Methylation Block treatment from basic to advanced

Discussion in 'Fibromyalgia Main Forum' started by richvank, May 22, 2007.

  1. richvank

    richvank New Member

    Hi, all.

    Some people on the board have asked that information about the methylation cycle block treatment for CFS be gathered together in one thread.

    I will attempt to do that in this thread.

    I realize that some people just want the simplest possible bottom line, so I will give that first.

    Other people want to delve more deeply, or want something they can give to their doctors, so I will include that later.

    The farther you read in this thread, the more detailed the discussion will be, in terms of the biochemistry. The material that is the easiest to read will be at the top.

    First, I will present the current version of the simplified treatment approach, which involves only five supplements, costs a little over $2.00 per day, and does not involve any testing. This treatment is intended to be a cure for CFS for many people. It remains to be seen whether that will prove out.

    Then I will post the article on treatment that I wrote in January, 2007, which was the first place the simplified treatment approach was described. This article also sketches the main aspects of the full treatment for the methylation cycle block that has been developed by Dr. Amy Yasko. The simplified approach is basically the core of step 2 of Dr. Yasko's full treatment, which I extracted with the help of Trina (who participates on this board).

    Since I wrote the treatment article, the simplified approach seems to be working better than I expected, and quite a few people are now trying it. There are also a number of people trying the full Yasko treatment. They participate in the Yahoo cfs-yasko discussion group. At this point, I don't yet know how to determine which of these approaches would work best for which people.

    After these things are posted, I will post my 2007 IACFS poster paper, which presents the details of the hypothesis on which this treatment of CFS is based. It is called the "glutathione depletion--methylation cycle block hypothesis." This paper discusses CFS at the basic biochemical level.

    After this, I will post an article that was published in a somewhat modified form in the October 2006 issue of the Townsend Letter, which describes the history of the connection I have made between autism and CFS. I was not the first person to note that there is a connection, but I was perhaps the first to establish this on the basis of the detailed biochemistry of these two disorders. Professor Malcolm Hooper in the UK realized the connection several years ago, as did Dr. Michael Goldberg in southern California.

    Next, I will post my 2004 AACFS poster paper about glutathione depletion in CFS.

    Finally, I will post another poster paper from the 2007 IACFS meeting in which I suggest a hypothesis to explain the greater prevalence of CFS in women than in men.

    I may add some other discussion as time permits, but I think this will give a fairly complete documentation of this subject.

    Rich Van Konynenburg, Ph.D.
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  2. springrose22

    springrose22 New Member

    Thank you so much Rich! Marie
  3. richvank

    richvank New Member

    Here is the current version of the simplified treatment approach based on the glutathione depletion--methylation cycle block hypothesis.

    All the supplements can be obtained from the holisticheal site, or you can obtain all but the Complete Vitamin and Neurological Health Formula elsewhere.

    These supplements and dosages have been selected by Dr. Amy Yasko as part of her complete treatment approach, as described in her book "The Puzzle of Autism." Substitutions or changes in dosages may not have the same effect as the combination of supplements and dosages suggested, although some people do better if they start with smaller dosages than those given below.

    It's important to "listen to your body" when doing this treatment. If the detox becomes too intense to tolerate, or if you begin to have significant cardiac or respiratory symptoms, or if you are unable to have regular bowel movements during this treatment, back off on the dosages or take a break for a while. This treatment should be done in cooperation with your doctor, so that any individual issues you have can be taken care of.

    People who known lung or heart conditions should consult with their doctors before deciding whether to try this treatment. One person with a history of lung disease and diastolic dysfunction reported shortness of breath and cardiac symptoms when trying this treatment.

    This treatment will produce die-off and detox symptoms as your immune system and detox system come back to normal operation and begin ridding your body of accumulated infections and toxins. This is inevitable, and has to be endured. However, while you experience detox symptoms, you should also experience improvement in your CFS symptoms over time. You can control the intensity of the detox symptoms by adjusting the dosages.

    Please resist the temptation to try to get better faster by increasing the suggested dosages. In particular, do not exceed the suggested dosages for the FolaPro and the Intrinsi/B12/folate supplements, at least until you have been detoxing for several weeks. Some who have done this have experienced very unpleasant levels of detox symptoms that had momentum and did not decrease rapidly when the supplements were stopped.

    As far as I know, there are no negative interactions between these supplements and the prescription medications used by physicians in treating CFS. However, I urge you to discuss this issue with your doctor if you are taking prescription medications.

    If you are taking prescription medications, I expect that you will need them less and less as you are on this treatment. However, be sure to consult with your doctor before stopping the use of prescription medications. Some of them can cause serious withdrawal symptoms if stopped too abruptly.

    Several people have reported that they no longer needed thyroid hormone supplementation shortly after starting this treatment. If you are taking thyroid hormones, be alert to the possibility that you may experience HYPER thyroid symptoms after starting this treatment, such as palpitations and sweats. Consult with your doctor about decreasing thyroid supplementation if this occurs.

    One person who has an autonomous multinodular goiter experienced respiratory and cardiac problems while doing this treatment, so if such a goiter is present, caution should be exercised and a doctor should be consulted before deciding whether to try this treatment.

    Here are the five supplements:

    1. one-quarter tablet (200 micrograms) Folapro (Metagenics)

    2. one-quarter tablet Intrinsi/B12/folate (Metagenics)

    3. (up to) 2 tablets (It’s best to start with ¼ tablet and work up as tolerated) Complete vitamin and antioxidant neurological health formula (Holistic Health Consultants)

    4. one softgel capsule Phosphatidyl Serine Complex

    5. one sublingual lozenge Perque B12

    The first two supplement tablets can be difficult to break into quarters. An alternative is to crush them into powders, mix the powders together, and divide the powders into quarters using a knife and a flat surface. The powders can be taken orally with water, with or without food, and do not taste bad.

    Some people have asked what time of the day to take the supplements. A few have reported that the supplements make them sleepy, so they take them at bedtime. If they don't make you sleepy, I don't think it matters when you take them.

    Since some questions have been asked about what ingredients are essential, and since some of the people here appear to be taking augmented versions of the simplified GD-MCB treatment approach that I wrote about in my January treatment paper, I want to give you some history and some comments about that to help you with your own choices about what to take. There's nothing proprietary about what I've written. I would just like to see people get healthy.

    I have been trying to figure out CFS for about 10 years, since a friend of my wife and myself developed it and wasn't given any hope by her doctor. I started studying biochemistry and physiology, joined some CFS internet lists, started using PubMed to study the published literature, went to the conferences, got Dr. Cheney's tapes, etc. In 1999 I picked up on Dr. Cheney's observation that many of his patients were depleted in glutathione. When I learned of all the things that glutathione normally does, and saw that many of these tied in with the symptoms of CFS, I became convinced that this is a fairly fundamental aspect of the pathophysiology of CFS. So for several years I encouraged PWCs to build their glutathione by various means. This helped quite a few, but it was not a cure for most. It was just a temporary help. Some couldn't tolerate it at all. In the fall of 2004 I reported this at the AACFS conference in Madison, WI. You can find that poster paper at the phoenix-cfs site, under research. It's also posted below.

    Then in late 2004, a paper came out by S. Jill James et al. on autism. I learned for the first time that glutathione was depleted in autistic kids, and that this was tied to a problem earlier in the sulfur metabolism, in the methylation cycle. This was a big BINGO for me. It looked as though the same thing was happening in CFS, and now I knew why PWCs could not build up their glutathione levels on a permanent basis by the methods I had been advocating.

    I went to the Long Beach DAN! conference and learned more about autism, and I became more convinced that we were dealing with the same mechanism.

    I started suggesting some DAN! treatments to the PWCs, using the Pangborn and Baker book, which is an excellent background book on the biochemistry of both autism and CFS, in my opinion, and I recommend it. Well, the people who tried this felt somewhat better at first, but then things turned south for them. Meanwhile, I learned about the approach of Amy Yasko, N.D., Ph.D., in autism, and I decided that I liked it better, because it started at the genetic level, and built the biochemistry on top of that, dealing with people individually based on their genetic variations. So about a year ago I started encouraging PWCs to try Amy's approach.

    Amy's approach is not simple, easy, quick or cheap, and it has not been easy for PWCs to do it, but the people doing it have experienced benefit and are continuing with it.

    For the 2007 IACFS conference, I decided to submit another paper, this time giving the rationale for a methylation block in CFS, connected to the glutathione depletion. It was accepted, but again only as a poster paper, so I printed up a lot of copies of it and did a personal sales job on as many people at the conference as I was able. One who was interested was Dr. David Bell, who is chairman of the federal CFS Advisory Committee. He asked me to write up a description of treatment based on this hypothesis. Later in January I emailed him a treatment writeup, which is what is on the internet. In writing this, I knew that the full Yasko treatment approach is probably not going to be practical for most clinicians. Amy has written me that she has not been able to interest many in doing what it takes to get up to speed on it and to apply it in individual cases. They just don't have the time, and frankly, in my opinion, many of them do not find biochemistry very easy to assimilate.

    So I decided to try including a simpler approach in addition to describing the full Yasko treatment approach. In doing so, I asked Trina in the cfs_yasko internet group for help, since she is very knowledgeable about the Yasko treatment approach and is using it herself.
    She pointed out some problems with what I had in my draft, and then suggested a better approach, which I adopted substantially. The simplified approach I put in my treatment article is essentilly what Trina suggested, because it made a lot of sense to me. So I must give the credit for this to her. She also suggested including nucleotides, but I left them out because there are some in the complete multi (now called the General multi).

    O.K., so now what do each of the ingredients do, and how important is each one?

    FolaPro--This is in there because a lot of PWCs have a SNP in their MTHFR enzyme that affects the production of 5-methyltetrahydrofolate, which is the same as FolaPro. This form of folate is the one used by the methionine synthase enzyme, and that's the enzyme that appears to be blocked in many or most cases of CFS. If a person had their genetics characterized, as in the full Yasko approach, they would know for sure whether they needed this one, but in the simplified approach we just suggest giving to everyone.

