International ME/CFS and FM Awareness Day Is On May 12, 2018
Thomas Hennessy, Jr., selected May 12th to be our international awareness day back in 1992. He knew that May 12th had also been the birthday of Florence Nightingale. She was the English army nurse who helped to found the Red Cross as well as the first school of nursing in the world.
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New here, want to understand basics

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by TamaraSlack, May 30, 2012.

  1. TamaraSlack


    Columbus, Ohio

    Brand new here. Spoke with Paul08 in chat and he said to come and make a thread. Good idea :)

    I am not new to CFS. Not new to chelation nor heavy metal toxicity, but I am new to methylation.

    Long (!!) story short:

    I am, for the most part, bedridden. I have nearly died detoxing in 2010 (using chelation - DMPS IVs, high thiol (sulfur) foods, etc.). Stopped that - husband said I was about 2 weeks away from him buying a coffin. I then went onto trying DMSA and Alpha Lipoic Acid - went crazy. Stopped, got back on the Klonopin I had stopped using over a 3.5 year Ashton manual protocol just to get some sanity and sleep back - didn't sleep for weeks except a bit here and there - completely out of my mind and suicidal. Body strengthened enough after stopping all detoxing enough that I could get up to go to the bathroom without assistance and get my own food now. About 1.5 month ago, histamine reactions became worse (they were bad! But now so bad, throat closing). Looked into methylation via Dr. Amy Yasko. I study through Hawthorn University but had to take a leave of absence because I'm getting so bad now, I can't do the homework and didn't get to the course on methylation. (ugh!).

    So, I am taking a little bit of hydroxocobalamin and methyltetrahydrofolate and then not taking it, then taking a lot, then little - not sure what to do. The doctor I had, Dr. Andrew Neville, recommended I come here because he said his "friend Rich" is understanding methylation and that I should get in touch with him. I hear this is his discussion board (??).

    I would like to get DNA tested, but not sure what to get tested and through whom. No doctor as of yet, but possibly a dr. in town who understands this stuff (I had put a craigslist ad out to sell some plants and the lady who came by is a nurse who used to work for a dr. who does EDTA IVs and helps autistic kids get better through methylation - what?! Nobody comes by here and here's this nurse asking me if I am methylating - I am a Christian so I don't believe in coincidences - I believe the Lord sent her - so I *may* get a dr. with some knowledge after all).

    Any help would be appreciated. I read around on the forum and see what Fredd (I think it's 2 d's) says and went to iHerb and my mother is going to buy the supplements he says. I know this about me: anything too fast and hard is too much for me. I believe I have so many toxins in me that when I do methylate / chelate, the toxins move around, not out enough. I do not know what Rich says as a protocol - can't find that yet. (Anyone know?)

    And if I do get tested, how do I read the test (Yasko's testing) and know which things to take?


    Tamara Slack
  2. Hanna

    Hanna Senior Member

    Jerusalem, Israel
  3. TamaraSlack


    Columbus, Ohio
    Okay, thank you Hanna!
  4. Sallysblooms

    Sallysblooms P.O.T.S. now SO MUCH BETTER!

    Southern USA
    Welcome. I have had huge success with the right supplements. Finding a good integrative MD is wonderful. They know testing and supplements.
  5. richvank

    richvank Senior Member

    Hi, Tamara.

    I, too, want to welcome you here. Yes, Dr. Neville is a friend of mine. I do participate here, and appreciate this forum a lot, but it is not "mine" in the sense that I had anything to do with starting it or maintaining it. Cort Johnson started it, and there is a faithful crew of administrators and moderators who keep it going, for the benefit of all of us.

    Hanna gave you a link to the most recent version of the protocol I have suggested. Freddd, on this forum, has proposed a somewhat different protocol, though it has some things in common with the one I have suggested. The same protocol does not seem to work well for everyone, and we continue to try to understand how to optimize treatment for all PWMEs. We do agree on the importance of supplementing methylfolate and also using a high dosage of one or more of certain forms of B12, either sublingually or by injection, but beyond that, there are differences in the protocols, and we have not come to complete agreement on everything concerning them.

    With regard to testing, Dr. Amy Yasko does offer a panel that characterizes about 30 genetic polymorphisms. It can be helpful, especially for those who follow her complete treatment program. This program involves a large number of supplements, frequent lab testing, and considerable complexity and cost. I have attempted to simplify this and lower the cost by extracting a "simplified" protocol from her overall program, because many PWMEs had difficulty following her complete treatment program.

    With regard to genetic testing, some people are running the genotyping panel. It costs less than the Yasko panel, and has many more polymorphisms on it. However, it does not include all of those on the Yasko panel, and it requires some interpretation, which some people in this forum have been working on.

    The testing that I most favor is the Health Diagnostics methylation pathways panel, which is a biochemical panel that evaluates the actual current status of the methylation cycle, the folate metabolism and glutathione, rather than genetic tendencies. This panel will tell you if methylation treatment is likely to help, and it will also give baseline data for comparison later, to evaluate the progress of the treatment. Contact information and an interpretive guide are pasted below.

    Since many people have deficiencies in necessary nutrients, I also favor running a Genova Diagnostics NutrEval profile or a Metametrix ION profile. These are available through some doctors, or without a doctor's order from These profiles will evaluate your overall energy metabolism and indicate whether there are deficiencies in vitamins, minerals or amino acids. They will also give some information about toxic metals and the condition of the digestive system.

