The simplified way of explaining the protocol is a genetic block. The particular gene in question is called the MTHFR gene, gene provides instructions for making an enzyme called methylenetetrahydrofolate reductase. This enzyme plays a role in processing amino acids, the building blocks of proteins. Methylenetetrahydrofolate reductase is important for a chemical reaction involving forms of the B-vitamin folate (also called folic acid or vitamin B9). Specifically, this enzyme converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. This reaction is required for the multistep process that converts the amino acid homocysteine to another amino acid, methionine. The body uses methionine to make proteins and other important compounds. Again this is all rather complicated but preliminary work has found the MTHFR defect in a variety of conditions associated with chemical toxicity, namely, Myalgic Encephalomyeltitis, Gulf War Syndrome, Autism and Spina Bifida.

Mount Sinai in New York, the Whittemore Peterson Institute for Neuroimmune Disease and the Institute for Neuroimmune Research, Nova Southeastern University (Professor Nancy Klimas and Dr Gordon Broderick) are studying genomes in such diseases and I hope within the next few years it provides answers for the neuroimmune disease community as a whole.

The protocol is based on the work of Dr Amy Yasko who is a pioneer in the treatment of autism, I attach links to her work for you to read.

Optimal methylation helps to keep toxins and foreign substances at safe levels, where they can’t harm the body. However, when the methylation cycle is not able to do its job, due to either genetic factors or toxic overload, we can’t eliminate toxins, which linger in the body, creating health problems.


Glutathione – an overview


Gluthathione is synthisized by most cells in the body, particularly those in the liver.


It is the most important antioxidant in the body.


It regulates the important nitric oxide cycle produced by the body from L-Arginine, Oxygen and NADPH with the help of nitric oxide synthase (NOS) enzymes.


It is essential for the production of lymphocytes, T cells, NK cells and controls apoptosis (cell death, important for cancer cells). High cells death is often seen in M.E patients.


Survival rates for wasting, as in AIDS and Cancer, are improved by supplementation with glutathione.


Glutathione neutralises heavy metals, carcinogens and foreign chemicals


It supports DNA synthesis, repair and enzyme activation


It supports the nervous system, the gastrointestinal system and the lungs


The Methylation Cycle


Rich Van Konynenburg in his study of M.E and autism has identified the methylation cycle as a critical element in the immune system. He saw similarities between the two disorders in the biochemistry and symptoms. Working with autistic children he was able to achieve remarkable results after supplementation with methylcobalamin, folinic acid and trimethylglycine in combination with dietary changes and possibly chelation to remove heavy metals. This protocol would unblock the methylation cycle and restore glutathione levels. Without enough gluthathione to remove toxins, a circular event is created – the supply of B12 is taken over by toxins, leading to further depletion in glutathione which attempts to rectify the situation. The job of B12 is to form methylcobalamin, one of the two active forms of B12 needed by the enzyme methionine synthase an essential link in the methylation and folate cycles.


Methylation is the process by which one molecule, a methyl donor, transfers a methyl group (a carbon atom and 3 hydrogen atoms or CH3) to another molecule, which becomes methylated. It is through the methylation cycle that the body produces gluthathione.


This is important for activating biochemical pathways and reactions with far-reaching effects:

  1. It is responsible for production of energy and creatine, co enzyme Q10, phosphatidylcholine and melatonin.

  2. It is responsible for synthesizing the proteins that make hormones, neurotransmitters, enzymes and other immune factors. It supplies methyl groups to be attached to DNA molecules. This “reading” of DNA is referred to as “gene expression”. If methyl groups are lacking they cannot prevent or silence the gene overexpression which has been observed in CFS.

  3. It regulates sulphur metabolism necessary for detoxification. Detoxificaion depends on the proper endogenous metabolism of sulphur. Sulfur in the diet comes from amino acids such as methionine, cysteine and taurine. People with CFS often have impaired levels of sulphur metabolities.

  4. It is involved in the production of myelin and phospholipids in the brain and nervous system.

  5. It takes part in the metabolism of folic acid

  6. It is essential for the cell mediated immune function (T cells, TH1/TH2 balance, NK cell function) necessary to keep viruses and bacteria lurking in the cells from reactivating themselves at will. When these cycles are working normally, pathogens will be dormant.



As the cycle proceeds, each element of the cycle gives up a methyl group to become the next one in the cycle through the actions of enzymes. Activated forms of B12 (methylcobalamin), folate (5-methyl-THF) and B6 (pyridoxyl-5-phosphate) are required for each of these steps. Without a properly functioning methylation cycle this conversation cannot happen.


