Hot Topics! 


Folate Deficiency and Depression

Literature suggests that depression is linked with folate deficiency and that patients with insufficient folate are less likely to respond to treatment and more likely to experience a relapse. Folate supplementation does help some patients, but the full story is more complicated. 

Folic acid in and of itself does not alleviate depression. Our brain must convert folic acid into L-methylfolate before it can manufacture enough serotonin, norepinephrine, and dopamine to alleviate depression. However, certain individuals lack the ability to convert folic acid to l-methylfolate, rendering folic acid supplements ineffective for this group of patients. 

This processing deficiency is caused by the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, which is quite common among patients with depression. Up to 70% of patients with depression test positive for the polymorphism and therefore cannot convert folic acid into L-methylfolate. For those individuals, it becomes important to not use folate but to use L-methylfolate directly. That way you don’t have to worry about the patient potentially having the genetic polymorphism.


What is………. L-Methylfolate?

Folate = Vitamin B9 and found in foods

Folic acid = synthetic form of Folate found in supplements

MTHFR stands for the methylenetetrahydrofolate reductase gene (methyl-ene-tetra-hydro-folate-reductase).


Is MTHFR a gene or an enzyme?

For some reason, scientists thought they should name the gene MTHFR and also name the enzyme MTHFR. This is confusing and causes confusion especially if MTHFR is not labeled as MTHFR gene or MTHFR enzyme. Think of it this way: a healthy non-mutated MTHFR gene is supposed to produce plenty highly functioning MTHFR enzyme.

Why is the MTHFR gene important?

The MTHFR gene is responsible for making a functional MTHFR enzyme. If the MTHFR gene is slightly altered (mutated), the MTHFR enzyme’s shape becomes distorted. Enzyme function depends a lot on shape. It is similar to the grooves on a key. If the grooves on a key are slightly different than the lock, the key may fit and turn the lock a little but it does not unlock the door. The genetic code of the MTHFR enzyme must be perfect in order for it to function properly. A dysfunctional MTHFR enzyme may lead to a slew of health problems.

“Medical food” is a nutraceutical—essentially, a vitamin—rather than a pharmaceutical. However, unlike a vitamin, a prescription medical food such as L-methylfolate is regulated by the US Food and Drug Administration (FDA). 

L-methylfolate (EnLyte, EnBrace, Deplin), is indicated for the distinct nutritional requirements of individuals who have suboptimal L-methylfolate levels in the CSF, plasma, and/or red blood cells and have major depressive disorder, with particular emphasis as adjunctive support for patients taking antidepressant medications.

Traditional drugs such as SSRIs and SNRIs block reuptake of neurotransmitters, while L-methylfolate spurs the production of more neurotransmitters.

Genetics and BMI

Body mass index (BMI) offers a clue as to how patients may respond to L-methylfolate. Data show that L-methylfolate is particularly effective in patients with depression and a BMI of 30 or greater. This may be because of the relationship between obesity, inflammation, and depression and because excess fat increases the body’s methylation needs to the point that some people may require a methyl donor such as L-methylfolate.

Research indicates that at least 45% of people have at least one MTHFR mutation and, as a consequence, have a 40% decreased ability to process folic acid (the process doesn’t actually stop; it merely decreases). If you have an MTHFR mutation, your body is less able to use folic acid in the methylation cycle, which can increase your risk for the conditions of:

  • heart disease
  • anxiety
  • miscarriages
  • fatigue

Why is The Methylation Cycle Important?

The methylation cycle is important because it takes the nutrients from our food (and vitamins) to make the energy our bodies need to work properly. It also makes healthy cells and balances our mood as well as removing toxins and fighting infections. It is quite amazing when you think about it that the processes involved can have such a significant influence throughout your body. When methylation is working, you’ll feel full of energy, in a good mood; you will feel generally well. When it is not working, you will feel tired, depressed, irritable, run-down, susceptible to infections, foggy-brained, and just plain “toxic.”

Understanding the methylation cycle starts with thinking of dominos lined up in a circular pattern. Just as when the dominos start to fall—each domino toppling the next—when enzymes start processing nutrients, one enzyme affects the next. And just as with dominos, if one is out of line and doesn’t topple onto the next one (or it stops working), it causes a backup that inhibits the enzymes that follow and this, in turn, affects how we feel and how well we function. More specifically:

  1. Research shows that decreased function of the enzymes in the methylation cycle can affect your health and increase your risk of heart disease, cancer, chronic fatigue, mood disorders, diabetes, and aging in general.
  1. These enzymes are important for mitochondrial function and energy production. Low mitochondrial function and low methylation can lead to low energy, low thyroid function, decreased memory, and more.
  1. These enzymes also affect your:
    – neurotransmitter levels, which can lead to anxiety and depression,
    – immune function, including the likelihood that you’ll experience allergies this spring,
    – liver detoxification, which has to do with how your body gets rid of toxins, and
    – fertility, including risk of miscarriage
  1. The end result of these enzyme pathways (the domino line) is the production of glutathione, a major antioxidant and protector of your cells.
  1. Ultimately these enzyme pathways affect the ability of your body to make new healthy cells.

Are all forms of methylfolate the same?  NO! Forms are grouped together here.

Good forms which are well absorbed:

L-5-Methyltetrahydrofolate  (L-5-MTHF)

6(S)-L-Methyltetrahydrofolate (6(S)-L-MTHF)

L-Methylfolate Calcium (Metafolin, Levomefolic Acid)

The forms of methylfolate that are biologically active are:

  • L forms
  • 6(S) forms
  • L-5 forms
  • Metafolin
  • L-Methylfolate Calcium
  • Levomefolic Acid
  • Quatrefolic


The forms of methylfolate that are NOT biologically active are:

  • D forms (ie, D-5-MTHF = D-5-Methyltetrahydrofolate)
  • 6(R) forms (ie, 6(R)-L-MTHF = 6(R)-L-Methyltetrahydrofolate)

What are the other forms of methylfolate?

The other forms of methylfolate may or may not be 99% pure biologically active methylfolate:

  • 5-MTHF
  • 5-Methylfolate
  • 5-Methyltetrahydrofolate

The forms of methylfolate that may or may not be biologically active are the:

  • forms which do not specify L, 6(S) or trademarked name of Metafolin
  • 5-MTHF
  • 5-methylfolate
  • 5-methyltetrahydrofolate


So, what’s the bottom line? The prescribed medical food is guaranteed to provide you the active form because it is regulated by the FDA. Purchasing a formulation considered “biologically active” online or in a vitamin store might provide you what is needed, but there is no way to be sure.

Example of why all this is important to know
A supplement company has a supplement called, “5-MTHF”

Let’s say this supplement states it contains 10 mg of 5-MTHF.

One assumes this contains 10 mg of biologically active L-methylfolate.

Don’t assume.

The likelihood of it containing 99% of the biologically active form of L-methylfolate is slim to none.


Check out these recent Hot Topic articles! Visit this page regularly to find links to new articles that will keep you informed and engaged.

This Veterans Day, more than 15 years have passed since the launch of Operation Enduring Freedom in 2001.
On average, more than 100 people die by suicide every day in the U.S. New research is leading to a better understanding of who is at greater risk.
Numerous “brain training” apps are available today and they often claim significant benefits for attention, memory, concentration and more.
Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) are nearly twice as likely to suffer an injury requiring a hospital visit compared to those without ADHD.
Social communication disorder is a recently defined condition in which a child has difficulty understanding how to interact and communicate with others.