    Some people just try the protocol without doing any testing, for reasons of cost or inability to get to a doctor or to find one who is knowledgeable and will cooperate. I don't recommend this, but sometimes it works out O.K. Other times it doesn't, because there are nutritional deficiencies or elevated toxic metals or serious intestinal dysbiosis, and then the person has to go back and try to detect and correct these problems. There have also been a small number of cases with serious adverse effects, so I recommend working with a physician while on this type of treatment. It sounds like you have had some high-level help in finding a knowledgeable physician, and that's great!

    If you would like to get more detailed information about methylation treatment and the rationale behind it, you could view the video (or look at the slides, which are available by clicking on the blue print below the video) at this site:${weburl}

    I am also attaching a simplified explanation of the Glutathione Depletion--Methylation Cycle Block hypothesis for ME/CFS.

    I hope this helps.

    Best regards,


    Methylation Pathways Panel

    This panel will indicate whether a person has a partial methylation cycle block and/or glutathione depletion. I recommend that this panel be run before deciding whether to consider treatment for lifting the methylation cycle block. I am not associated with the lab that offers this panel.

    The panel requires an order from a physician or a chiropractor. The best way to order the panel is by fax, on a clinician’s letterhead.

    Available from:

    Health Diagnostics and Research Institute540 Bordentown Avenue, Suite 2300
    South Amboy, NJ 08879 USA
    Phone: (732) 721-1234
    Fax: (732) 525-3288


    Lab Director: Elizabeth Valentine, M.D.

    Dr. Tapan Audhya, Ph.D., is willing to help clinicians with interpretation of the panel by phone, or you can use the interpretive guide below:

    March 25, 2012
    Interpretation of Results of the Methylation Pathways Panel
    Richard A. Van Konynenburg, Ph.D.
    Independent Researcher

    Disclaimer: The Methylation Pathways Panel is offered by the European Laboratory of Nutrients in the Netherlands and the Health Diagnostics and Research Institute in New Jersey, USA. I am not affiliated with these laboratories, but have been a user of this panel, and have written these suggestions at the request of Tapan Audhya, Ph.D., Director of Research for the Health Diagnostics lab, for the benefit of physicians who may not be familiar with this panel. My suggestions for the interpretation of results of the panel are based on my study of the biochemistry involved, on my own experience with interpreting panel results as part of the analysis of a fairly large number of cases of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) over the past four years, and on discussion of some of the issues with Dr. Audhya. I am a researcher, not a licensed physician. Treatment decisions based on the results of applying this panel and its interpretation to individual cases are the responsibility of the treating physician.

    Application: In addition to being useful in analyzing cases of ME/CFS, this panel can also be usefully applied to cases of autism and other disorders that involve abnormalities in glutathione, methylation and the folate metabolism.

    The panel includes measurement of two forms of glutathione (reduced and oxidized), S-adenosylmethionine (SAMe), S-adenosylhomocysteine (SAH), adenosine, and seven folate derivatives.

    According to Dr. Audhya (personal communication), the reference ranges shown on the lab reports for each of these metabolites were derived from measurements on at least 120 healthy male and female volunteer medical students from ages 20 to 40, non-smoking, and with no known chronic diseases. The reference ranges extend to plus and minus two standard deviations from the mean of these measurements.

    Glutathione (reduced): This is a measurement of the concentration of the
    chemically reduced (active) form of glutathione (abbreviated GSH) in the blood
    plasma. The reference range is 3.8 to 5.5 micromoles per liter.

    Glutathione plays many important roles in the biochemistry of the body, including serving as the basis of the antioxidant enzyme system, participating in the detoxication system, and supporting the cell-mediated immune response, all of which exhibit deficits in CFS. The level of GSH in the plasma is likely to be more reflective of tissue intracellular glutathione status than the more commonly and more easily measured red blood cell or (essentially equivalent) whole blood glutathione level, which is about three orders of magnitude greater, because red blood cells are normally net producers of glutathione. Also, knowledge of the level of the reduced form, as distinguished from total (reduced plus oxidized) glutathione, which is more commonly measured, is more diagnostic of the status of glutathione function.

    In order to be able to approximate the in vivo level of reduced glutathione when blood samples must be shipped to a lab, it is necessary to include special enzyme inhibitors in the sample vials, and these are included in the test kit supplied by these two laboratories.

    Most people with chronic fatigue syndrome (PWCs), but not all, are found to have values of GSH that are below the reference range*. This means that they are suffering from glutathione depletion. As they undergo treatment to lift the partial methylation cycle block, this value usually rises into the normal range over a period of a few months. I believe that this is very important, because
    glutathione normally participates in the intracellular metabolism of vitamin B12, and if it is low, a functional deficiency of vitamin B12 results, and insufficient methylcobalamin is produced to support methionine synthase in the methylation cycle. In my view, this is the mechanism that causes the onset of ME/CFS. This functional deficiency is not detected in a conventional serum B12 test, but will produce elevated methylmalonate in a urine organic acids test. In my opinion, many of the abnormalities and symptoms in ME/CFS can be traced directly to glutathione depletion.

    Anecdotal evidence suggests that PWCs who do not have glutathione depletion do have abnormalities in the function of one or more of the enzymes that make use of glutathione, i.e. the glutathione peroxidases and/or glutathione transferases. This may be due to genetic polymorphisms or DNA adducts on the genes that code for these enzymes, or in the case of some of the glutathione peroxidases, to a low selenium status.

    Glutathione (oxidized): This is a measurement of the concentration
    of the oxidized form of glutathione (abbreviated GSSG) in the blood
    plasma. The reference range is 0.16 to 0.50 micromoles per liter.