SAMe (s-adenosylmethionine) donates a methyl group to become a homocysteine. The methionine synthase enzyme (MS) energizes the activated form of B12 as it combines with the folate from the folate cycle to produce methionine. The methylation cycle connects the folate (required for DNA/RNA synthesis) and the gluthathione cycle.


Without the action of B12, folic acid and methyl donors such as choline or betaine (trimethylglycine) high homocysteine levels can lead to development of a number of serious conditions such as cardiovascular disease, osteoporosis, osteo and rheumatoid arthritis , depression, multiple sclerosis, Alzheimer’s’ pregnancy difficulties, renal failure and type II diabetes. Improving methylation restores the body’s production of serotonin and melatonin, eliminating the need for pharmaceutical drugs such as SSRIs for mental illness and depression.


High homocysteine levels are involved in neurological conditions such as Multiple Sclerosis and others. High homocysteine impairs methyl donations for the neurotransmitters necessary for nerve conduction. The transsulfuration pathway provides the sulphur needed for the detox pathways in the liver which bind heavy metals. The toxicity of the metals interferes with this pathway, stealing the sulphur groups from the proteins needed for cell rebuilding crucial enzymes synthesizing. Heavy metal toxicity thus contributes to neurological damage.


 Here is the revised Simplified Methylation Protocol as of today, August 25, 2010:


(AS ALWAYS, I RECOMMEND THAT ANYONE ON THIS TYPE OF TREATMENT BE UNDER THE CARE OF A LICENSED PHYSICIAN. Even though this protocol consists only of nutritional supplements, a small number of people have reported experiencing serious adverse effects while on it. If this occurs, the protocol should be discontinued.)


1. Neurological Health Formula (Holistic Health, Inc.) (Multivitamin-multimineral, plus

additional nutrients): Swallow one-quarter tablet and increase to 2 tablets daily. Go

up to 6 tablets daily if tolerated.

2. Activated B12 Guard (Perque) (2,000-microgram lozenge of hydroxocobalamin):

Take one lozenge per day, sublingually.

3. FolaPro (Metagenics) (800-microgram tablet of 5L-methyltetrahydrofolate): Swallow

one-quarter tablet daily, which amounts to 200 micrograms per day.

4. Folinic acid (800 micrograms of 5-formyltetrahydrofolate): Swallow one-quarter

tablet or one-quarter of the contents of a capsule daily, which amounts to 200

micrograms per day.

5. Lecithin (1200-milligram softgel): Swallow one softgel per day, which amounts to

1200 milligrams of lecithin. If finances permit, instead of lecithin, drink a 2-ounce

bottle of Smart Youthful Energy (NT-Factor)(Pure liposomal glycophospholipids)



All these supplements except Smart Youthful Energy can be obtained from, or all but the first one can be obtained from other sources. I do not have a financial interest in any of these supplements. A pill splitter (available from drugstores) will be needed to split tablets. These supplements can be taken with or without food. Different times of the day work better for different people, in regard to effects on sleep. It is best to start with lower dosages than those suggested above and to work up slowly, to check for tolerance. Some people have found that they are very sensitive to these supplements, and can take only much smaller dosages. Others find that they need somewhat larger dosages than those suggested. For those who wish to start the supplements one at a time, I suggest starting with the Neurological Health Formula first, then adding the lecithin, then the B12, and finally the folates, with FolaPro last.



In making this revision, I have been guided by the following goals:


1. To provide effective treatment to correct the vicious circle mechanism that I believe to be the core of the pathophysiology of ME/CFS, involving glutathione depletion, a functional B12 deficiency, a partial block of the methylation cycle, and loss of folates from the cells. This vicious circle mechanism is described by the Glutathione Depletion—Methylation Cycle Block hypothesis for the etiologies, pathogenesis and pathophysiology of ME/CFS. This hypothesis cannot be regarded as scientifically proven, but as far as I know, it is consistent with the current body of published research on ME/CFS.


2. To use only nonprescription nutritional supplements that are available via the internet.


3. To use supplements that are available from a single source, where possible.


4. To keep the protocol simple, with a minimum number of supplements, while preserving its effectiveness.


5. To keep the cost low while preserving effectiveness.


6. To improve the effectiveness of the protocol over that of the previous version, and in particular to increase its likelihood of being effective for more of the ME/CFS population.


7. To preserve the ability of individuals to adjust dosages of individual supplements to match their tolerances and needs.


8. To preserve the relevance of the clinical study of an earlier version of the protocol by Dr. Neil Nathan, M.D., and myself, to the degree possible.


With those goals in mind, I will discuss each of the supplements in the revised protocol.