    Intrinsi/B12/folate--This one has 3 forms of folate--FolaPro, folinic acid and folic acid. It also has some cyano-B12 and some intrinsic factor as well as some other things. The folinic is helpful because some people can't use ordinary folic acid well, as a result of genetic issues. Also, this helps to supply forms of folate that will make up for the low tetrahydrofolate resulting from the block in methionine synthase. This enzyme normally converts 5-methytetrahydrofolate to tetrahydrofolate, which is needed in other reactions. This supplement also has some intrinsic factor and some ordinary cyano-B12 supplement to help those who have a type of pernicious anemia that results from low production of intrinsic factor in the stomach and which prevents them from absorbing B12 in the gut. B12 is also needed by methionine synthase, in the form of methylcobalamin, but this supplement has cyanocobalamin, which must be converted in the body by glutathione and SAMe to form methylcobalamin. As glutathione and SAMe come up, this should become more effective.

    Complete vitamin and ultra-antioxidant (now called the General Vitamin Neurological Health Formula)--This is Amy Yasko's basic high-potency general nutritional supplement. This is kind of a foundation for the biochemistry in general. However, I think it's better for PWCs than other general supplements, because it has particular things needed for dealing with a methylation cycle block, including some TMG and sulfur metabolism supplements as well as nucleotides. It is also high on magnesium and low on calcium, and has no iron or copper. So I don't think other general supplements do everything this one does, and I think it's important in the treatment.
    The TMG helps to get the shortcut pathway in the methylation cycle going, and that helps to build SAMe, which is needed to get the methionine synthase reaction going. The nucleotides will help to supply RNA and DNA for new cells until the folate cycle is working right again.

    Phosphatidylserine complex--This has various phosphatidyls in it, which will help repair damaged membranes, including those in cells of the brain and nervous system. It should help with the cortisol response. It also has some choline, which can be converted to TMG (betaine) in the body, to help start the shortcut pathway.

    Perque B12--This is a hefty dose of sublingual hydroxocobalamin. As I said above, B12 is needed to get methionine synthase going. Methylcobalamin is actually the form needed, but some people cannot tolerate it for genetic reasons, and I'm also concerned that people with high body burdens of mercuric mercury could move mercury into the brain if they take too much methylcobalamin. Methylcobalamin is the only substance in biological systems that can methylate mercury, and methylmercury can cross the blood-brain barrier. This supplement is sublingual to compensate for poor B12 absorption in the gut of many people.

    There are also two others that were in the earlier version of the simplified approach:

    SAMe--This is normally part of the methylation cycle. Depending on genetic variations (SNPs or polymorphisms) some people can't tolerate much of this, and some need more. The dosage is a compromise. If people can't tolerate this, they should leave it out, because stimulating the shortcut pathway, using TMG and choline in the other supplements) will probably make enough for them.

    Methylation Support Nutriswitch Formula--This is a mixture of RNAs that is designed to help the methylation cycle. It is somewhat expensive, and is not essential, but is helpful and worthwhile if people can afford it. Note added on July 10, 2007: In commenting on the simplified treatment approach, Dr. Amy Yasko has written me the following: "If an individual can only afford a single RNA
    then I would actually have them use the Stress or HF rather than the methylation support formula, especially as it will take the edge off detox." So those wishing to try an RNA formula with the simplified approach may find one of these two to be a better option. They are available under RNA Products on the holisticheal site.

    O.K., now you know about as much as I do about the ingredients in the simplified GD-MCB treatment approach. I do think that the forms of folate and B12 are probably essential, because they go after the basic problem in CFS, in my opinion. I think the General supplement is important, and, and I think that some way to stimulate the shortcut is important, also. SAMe will help some people but perhaps not be tolerated by others, and if not, can be left out. The Methylation Support formula is helpful, but could be left out.

    I don't think there is a problem with taking other supplements together with these basic supplements, for the most part. One exception is that I would not recommend taking additional folate beyond what is suggested above, since the various forms of folate compete with each other for absorption, and it is important to get enough of the active forms into the body. Also, it is important not to take too much folate, because this can cause the detox to develop a momentum, so that it will take some time to slow it down if you want to do that.

    I would also not recommend taking additional trimethylglycine (TMG, also called betaine) or additional forms of choline, such as phosphatidylcholine or lecithin, since that will speed up the BHMT pathway too much at the expense of the methionine synthase pathway. The betaine-HCl used to augment stomach acid is something you may have to drop while doing this treatment, too, since it will contribute to this problem.

    Adding glutathione support will help some people, as will adding molybdenum. As more things are added, though, we are moving toward the full Yasko approach, which is fine, but it is more complicated and expensive, too. Maybe we should view this simplified approach as the front door to the full Yasko approach. It might work fine by itself for some people, but for others, maybe they should look at The Puzzle of Autism, sold on, to see what else there might help them. If the simplified approach seems to help to some degree, and it catches your attention for that reason, but it still doesn't do the whole job for you, then you could look further at the the full Yasko treatment. At least then you would have some reason to dig into it. Otherwise, it looks pretty daunting to a lot of PWCs.


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  4. richvank

    richvank New Member

    January 25, 2007

    Suggestions for Treatment of Chronic Fatigue Syndrome (CFS) based on the Glutathione Depletion—Methylation Cycle Block Hypothesis for the Pathogenesis of CFS

    Richard A. Van Konynenburg, Ph.D.

    (Independent Researcher and Consultant)

    I presented the Glutathione Depletion—Methylation Cycle Block Hypothesis for the pathogenesis of CFS in a poster paper at the 8th international conference of the International Association for Chronic Fatigue Syndrome in Ft. Lauderdale, Florida, on January 10-14, 2007. This poster paper is available on the internet at the following url:
    Since then I have received requests from some clinicians for a description of a treatment approach based on this hypothesis.

    I am a researcher, not a clinician, and I am well aware that it is one thing to believe that one understands the pathogenesis of a disorder, but quite another to know how to treat patients who suffer from this disorder. Nevertheless, I will respond to these requests to the degree I am able. What I can say in this regard will be based on what I perceive are the most successful treatment approaches currently used in autism, which I believe shares the same basic pathogenetic mechanism with CFS, and also on limited experience in communicating by internet with the small number of CFS patients so far who have elected to try these approaches. Of course, I am counting on clinicians to apply their judgment to what I write here, based on their expertise and clinical experience, since responsibility for treatment falls to them.

    I suspect that clinicians would like for me to supply a simple, straightforward approach that would be uniformly applicable to all CFS patients and thus readily useable in a typical busy practice in today’s medical climate, in which it is practicable to devote only a relatively short time to each individual patient. Believe me, I understand this, and I would very much like to be able to give such a response.

    Now comes the “however.” At this point it appears that it will actually be necessary in most cases to devote considerable time to each patient, and to tailor the treatment program to the individual patient. In my opinion, the reasons for this do not appear now to be lack of understanding of the pathogenesis, but to be inherent in the genetic individuality of the patients as well as in the variety of their concomitant medical issues and, for many, in their general state of debility. I now see this need for individual treatment and significant time investment in each patient as the most significant problem in the practicable delivery of treatment to these patients. Hopefully this will become clearer as I explain further, and hopefully also, this problem can be ameliorated to some degree in the future as more experience is gained.

    If you have read my pathogenesis paper, you know that I now believe that the fundamental biochemical issue in at least a large subset of the CFS patients is that the methylation cycle is blocked. Therefore, I think that the main goal of treatment must be to remove this block and to get the methylation cycle back into normal operation. I believe that it is also true that glutathione depletion is present in these patients and is directly responsible for many of the features of CFS, as I described in my recent poster paper, but I have found in interacting with clinicians as well as with many patients on the CFS internet lists, that it is usually not possible to normalize the glutathione levels on a permanent basis by direct approaches of glutathione augmentation. Instead, it appears that the methylation cycle block must be corrected first, to break the vicious circle that is holding down the glutathione levels. In addition to this, some patients, because of particular genetic polymorphisms, cannot tolerate supplementation with glutathione or other substances intended to help them directly to build glutathione. One clinician estimated to me that this group amounts to about one-third of the patients.

    Based on what is being done in autism by the Defeat Autism Now! (DAN!) researchers and clinicians and independently by Dr. Amy Yasko, N.D., Ph.D., I am going to suggest two treatment approaches for CFS. The first is a simplified approach which may be applicable to patients who have not been ill for an extended period, and who are not very debilitated. Use of this simplified approach would be based on the hope that the patient does not have certain genetic polymorphisms, which would not be known in this simplified approach. If the patient does in fact have these polymorphisms, the simplified approach will not be successful, and then you will have to move on to the more complex treatment. This simpler treatment approach is based partly on the treatment that was used by Dr. S. Jill James, Ph.D., et al. in the study that found the connection between the methylation cycle block and glutathione depletion in autism (This was Ref. 2 in my pathogenesis paper), but it makes use of supplements that are part of Dr. Amy Yasko’s treatment program. The second treatment approach is much more involved and is based on Dr. Yasko’s complete autism treatment. I currently believe that the second approach is the type of treatment that will be necessary also for most CFS patients, and certainly those of longer standing or greater debility, as well as those having certain genetic polymorphisms. However, I am including the simpler approach in an effort to match the practical demands of current medical practice, to the degree I understand them.

    In the simplified treatment approach, potentially applicable to patients who have not been ill for an extended period, who are not very debilitated, and who will initially be assumed not to have certain genetic polymorphisms, one would proceed directly toward the goal of restarting the methylation cycle, together with some general nutritional support. If this treatment is tolerated and is efficacious in a particular case, I think it could actually be relatively straightforward. I think it should be borne in mind, though, that if the simplified approach is not effective for a particular patient, there is the risk that trying it could discourage the patient before she or he reaches the second option. So I think it would be proper and wise to discuss this issue with the patient up front, and to apply considerable clinical judgment as to whether the simplified approach should be tried on a particular patient.

    The simplified approach would involve giving the following oral supplements daily, all of which are available from Dr. Yasko’s supplement website at

    ¼ tablet (200 micrograms) Folapro (Folapro is 5-methyl tetrahydrofolate, an active form of folate, which is sold by Metagenics with a license from Merck, which holds the patent on synthesis).