    Normally, oxidized glutathione in the cells is recycled back to reduced glutathione by glutathione reductase, an enzyme that requires vitamin B2 and NADPH. If this reaction is overwhelmed by oxidative stress, the cells export excess GSSG to the plasma. In some (but not all) PWCs, GSSG is elevated above the normal
    range, and this represents oxidative stress. It is more common in CFS to see this level in the high-normal range. This value may increase slightly under initial treatment of a partial methylation cycle block.*

    Ratio of Glutatione (reduced) to Glutathione (oxidized): This is not shown explicitly on the panel results, but can be calculated from them. It is a measure of the redox potential in the plasma, and reflects the state of the antioxidant system in the cells. The normal mean value is 14. PWCs often have a value slightly more than half this amount, indicating a state of glutathione depletion and oxidative stress. This ratio has been found to increase during treatment of a partial methylation cycle block, but other types of treatment may be necessary to bring it to normal.*

    S-adenosymethionine (RBC): This is a measure of the concentration of S-adenosylmethionine (SAMe) in the red blood cells. The reference range is 221 to 256 micromoles per deciliter.

    SAMe is produced in the methylation cycle and is the main supplier of methyl (CH3) groups for a large number of methylation reactions in the body, including the methylation of DNA and the biosynthesis of creatine, carnitine, phosphatidylcholine, coenzyme Q10, melatonin and epinephrine. This measurement is made in the red blood cells because the level there reflects an average over a longer time and is less vulnerable to fluctuations than is the plasma level of SAMe.

    Most PWCs have values below the reference range, and treatment raises the value.* A low value for SAMe represents a low methylation capacity, and
    in CFS, it usually appears to result from an inhibition or partial block of the enzyme methionine synthase in the methylation cycle. Many of the abnormalities in CFS can be tied to lack of sufficient methylation capacity.

    S-adenosylhomocysteine (RBC): This is a measure of the
    concentration of S-adenosylhomocysteine (SAH) in the red blood cells. The reference range is 38.0 to 49.0 micromoles per deciliter.

    SAH is the product of the many methyltransferase reactions that utilize SAMe as a source of methyl groups. In CFS, its value ranges from below the reference range to above the reference range. Values appear to converge toward the reference range with treatment.

    Sum of SAM and SAH: When the sum of SAM and SAH is below about 268
    micromoles per deciliter, it appears to suggest the presence of
    upregulating polymorphisms in the cystathionine beta synthase (CBS)
    enzyme, though this may not be true in every case. For those considering following the Yasko treatment program, this may be useful information.

    Ratio of SAM to SAH: A ratio less than about 4.5 represents low
    methylation capacity. Both the concentration of SAM and the ratio of
    concentrations of SAM to SAH are important in determining the
    methylation capacity, because they affect the rates of the methyltransferase reactions.

    Adenosine: This is a measure of the concentration of adenosine in the
    blood plasma. The reference range is 16.8 to 21.4 x 10(-8) molar.

    Adenosine is a product of the reaction that converts SAH to homocysteine. It is also exported to the plasma when mitochondria develop a low energy charge, so that ATP drops down to ADP, AMP, and eventually, adenosine. Adenosine in the plasma is normally broken down to inosine by the enzyme adenosine deaminase.

    In some PWCs adenosine is found to be high, in some it is low, and in some it is in the reference range. I don't yet understand what controls the adenosine level in these patients, and I suspect that there is more than one factor involved. In most PWCs who started with abnormal values, the adenosine level appears to be moving into the reference range with methylation cycle treatment, but more data are needed.

    5-CH3-THF: This is a measure of the concentration of 5L-methyl
    tetrahydrofolate in the blood plasma. The reference range is 8.4 to 72.6 nanomoles per liter.

    This form of folate is present in natural foods, and is normally the most abundant form of folate in the blood plasma. It is the form that serves as a reactant for the enzyme methionine synthase, and is thus the important form for the methylation cycle. It is also the only form of folate that normally can enter the brain. Its only known reactions are the methionine synthase reaction and reaction with the oxidant peroxynitrite.

    When there is a partial block in methionine synthase, the other forms of folate continue to be converted to 5L-CH3-THF by the so-called “methyl trap” mechanism. Some of the 5L-CH3-THF is broken down by reaction with peroxynitrite, which results from the condition of oxidative stress that is usually concomitant with glutathione depletion.

    Many PWCs have a low value of 5L-CH3-THF, consistent with a partial block in the methylation cycle. Most methylation treatment protocols include supplementation with 5L-CH3-THF, which is sold over-the-counter as Metafolin, FolaPro, or MethylMate B (trademarks), as well as the newer Quatrefolic (trademark) and in the prescription “medical foods” supplied by PamLab, including Deplin, CerefolinNAC and Metanx. There are some others on the market that include both racemic forms (5L and 5R) of this folate.

    When methylation treatment is used, the level of 5-CH3-THF rises in nearly every PWC. If the concentration of 5-CH3-THF is within the reference range, but either SAM or the ratio of SAM to SAH is below the reference values, it suggests that there is a partial methylation cycle block and that it is caused by inavailability of sufficient bioactive B12, rather than inavailability of sufficient folate. A urine organic acids panel will show elevated methylmalonate if there is a functional deficiency of B12. I have seen this combination frequently, and I think it demonstrates that the functional deficiency of B12 is the immediate root cause of most cases of partial methylation cycle block. Usually glutathione is low in these cases, which is consistent with such a functional deficiency. As the activity of the methylation cycle becomes more normal, the demand for 5-CH3-THF will likely increase, so including it in the treatment protocol, even if not initially low, will likely be beneficial.