1. Neurological Health Formula: I have decided to continue recommending this multi for a variety of reasons. First, we have a track record with it that shows that it is helpful to most PWMEs. It contains the vitamins and essential minerals to cover possible nutritional deficiencies, as well as several supplements to support the methylation cycle and related pathways that are not in other multis. Use of this multi allows the active folates to be given separately, so that people can adjust their dosages separately from that of the multi. The cost is reasonable.


This formula does have some disadvantages as well, in my opinion. It lacks copper and iron, which are essential nutrients, and which are deficient in some PWMEs, but which are also capable of promoting oxidative stress if present in excess as free ions. This formula is also rather low in some of the other essential nutrients. Thus, it would be wise to test for levels of vitamins and essential minerals and add appropriate supplements if some are low (see below).


This formula includes some folic acid and some cyanocobalamin, which I do not prefer.

Folic acid is not utilized well by some people, and it competes for absorption and transport with the active forms of folate. Cyanocobalamin contains cyanide, but the amount in this multi should be well dealt with, especially since so much more hydroxocobalamin will enter the blood with this protocol.


The fact that this formula includes several extra nutrients can be a disadvantage for some PWMEs who have sensitivities to one or more of the ingredients, and thus are not able to

take the formula. These people will need to explore other alternatives for covering possible deficiencies in vitamins and essential minerals, and they may also need some of the additional nutrients that are in this formula.


I had considered use of the Thorne Basic V supplement, and some people tried it and reported that they did well with it. However, others did not respond well to it, and use of it does not allow separate adjustment of dosages for the active folates, which some PWMEs must limit to very small amounts because they react very strongly to it. Also, this multi does not include some of the helpful nutrients that are in the Neuro Health Formula, and it does include lipoic acid, which reportedly can mobilize and redeposit mercury if not dosed frequently enough.


2. Activated B12 Guard: This was used in earlier versions of the protocol to supply the high dosage of B12 that is needed to overcome the functional B12 deficiency. In the previous version of the SMP, I changed the recommendation to Hydroxy B12 Megadrops taken under the tongue. Several people have reported that this has not been as effective as the Perque Activated B12 Guard, so I am now changing back to that. Perhaps the length of time that the liquid drops are in contact with the mucosa is just too short to allow enough absorption sublingually.


I had also considered changing the form of B12 to methylcobalamin. Some PWMEs do need to use this form, particularly if their glutathione and/or S-adenosylmethionine are very low. However, use of hydroxocobalamin is a “gentler” approach to lifting the partial methylation cycle block, and many PWMEs need such an approach. Use of hydroxocobalamin also keeps the cells in control of the rate of the methylation cycle, preventing it from being overdriven, which slows the rise of glutathione. So I have decided to stay with hydroxocobalamin as the first form of B12 to try. For people who do not get a response from the SMP within a couple of months, switching to methylcobalamin would be an option to try. Another option would be to try adding some adenosylcobalamin (dibencozide). However, I do not favor raising the overall dosage of B12 very much above 2,000 micrograms per day, and especially not when it is combined with dosages of methyfolate that are much above the RDA range of 400 to 800 micrograms per day. This combination can overdrive the methylation cycle and hinder the rise of glutathione.


3. FolaPro: This was also used in earlier versions. In the previous version, I changed the recommendation to the liquid MethylMate B, on the basis of convenience, not having to split tablets. However, I have received reports that some PWMEs have a sensitivity to something in MethylMate B. Therefore, I am now changing back to FolaPro. Solgar Metafolin could be used instead, and it is probably less expensive, but it also contains additional additives, including mannitol and magnesium stearate, which may cause sensitivity problems for some people. The function of this supplement in the protocol is to replenish the form of folate directly needed by the methionine synthase reaction, which is partially blocked. This form has been depleted by reactions with peroxynitrite, and some people are not able to convert other forms of folate into methylfolate readily.


4. Folinic acid: This is a buffer form of folate that most people can readily convert to other active forms of folate. Its role in the protocol is to supply these other forms while the methionine synthase reaction has still not come up to normal. This is particularly important for making new DNA and RNA for replacing cells. In the early versions of the protocol, Actifolate was used to supply folinic acid. However, it also contains some folic acid, which I would prefer to minimize. Folinic acid can be obtained either in tablet or capsule form.


5. Lecithin: The role of lecithin is to help with repair of cell membranes, especially mitochondrial membranes, which have been damaged by oxidative stress. I suspect that the damaged mito membranes are one of the main reasons why many PWMEs have found that recovering their energy status is one of the slowest aspects of recovery from ME/CFS. In early versions of the SMP, I recommended phosphatidylserine complex to fill this role. However, the phosphatidylserine component tends to lower cortisol initially, and most PWMEs already have below-normal cortisol. Most lecithin is derived from soy, but for those who do not tolerate soy, lecithin is also available that is derived from sunflower, canola or eggs.


