Why aren't all PWCs helped by methylation treatment?

Discussion in 'Fibromyalgia Main Forum' started by richvank, May 22, 2009.

  1. richvank

    richvank New Member

    Hi, all.

    While the methylation cycle treatment appears to help most
    PWCs who try it, there are some who report that it hasn't helped them at all, and others
    whose recovery is painfully slow.

    In keeping with my goal of "no PWC left behind," I've been trying to understand
    the cause or causes of this.

    Recently I've been analyzing some individual cases that fall into this category,
    and I think I am beginning to understand at least one possible cause.

    Namely, low methionine. As you may know, methionine is the raw material for
    the methylation cycle. It's what feeds this cycle, and the whole sulfur
    metabolism (though cysteine, taurine, and sulfate from the diet also
    contribute). If methionine is low, the methylation cycle will not operate well,
    even though the partial block at methionine synthase has been lifted.

    It's true that there is some methionine in the Yasko multi that is part of the
    protocol, but this doesn't seem to be enough to keep methionine high enough by
    itself at the dosages used.

    The bulk of our methionine comes in as part of the protein in the diet. I think
    there are several possible reasons why the body's methionine status might be
    low. The first is that there might be insufficient intake of total protein or
    specifically of methionine-containing protein in the diet.

    Another might be low stomach acid, which seems to be very prevalent in CFS.
    Stomach acid is necessary to convert pepsinogen into pepsin in the stomach to
    begin the digestion of protein. It's also needed to signal the pancreas to
    secrete digestive enzymes when food enters the duodenum.

    Another reason might be pancreatic insufficiency. If the pancreas is unable to
    secrete enough proteolytic enzymes, the protein will not be broken down properly.

    Another might be small bowel overgrowth of dysbiotic bacteria. These bacteria
    can compete with the body for the amino acids.

    So I would like to encourage people who are on the methylation cycle treatment
    to make sure that a normal methionine status is maintained. For those who want
    to test for this, a urine amino acids test or a plasma amino acids test will
    show the methionine status.

    Of course, it's important that the other essential amino acids be at normal
    levels as well, since they are the building blocks of protein, and a great deal
    of the body's overall biochemistry depends on being able to make proteins.

    If methionine and the other essential amino acids are low, the above listed
    possible reasons should be considered, and appropriate actions taken to correct

    I hope this is helpful.

    Best regards,


    [This Message was Edited on 05/22/2009]
  2. AuntTammie

    AuntTammie New Member

    That makes sense - thanks for posting.

    Also, just out of curiosity - since you said that this is also what feeds sulfur metabolism, would being low in methionine be a possible reason for having major problems with taking MSM?
  3. m1she11e

    m1she11e New Member

    This is a little off subject but have been meaning to ask you something. I had a B12 test done and it was HIGH. Quite high. My doctor said it meant nothing as B12 was water soluble. I was taking the B12 you recommend and the Folate. I was taking it at a very low dose though. Ive read alot of different things about this and no one has the same view. Ive read the body isnt absorbing B12 so it is floating around in your blood stream, I have read too much can cause the same symptoms as too little. I dont know if the supplements were enough to bring it so high? I am no longer taking them but felt it was interesting and cant seem to get a good answer. Any thoughts?

    I have problems with MSM too Aunt Tammie and never really knew why. I avoid anything with even the smallest amount of MSM.

  4. richvank

    richvank New Member

    Hi, Aunt Tammie.

    I believe that when MSM is not tolerated well, it means that there is a problem at the sulfite oxidase step in the sulfur metabolism. This is the reaction that oxidizes sulfite to form sulfate. If it is operating too slowly, sulfite can build up, and it is toxic at high levels. It can produce headaches and other symptoms, and it can also further deplete glutathione.

    Molybdenum forms a cofactor for the sulfite oxidase enzyme, which helps it to process sulfite. Some people have reported that supplementing molybdenum up to as much as 500 micrograms per day helps them to tolerate sulfur-containing supplements.