    10-Formyl-THF: This is a measure of the concentration of 10-formyl
    tetrahydrofolate in the blood plasma. The reference range is 1.5 to 8.2 nanomoles per liter.

    This form of folate is involved in reactions to form purines, which form part of RNA and DNA as well as ATP. It is usually on the low side in PWCs, likely as a result of the methyl trap mechanism mentioned above. This deficiency is likely the reason for some elevation of mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) often seen in PWCs. This deficit may also impact replacement of cells lining the gut, as well as white blood cells.

    Rarely, 10-formyl-THF is found to be much higher than the normal reference range. If this is found, the patient should be examined for cancer, since cancer cells upregulate this form of folate in order to make purines more rapidly to support their rapid cell division.

    5-Formyl-THF: This is a measure of the concentration of 5-formyl
    tetrahydrofolate (also called folinic acid) in the blood plasma. The reference range is 1.2 to 11.7 nanomoles per liter.

    This form is not used directly as a substrate in one-carbon transfer reactions, but it can be converted into other forms of folate, and may serve as a buffer form of folate. Most but not all PWCs have a value on the low side. It is one of the
    supplements in some methylation protocols. It can be converted to 5L-CH3-THF in the body by a series of three reactions, one of which requires NADPH, and it may also help to supply other forms of folate to the cells until the methionine synthase reaction comes up to more normal activity.

    THF: This is a measure of the concentration of tetrahydrofolate in
    the blood plasma. The reference range is 0.6 to 6.8 nanomoles per liter.

    This is the fundamental chemically reduced form of folate from which several other reduced folate forms are synthesized, and thus serves as the “hub” of the folate metabolism. THF is also a product of the methionine synthase reaction, and participates in the reaction that converts formiminoglutamate (figlu) into glutamate in the metabolism of histidine. If figlu is found to be elevated in a urine organic acids panel, it usually indicates that THF is low. In PWCs it is lower than the mean normal value of 3.7 nanomoles per liter in most but not all PWCs.

    Folic acid: This is a measure of the concentration of folic acid in
    the blood plasma. The reference range is 8.9 to 24.6 nanomoles per liter.

    Folic acid is a synthetic form of folate, not found in nature. It is added to food grains in the U.S. and some other countries in order to lower the incidence of neural tube birth defects, including spina bifida. It is the oxidized form of folate, and therefore has a long shelf life and is the most common commercial folate supplement. It is normally converted into THF by two sequential reactions catalyzed by dihydrofolate reductase (DHFR), using NADPH as the reductant. However, some people are not able to carry out this reaction well for genetic reasons, and PWCs may be depleted in NADPH, so folic acid is not the best supplemental form of folate for these people.

    Low values suggest folic acid deficiency in the current diet. High values, especially in the presence of low values for THF, may be associated with inability to convert folic acid into reduced folate readily, such as because of a genetic polymorphism in the DHFR enzyme. They may also be due to high supplementation of folic acid.

    Folinic acid (WB): This is a measure of the concentration of folinic acid in the whole blood. The reference range is 9.0 to 35.5 nanomoles per liter.

    See comments on 5-formyl-THF above. Whole blood folinic acid usually tracks with the plasma 5-formyl-THF concentration. They are the same substance.

    Folic acid (RBC): This is a measure of the concentration of folic acid in the red blood cells. The reference range is 400 to 1500 nanomoles per liter.

    The red blood cells import folic acid when they are initially being formed, but during most of their lifetime, they do not normally import, export, or use it. They simply serve as reservoirs for it, giving it up when they are broken down.

    Many PWCs have low values of this parameter. This can be caused by a low folic acid status in the diet over the previous few months, since the population of RBCs at any time has ages ranging from zero to about four months. However, in CFS it can also be caused by oxidative damage to the cell membranes, which allows folic acid to leak out of the cells. Dr. Audhya reports that treatment with omega-3 fatty acids has been found to raise this value over time in one cohort.

    If anyone finds errors in the above suggestions, I would appreciate being notified at

    * Nathan, N., and Van Konynenburg, R.A., Treatment Study of Methylation Cycle Support in Patients with Chronic Fatigue Syndrome and Fibromyalgia, poster paper, 9th International IACFS/ME Conference, Reno, Nevada, March 12-15, 2009. (

    Simpler explanation of GD-MCB hypothesis for ME/CFS

    1. To get an isolated case of ME/CFS (I'm not talking here about the epidemics or clusters), you have to have inherited some genetic variations from your parents. These are called polymorphisms or single-nucleotide polymorphisms. We know what some of the important ones are, but we don't know all of them yet. I think it’s likely that at least some make it difficult for a person to maintain a normal level of glutathione. This is a topic that needs more research.

    2. You also have to have some things happen in your life that place demands on your supply of glutathione. Glutathione is like a very small protein, and there is some in every cell of your body, and in your blood. It protects your body from quite a few things that can cause problems, including chemicals that are toxic, and oxidizing free radicals. It also helps the immune system to fight bugs (bacteria, viruses, fungi) so that you are protected from infections by them.

    3. Oxidizing free radicals are molecules that have an odd number of electrons, and are very chemically reactive. They are normally formed as part of the metabolism in the body, but if they rise to high levels and are not eliminated by glutathione and the rest of the antioxidant system, they will react with things they shouldn't, and cause problems. This situation is called oxidative stress, and it is probably the best-proven biochemical aspect of chronic fatigue syndrome. One of the important oxidizing free radicals is peroxynitrite.