    ¼ tablet Intrinsic B12/folate (This includes 200 micrograms of folate as a combination of folic acid, 5-methyl tetrahydrofolate, and 5-formyl tetrahydrofolate, aka folinic acid or leucovorin (another active form of folate), 125 micrograms of vitamin B12 as cyanocobalamin, 22.5 milligrams of calcium, 17.25 milligrams of phosphorus, and 5 milligrams of intrinsic factor)

    (up to) 2 tablets (It’s best to start with ¼ tablet and work up as tolerated) Complete vitamin and ultra-antioxidant from Holistic Health Consultants (This is a multivitamin, multimineral supplement with some additional ingredients. It does not contain iron or copper, and it has a high ratio of magnesium to calcium. It contains antioxidants, some trimethylglycine, some nucleotides, and several supplements to support the sulfur metabolism.)

    1 softgel capsule Phosphatidyl Serine Complex (This includes the phospholipids and some fatty acids)

    1 sublingual lozenge Perque B12 (2,000 micrograms hydroxocobalamin with some mannitol, sucanat, magnesium and cherry extract)

    1 capsule SAMe (200 mg S-adenosylmethionine)

    1/3 dropper, 2X/day Methylation Support Nutriswitch Formula (This is an RNA mixture designed to help the methylation cycle. It is not essential, but is reported to be helpful.)

    Note that I have specified hydroxocobalamin rather than methylcobalamin as the main supplemental form of vitamin B12. I’ve done this to accommodate patients who may have downregulating polymorphisms in their COMT (catechol-O-methyltransferase) enzyme, which many CFS patients seem to have. If they do not have these polymorphisms, methylcobalamin would be more effective, but in this simplified treatment, the patient’s polymorphisms will not be known. I am also including a small amount of SAMe, which is also a compromise, since the amount needed will again depend on COMT polymorphisms, which will not be known for this simplified treatment. The amount of B12 specified is also a compromise, since those with certain polymorphisms will benefit from a higher dosage than will those without them.

    After this treatment is begun, you can expect the patient to feel worse initially, and I think it would be proper and wise to make the patient aware of this before the treatment is begun. It is necessary to determine whether this feeling is occurring because the treatment is working and the patient’s body is beginning to detox and kill viruses, or whether it is occurring because the patient does in fact have upregulation polymorphisms in their CBS (cystathionine beta synthase) enzyme, in which case you will have to move on to the more complicated complete treatment regimen. Which of these is the case can be determined by taking spot urine samples for a urine toxic metals test and a urine amino acids test from Doctor’s Data Laboratories. These can be ordered through Dr. Yasko (at if you would like to receive her interpretation of the results, or they can be ordered directly from Doctor’s Data Laboratories ( If the toxic metals are elevated on the urine toxic metals test, this will indicate that the patient has begun to detox, which is desirable. If taurine and ammonia are elevated on the urine amino acids test, this will suggest that the patient does have CBS upregulation polymorphisms, in which case you will have to stop this treatment and move to the more complicated approach described below. It would be best to do this treatment for a week or two before doing the urine tests, so that meaningful results can be obtained on these tests, unless the patient cannot tolerate it. If the latter is the case, then you will have to go on to the more complicated treatment approach described below.

    As I have emphasized, the simplified treatment approach may or may not be tolerated by a particular patient, and I will explain why it might not be tolerated later in this discussion.

    Now I will move on to the more complicated treatment approach that I currently believe will be necessary for most of the patients. I will not supply all the details of this treatment approach in this letter, but will try to give you an overall picture of the sequence of steps involved. I recommend reading Dr. Yasko’s book “The Puzzle of Autism,” and consulting her other materials as well. These are available from by searching on “Amy Yasko.”

    Before getting into this treatment approach, I first want to discuss some important issues, and then I will discuss the treatment, step by step:

    1. It is necessary to minimize the use of pharmaceuticals in treating CFS patients. There are at least two reasons for this. As you know, the use of pharmaceuticals is based on their being eliminated at certain rates by the body’s detox system, found primarily in the liver, kidneys and intestines. However, many CFS patients have polymorphisms in their detox enzymes, including CYP450 enzymes and Phase II detox enzymes. (If desired, these can be characterized by the Detoxigenomic panel offered by Because of these polymorphisms, many patients are genetically unable to detox pharmaceuticals at normal rates, and cannot tolerate them. In addition to this, all patients who have the glutathione depletion and methylation cycle block suffer from biochemical inhibition of their detox systems, whether they have these polymorphisms or not. Because of these two factors, CFS patients suffer from the toxic effects of pharmaceuticals. Treatment using nutritional supplements is necessary, and some herbals can be tolerated as well.

    2. Because of the broad nature of the current case definition for CFS, the population defined by it is very heterogeneous. It is likely that the pathogenesis model I have presented for CFS will not fit all patients. For this reason, I recommend a relatively inexpensive glutathione measurement initially, such as the red blood cell total glutathione test offered by (phone them for details) or by Mayo Laboratories. Perhaps a better test is the serum reduced glutathione test offered as part of the Comprehensive Detox Panel at If a below-normal value is found in either of these tests, I think that there is a good chance that this pathogenesis model fits the patient.

    3. Different patients have different genetic polymorphisms in the enzymes and other proteins that impact the methylation cycle and the associated biochemical cycles and pathways. Some of these polymorphisms will have important impacts on the choice of specific parts of the treatment program. In using the more complicated treatment approach, it will be necessary to characterize the polymorphisms before it will be possible to make some of the decisions about selection of particular treatment aspects. The most comprehensive panel for this is Dr. Yasko’s Comprehensive Basic SNP (single nucleotide polymorphism) Panel I, available from Dr. Yasko has selected the polymorphisms on this panel by correlating their presence with severity of autism symptoms and with the results of biochemical testing (mainly spot urine tests for organic acids, amino acids, and essential and toxic metals). This is a somewhat unorthodox method that jumps over the usual intermediate steps involved in studying polymorphisms, and there is not universal agreement about her results in the research community, but I think Dr. Yasko’s treatment outcomes are speaking for themselves, as can be seen from the voluntary testimonials of parents of autistic children on the parents discussion group at As a researcher, of course, I look forward to the day when these polymorphisms will be thoroughly researched and characterized, and have encouraged those involved in such work to forge ahead. The results from this genetic panel require interpretation. One can either study Dr. Yasko’s materials to gain her insights on interpreting the results in general, or order her interpretation of the particular results, which is called a Genetic Analysis Report or GAR. The GAR is a computer-generated report with some general material that applies to all the cases, and specific sections that are chosen in response to the particular genetic polymorphisms found in the individual patient. As such, the continuity of the discussion in the GAR is not what would be found in a report written from scratch for each particular patient, and it may have to be read more than once to make all the connections in one’s mind, but the material contained is specific to the particular genetic panel results, and Dr. Yasko updates the material used in generating the GARs as more is learned.

    4. As I have discussed in my paper, people who have been ill for an extended period of time (many months to many years) will have accumulated significant infections and significant body burdens of toxins, because both their cell-mediated immune response and their detox system will have been dysfunctional during this time. When the methylation cycle is then restarted, both the immune system and the detox system will begin to function better. When they do, pathogens and infected cells will begin to die off at higher rates, and toxins will be mobilized. The resulting detoxification will be unpleasant, and may even be intolerable. If the patient has not been prepared in certain ways, discussed below, she or he may not be willing to continue this and may drop out of the treatment program.

    5. One of the most important preparatory activities is to make sure the gastrointestinal system is operating well enough to be able to absorb nutrients, including both food and the oral supplements used in the treatment, and also well enough to be able to dispose of toxins into the stools on a regular basis. If this is not done, it is likely that the treatment will not be successful. Treatments for the G.I. system, as well as for other aspects described below, are discussed in Dr. Amy Yasko’s book. Some CFS patients have reported benefit from Xifaxan to treat deleterious bacteria in the gut. This antibiotic is not absorbed from the G.I. tract, so it does not present problems for the detox system.

    6. Another very important aspect of the preparation is to deal with the overstimulation or overexcitation of the nervous system that is present in CFS. This probably results from several causes, including depletion of magnesium and in some cases depletion of taurine, low blood flow to the brain because of low cardiac output, glutathione depletion in the brain producing mitochondrial dysfunction, and dietary and other factors causing elevation of excitatory neurotransmitters and depletion of inhibitory neurotransmitters. It is important that this be dealt with because if it is not, the patient will be less able to tolerate the detox inherent in the treatment.

    7. Another important step is to ensure that the patient’s nutritional status is supported. Many CFS patients are in a rather debilitated state, partly because of deficiencies of essential nutrients. They are also in a state of oxidative stress. Appropriate nutritional supplements can correct these problems at least to some degree and get the overall metabolism of the patient into a better state, so that they can better tolerate the detox part of the treatment.

    8. Particular organs or systems may not be functioning well and may need extra nutritional or herbal support. Which ones will vary from one patient to another, so this part of the treatment must be tailored to the individual patient.

    9. Chronic bacterial infections should be addressed. According to Dr. Yasko, females in particular appear to be prone to streptococcal infections. She also finds that aluminum appears to be associated with the bacteria, so that when the bacteria die off, aluminum is excreted. While antibiotics can be used, there are downsides to this, both in terms of difficulty in detoxing some of the antibiotics and in terms of killing beneficial intestinal flora and encouraging deleterious ones, such as Clostridia dificile. In addition, some CFS patients have experienced tendon problems from the fluoroquinolone antibiotics. Dr. Yasko prefers natural antimicrobial treatments.

    10. When the methylation cycle is restored, the normal detox system is able to deal with more of the toxins. Dr. Yasko also uses low doses of oral EDTA, but not the sulfur-containing chelators (DMSA and DMPS), to help remove aluminum as well as other metals, including mercury. DMSA and DMPS are not used because they can also bind glutathione, so that if a patient who is low in glutathione receives these chelators, their glutathione status can be worsened. Also, DMSA and DMPS are rich in sulfur, and CFS patients with certain polymorphisms cannot tolerate them. She also uses some natural RNA formulas for detoxing, as well as for a number of other purposes during the treatment. These are somewhat costly, and are not required as part of the treatment, but are reported to be helpful.

