A Simplified Methylation Protocol is Effective for Addressing Chronic Fatigue and Fibromyalgia

Published: August 6, 2012

By Neil Nathan, M.D.

I suspect that the words methylation protocol are, at first glance, intimidating. But if you will hang in with me for a few paragraphs, I would like to make this both understandable and useful.

First of all, what is most important is that we have recently shown that the use of tiny doses of very specific combinations of vitamin B-12 and folic acid, has resulted in significant improvement in patients with fibromyalgia and chronic fatigue. That's the bottom line.

So, if you are suffering with chronic fatigue and/or fibromyalgia, you may be interested in learning more about our research, and what we learned.

Let's start with the word "methylation" and de-mystify it. In chemistry, a methyl group is simply a carbon atom surrounded by 3 hydrogen atoms, with chemically looks like this:

C — H

This grouping acts as a unit and if we tack this unit, this methyl group, on to another molecule, that is what we mean by methylation.

You don’t need to be a chemist to understand that this process of methylation is absolutely critical to a host of the most important chemical reactions in our bodies. Most important is that we need methylation to create glutathione, energy, impact brain chemistry, repair DNA, and make melatonin from serotonin. These are only a few of the essential reactions that require our ability to methylate.

What we have recently begun to understand, is that many of us are genetically a bit compromised in our ability to methylate, and that when we get sick that adds another dimension of difficulty to our illness, one that we can no longer compensate for.

What we have also begun to understand, is that we can fix this. By taking a combination of what are essentially vitamins, we can bypass these genetic “blocks” to methylation, and restore the body’s normal chemistry.

This concept was pioneered by Dr. Amy Yasko, who was working primarily with autistic children. She found that by addressing methylation blocks many autistic children recovered to a remarkable extent. She suspected that other illnesses, such as chronic fatigue, fibromyalgia, Parkinson’s disease and other neurodegenerative diseases had a similar problem. Dr. Rich van Konynenburg, a biochemist, picked up on her concept and applied it to chronic fatigue and fibromyalgia. In a series of papers, he demonstrated that virtually every known biochemical imbalance known to occur in fibromyalgia and chronic fatigue could be explained by this inability to methylate properly.

Hearing Rich’s lecture in 2007, and having a huge practice of fibromyalgia and chronic fatigue patients, I was excited to try out this hypothesis on some of my sickest patients. These patients had not fully responded to the therapy program pioneered by Dr. Teitelbaum, which I have utilized for over 15 years now. As soon as I got back to my office, I gave 50 patients this combination of B-12, folic acid and vitamins recommended by Dr. van Konynenburg which was based on recommendations from Dr. Yasko.

To my delight, 70% of my patients had improved within 3 months, and 20% reported that they were much better.

This was exciting news. I was fortunate enough to obtain a private research grant to do a more formal study. With the assistance of Dr. van Konynenburg and Dr. Yasko, along with input from Dr. Teitelbaum who helped design the data collecting research tools, and Dr. Richard Deth, a well-known expert on methylation chemistry, we put this together. The project went as follows: I took 30 patients (none of whom were part of the first pilot project), all of whom I had helped with Dr. Teitelbaum’s program, all of whom had made some progress (ranging from 30-70% improvement) but were still not where they needed to be health-wise. All had their methylation chemistry measured prior to the start of the supplements, and all took the supplements for the next 6 months, while we measured their chemistry and they reported on their health status throughout. All patients took exactly the same supplements.

After six months, we individualized the patient’s protocol based on their chemistry results, and continued to follow their progress and monitor their chemistry.

The Results Are Exciting

Several important questions are addressed and answered:

1) First of all, do we find that fibromyalgia and chronic fatigue patients do, indeed, have abnormal methylation chemistry?


The initial methylation testing showed that every single patient had abnormal results. The average starting value of glutathione in our patients was 3.2 mmol/L (normal being 3.9-5.5 mmol/L)), and the average starting value for SAM (the major methylator) was 218 mmol/L (normal being 221-256 mmol/L). 83% started with low glutathione levels.

2) Can we demonstrate that taking these supplements raises those numbers into the normal range?


  • After 3 months, the average glutathione level was 3.8 mmol/L
  • After 6 months, the average glutathione level was 4.3 mmol/L
  • After 9 months, the average glutathione level was 4.7 mmol/L, which represents a 47% improvement, and ALL patients now had a normal level.
  • After 3 months, the average SAM level was 227 mmol/L
  • After 6 months, the average SAM level was 238 mmol/L
  • After 9 months, the average SAM level was 241 mmol/L, with only one patient not up into the normal range.

3) Does this rise in glutathione and SAM correlate with clinical improvement?


We had our patients rate 5 important areas of function on a 1-10 scale. This included energy, sleep, pain, cognitive function (memory, focus, concentration, and “brain fog”), and overall sense of well being.

We can demonstrate progressive improvement in all of these areas in most patients, over the 9 months of the study:

  • Sleep improved from an initial score of 4.7 to 6.0, with 73% of patients reporting improvement.
  • Energy improved from an initial score of 3.9 to 6.6, with 86% of patients reporting improvement.
  • Pain relief improved from an initial score of 5 to 6.6, with 80% of patients reporting improvement.
  • Cognitive function improved from an initial score of 5.0 to 6.3, with 73% reporting improvement.
  • Overall sense of well being improved from 4.3 to 6.8, with 79% reporting improvement.

4) How much better were our patients?

A lot!

The average improvement was rated by our patients as 48%. Note that 27% reported so much improvement that they now felt essentially well! Several, who had not worked in over 5 years, were able to resume full-time employment without difficulty. It took an average of 5-6 weeks before the supplements started to work, and we can clearly show that the longer patients stayed on this program, the better they got.

Not everyone got better, but the vast majority (86%) improved.

In doing a study of this sort, we must look at how many patients completed the study so that we know whether these numbers are valid. (The data for improvement in glutathione and SAM has a p value of <.05, which is quite statistically significant.)

Of the original 30 patients, all 30 completed the first three months, and 29 completed the first six months. 25 of 30 completed the full 9 month program. It is rare to conduct a study this long, with this type of compliance. It is also interesting to look at those who dropped out of the study. Three dropped out because they were so well that they saw no point in continuing. One dropped out because she needed to have bilateral hip replacement, and one dropped out because she did not feel any better after 6 months.

Although the natural components of this protocol have no known side effects, when we do, indeed improve the body’s ability to methylate and make more glutathione, this may lead to a detoxification reaction which can range from mild to severe. So please do not embark on this program without the supervision of a knowledgeable health care provider.

My New Book "On Hope and Healing"

The details of this study, along with a much longer description of methylation chemistry is available in my new book, “On Hope and Healing: For Those Who Have Fallen Through the Medical Cracks.” It also contains a description of the entire biochemical underpinning of chronic fatigue and fibromyalgia, in what I hope is a readable and concise format. This includes discussions of adrenal, thyroid, sex hormone imbalances, deficiency of magnesium and amino acids, food allergy, intestinal dysbiosis, toxicity from heavy metals, mold, and infectious agents such as Lyme disease and chronic viral infections.

On Hope and Healing is available at Amazon.com for $19.95.

For excerpts of the book, to learn more, to ask questions and to access my blogs, please check out www.etaliapress.com.

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