    4. There are a variety of things in your life that can place demands on your glutathione. These include physical injuries or surgery to your body, exposure to toxic chemicals such as pesticides, solvents, or heavy metals like mercury, arsenic or lead, exposure to infectious agents such as viruses or bacteria, or vaccinations, or emotional stress that causes secretion of a lot of cortisol and adrenaline, especially if it continues over a long time. Just about anything that "stresses" your body or your mind will place a demand on glutathione. All people experience a variety of stressors all the time, and a healthy person's body is able to keep up with the demands for glutathione by recycling used glutathione molecules and by making new ones as needed. However, if a person's body cannot keep up, either because of extra-high demands or inherited genetic polymorphisms that interfere with recycling or making glutathione, or both, the levels of glutathione in the cells can go too low. When glutathione is properly measured in most people with ME/CFS (such as in the Health Diagnostics methylation pathways panel), it is found to be below normal.

    5. One of the jobs that glutathione normally does is to help your cells to convert incoming vitamin B12 to the right amounts of the two forms of B12 that they use. If there is not enough glutathione, this won’t happen. This is called a “functional deficiency” of vitamin B12. A conventional blood test for vitamin B12 will not reveal this problem. In fact, many people with ME/CFS appear to have elevated levels of B12 in their blood, while their bodies are not able to use it properly. The best test to reveal this is a urine organic acids test that includes methylmalonic acid. It will be high if the B12 is being sidetracked, and this is commonly seen in people with ME/CFS.

    6. When your glutathione level goes too low, your B12 also becomes naked and vulnerable, and is hijacked by toxins. Also, the levels of toxins rise in the body when there isn't enough glutathione to take them out, so there are two unfortunate things that work together to sabotage your B12 when glutathione goes too low.

    7. The most important form of B12 in the body is methylcobalamin, which is one of the two active forms of B12. This form is needed by the enzyme methionine synthase, to do its job. An enzyme is a substance that catalyzes, or encourages, a certain biochemical reaction.

    8. When there isn't enough methylcobalamin, methionine synthase has to slow down its reaction. Its reaction lies at the junction of the methylation cycle and the folate cycle, so when this reaction slows down, it affects both these cycles.

    9. The methylation cycle is found in all the cells of the body (not counting the red blood cells, which are unusual in a lot of ways). The methylation cycle has some important jobs to do. First, together with the folate metabolism, it acts as a little factory to supply methyl (CH3) groups to a large number of reactions in the body. Some of these reactions make things like creatine, carnitine, coenzyme Q10, phosphatidylcholine, melatonin, and lots of other important substances for the body. It is not a coincidence that these substances are found to be low in ME/CFS, so that people try taking them as supplements. Not enough of them is being made because of the partial block in the methylation cycle. The methylation cycle also supplies methyl groups to be attached to DNA molecules, and this helps to determine whether the blueprints in the DNA will be used to make certain proteins according to their patterns. This "reading" of DNA is referred to as "gene expression." Methyl groups prevent or "silence" gene expression. Overexpression of genes has been observed in CFS patients, and I suspect this is at least partly due to lack of sufficient methylation to silence gene expression.

    10. Another thing that the methylation cycle does is to regulate the overall use of sulfur in the body. Sulfur comes in from the diet in the form of amino acids in protein (methionine and cysteine) and as taurine and some as sulfate. The methylation cycle regulates the production of the various substances that contain sulfur that are needed by the body. The levels of various sulfur metabolites are often found to be abnormal in people with ME/CFS.

    11. One of the most important sulfur-containing substances in the body is glutathione, so now you can see how this is starting to look like a dog chasing its tail! The thing that causes chronic fatigue syndrome to be chronic, and keeps people ill for years and years, is this interaction between glutathione, vitamin B12, and the methylation cycle. When glutathione goes too low, the effect on vitamin B12 slows down the methylation cycle too much. The sulfur metabolites are then dumped into the transsulfuration pathway (which is connected to the methylation cycle) too much and are eventually converted to thiosulfate and sulfate and are excreted in the urine. This lowers the production of glutathione, which requires cysteine, and now there is a vicious circle mechanism that preserves this malfunction and keeps you sick.

    12. Meanwhile, the folate metabolism in the cells becomes depleted, because other forms of folate are converted to methylfolate, and peroxynitrite, the free radical, breaks down methylfolate.

    13. That's the basic biochemical mechanism of ME/CFS. I believe that everything else flows from this. As you know, there are many symptoms in ME/CFS. I won't discuss all of them in detail here, but here's how I believe the fatigue occurs: The cells have little powerplants in them, called mitochondria. Their job is to use food as fuel to produce ATP (adenosine triphosphate). ATP acts as a source of energy to drive a very large number of reactions in the cells. For examples, it drives the contraction of the muscle fibers, and it provides the energy to send nerve impulses. It also supplies the energy to make stomach acid and digestive enzymes to digest our food, and many, many other things.

    When glutathione goes too low in the muscle cells, the levels of oxidizing free radicals rise, and these react with parts of the "machinery" in the little powerplants, lowering their output of ATP. So the muscle cells then experience an energy crisis, and that's what causes the fatigue. Over time, because of the lack of enough glutathione, more problems accumulate in the mitochondria, including toxins, viral DNA, and mineral imbalances. These have been observed in the ATP Profiles and Translocator Protein test panels offered by Acumen Lab in the UK.

    14. There are explanations that flow from this basic mechanism for other aspects of ME/CFS. I haven't figured out explanations for all of the aspects of ME/CFS, but I do think I understand a large number of them in some detail, and I've been able to explain enough of them that I believe this mechanism will account for the rest as well, if we can figure out the underlying biochemistry. My 2007 IACFS conference poster paper presented outlines of many of these explanations.