I have also recommended that if finances permit, it would be preferable to use Smart Youthful Energy rather than lecithin. This is more costly, but I think it would be worth it, for those who can afford it. Smart Youthful Energy is composed of a liposomal form of pure glycophospholipids of the types needed by the cell membranes, including the mitochondrial membranes. This product has the capability to deliver these lipids to where they are needed, unchanged. Unlike other NT Factor products, there are no additional supplements besides the lipids in this product. It is derived from soy, but it does not contain soy protein, and should not provoke any reactions. Use of these lipids constitutes what has been called “Lipid Replacement Therapy,” a trademarked name.

This approach has been tested by Dr. Garth Nicolson and others, and has been found to be very beneficial in conditions that involve fatigue, including ME/CFS.


6. Amino acids supplementation: I considered adding this to the protocol, because I have found that some PWCs are depleted in amino acids, but issues were raised by commenters, including the possibilities that this would provoke yeast growth or increased excitotoxicity or ammonia generation. Since I don’t have much experience with supplementation with free amino acids, I have decided not to add this now. Hopefully PWMEs can consume enough protein in their diets to supply the amino acids they need.

Those who are able to do lab testing will be able to determine their amino acids levels and correct them if necessary.



I want to add that I have written the above keeping in mind that many PWMEs are not able to do much if any lab testing, largely for financial reasons. However, I do want to note that my preference would be for people to do lab testing before entering upon this protocol, as well as other additional treatments that may be needed, as indicated by the results of testing.


I particularly favor running the methylation pathways panel that is offered by the Health Diagnostics and Research Institute in New Jersey, USA, and the European Laboratory of Nutrients (ELN) in the Netherlands. This panel will identify whether there is glutathione depletion, a partial methylation cycle block and folate depletion, and thus whether methylation treatment is likely to help. It will also provide baseline data

for comparison later, to gauge the progress of the treatment.


If there are problems with the digestive system, I favor running comprehensive stool analyses to identify them so that they can be treated. I particularly like the Metametrix G.I. Function Profile and the Diagnos-Techs Expanded G.I. Panel. If finances permit running both of them, I think it would be worthwhile. If not, I think I would choose the Metametrix panel. It is important to have the digestive system operating fairly well in order for the methylation protocol to work properly, because it is necessary to have sufficient absorption of nutrients and sufficient ability to excrete toxins, rather than recirculating them. Friendly bacteria produce some of the vitamins needed by the body. Also, correcting a “leaky gut” will take a major load off the immune system, which is dysfunctional in ME/CFS.


I also believe it is helpful to test for deficiencies in the vitamins, minerals and amino acids and augment those that are low. They can either be measured directly, as in the vitamin,minerals and amino acids panels offered by Health Diagnostics or the ELN, or by metabolic-type testing, such as with the Metametrix ION Profile or the Genova Diagnostics NutrEval Profile.


For people who suspect high body burdens of toxic metals, tests involving feces, urine and hair are available. High levels of some toxic metals can block enzymes in the methylation cycle and related pathways. Chelation treatment may be necessary to lower the levels enough to permit normal operation of this part of the metabolism.


People who are sensitive to biotoxins and are being exposed to them in their homes will need to correct this situation in order for the methylation protocol to be helpful to them.

I would particularly refer you to Dr. Ritchie Shoemaker’s website


I also want to note that increased excitotoxicity (causing anxiety, insomnia, nervousness and a “wired” feeling) has been reported by many people on the SMP. I believe that this is caused by an initial further drop in glutathione in the brain when this protocol is started. I have suggested that supplementing with L-cystine (not the same as L-cysteine) may help with this. However, people who have a high mercury body burden should not do this, because L-cystine has the potential to move mercury into the brain.


Best regards,


Rich Van Konynenburg


The Methylation Pathways Panel by the Health Diagnostics and Research Institute (formerly Vitamin Diagnostics) targets the most essential genes and focuses on genetic weaknesses in the body. Genetic weaknesses (or mutations) can lay the groundwork for further assault of environmental and infectious agents, which can result in a wide range of increased risk for additional health conditions, including diabetes, depression, cardiovascular disease, thyroid dysfunction, neurological inflammation, chronic viral infection, neurotransmitter imbalances, atherosclerosis, cancer, Alzheimer’s disease and autism.* The Methylation Pathways Panel uncovers these weaknesses helping you to optimize supplementation to address these mutations.



Genome testing to reveal which conditions you are predisposed to and where the methylation blocks lie, for example if you have a the MTHFR C677T defect, if you are heterozygous or homozygous.


Simply take the 23andme test and upload to for a free interpretation panel.


Some might prefer to be a little more thorough and take the full Amy Yasko test which is available from but at a much more expensive price.