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Methylfolate Improves Severe Depression: Is this Relevant for the Biochemistry of ME/CFS?

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If you’ve been diagnosed with ME/CFS, (myalgic encephalomyelitis/chronic fatigue syndrome), you might consider looking into whether or not your symptoms are caused or exacerbated by a genetic variant on MTHFR, a gene, which is responsible for creating an enzyme to help the body breakdown folate into a more active form via a process known as methylation. Impaired methylation may lead to ME/CFS symptoms like inflammation, cognitive impairment, autoimmune issues, and more. Let’s take a closer look at how MTHFR functions in the body.

An Overview of MTHFR

Our body requires small proteins called enzymes to drive key steps of biochemical metabolism.  Specific genes direct the production of specific enzymes. But, if a gene undergoes a mutation, the enzyme it produces is likely to be physically distorted or misshaped. Such enzymes may be less effective drivers of their relevant biochemical pathways.

One example is the MTHFR enzyme, a key player in folic acid metabolism. We need the MTHFR enzyme to transform folic acid (a synthetic form of the folate vitamin) into methylfolate, which is the active form of the vitamin (also known as vitamin B9).  Folic acid has been added to most commercial grains and most multi-vitamin and B-complex supplements.

But there’s a problem: A great many people have mild, moderate, or severe distortions of their MTHFR enzyme because of mutations to the specific genes that produce this enzyme.  Among 1000 newborn babies in Wisconsin, 8% were homozygous for the gene for the MTHFR gene mutation.  With a double dose mutation—one “bad” gene from each parent—the ability to activate synthetic folic acid can be reduced by 60% or more.  With a single dose mutation (heterozygous), the MTHFR enzyme might be 30% less efficient. About 30% of the Wisconsin babies had the single dose mutation.

People who eat lots of raw green vegetables don’t have to worry. The form of folate in greens veggies is methylfolate—which is already active.  But many, perhaps most, Americans don’t eat large amounts of leafy greens. Instead they rely on the folic acid added to breads, cereals and vitamin pills.

The result? If you don’t eat a lot of greens, and you have an MTHFR gene mutation, your folate metabolism is liable to be weak. This in turn could compromise your ability to make a broad range of key biochemicals.  For example, s-adenosyl methionine (SAMe) a natural anti-depressant; also neurotransmitters such as dopamine, serotonin, norepinephrine; also carnitine, creatine and others.  Lack of active methylfolate may also compromise the ability to repair damage to our DNA.

Is Increasing in Methylfolate Helpful for ME/CFS Symptoms and Other Chronic Illnesses?

Medical scientists accept these relationships in principle. But what we don’t know for sure is whether the theoretical harm caused by low methylfolate is or is not clinically important. Would taking more methylfolate substantially augment ME/CFS treatment, or treatment for depression, Alzheimer’s, coronary disease, or any other health problems?  Animal studies and anecdotal reports on internet sites suggest that it can.

Unfortunately, there is a lack of placebo-controlled double-blind studies testing whether people with any common diseases and an MTHFR gene mutation actually do better when treated with methylfolate.

That academic researchers have been slow to do expensive double-blind clinical trials with methylfolate is not entirely surprising. You can’t patent methylfolate, so pharmaceutical companies are not likely to fund studies. And there’s long-standing (but hopefully fading) legacy among academics that “natural” treatments border on quackery.

Happily, I did find one exception to the absence of controlled clinical research. This was a multi-center study captained by psychiatrists from Harvard Medical School’s Massachusetts General Hospital. Several years ago, the MGH group reported that the natural supplement SAMe (s-adenosyl methionine) was superior to placebo for treating patients whose unipolar depression had not responded well to serotonin reuptake inhibitor medicine (SSRI’s). Recall that you need active methylfolate in order to make SAMe.

In 2012, the Mass General group published a similar study of methylfolate versus placebo. Again, the subjects were patients with unipolar depression who remained depressed despite continuing use of an SSRI.

The result: A very high dose of methylfolate (15 mg) was superior to placebo within 30 days of treatment. Note: the recommended daily allowance (RDA) for folic acid is only 0.4 mg daily or 400 micrograms. However, a lower dose of methylfolate was not much better than placebo.

In 2014, the MGH team reported further data from their 2012 study.  They classified the 2012 study patients according to several clinical parameters  and also the mutation status of 16 specific genes that are relevant either to methylfolate metabolism or related methylation pathways.

Patients whose initial blood levels of s-adenosyl methionine were fairly low were more likely to improve from methylfolate treatment than were patients whose baseline SAMe levels were fairly high. That’s what we should expect, since methylfolate is required to produce methionine. Methionine is then converted into SAMe.

