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A Simplified Methylation Protocol is Effective for the Treatment of Chronic Fatigue Syndrome and Fibromyalgia

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Drs Nathan and Van Konynenburg

Drs Nathan and Van KonynenburgReporting on an important trial to determine whether FM and CFS patients are affected by compromised methylation ability, and whether nutrients the body employs in methylation might support improvements.

Dr. Neil Nathan is a noted specialist in integrative treatment of complex medical illnesses such as fibromyalgia, chronic fatigue syndrome, and Lyme. In addition to his clinical work with Gordon Medical Associates near Mendocino, CA, he is a respected educator, and author of the new book, On Hope and Healing: For Those Who Have Fallen Through the Medical Cracks.

Note: Dr. Nathan initially invited reader questions regarding the protocol he describes below. To review his answers to these questions, see “Q&A on the Simplified Methylation Protocol with Neil Nathan, MD.”


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 syndrome. That’s the bottom line.

So, if you are suffering with chronic fatigue syndrome 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, which 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 (the body’s ‘master’ antioxidant and detoxifier),

• Produce 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.

Genetically a Bit Compromised

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 Amy Yasko, PhD, who was working primarily with autistic children.

She found that with treatment of methylation blocks many autistic children recovered to a remarkable extent. She suspected that other illnesses, such as chronic fatigue syndrome, fibromyalgia, Parkinson’s disease and other neurodegenerative diseases had a similar problem.

Rich Van Konynenburg, PhD, a biochemist, picked up on her concept and applied it to chronic fatigue syndrome and fibromyalgia.

In a series of papers, he demonstrated that virtually every known biochemical imbalance known to occur in fibromyalgia and chronic fatigue syndrome 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 syndrome patients, I was excited to try out this hypothesis on some of my sickest patients. These patients had not fully responded to the treatment program pioneered by Jacob Teitelbaum, MD, which I have utilized for over 15 years now.(1)

As soon as I got back to my office, I gave 50 patients this combination of B-12, folic acid, and vitamins(2) 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, occasionally to the point of feeling cured.

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 treated with Dr. Teitelbaum’s program, all of whom had made some progress (ranging from 30% to 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(3), 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 patients’ treatment program based on their chemistry results, and continued to follow their progress and monitor their chemistry.

The Results Are Exciting(4)

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? YES

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 (S-Adenosyl methionine, aka SAM-e, 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? YES

• 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? YES

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 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!

It took an average of 5 to 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.

• The average improvement was rated by our patients as 48%.

• And notably, 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.

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; 29 completed the first six months; and 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.

Protocol Supplements are Very Safe, But Medical Supervision is Essential

I would like to emphasize that the natural supplement components of this protocol are really very safe, with virtually no known side effects.

However, when we do, indeed, improve the body’s ability to methylate and make more glutathione – that is, when the nutrients work – they may improve the body’s ability to detoxify, thereby creating a toxic load that the body can’t handle. This may lead to a detoxification reaction which can range from mild to severe, making those patients quite ill.

I recently talked with Dr. Patricia Kane, PhD,  (director of the nonprofit NeuroLipid Research Foundation) about this, and she believes that the protocol may release toxins bound to cell membranes, which sets this reaction off.

So it is imperative that patients find a knowledgeable health care provider to work with who understands this, can adjust the protocol to their needs, and help them get around that reaction if it occurs.

And importantly, if an individual gets worse in any way after starting the methylation protocol, they should stop, immediately. Continuing the protocol without supervision has made a number of patients very, very ill and I really would hate to see that happen to anyone.

For More Information

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

The book also contains a description of the entire biochemical underpinning of chronic fatigue syndrome 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.

Neil Nathan, MD, May 2011


1. I am referring to Dr. Teitelbaum’s  SHINE approach to treating CFS & FM in toto (Sleep, Hormones, Infections, Nutrition, Energy), as outlined in his book, From Fatigued to Fantastic. To me, this means evaluating and treating adrenal, thyroid, sex hormone, magnesium, dysbiosis, candida, heavy metal toxicity, infections,and mold toxicity in its fullest scope. Dr. Teitelbaum was with me when we put together the methylation research, helped with developing some of the forms we used, and subsequently publicized the findings.