    11. As mentioned in item 3 above, it is important to characterize relevant polymorphisms prior to bringing up the methylation cycle operation. One of the most important aspects of this is to evaluate polymorphisms in the CBS (cystathionine beta synthase) enzyme, which is located at the entrance to the transsulfuration pathway and converts homocysteine to cystathionine. Although this is somewhat controversial within the research community, Dr. Yasko finds that certain polymorphisms cause an increase in the activity of this enzyme. The result is that there is too large a flow down the transsulfuration pathway, and somewhat counterintuitively this results in lowered production of glutathione, as well as elevated production of taurine, ammonia, sulfite and hydrogen sulfide. The last three of these substances are toxins. If a patient has CBS polymorphisms, it is necessary to deal with this aspect before restarting the methylation cycle. If this is not done, efforts to start this cycle will result in increased production of these toxins. This may explain why some patients cannot tolerate direct efforts to build glutathione using sulfur-containing substances, while others derive some benefit from this. Dealing with this CBS upregulation situation can take a month or longer.

    12. Only after all these issues have been addressed is the patient ready to start supplementing with larger amounts of the folates and cobalamins to begin major restoration of operation of the methylation cycle.

    13. As you can see from the diagram in my pathogenesis paper, there are two possible pathways from homocysteine to methionine. One involves the enzyme methionine synthase, which requires methylcobalamin and is linked to the folate cycle as well, and the other involves the enzyme betaine homocysteine methionine transferase (BHMT), and requires trimethylglycine or one of the phospholipids (phosphatidyl-serine, -choline, or -ethanolamine). Ultimately, it is important to get the methionine synthase pathway back into operation, but in Dr. Yasko’s practice it has been found that it is easier to start up the BHMT pathway first. I think the reason is that S-adenosylmethionine (SAMe) interacts with methionine synthase, and by first starting up the BHMT pathway, one ensures that there is enough SAMe to start up the methionine synthase pathway.

    14. As these steps are taken, the immune system and the detox system will start to function at higher levels, and die-off and detox will begin. These processes are monitored using periodic spot urine testing, and decisions about when to proceed to the next step in the treatment program are based on this urine testing.

    15. Viral infections are dealt with naturally as the immune system recovers, though Valtrex is used in some cases. As the viruses die off, it is observed that heavy metal excretion increases. Heavy metal excretion is tracked using periodic spot urine tests and is plotted as a function of time to determine the progress.

    16. When appropriate indications are seen in the urine testing, the BHMT pathway is slowed using dimethylglycine, which is a product of the BHMT reaction, and thus exerts product inhibition on it. This shunts the flow through the parallel methionine synthase pathway. This has the effect of bringing up the folate cycle, which is linked to it, and also bringing up the biopterin cycle, which is linked to the folate cycle. The folate cycle is needed to make new RNA and DNA to proliferate new cells, such as T cells in cell-mediated immunity. The biopterin cycle is necessary for the synthesis of serotonin and dopamine as well as for the operation of the nitric oxide synthases. Some patients benefit from direct supplementation of tetrahydrobiopterin, often in very small amounts.

    17. The treatments up to this point should resolve most of the symptoms of CFS. The last step is to support remyelination, which has been dysfunctional during the time when the methylation cycle was blocked, because methylation is necessary to synthesize myelin basic protein. This should improve the operation of the nervous system.

    That is a rough outline of the treatment process, and again, I refer you to Dr. Yasko’s materials for the details.

    I’m sorry that this treatment approach is not simple, quick, easy and inexpensive, but unfortunately, I think this rather complex process is what is required, for the reasons I’ve given. I hope this is helpful, and I would very much appreciate it if you decide to try this treatment approach, that you will keep me informed of how it works out for your patients. If I can answer questions that come up, please let me know.

    Rich Van Konynenburg
  5. richvank

    richvank New Member




    Richard A Van Konynenburg, Ph.D.
    (Independent Researcher and Consultant)

    8th International IACFS Conference on
    Chronic Fatigue Syndrome, Fibromyalgia
    and other Related Illnesses

    Ft. Lauderdale, Florida, U.S.A.
    January 10-14, 2007


    At the Seventh International Conference of the AACFS in 2004, the author proposed and defended the hypothesis that glutathione depletion is an important part of the pathogenesis of CFS (1).

    In the conclusions of that paper it was noted that it seemed likely that there are vicious circle mechanisms involved in CFS that prevent glutathione repletion from being the complete answer for treating this disorder.

    Recent autism research (2,3) suggests that in that disorder a vicious circle involving the methylation cycle apparently chronically holds down the level of glutathione.

    The present author has recently proposed (4) that this same mechanism is active in many cases of CFS. This model for CFS will be referred to as the Glutathione Depletion—Methylation Cycle Block (GD-MCB) Hypothesis.

    This mechanism appears to be capable of explaining and drawing together numerous features of CFS that have been reported in the peer-reviewed literature.

    (See diagram)

    The methylation cycle (also called the methionine cycle) (5) is a major part of the biochemistry of sulfur and of methyl (CH3) groups in the body. It is also tightly linked to folate metabolism and is one of the two biochemical processes in the human body that require vitamin B12 (the other being the methylmalonate pathway, which enables use of certain amino acids to provide energy to the cells).

    This cycle supplies methyl groups for a large number of methylation reactions, including those that methylate (and thus silence) DNA (6), and those involved in the synthesis of a wide variety of substances, including creatine (7), choline (7), carnitine (8), coenzyme Q-10 (9), melatonin (10), and myelin basic protein (11). Methylation is also used to metabolize the catecholamines dopamine, norepinephrine and epinephrine (12), to inactivate histamine (13), and to methylate phospholipids (14), promoting transmission of signals through membranes.

    The role of the methylation cycle in the sulfur metabolism is to supply sulfur-containing metabolites to form a variety of important substances, including cysteine, glutathione, taurine and sulfate, via its connection with the transsulfuration pathway (5).

    This cycle balances the demands for methylation and for control of oxidative stress (15)


    In autism the methylation cycle was found by James et al. (2,3) to be blocked at methionine synthase, which is the step involving methylation of homocysteine to form methionine (see diagram).

    Two effects of this block that they measured are a significant decrease in the level of plasma methionine and lowering of the ratio of S-adenosylmethionine to S-adenosylhomocysteine. The latter causes a decreased capacity for promoting methylation reactions (16).

    In addition, they found (2,3) that the flow through the transsulfuration pathway (see diagram) was also decreased, resulting in lower plasma levels of cysteine and glutathione and a lowered ratio of reduced to oxidized glutathione, all of which they measured. This lowered ratio reflects a state of oxidative stress (17).

    The block in the methylation cycle and the glutathione problem were found to be linked, since supplements used to restore the methylation cycle to normal operation (methylcobalamin, folinic acid and trimethylglycine) also restored the levels of reduced and oxidized glutathione (2).


    It is known from studies of twins that genetics plays an important predisposing role in autism (18). The fact that the rate of incidence of autism has increased dramatically in recent years is evidence that there is also an important environmental component in the development of cases of autism (3), since the population’s genetic inheritance is relatively constant over much longer periods.

    James et al. (3) found that there are measurable genetic differences between children with autism and healthy controls. The differences they measured are associated with genes that encode enzymes and other proteins impacting the methylation cycle, the folate metabolism and the glutathione system.

    In particular they found differences in allele frequency and/or significant gene-gene interactions for genes encoding the reduced folate carrier (RFC), transcobalamin II (TCN2), catechol-O-methyltransferase (COMT), methylenetetrahydrofolate reductase (MTHFR), and one of the glutathione transferases (GST M1).

    These genetic results, combined with the biochemical observations of dysfunction in the methylation cycle, strongly suggest that variations in genes associated with this cycle and its related biochemistry are involved in the genetic predisposition to developing autism.


    1. Methionine concentrations are reported to be below normal in both plasma (19) and urine (20) in CFS patients. Low methionine can be caused by a methylation cycle block.

    2. Four magnetic resonance spectroscopy studies in CFS (21-24) have found elevated choline-to-creatine ratios in various parts of the brain. Both choline and creatine arise partly from the diet and partly from synthesis in the body. Since the syntheses of these two substances are the main users of methylation (7), a methylation deficit would be expected to decrease the rate of synthesis of both of them, and hence to decrease their levels in the cells. When this occurred, it would be unlikely that their ratio would remain the same, since the fractions of each supplied by synthesis would not likely be the same, nor would the decrease in rates of synthesis of these two substances likely to be proportional to their levels in the cells. Since creatine synthesis is the greater user of methylation (7), it might be expected that the choline-to-creatine ratio would increase, as is observed. It therefore appears that a methylation cycle block could explain this well-replicated observation in CFS.

    3. Some substances that require methylation for their biosynthesis have been found to be at below-normal levels in CFS patients, and/or patients have been found to benefit by supplementing them. This has been reported in eleven of the studies in CFS of carnitine, beginning with the work of Kuratsune et al. (25-34), both the studies of coenzyme Q10 (35, 36), a study that included choline as phosphatidylcholine in a combination supplement (37), and one recent study of melatonin (38) (though it should be mentioned that earlier studies of melatonin in CFS found normal or elevated levels, and/or did not find benefit from supplementation (see review in ref. 39), suggesting that other issues in addition to the methylation deficit might be involved in the case of melatonin. See “Magnesium depletion” later in this paper).

    4. Vitamin B12, which plays a key role in the methylation cycle and was one of the supplements used to restore this
    cycle in the autism work (2), has a long history (39,40) as one of the most helpful of the essential nutrients in CFS when given in high-dosage injections. Lapp and Cheney (41, 42) found that in urine organic acids testing of 100 CFS patients, 33% had elevated homocysteine, 38% had elevated methylmalonate, and 13% had both (29,30). The elevated homocysteine implicates the methylation cycle,
    while the elevated methylmalonate indicates that the other pathway that requires vitamin B12 showed deficiency as well. Lapp and Cheney (42) found that 50 to 80% of over 2,000 patients reported benefit from high-dose vitamin B12 injections. Evengard et al. (43) reported that vitamin B12 levels in the cerebrospinal fluid of 10 of 16 CFS patients were below their detection limit of 3.7 pmol/L. Regland et al. (44) found both low vitamin B12 (in 10 out of 12 patients) and high homocysteine (in all 12 patients studied) in the cerebrospinal fluid of CFS patients. There were significant correlations between these parameters and symptoms.