Surprisingly, having an MTHFR  mutation did not significantly predict a better outcome from methylfolate treatment. But when an MTHFR mutation was combined with certain other specific mutations, that combination did predict that most of those patients would experience benefits.  Mutations in other methylation genes also predicted benefit from treating with methylfolate.

Hopefully, the Mass General/Harvard halo will attract other researchers and funding agencies to support clinical studies of methylfolate, not just for depression but also for “orphan,” chronic illnesses such as ME/CFS.

The Takeaway?

So, where does this leave people who suffer from ME/CFS?  I and other ME/CFS specialists recommend testing for the MTHFR mutation.  For those who are homozygous or heterozygous, I think it’s justified to have an empirical trial for me/cfs treatment with a combination of methylfolate together with vitamins B12 and B6—starting at low doses and then working up.  At the same time, please keep in mind: MTHFR treatment for ME/CFS is not yet well proved.


  1. Methylfolate should usually be accompanied by vitamins B12 and B6. If B12 or B6 activity is weak, adding methylfolate could make things worse. For example. One patient in the Massachusetts General study developed new symptoms of mania while on methylfolate.  Essentially, all standard anti-depressants medicines and also SAMe also share this potential risk.  If a patient already has a history of mania or bipolar disorder, then most patients should be referred to a psychiatry specialist before beginning methylfolate.
  2. Several dozen genes potentially interact with the MTHFR-related biochemical pathways. We don’t understand their interactions as well as we might wish. There are very few true experts in this field, and even they quickly admit that they still have much to learn.  When multiple gene abnormalities are present, side effects from MTHFR–related treatments can become problems.

This article was first published on on February 7, 2015 and was updated on July 18, 2019


The following web pages discuss MTHFR and related issues:

MTHFR Support
Dr. Amy Yasko

Richard Podell, M.D., MPH
Clinical Professor, Dept of Family Medicine
Rutgers-Robert Wood Johnson Medical School


1. Qi Z, Hoffman G, Kurtycz D, Yu J.   Prevalence of the C677T substitution of the methylenetetrahydrofolate reductase(MTHFR) gene in Wisconsin, Genet Med. 2003 Nov-Dec;5(6):458-9.
2. Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. S-Adenosyl Methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant non-responders with majordepressive disorder: a double-blind, randomized clinical trial.   Am J Psychiatry. 2010 Aug;167(8):942-8. doi: 10.1176/appi.ajp.2009.09081198.
3. Papakostas, G et al, L-Methylfolate as Adjunctive Therapy for SSRI-Resistant Major Depression: Results of Two Randomized Double-Blind, Parallel-Sequential Trials Am J Psychiatry 169;12, December 2012 . To see abstract from
4, Papakostas, G, Cassiello, B, Iovieno, N, Folates and S-Adenosylmethionine, Folates and S-Adenosylmethionine for Major Depressive Disorders, CanJ Psychiatry 2012:57(7):406-413.
5. Papakostas, G, Shelton R…Fava, M, Effects of Adjunctive L-Methylfolate 15 mg Among Inadequate Responders to SSRIs in Depressed Patients Who Were Stratified by Biomarker levels and Genotypes: Results from a Randomized Trial. J Clin Psychiatry 75: 855-863, August 2014.. To see abstract from

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2 thoughts on “Methylfolate Improves Severe Depression: Is this Relevant for the Biochemistry of ME/CFS?”

  1. MikeD82 says:

    There is nothing worse, then going through hell of depression. You wake up each day, not knowing if you will make it
    ’till night, or you will simply give in, and end it all yourself. The drugs sometimes help, and sometimes make it worse.
    Felt like I had no control whatsoever over my own life. But with some help from my family, the people who truly love me, I
    managed to get myself out of that hell-hole. It took me a while, but I managed to teach myself how to push trough the day, and keep on fighting.
    In the end, it all comes down to helping yourself get up and fight, because without that no one can truly help you, no matter how much they would want to.
    To conclude, help yourself, so you could go out into the world, and start truly living, and that will be a cure on it’s own.

  2. Photo1776Bill says:

    I’ve also read that folate can mask a B12 deficiency, another reason for taking the two together. B12 deficiency is very serious — my levels were found to be dangerously low when blood tests were done after CFS diagnosis. B12 is essential for a healthy brain, nervous system and other functions. I, like a significant portion of the population, lack an intrinsic factor in the gut necessary for producing/absorbing B12, and must obtain B12 either by injection or sublingual tablets (absorbs the vitamin directly into the blood via the tongue). Since the main dietary source of B12 is red meat (esp. organ meats), those abstaining are also at risk for deficiency.

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