2.  Though lots of people have lots of other ideas on nutrients that can be included in the protocol, most of that is speculation. All we can say with any degree of accuracy is that the protocol we used works – and for our international readers, most of the ingredients will be available to them as a starting point.

The essence of the simplified protocol that we used – the ingredients that I view as central to the protocol – are:

The B-vitamin folic acid (specifically including the two most bio-available forms of folic acid – 5-methyl tetrahydrofolate, and 5-formyl tetrahydrofolate),

And several types of B-12, of which the hydroxycobalamin type is the main ingredient.

• Then, the addition of Dr. Yasko’s multivitamin-mineral added a number of co-factors which are important. Formulated for her autism patients, this “Neurological Health Formula” includes antioxidants, trimethylglycine, nucleotides, supplements to support the sulfur metabolism, a high ratio of magnesium to calcium, and no iron or copper.

Phosphatidyl serine, included in some versions of the protocol, is helpful, but not central.

And there are two supplements associated with some methylation protocol versions that we do NOT use, at least initially:

• We have some doubts about using glutathione, since taking it gives the body the wrong message about how much it has available, and may, in fact, give the body the wrong message so that it stops making it properly. So, although I do use glutathione in a variety of circumstances, I believe that stimulating the body to make it, as in our protocol, is a much wiser approach.

• Similarly, we may use SAMe, but not initially, for the same reason.

3. The best methylation test (the one we used in our study) is simply called a “methylation panel” from Vitamin Diagnostics Lab in New Jersey. [Now Health Diagnostics and Research Institute, phone 732 721-1234]. It runs about $325 for 11 measures of methylation chemistry, so it would be cheaper to just start the protocol, which is what I advise. I don’t typically order the panel unless the patient is not responding to it adequately, so we can figure out what they are missing.

4. As described in the paper titled “Treatment Study of Methylation Cycle Support in Patients with Chronic Fatigue Syndrome and Fibromyalgia” by Neil Nathan, MD, and Richard A Van Konynenburg, PhD. Presented at the March, 2009 International IACFS/ME Conference in Reno, Nevada.


Note: This information has not been reviewed by the FDA. It is general information, is not intended to take the place of personal attention by a medical professional, and is not intended to prevent, diagnose, treat, or cure any illness, condition, or disease. It is very important that you make no change in your healthcare plan or health support regimen without researching and discussing it in collaboration with your professional healthcare team.

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4 thoughts on “A Simplified Methylation Protocol is Effective for the Treatment of Chronic Fatigue Syndrome and Fibromyalgia”

  1. mrussell says:

    Do you offer a “package” that includes all the required supplements together, as described in the article? Thank you!

    1. IanH says:

      Interesting. It has been established in other studies that glutathione levels are low in ME/CFS. The question of whether ME/CFS is due to impaired methylation is doubtful. The immune signature of ME/CFS is now better understood and widely accepted by key researchers in this field. We need to be wary of simplistic biochemical explanations like this but by all means supplement with folate and B12 as well as glutathione, even N-acetyl cysteine.

    2. Lmwh says:

      I’m just starting this journey…I’m having neuro symptoms of severe HAs and numbness tingling in extremities. I was hospitalized last year for what they thought may be Guillain Barre but the only negatives in testing was B6 @ 382 and B12 1051. Current B6 is 277….my symptoms not enough to hospitalize due to weakness numb extremities but nothing is helping me. They want to treat the headaches only and “aren’t familiar with the elevated B6 serum level.”

      How do I address the elevated B vits? I do NOT take any supplements to cause this elevation and eat a strict keto diet, thinking it better for my neuro health…. How do rid myself of the excess Bs ? I am desperate! Thank you!
      p.s. I am an RN and understand the chemistry, though not expert. Please help. Thanks again!

  2. Sandy10m says:

    Most of the links on this page are broken, and the references for the article are missing (they are scattered throughout the article). Would you please fix this? Thanks.

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