance of also developing depression at some stage in life. 
  • Personality
    Those with low self-confidence, poor self-esteem, or who struggle to deal with stress are more likely to experience depression.
  •  Environmental factors
    Regular exposure to negative situations such as neglect, violence, abuse, or poverty can increase the risk of developing depression. 

What is the methylfolate and depression relationship?

The link between folate deficiency and depression was first postulated in the 1960s with the advent of assay techniques. Since then, scientists have established evidence linking low folate status and depression from two sources:

  • A significant percentage of patients with depression are reported to have low folate levels
  • Studies have shown that folate is effective in improving the outcome of conventional treatments for depression

One of the key features of depression is reduced appetite, which often leads to poor nutritional status and therefore reduced folate. 

Depression is also linked to excess alcohol consumption, which is known to reduce folate absorption and deplete stores of folate. These are just two factors that may affect the relationship between folate, folate metabolism and depression.

What is methylfolate?

To understand methylfolate, it’s important to first understand folate and the process of methylation. 

Folate is the natural form of vitamin B9 in food. It’s required for many different functions within the human body, particularly the production of red blood cells. Folate occurs naturally in many foods such as legumes and leafy greens. 

Deficiency or low levels of folate can be caused by genetics, certain diseases, medications, or by not obtaining folate from your food. Folate deficiency can lead to decreased red blood cell count, also known as anemia. 

The folate vitamin is most active when converted into methylfolate. 

Methylation is a metabolic process crucial to every cell and organ in your body. It’s the transfer of a methyl group (one carbon atom and three hydrogen atoms) onto the amino acids, proteins, enzymes, and DNA within your body. This is necessary for certain biochemical reactions that allow important functions such as thinking, repairing DNA, turning genes on and off, fighting pathogens and triggering detoxification (especially in the liver). It’s like billions of little switches turning on and off every second, controlling everything from your metabolism and your stress response, to your brain chemistry and detoxification.

Methylation is also crucial for the proper functioning of the Hypothalamic-Pituitary-Adrenal (HPA) axis, as well as the creation of all neurotransmitters. For example, the conversion of norepinephrine to epinephrine depends on an enzyme that must first be activated by methylation.

In short, your body simply would not function without methylation.

The link between MTHFR and depression

The MTHFR gene (methylenetetrahydrofolate reductase) is inherited from our parents (one from each parent). Mutations of these genes have been found to lead to high levels of homocysteine in the blood along with low levels of folate. 

The MTHFR gene is also responsible for making an enzyme called methylenetetrahydrofolate reductase. This enzyme plays many important roles in your body, including the processing of amino acids. More importantly, it’s required for the conversion of a form of folate called 5,10-methylenetetrahydrofolate to a form called 5-methyltetrahydrofolate. This is the primary active form of folate in your body, which is required for the conversion process of the amino acid homocysteine into methionine.

However, the MTHFR gene can mutate, which will either affect the enzyme’s ability to function normally or completely inactivate it. This can have severe implications for the nervous system. 

Several studies have suggested that those with depression are found to have a genetic variant of the methylenetetrahydrofolate reductase enzyme that compromises their ability to convert dietary folate and particularly synthetic folic acid into L-Methylfolate. 

The MTHFR polymorphism appears to be more common in the individuals with depression history than in healthy controls. In addition, those with MTHFR gene mutations are associated with poor response to antidepressant treatment. Some studies have shown that depressed patients identified as having “treatment resistant depression” have a 76% chance of a MTHFR mutation.  

A 2007 meta-analysis of 10 epidemiological studies found a statistically significant but small relationship between low folate levels and increased risk for depression. A study involving over 2000 male patients with lower than average folate intake showed that the men were about 2.5 times as likely to be hospitalized for depression at follow-up compared to patients with higher than average folate intake.

How can methylfolate help with depression?

Folate is essential for both methylation processes and the synthesis of important neurotransmitters in the central nervous system. Folate deficiency or malabsorption due to illness, taking certain medications, or other issues is a major risk factor in depression, and also makes it more difficult to treat.

The bioavailability of L-Methylfolate is much higher than folic acid alone. Folic acid, on the other hand, is the synthetic (man-made) form of folate that is added to fortified foods or dietary supplements.