    Regland et al. (45) performed an open trial in which they gave 1,000 microgram weekly injections of hydroxocobalamin for at least 3 months to the 10 female patients from this study who had both low B12 and elevated homocysteine. They found that the treatment was significantly more beneficial if the patient did not have the thermolabile allele of the polymorphic gene for MTHFR. They concluded that vitamin B12 deficiency was probably contributing to the increased homocysteine levels. They also found that the effect of vitamin B12 supplementation was dependent on whether the available methyl groups were further deprived by the existence of thermolabile MTHFR. This work implicated the methylation cycle in
    the pathogenesis of CFS, and it also pointed to the importance of a genetic component, involving one of the same genes that have been implicated in autism (3).

    5. Folinic acid was recently found to produce subjective improvement in symptoms in 81% of 58 CFS patients tested (46). This was also one of the supplements used to restore the methylation cycle in the autism research (2).

    6. Many studies have reported evidence for oxidative stress in CFS (47-61).

    7. There have been several reports of depletion of reduced glutathione in at least a substantial subset of CFS patients (49-51, 53,54,59,62). Reduced glutathione augmentation is now widely used by CFS clinicians, who have found that augmenting glutathione by various means has been helpful to many of their patients (49,50,63-65).

    8. Polymorphisms in the gene coding for the COMT enzyme were found by Goertzel et al. (66) to be some of the most important of those examined for distinguishing CFS cases from controls. As noted earlier, COMT is a methyltransferase, associated with the methylation cycle. In autism, the COMT 472G>A polymorphism showed significant difference between cases and controls (3).


    Major differences are seen in the gender ratio and in the symptoms of these two disorders.
    Autism is found primarily in boys, at a ratio of about 4 to1 (boys to girls) (67), while CFS occurs mainly in adult women at a ratio measured at 1.8 to 1 (women to men) by Jason et al. (68) in one large epidemiological study and 4.5 to 1 (women to men) by Reyes et al. (69) in another.
    The most striking symptoms in autism involve the brain and are very characteristic of this disorder. They are described as follows by the Diagnostic and Statistical Manual of Mental Disorders (70):

    1. Qualitative impairment in social interaction, as manifested by at least two of the following:
    a. Marked impairment in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures to regulate social interaction.
    b. Failure to develop peer relationships appropriate to developmental level.
    c. A lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (e.g., by a lack of showing, bringing, or pointing out objects of interest).
    d. Lack of social or emotional reciprocity.

    2. Qualitative impairments in communication as manifested by at least one of the following:
    a. Delay in, or total lack of, the development of spoken language (not accompanied by an attempt to compensate through alternative modes of communication such as gestures or mime).
    b. In individuals with adequate speech, marked impairments in the ability to initiate or sustain a conversation with others.
    c. Stereotyped and repetitive use of language or idiosyncratic language.
    d. Lack of varied, spontaneous make-believe play or social imitative play appropriate to developmental level.

    3. Restricted repetitive and stereotyped patterns of behavior, interests, and activities, as manifested by at least one of the following:
    a. Encompassing preoccupation with one or more stereotypic and restricted patterns of interest that is abnormal either in intensity or focus.
    b. Apparently inflexible adherence to specific, nonfunctional routines or rituals.
    c. Stereotypic and repetitive motor mannerisms (e.g., hand or finger flapping or twisting, or complex whole-body movements).
    d. Persistent preoccupation with parts of objects.
    CFS involves a large variety of symptoms (71,72), the chief ones being extreme fatigue, post-exertional malaise and/or fatigue, sleep dysfunction, muscle pain, and symptoms involving the brain that are significant but less profound than in autism (e.g. cognitive and memory difficulties).

    The author proposes that these differences result at least in part from the different ages at onset. Autism develops early in life, before the brain is completely developed and before puberty, while the onset of CFS occurs after brain development is completed and (for the most part) after puberty.

    Pangborn (73) has discussed five hypotheses that have been suggested to explain the higher prevalence of autism in boys. Of these, the one that appears to be most consistent with the present author’s hypothesis of a common pathogenesis between CFS and autism is the one put forward by Geier and Geier (74). Their hypothesis proposes
    that the higher prevalence of autism in boys results from the potentiation of mercury toxicity by testosterone, while estrogen is protective. There is increasing evidence that mercury was a significant factor in the etiology of many cases of autism, because mercury-containing thimerosol was used as a preservative in vaccines given to them. Since thimerosol was removed from childhood vaccines, the number of new cases of neurodevelopmental disorders, including autism, has been found to be dropping (75).

    The present author has proposed a hypothesis (76) to explain the higher prevalence of CFS in women, involving an additional bias toward oxidative stress due to redox cycling in the metabolism of estradiol when certain polymorphisms are present.

    With regard to symptoms, it seems likely that the role of methylation in the formation of myelin basic protein (77) is at least part of the explanation for the major problems in brain development in autism and the symptoms that result from them.

    Fatigue is not recognized to be a major feature of autism. However, it should be noted that the evaluation of fatigue is usually based on self-report, which is not possible in children who are unable to speak. Also, it seems possible that fatigue may be manifested differently in very young children as compared with adults. Features such as hyperactivity and irritability may reflect fatigue in these patients.

    Chronic pain may also be difficult to identify and characterize in children who do not have speech. A recent paper suggests that chronic pain may be the initial presenting symptom in cases of undiagnosed autism (78).

    Many of the other phenomena found in CFS are also found in autism, but historically they have not received as much attention in autism as the brain-related symptoms, perhaps because the latter are so striking and profound. Some of the other phenomena that autism has in common with CFS in addition to those already mentioned are elevated proinflammatory cytokines (79), Th2 shift in the immune response (80), low natural killer cell activity (81), mitochondrial dysfunction (82, 83), carnitine deficiency (83), hypothalamus-pituitary-adrenal (HPA) axis dysfunction (84), gut problems (85), and sleep problems (86).


    Etiology: According to the GD-MCB Hypothesis, CFS is caused by a combination of two factors:
    (1) a genetic predisposition (87), which is currently only partly known, and
    (2) some combination of a variety of physical, chemical, biological and/or psychological/emotional stressors, the particular combination differing from one case to another (See Ref. 1 for a review.).

    So far, polymorphisms in genes coding for the following proteins have been found to be associated with CFS in general or with a subset:

    (1) Serotonin transporter (5-HTT) gene promoter (88)
    (2) Corticosteroid binding globulin (CBG) (89)
    (3) Tumor necrosis factor (TNF) (90)
    (4) Interferon gamma (IFN-gamma) (90)
    (4) Proopiomelanocortin (POMC) (91)
    (5) Nuclear receptor subfamily 3, group C, member 1, glucocorticoid receptor (66,91)
    (6) Monoamine oxidase A (MAO A) (91)
    (7) Monoamine oxidase B (MAO B) (91)
    (8) Tryptophan hydroxylase 2 (TPH2) (66,91)
    (9) Catechol-O-methyltransferase (COMT) (66)

    In addition, a COMT polymorphism has reported to be associated with fibromyalgia (92, 93), and polymorphisms in the genes for the detoxication enzymes CYP2D6 (cytochrome P450 2D6) and NAT2 (N-acetyl transferase 2) have been found to be associated with multiple chemical sensitivities (94). These may be relevant to CFS because of its high comorbidities with these two disorders.

    All these proteins touch on the pathogenesis mechanism described in this paper, which is what would be expected if this Hypothesis is valid.

    With regard to the stressors found to precede onset of CFS, they are known to raise cortisol secretion (prior to onset and early in the course of the illness), to raise epinephrine secretion and to place demands on glutathione, leading to oxidative stress (1).

    According to this Hypothesis, when reduced glutathione is sufficiently depleted and the oxidative stress therefore becomes sufficiently severe in a person having the appropriate genetic predisposition, a block is established at methionine synthase in the methylation cycle (95,2,3). Because the methylation cycle is located upstream of cysteine and glutathione in the sulfur metabolism, these are further depleted, and a vicious circle is formed.

    Note that infectious pathogens are included among the possible biological stressors that can contribute to the onset of CFS. In particular, Borrelia burgdorferi, the bacterium responsible for Lyme disease, has been found to deplete glutathione in its host (96). This may explain the very similar pathophysiologies of chronic Lyme disease and CFS. This may also explain the epidemic clusters of CFS, which seem to have been produced by a virulent infectious pathogen (or pathogens). Perhaps the genetic factors are less important in producing the onset if a very virulent pathogen is present.

    Epidemiology: According to the GD-MCB Hypothesis, the prevalence of CFS is determined by the frequency in the population of the combined presence of certain genetic polymorphisms (yet to be completely identified) and of the above described stressors occurring coincidentally in those having the polymorphisms. As noted earlier, the author has proposed that the higher prevalence in women is a result of increased bias toward oxidative stress, resulting from redox cycling in the metabolism of estradiol when certain polymorphisms in detoxication enzymes are present (76).

    Suppression of parts of the immune response: Elevation of cortisol due to long-term stressors causes a suppression of the cell-mediated immune response and a shift to Th2 (97).

    Depletion of reduced glutathione likewise causes a shift to Th2 (98, 99).

    The elevation of cortisol prior to onset and in the early course of the illness also (temporarily) suppresses inflammation (100).

    The cytotoxicity of natural killer (NK) cells and CD8 T cells in CFS has been found to be low, and Maher et al. found this to be associated with a deficiency of perforin secretion (101). According to the GD-MCB Hypothesis, in CFS perforin secretion is inhibited by depletion of reduced glutathione because glutathione is needed to form the disulfide bonds in their proper configurations in secretory proteins (102). Depletion of glutathione therefore causes misfolding and recycle of perforin molecules, which have twenty cysteine residues and thus ten disulfide bonds (103). This misfolding mechanism would affect other secretory proteins in CFS that are synthesized in cells having glutathione depletion as well, which may account for the observation of misfolded proteins in the spinal fluid of CFS patients by Baraniuk et al. (104).

    Proliferation of T lymphocytes is inhibited by the block in the folate cycle, which inhibits production of new RNA and DNA (105).