    Another possibility is that MSM is stimulating the operation of the detoxication system, which depends on sulfur-containing substances to a large degree. If so, it could be mobilizing stored toxins into the blood. There is a limit to how fast these can be removed from the blood and excreted. Taking a lower dosage might help if this is the situation.

    Best regards,

  5. richvank

    richvank New Member

    Hi, Michelle.

    The form of B12 that is included in the simplified treatment approach is hydroxocobalamin, and no adverse effects have been reported from excess intake of it. The Institute of Medicine of the U.S. National Academy of Sciences has not set an upper limit for B12, because of the lack of adverse effects.

    Most people with CFS are in a state of oxidative stress, because their glutathione is depleted. One result of this is that B12 is oxidized by reacting with toxins. In my hypothesis, that is what maintains the partial methylation cycle block and makes CFS a chronic condition.

    To correct this situation, it is necessary to take a high enough daily dosage of hydroxocobalamin, together with a more normal dosage of folate in the active form of 5-methyl tetrahydrofolate (FolaPro or Metafolin) to overcome this problem and get the methylation cycle operating more normally again.

    So it's true that the B12 level in the blood must be pushed higher than normal, temporarily, to overcome the loss of much of the B12 to oxidation. This "brute force" approach is the only way I know of to correct this partial block. As the methylation cycle begins to operate more normally, the glutathione levels rise, and the state of oxidative stress is corrected. When that occurs, the dosage of B12 can be decreased.

    The best way to determine what the situation is in a particular case is to run the Vitamin Diagnostics methylation pathways panel. Here is the contact information:

    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 costs $300 and requires an order from a physician or a chiropractor. The best way to order the panel is by fax, on your clinician’s letterhead.

    Available from:

    Vitamin Diagnostics, Inc.
    Rt. 35 & Industrial Drive
    Cliffwood Beach, NJ 07735
    Phone:+1 (732) 583-7773
    Fax: +1 (732) 583-7774)

    Lab Director: Tapan Audhya, Ph.D.
    (usually at the lab on Tues. and Wed. from 1 to 3 p.m., Eastern time)

    Dr. Audhya is willing to help clinicians with interpretation of the panel by phone, or you can use the following comments on interpretation of the panel:

    Several people have asked for help in interpreting the results of
    their Vitamin Diagnostics, Inc., methylation pathway panels. Here are my
    suggestions for doing so. They are based on my study of the
    biochemistry involved, on my own experience with interpreting more
    than 120 of these panel results to date, and on discussion of some of
    the issues with Tapan Audhya, Ph.D., who is the director of the
    Vitamin Diagnostics lab.

    The panel consists of measurement of two forms of glutathione
    (reduced and oxidized), adenosine, S-adenosylmethionine (SAM) , S-
    adenosylhomocysteine (SAH), and seven folic acid derivatives or

    According to Dr. Audhya, the reference ranges for each of these
    metabolites was 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: This is a measurement of the concentration of the
    reduced (active) form of glutathione (abbreviated GSH) in the blood
    plasma. From what I've seen, most people with chronic fatigue
    syndrome (PWCs) have values below the reference range. This means
    that they are suffering from glutathione depletion. As they undergo
    the simplified treatment approach to lift the methylation cycle
    block, this value usually rises into the normal range over a period
    of months. I believe that this is very important, because if
    glutathione is low, vitamin B12 is likely unprotected and reacts with toxins
    that build up in the absence of sufficient glutathione to take them
    out. Vitamin B12 is thus “hijacked,” and not enough of it is able to
    convert to methylcobalamin, which is what the methylation cycle needs
    in order to function normally. Also, many of the abnormalities and
    symptoms in CFS can be traced to glutathione depletion.

    Glutathione (oxidized): This is a measurement of the concentration
    of the oxidized form of glutathione (abbreviated GSSG) in the blood
    plasma. In many (but not all) PWCs, it is elevated above the normal
    range, and this represents oxidative stress.