    15. The involvement of infections by bacteria, viruses and fungi appears to have three aspects in ME/CFS. First, as mentioned above, infectious agents can act as one of the stressors that initially bring down the level of glutathione and produce the onset of isolated cases of ME/CFS in people who are genetically susceptible. I suspect that the clusters or epidemic occurrences of ME/CFS (such as at InclineVillage in the mid-80s) were caused by particularly virulent infectious agents, such as powerful viruses, and the genetic factor is less important in these cases.

    16. Second, when a person's glutathione, methylation cycle, and folate cycle are not operating normally because of the vicious circle described above, the immune system does not function properly. In this case, viruses and bacteria that reside inside our cells and that are always in the body in their dormant, resting states are able to reactivate and produce infections, which the immune system is not able to totally put down. This accounts for the observation that most of the viral and intracellular bacterial infections seen in CFS patients are caused by pathogens that most of the population is carrying around in their dormant states.

    17. Third, when the immune system's defenses are down, a person can catch new infections from others or from the environment, and the immune system is not able to defeat them, so they accumulate over time. Dr. Garth Nicolson has found that the longer a person has been ill, the more infections they have, on the average.

    18. Other things that accumulate over time are various types of toxins, because the detox system depends to a large extent on the sulfur metabolism, and it will not be operating properly as long as the person has ME/CFS. The body stores much of these toxins in fat, but as the levels get higher, they begin cause problems throughout the biochemistry of the cells. Many people with ME/CFS have been tested for toxins (most commonly the heavy metal toxins, which are the most easily tested) and they are commonly found to be elevated.

    19. The longer a person is chronically ill with ME/CFS, the more toxins and infections accumulate in their body, and the more symptoms they experience. This explains why the disorder changes over time, and why some people become extremely debilitated after being ill for many years.

    20. The main key to turning this process around is to help the methionine synthase enzyme to operate more normally, so that the partial block in the methylation cycle and the folate cycle are lifted, and glutathione is brought back up to normal. That is what the simplified methylation protocol is designed to do, and so far, the evidence is that it does do these things in most people who have ME/CFS. I recommend that people with ME/CFS have the Health Diagnostics methylation pathways panel run to find out if they do in fact have a partial methylation cycle block and glutathione depletion before deciding, with their doctors, whether to try this treatment. This also provides a baseline so that progress can be judged later on by repeating it every few months during the treatment. Symptoms may not be a good guide to judge progress during treatment, because detoxing and die-off can make the symptoms worse, while in fact they are exactly what is needed to move the person toward recovery.

    21. The main question I'm working on now is what else needs to be done to bring people to recovery? I don't have complete answers to this question yet. A few people recover from this treatment alone, but most require additional treatments. It does appear that people who suffer from illness due to toxic molds do need to remove themselves from environments where these are present. People who have Lyme disease will need to have that treated, also. Certain viral infections may also need to be treated. If the load of toxic metals is very high, they may need to be removed first. If the digestive system is in bad condition, it needs to be helped before the methylation cycle can be restored. If there are major deficiencies in important essential nutrients, they need to be restored before methylation can be corrected. We still have a lot to learn, but I'm convinced that the mechanism I have described above is the core of the abnormal biochemistry in CFS, and correcting it needs to be a cornerstone of the treatment.

    RosieBee likes this.
  6. justy

    justy Donate Advocate Demonstrate

    OOPS! sorry Tamara and Rich - our posts crossed!

    Hi Tamaraslack, and welcome. It sounds like you have had a really tough time of it! But i'm glad you are finding a way through. Like you i don't believe in coincidences - it seems that something is leading you to a methylation protocol. I havent done the full protocol, but i have been injecting MB12 daily for over 6 months with great results for me. My main issue is not having a doctor to keep an eye on me while i try the full lot - i have had bad reactions to drugs and supplements in the past.

    The link above is a good starting point - i also suggest that you watch Rich's presentation in Sweden of the Simplified methylation protocol (SMP)${weburl}

    Its a really great talk and gives a lot of info.
    Due to the reactions you already have had to supplements etc and the poor state of your health, i really do suggest that you go very very slowly - some start with tiny crumbs if need be.

    If you need more specific info i suggest you start a thread asking Richvank for help - he has always been very helpful and courteous whenever i have asked him questions.
    Take care, Justy.
  7. Kina


    Sofa, UK
    Hi TamaraSlack

    Welcome to the forum. There is a ton of information here and lots of very knowledgeable and nice people :)

  8. TamaraSlack


    Columbus, Ohio

    Thank you for the warm welcome! I appreciate you all :)

    I will go through the slides and everything that Rich (is that what I call you?) posted in a bit, but for now, I'd like to ask some basic questions if I may and then I'll go back and read:

    1. I saw a post by Fredd yesterday talking about if you go slow then you are always in that kick start phase, so to go higher (not verbatim, but something like that). I'm wondering since I believe going slow is better for lots of reasons, if it's true that going slow always keeps you in that first stage instead of really getting things going (I'm thinking of mitochondrial activity raising and liver pathways working better).

    2. I saw the simplified protocol and went through all the supplements that Rich advised from Yasko. Questions:

    ..... a. I see hydroxocobalamin in the HydroxyB12 Drops and I see Cyanocobalamin in the Neurological Health Formula, but that's it for B12. What about using methylcobalamin - why is that not on the list of supplements? (surprised Yasko uses cyano).

    ..... b. The startup protocol from Rich is 2,130mcg of B12 (hydroxo and cyano). Is this taken all at once?