    Viral and intracellular bacterial reactivation: According to the GD-MCB Hypothesis, depletion of reduced glutathione is the trigger for the reactivation of latent viral and intracellular bacteria in CFS. The infections found initially in a case of CFS are usually due to those pathogens that are capable of residing in the body in the latent state, suggesting that these infections arise by reactivation (106). In general, intracellular glutathione depletion is associated with the activation of several types of viruses (1, 107-111) as well as Chlamydia (112), and it may account for reactivation of other latent intracellular bacteria as well. In herpes simplex type 1 viral infection, raising the glutathione concentration inhibits viral replication by blocking the formation of disulfide bonds in glycoprotein B (111). Since glycoprotein B appears to be present in all herpes virus types (113), it is likely that glutathione depletion is responsible for reactivation of Epstein-Barr virus, cytomegalovirus and HHV-6 in CFS.

    The Coxsackie B3 virus genome is known to code for glutathione peroxidase, a selenium-containing enzyme (114). Taylor has suggested (115) that such viruses suppress the immune system of the host by depleting its selenium, thus inhibiting the host’s use of glutathione peroxidase. Since glutathione peroxidase makes use of
    glutathione, depletion of reduced glutathione itself would therefore assist this virus in its mechanism of infection.

    Populations more deficient in selenium would be expected to be more vulnerable to Coxsackie B3 infection. It is interesting to note that nearly all the studies of Coxsackie virus in CFS have come from the UK. The population there has become more deficient in selenium since the 1970s, when major sources of grain in the diet were changed to areas with selenium-deficient soils (116).

    Immune activation: This occurs when the immune system detects the reactivation of pathogens (117).

    Activation of 2-5A, RNase-L pathway (118): This pathway is activated by interferon and double stranded RNA as part of the cellular response to viral reactivation. According to the GD-MCB Hypothesis, RNase-L remains activated in CFS because of the suppression of the cell-mediated immune response and the consequent failure to defeat the viral infection (See Suppression of parts of the immune response, above.)

    Mitochondrial dysfunction and the onset of physical fatigue: As hypothesized by Bounous and Molson (119), competition between the oxidative skeletal muscle cells and the immune system for the decreased supply of glutathione and cysteine causes depletion of reduced glutathione in the skeletal muscles. According to the GD-MCB Hypothesis, this inhibits the glutathione peroxidase reaction and allows hydrogen peroxide to build up. This in turn probably exerts product inhibition on the superoxide dismutase reaction, which allows superoxide, produced as part of normal oxidative metabolism, to rise in the mitochondria of the oxidative skeletal muscle cells. Superoxide reacts with nitric oxide to produce peroxynitrite, as Pall (120) has pointed out. Superoxide also interacts with aconitase in the Krebs cycle to inhibit it (121), and peroxynitrite can cause partial blockades in the Krebs cycle and also the respiratory chain (120, 122). These reactions lower the rate of production of ATP, and this constitutes mitochondrial dysfunction. Since ATP is needed to power muscle contraction, lack of it produces physical fatigue.

    RNase-L cleavage, leading to formation of the low molecular weight version (123): Depletion of reduced glutathione removes inhibition of the activity of calpain (124), which is located in the cytosol with RNase-L, and calpain cleaves RNase-L (125). (Elastase, the other enzyme found by Englebienne et al. (125) to be able to cleave RNase-L in the laboratory, is confined to granules and vesicles inside living cells (126), and thus is not in contact with RNase-L.)

    Failure to defeat viral and intracellular bacterial infections and continuing immune activation: According to the GD-MCB Hypothesis, these occur because of depletion of reduced glutathione (127) and also because the folate metabolism block prevents production of new DNA and RNA for proliferation of T lymphocytes (105).

    Depletion of magnesium: There is a long history showing depletion of magnesium in CFS and benefits of supplementation, both orally and by injection (See review in Ref. 39). Magnesium depletion may be responsible for a variety of symptoms that are found in CFS (128), including mitochondrial dysfunction, muscle twitching, muscle pain, sleep problems and cardiac arrhythmia. In connection with sleep problems, Durlach et al. have found that magnesium depletion is associated with abnormalities in the level of melatonin and dysregulation of biorhythms (129). Manuel y Keenoy et al. (54) found that the subset of CFS patients that was resistant to repletion of magnesium in their clinical study also showed glutathione depletion. It has also been found that glutathione depletion causes magnesium depletion in red blood cells (130). According to the GD-MCB Hypothesis, the depletion of intracellular magnesium in CFS is another result of depletion of reduced glutathione.

    Buildup of toxins: Glutathione depletion allows toxins, including heavy metals, to build up, because there is not
    enough glutathione to conjugate these toxins as rapidly as they enter the body. Mercury is of particular concern, because the population in general has considerable exposure to it from dental amalgams, fish consumption, and environmental sources such as nearby coal-fired power plants. There is considerable clinical experience of mercury buildup in CFS patients (1). Immune testing has also shown evidence that the immune system has responded to elevated mercury in CFS patients (131-133).

    Solidification of the vicious circle: After the vicious circle has developed involving the methylation cycle block and the depletion of glutathione, another factor must come into play to lock in this situation chronically. It seems likely that buildup of toxins is the factor responsible for this, by blocking the formation of methylcobalamin and thus the activity of methionine synthase. It has been shown that one of the important roles of glutathione normally is to protect the very much smaller (by six orders of magnitude) concentrations of cobalamins from reaction with toxins by forming glutathionylcobalamin (134). Without this protection, cobalamins are vulnerable to reaction with a variety of toxins. An example is mercury. It has been found that very small concentrations of mercury are required to block the methionine synthase reaction (135). Because of this additional factor, attempts simply to correct the glutathione depletion and the oxidative stress after the cobalamins have reacted with toxins in most cases will not restore normal function of the methylation cycle (1).

    Neurotransmitter dysfunction: The production of melatonin from serotonin as well as the metabolism of the catecholamines require methylation, as noted earlier, and according to the GD-MCB Hypothesis, they are inhibited because of the decreased methylation capacity. Also, genetic polymorphisms involving enzymes in the neurotransmitter system have been found to be more frequent in at least some subsets of CFS patients, as noted earlier. These factors cause dysfunction of the neurotransmitters.

    Further development of mitochondrial dysfunction: As the course of the illness progresses, it is likely that other factors that result from glutathione depletion and the methylation cycle block come into play and further suppress the operation of the mitochondria. These include the buildup of toxins and infections, depletion of magnesium, and damage to the phospholipid membranes of the mitochondria by oxidizing free radicals (136). Because the essential fatty acids in these membranes are polyunsaturated, they are the most vulnerable to oxidation (137), and they become depleted, at least in some CFS patients (See review in Ref. 39).

    HPA axis blunting (138): According to this Hypothesis, glutathione depletion in the pituitary gland inhibits production of proopiomelanocortin (POMC) (which has
    two disulfide bonds in its N-terminal fragment (139)), and hence secretion of ACTH (which is part of POMC), by the same mechanism as inhibition of perforin synthesis (102) (See Suppression of parts of the immune response, above.). This results in the lowering of cortisol secretion by the adrenal glands, which is a late finding in the course of the illness (140). As noted earlier, genetic polymorphisms in POMC may also be involved in a subset of CFS patients (91).

    Diabetes insipidus (excessive urination, thirst, decrease in blood volume): According to this Hypothesis, glutathione depletion inhibits production of arginine vasopressin (141), which has one disulfide bond (142), by the same biochemical mechanism by which it inhibits perforin and ACTH synthesis (102). It is likely that the secretion of oxytocin, which also has one disulfide bond and is also synthesized in the hypothalamus, is also inhibited. Measurements of oxytocin in CFS have not been reported, but there is evidence that it is low in some fibromyalgia patients (143), which may be relevant because of the high comorbidity of CFS and fibromyalgia. A clinician has reported benefit from oxytocin injections in fibromyalgia patients (144).

    Low cardiac output (145): According to this Hypothesis, this occurs because depletion of reduced glutathione in the heart muscle cells lowers the rate of production of ATP, as in the skeletal muscle cells. This produces diastolic dysfunction as observed by Cheney (146, 147). Both low blood volume (see Diabetes insipidus, above), which produces low venous return, and diastolic dysfunction, which decreases filling of the left ventricle, produce low cardiac output. In addition, in some cases, as observed by Lerner et al., viral infections produce cardiomyopathy (148). According to the GD-MCB Hypothesis, this is a result of depletion of reduced glutathione and suppression of cell-mediated immunity. This is another factor that can decrease cardiac output in CFS.

    Orthostatic hypotension and orthostatic tachycardia (149): According to this Hypothesis, these occur because of low blood volume, low cardiac output and HPA axis blunting (See Diabetes insipidus, Low cardiac output, and HPA axis blunting, above.).

    Loss of temperature regulation: As pointed out by Cheney (146), this occurs because of low cardiac output (see Low cardiac output, above), which causes the autonomic nervous system to decrease blood flow to the skin. This removes the ability to regulate the rate of heat loss from the skin.

    Hashimoto’s thyroiditis (150) and elevated incidence of thyroid cancer (151): According to this Hypothesis, Hashimoto’s thyroiditis occurs in CFS because depletion of reduced glutathione in the thyroid gland allows damage to thyroglobulin by hydrogen peroxide, as proposed by Duthoit et al. (152). In addition, hydrogen peroxide damage to DNA in the thyroid gland may be responsible for the elevated incidence of cancer there. Hydrogen peroxide is produced normally by the thyroid to oxidize iodide in the process of making thyroid hormones (153).

    Increasing variety of infections (154) and inflammation (155): According to this Hypothesis, viral, intracellular bacterial and fungal infections accumulate over time because the cell-mediated immune response is dysfunctional (See Suppression of parts of the immune response, above.). Inflammation becomes more severe because of the decreased secretion of cortisol later in the course of the illness (See HPA axis blunting, above), and because of the rise in histamine as a result of lack of sufficient methylation capacity to deactivate it (156).

    Slow gastric emptying (157) and gastroesophageal reflux: According to this Hypothesis, in CFS these result from mitochondrial dysfunction in the parietal cells of the
    stomach, due to depletion of reduced glutathione, which results in low production of stomach acid. (Anecdotally, many CFS patients have reported absence of eructation after ingestion of sodium bicarbonate solution on an empty stomach, suggesting low stomach acid status.) A slower rate of gastric emptying was found to be associated with higher pH, i.e. lower acid status (158).