    Adenosine: This is a measure of the concentration of adenosine in the
    blood plasma. Adenosine is a product of the reaction that converts
    SAH to homocysteine. In some PWCs it is 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, and I suspect 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.

    S-adenosymethionine (RBC) (SAM): This is a measure of the
    concentration of SAM in the red blood cells. Most PWCs have values
    below the reference range, and treatment raises the value. S-
    adenosylmethionine is the main supplier of methyl groups in the body,
    and many biochemical reactions depend on it for their methyl
    groups. A low value for SAM represents low methylation capacity, and
    in CFS, it appears to result from a partial block at the enzyme methionine
    synthase. Many of the abnormalities in CFS can be tied to lack of
    sufficient methyation capacity.

    S-adenosylhomocysteine (RBC) (SAH): This is a measure of the
    concentration of SAH in the red blood cells. In CFS, its value
    ranges from below the reference range, to within the reference range,
    to above the reference range. Values appear to be converging toward
    the reference range with treatment. SAH is the product of reactions
    in which SAM donates methyl groups to other molecules.

    Sum of SAM and SAH: When the sum of SAM and SAH is below 268
    micromoles per deciliter, it appears to suggest the presence of
    upregulating polymorphisms in the cystathione beta synthase (CBS)
    enzyme, though this may not be true in every case.

    Ratio of SAM to SAH: A ratio less than about 4.5 also 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.

    5-CH3-THF: This is a measure of the concentration of 5-methyl
    tetrahydrofolate in the blood plasma. It 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 most important form for the methylation cycle. Many PWCs have a
    low value, consistent with a partial block in the methylation cycle.
    The simplified treatment approach includes FolaPro, which is
    commercially produced 5-CH3-THF, so that when this treatment is used,
    this value 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. I have seen this frequently,
    and I think it demonstrates that the “hijacking” of B12 is the root
    cause of most cases of partial methylation cycle block. Usually
    glutathione is low in these cases, which is consistent with lack of
    protection for B12, as well as with toxin buildup.

    10-Formyl-THF: This is a measure of the concentration of 10-formyl
    tetrahydrofolate in the blood plasma. It is usually on the low side in PWCs.
    This form of folate is involved in reactions to form purines, which
    form part of RNA and DNA as well as ATP.

    5-Formyl-THF: This is a measure of the concentration of 5-formyl
    tetrahydrofolate (also called folinic acid) in the blood plasma.
    Most but not all PWCs have a value on the low side. This form is not used
    directly as a substrate in one-carbon transfer reactions, but it can
    be converted into other forms of folate. It is one of the
    supplements in the simplified treatment approach, which helps to
    build up various other forms of folate.

    THF: This is a measure of the concentration of tetrahydrofolate in
    the blood plasma. In PWCs it is lower than the mean normal value of 3.7
    nanomoles per liter in most but not all PWCs. This is the
    fundamental chemically reduced form of folate from which several
    other reduced folate forms are made. The supplement folic acid is
    converted into THF by two sequential reactions catalyzed by
    dihydrofolate reductase (DHFR). THF is also a product of the
    reaction of the methionine synthase enzyme, and it is a reactant in
    the reaction that converts formiminoglutamate (figlu) into
    glutamate. If figlu is high in the Genova Diagnostics Metabolic
    Analysis Profile, it indicates that THF is low.

    Folic acid: This is a measure of the concentration of folic acid in
    the blood plasma. Low values suggest folic acid deficiency in the
    current diet. High values are sometimes associated with inability to
    convert folic acid into other forms of folate, such as because of
    polymorphisms 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. See comments on 5-formyl-THF above. It
    usually tracks with the plasma 5-formyl-THF concentration.

    Folic acid (RBC): This is a measure of the concentration of folic
    acid in the red blood cells. The red blood cells import folic acid
    when they are initially being formed, but during most of their
    approximately four-month life, 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. 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 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 can raise this value over time.

    Best regards,


  6. AuntTammie

    AuntTammie New Member

    Thanks for your answer re: MSM. Your explanations make so much sense.

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