    ..... c. If I end up getting B12 shots, is there a certain kind of B12 I should ask the dr. for - I know they *ought* to know, but are there different kinds?? And since it is by IV, would the dosage be lowered?

    3. What about using TMG? That's not on the protocol except about 50mg in 1 pill of the Neurological Health Formula. Do you see people using more TMG than in that supplement? And outcomes?

    4. Regarding folic acid. I see in the most recent protocol from Rich, the Neurological Health Formula has Folic Acid in it (not in active form). Why is this? I thought we were bypassing the problem by using methyltetrahydrofolate - is adding straight folic acid not a concern? I'm thinking about the homocysteine levels - adding folic acid to a person who can't process it into the usable forms have problems, why add regular folic acid?

    5. The protocol says to take 3 drops of MethylMate B under the tongue daily - is that 1 drop 3x daily?

    6. What is the product Folinic Acid from Yasko? I'm not used to that term / is it methyl, regular folic acid???

    7. If I get testing done by what Yasko says, what is the cost? And how would I know how to read it? (I don't mean testing done by her; I mean her recommendations).

    8. I haven't read anywhere about using angstrom sized minerals; only minerals in pill form. Since I like to use either angstrom or colloidal minerals so the absorbability is better, would I just change the dosage to fit right or do Yasko's minerals in the Neurological Health Formula take this into consideration and maybe are colloidal?

    9. I didn't see any supplements that support the liver / kidneys while detoxing (opening the methylation pathway) except a little Milk Thistle in Neurological Health Formula (not sure if Pine Bark also helps) - but when I read Yasko's ebook - and I have only gotten 1/4 of the way through, she talks about making sure to support the organs before detoxing / methylation. Are there suggestions anyone has on this?

    Okay that's it for now. I am a very inquisitive person and used to get in trouble for that! I am 40 now (haven't felt well since age 14 *sad face*) - and as a kiddo, I would read books / the dictionary / do extra homework for "fun" and my mom would yell at me to go outside to play. My fun was research at 10! Hello! lol .... she still rolls her eyes at me and says "I have no idea what you are talking about" - I'm the only "reader" in the family, but I'm also the only really sicko in the family too.

  9. Merry

    Merry Senior Member

    Columbus, Ohio, USA
    Welcome, Tamara. Sorry to hear you've had such a rough time -- ill for your entire life.

    I found Rich's video of his lecture in Sweden helpful and started the protocol in September. My head cleared right away and over time I've had less and less problem with fluey symptoms.

    Good luck and best wishes.
  10. TamaraSlack


    Columbus, Ohio
    Started watching Rich's video and it quit on me! Very good info. So happy I found you guys.

    Glad you are feeling some better Merry. That's wonderful :)

    I am wondering also with my plethora of questions what the potassium is all about when we use the B12 and MTHF? I just took some along with 1mg hydrox b12 and about 150mcg MTHF (I have been using Metagenics FolaPro and it is 800mcg per pill - hard to judge exactly how much I am getting when I bite off a bit). I feel SO MUCH better when I take the B12 and MTHF *sometimes* like right now. Other times - no.

    So I am wondering if I should be on the potassium and if that would make a difference and how much.

  11. brenda

    brenda Senior Member

    Hi Tam and welcome.

    I just wanted you to be aware that a number if us have tried Rich`s and Freddd`s protocols and were not helped by them, and some have in fact ended up worse on them or at best seen no improvement. I think the reason for this is that there were significant deficiencies which became worse due to the supplements taken.

    We have had someone posting but since banned, who had a theory about these deficiencies and who kindly ordered hair mineral analysis and interpreted them for us and gave her recommendations. The principle deficiencies were riboflavin and manganese which she found in all of us.Her interest is in providing the substances the mitochondria needs in the production of ATP and these two are often overlooked especially manganese. The emphasis has been on B12 and magnesium, but something is missing as few people are really getting better.

    I was quite shocked to be told that I was severely deficienet in B2 because I had been taking a b-complex for a good while and eating an organic natural diet, juicing green vegetables including dandelion leaves. Dog Person, says that a b-complex will do this because B2 is used up in the synthesis of the other b vitamins.

    It is also her belief that when B2 and manganese in particular, are in place sufficiently, the methylation cycle will automatically come up. She believes that detoxification will also occur without needing chelators.

    I am trying out her ideas and have had more success with them than anything else I have done and have recently come off my thyroid medication because my Hashimotos seems to have been healed.

    I wonder if it is the very sick amongst us that need to do other work before taking the large doses of b vits being recommended here. I have been sick all of my long life Maybe they will not be needed if Dog Person is right She has been right so far with me and the first person to really help me.

    I just wanted you to be aware of all of your options on here and wish you well with your decisions.

    merylg and TamaraSlack like this.
  12. TamaraSlack


    Columbus, Ohio
    Thank you Brenda. I would like you to share more. If you are taking a multi B, how are you becoming B2 deficient?

    I buy my B vitamins from to take them separately with no fillers, except the B12 and MTHF. I've heard this B2 prob. thrown around, but don't know much about it - please explain it (unless that would get you kicked off the board - then email it to me). And how can I get in touch with this person?

    I was taking manganese (with a host of other things: molybdenum, zinc, chromium, etc. that seemed to be working, but added in some B vitamins at the same time - I am a wreck so I am not sure what works, what doesn't right now).