    Gut problems: According to this Hypothesis, several of the above factors converge to produce problems in the gut in CFS, often referred to as irritable bowel syndrome (IBS). These factors include glutathione depletion, low cardiac output, immune suppression, low stomach acid production, neurotransmitter dysfunction (note that serotonin plays a major role in gut motility), and increasing variety of infections and inflammation.

    The degree of abnormality of a lactulose breath test (indicating small intestinal bacterial overgrowth) in fibromyalgia patients was found by Pimentel et al. to be greater than in IBS patients without fibromyalgia (159). In addition, they found that the abnormality was correlated with somatic pain (159). (This may be relevant because of the high comorbidity of CFS with fibromyalgia.)

    Brain-related problems: According to this Hypothesis, several of the above factors also converge to produce problems in the brain. These include glutathione (and cysteine) depletion, low cardiac output, failure to defeat infections and continued immune activation, neurotransmitter dysfunction, decreased methylation
    capacity to maintain myelin, and increasing variety of infections and inflammation.

    Relapsing (Crashing) (160): Many CFS patients have chronically low glutathione levels. According to this Hypothesis, when the level of stressors is temporarily increased, the levels of reduced glutathione become more severely depleted, and this produces the so-called crashing phenomenon. After a period of rest, reduced glutathione levels are increased to the chronically low levels that existed prior to the increased stressors.

    Alcohol intolerance (161): According to this Hypothesis, because of mitochondrial dysfunction, the skeletal muscles of CFS patients depend more than normal on glycolysis for ATP production. Increased use of glycolysis requires increased use of gluconeogenesis by the liver to convert lactate and pyruvate back to glucose (Cori cycle). In CFS, this is hampered by low cortisol levels. The metabolism of ethanol by the liver further inhibits gluconeogenesis, producing hypoglycemia and lactic acidosis. This accounts for the alcohol intolerance reported by many CFS patients.

    Weight gain: According to this Hypothesis, the weight gain often seen in CFS results from the inability to metabolize
    carbohydrates and fats at normal rates, because of partial
    blockades in the Krebs cycle produced by depletion of reduced glutathione. Excess carbohydrates are cycled back to glucose by gluconeogenesis, and ultimately are converted to stored fat.

    Low serum amino acid levels (19): According to this Hypothesis, these result from the burning of amino acids as fuel at higher rates than normal. Amino acids are able to enter the Krebs cycle by anaplerosis, downstream of the partial blockades, so they can be used as fuel in place of carbohydrates and fats.

    The pathogenesis of CFS becomes increasingly complex as it proceeds, because of the interactions and feedback loops that develop. For this reason, determining the cause-effect relationships for all the aspects of the resulting pathophysiology is a problem that is exceedingly difficult. Nevertheless, understanding the etiology and early pathogenesis provides a basis for developing a more effective treatment approach.


    There is abundant and compelling evidence that the glutathione depletion—methylation cycle block mechanism is an important part of the pathogenesis for at least a substantial subset of chronic fatigue syndrome patients.

    A pathogenesis hypothesis based on this mechanism is capable of explaining and unifying many of the published observations regarding chronic fatigue syndrome, and it provides a basis for developing a more effective treatment approach.


    The diagram shows the methylation cycle at the top right, the folate cycle at the top left, and the transsulfuration pathway at the bottom right.

    The enzymes that catalyze the reactions are shown in boxes:

    BHMT Betaine homocysteine methyltransferase
    CBS Cystathionine beta synthase
    CDO Cysteine dioxygenase
    CGL Cystathionine gamma lyase
    GCL Glutamate cysteine ligase
    GS Glutathione synthase
    MAT Methionine adenosyltransferase
    MS Methionine synthase
    MSR Methionine synthase reductase
    MTase Methyltransferase (a class of enzymes)
    MTHFR Methylene tetrahydrofolate reductase
    SHT Serine hydroxymethyltransferase
    TS Thymidylate synthase

    Most of the metabolites are spelled out. The ones that are abbreviated are as follows:

    DMG Dimethylglycine
    SAH S-Adenosylhomocysteine
    SAM S-Adenosylmethionine
    THF Tetrahydrofolate
    TMG Trimethylglycine (betaine)

    The cofactor and coenzyme are as follows:

    P5P--Pyridoxal phosphare, the active form of vitamin B6
    B12--Methylcobalamin, one of the acive forms of vitamin B12


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    94. McKeown-Eyssen, G., Baines, C., Cole, D.E., Riley, N., Tyndale, R.F., Marshall, L., and Jazmaji, V., Case-control study of genotypes in multiple chemical sensitivity: CYP2D6, NAT1, NAT2, PON1, PON2 and MTHFR, Int. J. Epidem. (2004); 33: 971-978.

    95. Lertratanangkoon, K., Orkiszewski, R.S., and Scimeca, J.M., Methyl-donor deficiency due to chemically induced glutathione depletion, Cancer Research (1996); 56: 995-1005.

    96. Pancewicz, S.A., Skrzydlewska, E., Hermanowska-Szpakowicz, T., Zajkowska, J.M., and Kondrusik, M., Role of reactive oxygen species (ROS) in patients with erythema migrans, an early manifestation of Lyme borreliosis, Med. Sci. Monit. (2001); 7 (6): 1230-1235.

    97. Elenkov, I.J., Glucocorticoids and the Th1/Th2 balance, Ann. N.Y. Acad. Sci. (2004); 1024: 138-146.

    98. Peterson, J.D., Herzenberg, L.A., Vasquez, K., and Waltenbaugh, C., Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns, Proc. Natl. Acad. Sci. U.S.A. (1998); 95: 3071-3076.

    99. Murata, Y., Shimamura, T., and Hamuro, J., The polarization of Th1/Th2 balance is dependent on the intracellular thiol redox status of macrophages due to the distinctive cytokine production, Internat. Immunol. (2002); 14 (2): 201-212.

    100. Katler, E., and Weissmann, G., Steroids, aspirin and inflammation, Inflammation (1977); 2 (4): 295-307.

    101. Maher, K.J., Klimas, N.G. and Fletcher, M.A., Chronic fatigue syndrome is associated with diminished intracellular perforin, Clin. Exp. Immunol. (2005); 142 (3): 505-511.

    102. Chakravarthi, S. and Bulleid, N.J., Glutathione is required to regulate the formation of native disulfide bonds within proteins entering the secretory pathway, J. Biol. Chem. (2004); 279 (38): 39872-39879.

    103. Li, F., Zhou, X., Qin, W., and Wu, J., Full-length cloning and 3’-terminal portion expression of human perforin cDNA, Clinica Chimica Acta (2001); 313: 125-131.

    104. Baraniuk, J.N., Casado, B., Maibach, H., Clauw, D.J., Pannell, L.K., and Hess, S.S., A chronic fatigue syndrome-related proteome in human cerebrospinal fluid, BMC Neurol. (2005); 5: 22.

    105. Dhur, A. Galan, P. and Hercberg, S., Folate status and the immune system, Prog. Food Nutr. Sci. (1991); 15 (1-2): 43-60.

    106. Komaroff, A.L., and Buchwald, D.S., Chronic fatigue syndrome: an update, Annual Reviews of Medicine (1998); 49:1-13.

    107. Roederer, M., Raju, P.A., Staal, F.J.T., Herzenberg, L.A., and Herzenberg, L.A., acetylcysteine inhibits latent HIV expression in chronically infected cells, AIDS Research and Human Retroviruses (1991); 7: 563-567.

    108. Staal, F.J.T., Roederer, M., Israelski, D.M., Bubp, J., Mole, L.A., McShane, D., Deresinski, S.C., Ross, W., Sussman, H., Raju, P.A., Anderson, M.T., Moore, W., Ela, S.W., Herzenberg, L.A., and Herzenberg, L.A., Intracellular glutathione levels in T cell subsets decrease in HIV-infected individuals, AIDS Research and Human Retroviruses (1992); 8: 305-311.

    109.. Ciriolo, M.R., Palamara, A.T., Incerpi, S., Lafavia, E., Bue, M.C., De Vito, P., Garaci, E., and Rotilio, G., Loss of GSH, oxidative stress, and decrease of intracellular pH as sequential steps in viral infection, J. Biol. Chem. (1997); 272 (5): 2700-2708.

    110. Cai, J., Chen, Y., Seth, S., Furukawa, S., Compans, R.W., and Jones, D.P., Inhibition of influenza infection by glutathione, Free Radical Biology & Medicine (2003); 34 (7): 928-936.

    111. Palamara, A.T., Perno, C.-F., Ciriolo, M.R., Dini, L., Balestra, E., D'Agostini, C., Di Francesco, P., Favalli, C., JRotilio, G, and Garaci, E., Evidence for antiviral activity of glutathione: in vitro inhibition of herpes simplex virus type 1 replication, Antiviral Rese
    [This Message was Edited on 07/01/2007]
  6. richvank

    richvank New Member

    February 21, 2006

    Chronic Fatigue Syndrome and Autism

    Richard A. Van Konynenburg, Ph.D.

    For the past ten years I have been studying chronic fatigue syndrome as an independent researcher. Over the course of several years I developed a hypothesis for the pathogenesis of this disorder that prominently featured the depletion of glutathione. I presented a poster paper on this hypothesis at the AACFS (now the International Association for Chronic Fatigue Syndrome) meeting in October, 2004, in Madison, Wisconsin. This paper can be found at the following url:

    Anecdotal experience of people with CFS who acted upon my hypothesis suggested that while some were able to raise their glutathione levels by various means and experienced benefit from doing so, others were not able to do so. At the time I wrote my poster paper, I was aware of this, and I acknowledged in the conclusions of the paper that there appeared to be factors that were blocking the raising of glutathione in CFS. At that time, I was not sure specifically what they were. I also knew that there was evidence for a genetic predisposition in CFS, but I did not know the details of the genetic variations involved.

    Shortly after that, I became aware of the work of S. Jill James et al. in autism (American Journal of Clinical Nutrition 2004 Dec; 80(6):1611-7). They found that glutathione was also depleted in autistic children, that this was associated with a partial block in the methylation cycle (also called the methionine cycle), that this partial block was associated with genetic variations in the genes for certain enzymes and other proteins associated with the sulfur metabolism, and that it interfered with the synthesis of glutathione. They also found that by using certain supplements (methylcobalamin, folinic acid and trimethylglycine) they could lift the block in the methylation cycle and restore the glutathione level.