Folate must be reduced to tetrahydrofolate (THF) within the body before it can become metabolically active with its conversion into 5-Methyltetrahydrofolate (5-MTHF). This is the fully-activated folate derivative normally found in healthy circulation of those who do not have MTHFR genetic variants. Most importantly, it is the already-converted form of folate that can be absorbed and used by the body’s cells immediately.

L-Methylfolate is the only form of folic acid that crosses the blood-brain barrier and plays a role in the synthesis of neurotransmitters: particularly serotonin, dopamine, and norepinephrine. These are the three neurotransmitters most important for mood regulation and other nervous system functions. These are also involved in the mechanism of action for antidepressants. Serotonin is particularly important: it’s your ‘happy’ chemical that plays a major 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 - particularly those who have not responded adequately to treatment with antidepressant medications.

L-methylfolate has been shown in several studies to enhance the efficacy of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), two commonly prescribed classes of antidepressants.

Patients taking l-methylfolate showed statistically significant improvements in self-reported depression symptoms and functioning and greater satisfaction with their medication treatment.

L-methylfolate has also been used to successfully treat patients with both clinical depression and folate deficiency. It has also been effective in treating those with schizophrenia who have hyperhomocysteinemia related to folate deficiency.

Dealing with Depression? Check Out our Methylfolate Product Line:

7.5 mg Methylfolate + 2.5 mg Active B12s
Methylfolate 15+ Magnafolate PRO & Active B12
New Look Methylfolate 15

How much methylfolate should I take for depression?

As mentioned above, every case of depression is different. Your unique body chemistry and health history will need to be assessed by a qualified health practitioner before you begin experimenting with supplements.

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. 

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. 

Where to buy methylfolate supplements

Folate 5-MTHF has been classified as a ‘medical food’ and is also available as a dietary supplement. There is a huge range of methylfolate supplements available in health stores, at pharmacies, and online.

However, with so many products to choose from, it’s difficult to know which ones are effective, and which are not. 

Some of the best methylfolate supplements for depression currently on the market include Methyl-Life™ products (Methylfolate 7.5+, Methylfolate 10, and Methylfolate 15). These have been created by a team of natural health experts and used successfully by hundreds of people all over the world. It’s worth noting that Methyl-Life™ recently received data from a study which showed theirs to be the most pure, stable and potent of four of the world’s industry-leading, patented L-Methylfolates. Check out the study comparison details to learn more.

Methyl-Life™ Methylfolate 15 (physician-recommended, depression-level dose) 

3 month supply - 90 chewable tablets

Active Ingredients

Folate: 15,000 mcg from (6S)-5-Methylfolate,Calcium – Magnafolate® PRO

Methyl-Life™ Methylfolate 15 is a high dose (15 mg) of internationally-patented Magnafolate® PRO [(6S)-5-methyltetrahydrofolic acid, Calcium salt, Type C Crystalline molecule (L-Methylfolate)]. It is our best-selling, serotonin-enhancing supplement, providing essential support for healthy mood, immune system function, and nervous system function. 

This unique and internationally-patented L-5-Methylfolate ingredient is crystalline calcium salt-based for superior stability and absorption. This proprietary form of methylfolate offers greater purity: approximately 3x more pure than any other competing form of methylfolate. It is also known as L-MTHF, L-Methylfolate, L-5-MTHF, and (6S)-5-Methylfolate.

Benefits of Methyl-Life™ Methylfolate 15

  • Formulated specially for people with heightened need for folate due to genetic (MTHFR) defects, dietary deficiencies or drug-induced need (i.e. taking warfarin, coumadin, metformin, etc.)
  • Bypasses MTHFR gene mutations to optimize the body’s methylation process
  • Boosts energy and motivation
  • Helps protect against toxins and disease by boosting glutathione
  • Supports overall wellbeing
  • May reduce symptoms of depression by promoting SAMe and therefore serotonin
  • May help manage homocysteine levels caused by folate deficiencies
  • May reduce the risk of cardiovascular disease
  • Third-party testing to ensure safety and efficacy 

In order to prevent masking a B12 deficiency while taking high dose methylfolate, be sure to choose an active form of B12 that can be absorbed well and transported to the cells for optimal methylation support.



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