    I'm all ears!!! :)

    Thanks for talking about this - I think people need to hear not only scientific stuff, but anecdotal stories too - and have discernment and use their best judgment. The medical field had failed me for many, many years, but so has me trying to fix myself through stories I've heard. I really want to know what you have to say....

    merylg and brenda like this.
  13. Ema

    Ema Senior Member

    Midwest USA
    Re-hashing past moderation decisions ad nauseum is a rule breach in and of itself. Please refrain from this in the future.

    The poster in question was banned not for expressing her theories but for actively soliciting business for her company on this forum. This is a severe rule breach and ample cause for a ban.

    This is an important distinction and one that has been explained clearly in previous posts on the issue. Insinuating that someone was banned for expressing an opinion is offensive (at best) to the moderation team.
  14. brenda

    brenda Senior Member

    If you read what I said properly you will see that I did not say she was banned for expressing her theories. I merely stated the fact that the person was posting but is now banned so that the OP knows she cannot contact DP on the forum. Thanks.


    I am no longer taking b-complex. I take riboflavin and get the rest of the b vits from foods - cheese is a good source. Previously I was not eating dairy because I thought I was sensitive but Dog Person told me to eat unpasturised and indeed it causes me no problems. DP found by experience through her business of hair mineral analysis that b-complexes deplete riboflavin and I found this to be true in my own case as I had an immediate result from my first dose and had a reversal of long term insomnia straight away, despite the fact that I had shown none of the typical deficiency signs. The same thing occurs with manganese - other minerals `take it down`. I will give you more information privately to avoid offending anyone further.
    merylg and Asklipia like this.
  15. Asklipia

    Asklipia Senior Member

    Welcome. There is hope. I agree with brenda. I also tried B2/manganese and it helped me and my husband (we both have the same problem). We are in much better shape than you are, obviously. This was not the case 15 years ago.
    I found this forum 3 months ago around 1st March. At that point I felt 90% cured but the last 10% was not improving. We tried metafolin/mb12. All was well in a kind of manic way. It did not feel "normal" though. Then the benefits stopped and we started sliding down again. I was unwilling to up dosages as we were feeling some deficiency was being created.
    This is when we decided we could live at 90% and stopped the mb12/metafolin.

    Then I found out about DogPerson and her theories (here and and
    We started on B2/Manganese six weeks ago I think. This is without anybody's supervision (DogPerson's or any doctor's), with no hair testing or blood work etc.
    Maybe at one point the benefits of B2/manganese will stop. But we are now both covering that distance between 90% and 100% healed, and this for us in very comfortable (most probably because we were not so sick anymore).

    Also we realized that we were both B2/manganese deficient BEFORE we got sick. We are healing things we thought we parts of our "normal" selves. This is only possible if our "normal" selves were already deficient. Could be one of the reasons why we got sick in the first place. Could be one of the reasons why we could come out of this completely.
    Suddenly memories come up of HOW we made ourselves sick. All along that journey to 90% healed these flashbacks of memory were always a sign of some healing taking place. We get a lot of those on B2/Manganese, at least at the moment (they only came in about 3 weeks after we started - and now we get them more and more often).

    So, No I am not in a position to give any medical advice. Yes, I would encourage you to ponder over the posts I gave a link to.
    I wish you all the best.
    Be well!
    merylg and brenda like this.
  16. Freddd

    Freddd Senior Member

    Salt Lake City
    Hi Tamara,

    I bet you have anxiety too. I have recently found the problems and a probably specific titration of supplements for dealing with your situation. I go WAY WAY WAY past the methylation and deal with the whoel business. Your apprant specific situation I now have a probable method of dealing with. To be sure I would need you rto fill out a history which I have an Excel file questionaire in preparation that I can send you if you start a private conversation with me and give me your email address. It will give me the detail needed to be sure od your situation. I have a post in preparation which takes the hypersensitive responses into account.
  17. Catseye

    Catseye Senior Member

    SW Florida
    You may have run into problems with the IV chelation because you didn't remove the lead first. My chelation doc has been doing this a very long time, over 20 years, and one thing he's seen is that mercury will not come out in the presence of lead. So you may have had trouble with DMPS and DMSA because you were just moving mercury around instead of removing it. It took me 8 months of EDTA IVs twice a week to get lead down to an acceptable level. Then I started in DMPS IVs and got some huge relief. I'm on DMSA pills now. You're looking at several months of EDTA IVs before you should start on mercury removal or it's a waste of time. Everyone at the chelation center goes for lead first, it's just the way you do it. Mercury is the main problem but you have to approach it a certain way.

    Have you had a CDSA (comprehensive digestive stool analysis) to check for leaky gut? It's likely you have it, that's usually what messes up methylation and makes heavy metals problematic in the first place. Mainly because yeast and certain bacteria convert the relatively benign form of mercury that's in our teeth into the horrible methyl mercury, and when you have leaky gut your liver is too overwhelmed to do its job and could stop methylating. I explain that test here:

    Also see my tips for making chelation bearable:
  18. Xandoff

    Xandoff Michael

    Northern Vermont
    I am not on the protocol but have had ME/CFS for 10 years, I read your piece about your histamine reaction and your throat closing. I just wanted to share an unusual reaction I had that caused my throat to close when I coughed. It was quite frightening. After being tested for alleges I showed a allergy to mold. The Allergist asked me if I had recently brought up an old rug from my basement, I said yes how do you know. He said because this happens a lot, people will bring up an old rug from their basement and when they walk on it the spores come up. I got rid of the rug and the coughing and throat closing. This was all pre ME/CFS but I thought it was worth mentioning since we all seem to have mold issues. I am on GcMAF and I take B-12 injections daily. Good Luck Tamaraslack! Welcome to PR!

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