    Upon learning of this work, I became very interested in possible parallels between chronic fatigue syndrome and autism. I attended the conference of the Defeat Autism Now! (DAN!) project in Long Beach, California in October, 2005, sponsored by the Autism Research Institute, headed by Dr. Bernard Rimland. As a result I became convinced that the genetic predisposition found in autism must be the same or similar to that in a major subset of chronic fatigue syndrome, and that the resulting biochemical abnormalities were also the same or similar. As far as I know, the genetic variations in people with chronic fatigue syndrome have not yet been studied in detail or published, but I am optimistic that this will occur soon, because of the rapid advances in the technology for doing so, and because of the current active interest of at least three groups in the U.S. and the U.K. in genomic aspects of CFS.

    There are obviously major differences between chronic fatigue syndrome and autism. I believe that these result primarily from the different ages of onset. Autistic children experience onset early in life, before their brains are fully developed. I believe that this gives rise to the very different brain-related symptoms seen in autistic children from those seen in adults with CFS. However, there are many similarities in the biochemistry and symptoms of these two disorders as well, including oxidative stress, buildup of toxins, immune response shift to Th2, and gut problems, for examples.

    The triggering factors for autism and chronic fatigue syndrome are also largely different. Although this subject remains controversial, there appears to be substantial evidence that vaccinations (containing either a mercury-based preservative or live viruses, many given within a short period of time) were responsible for triggering many of the cases of autism in genetically-susceptible children (D. Geier and M.R. Geier, International Journal of Toxicology 2004 Nov-Dec; 23(6):369-76; and A.J. Wakefield, several publications beginning in 1997).
    In CFS, a variety of triggering factors (physical, chemical, biological, or psychological/emotional) have been found to be involved in various cases, as reviewed in my poster paper, cited above. All these factors have in common that they place a demand on glutathione.

    It appears that genetically susceptible persons are unable to maintain normal glutathione levels when the total demand for it is high, and that once glutathione drops sufficiently in a genetically susceptible person, the sulfur metabolism becomes disrupted. In many cases the methylation cycle (part of the sulfur metabolism) becomes partially blocked, and the result can be a depletion of some or all of several important sulfur-containing metabolites, including S-adenosylmethionine (SAMe), cysteine, glutathione, taurine and sulfate. A vicious circle is thus formed, and the depletion in these metabolites causes an avalanche of pathogenesis, since they all have very important functions in the body. I think that much of this pathogenesis is common between autism and CFS. In autism, the loss of methylation capacity because of the drop in SAMe appears to be responsible for much of the interference with normal brain development.

    There is also a major difference in the sex ratio between autism and
    CFS. In the book mentioned below, Dr. Jon Pangborn discusses possible
    reasons why autism is more prevalent in boys. In my poster paper, cited
    above, I suggested a hypothesis to explain the female dominance in the
    prevalence of CFS in adults.

    I think that the reason why the people who have developed CFS as adults did not develop autism as children (even though I suspect that they have the same or a similar genetic predisposition) is that when they were children, not as many vaccinations were required. The schedule of vaccinations required for children in the U.S. has grown substantially over the past two or three decades, as has the incidence of autism. This is also true in the U.K.

    Shortly after attending the DAN! conference, I also learned of the work of Dr. Amy Yasko, primarily in autism, but extending to a number of other disorders as well. Working independently of the DAN! project, Dr. Yasko develops her treatment recommendations by analyzing the specific gene variations in each patient. In addition to studying effects on the methylation cycle, Dr. Yasko has gone on to consider the effects on associated biochemistry, including folate metabolism, biopterin, the urea cycle and the synthesis of neurotransmitters.

    My main message is that a great deal has already been worked out in autism by the researchers and clinicians associated with the Defeat Autism Now! project, and also by Dr. Yasko, and that I believe that the CFS community would benefit greatly by looking carefully at what they have already done. The doctors associated with the DAN! project treat autism by the use of nutritional supplements that compensate for genetic mutations in the sulfur metabolism. These include such supplements as magnesium sulfate, taurine, molybdenum, vitamin B6 and its active form P5P, magnesium, methylcobalamin, folinic acid, trimethylglycine, and dimethylglycine. They also use certain diets, and they perform chelation treatments to remove heavy metals. The results in many autistic children have been astounding, as can be seen in the webcast cited below, where several are interviewed.

    Dr. Yasko, in cooperation with Dr. Garry Gordon, uses many of the same supplements as are used by the DAN! project doctors as well as some additional ones, including RNA supplements, and she is also reporting great success.

    So I want to encourage everyone who has an interest in CFS to look at the results of the DAN! project and of Dr. Amy Yasko in autism.

    To view videos of the talks given at the latest two DAN! conferences on the internet at no cost (unless you are paying for the internet time!), go to this site:

    You can choose the more recent Long Beach conference or the earlier Boston conference. They cover much of the same material, but both are worthwhile to watch. If you want to see and hear a good explanation of the methylation cycle research, go to the Boston meeting first, so you will be able to view the talk by Jill James, who did not attend the Long Beach meeting.

    After selecting one of the conferences, go to the lower left and register. This is free. They will email a password to you right away, and then you can choose a talk to watch.

    Beyond this, I also want to recommend a book entitled Autism: Effective Biomedical Treatments. This is a new book (Sept. 2005). It is by Jon Pangborn, Ph.D. and Sydney Baker, M.D., a biochemist and an autism clinician, respectively. It is available on Amazon for people within the U.S. For people outside the U.S., it can be obtained from the following website by means of PayPal:

    The cost for the book is $30 U.S.

    This is an excellent book. It is a reference book, full of good information and good science, explained clearly. This book deals very practically with developing a treatment program for an individual child. I think that most of it will turn out to apply directly to adults with CFS as well.

    In addition, I want to recommend the book by Amy Yasko entitled Genetic ByPass. It is available from the website

    as part of the "Nutrigenomics Educational Starter Packet." The price is $49.95. This is also an excellent book. It discusses treatments specifically tailored to the particular combinations of genetic variations found in different patients.

    I think these two books complement each other. I would recommend reading the Pangborn and Baker book first, as it provides a good basis for understanding the technical aspects of the genetics found in the Yasko book.

    Although I have been suggesting consideration of the DAN! treatments and the Yasko testing to people with CFS for only a short time, and it is too soon to draw conclusions, early feedback is very encouraging. While I am going out on a limb to some extent in announcing this now, I don't want to wait any longer, because I think this could help a lot of people. Of course, we should all keep in mind that with the current case definition of CFS we have a very heterogeneous population, and the autism treatments will very likely not help everyone who has CFS, but I am convinced that they will help a substantial subset. So I want to encourage those who have CFS and those who treat it to look into this in the strongest way I can. It could be the answer for many of you.

    [Disclaimer: I have no financial interest in anything recommended in this article.]

  7. richvank

    richvank New Member



    Richard A. Van Konynenburg, Ph.D.
    (Independent Researcher)

    AACFS Seventh International Conference
    Madison, Wisconsin
    October 8-10, 2004

    [Refs. 1--5]

    • A tripeptide composed of the amino acids glutamic acid, cysteine, and glycine. Its molecular weight is 307.33 Da.

    • Found in all cells in the body, in the bile, in the epithelial lining fluid of the lungs, and, at much smaller concentrations, in the blood.

    • The predominant nonprotein thiol (molecule containing an S-H or sulfhydryl group) in cells.

    • Its active form is the chemically reduced form, called "GSH."

    • GSH is compartmentalized, with concentrations ranging from 0.5 to 10 millimolar in various organs and cell types.

    • GSH serves as a substrate for enzymes, including the glutathione peroxidases and the glutathione-S-transferases.

    • When oxidized, two glutathione molecules join together via a disulfide bond to form "oxidized glutathione," or "glutathione disulfide," referred to as "GSSG."

    • Inside cells, the concentration of GSSG is normally maintained at less than 1% of total glutathione by the enzyme glutathione reductase, which is powered by NADPH, produced by the pentose phosphate shunt, part of normal carbohydrate metabolism.

    [Refs. 1--5]

    • Maintains proper oxidation-reduction (redox) potential inside cells. Redox affects the oxidation state of sulfur in enzymes, and thus affects the rates of biochemical reactions in cells.

    • Scavenges peroxides and oxidizing free radicals directly and also serves as the basis for the antioxidant network.

    • Performs Phase II detoxication of heavy metals (such as mercury), organophosphate pesticides, chlorinated hydrocarbon solvents, estradiol, prostaglandins, leukotrienes, acetaminophen, and other foreign and endogenous toxins.

    • Stores and transports cysteine throughout the body.

    • Transports amino acids, especially cystine into kidney cells.

    • Regulates the cell cycle, DNA and protein synthesis and proteolysis, and gene expression.

    • Regulates signal transduction.

    • Participates in bile production.

    • Protects thyroid cells from self-generated hydrogen peroxide.

    In carrying out several of the above functions, GSH plays very important roles in (1) maintaining mitochondrial function and integrity, (2) regulating cell proliferation, and (3) supporting the immune system.

    [Refs. 1--5]

    • GSH is synthesized inside cells by a two-step process. The first step involves the ATP-powered enzyme glutamate cysteine ligase (formerly called gamma-glutamylcysteine synthetase). This step is normally the rate-limiting reaction, and is controlled by the cellular redox state and feedback inhibition, among other factors. The second step makes use of the ATP-powered enzyme glutathione synthetase.

    • The necessary substrates are cysteine (which is often the rate-limiting substrate when GSH is depleted), glutamic acid (or glutamine) and glycine. Cysteine and glutamic acid are joined together in the first step, and glycine is added in the second step.

    • The liver is the main producer and exporter of GSH.

    • A few epithelial cell types can import GSH molecules intact.

    • Most cell types use the gamma glutamyl (or GSH scavenging) cycle. This cycle makes use of the plasma-membrane-bound exoenzymes gamma-glutamyl transpeptidase and dipeptidase. This cycle disassembles GSH outside the cell and imports the parts for reassembly inside. It also serves as a transport mechanism to bring other amino acids into the cell, cystine
    (di-cysteine) being favored.


    There is considerable evidence that GSH is depleted in at least a substantial fraction of CFS patients. Here are the results of all the published studies that bear on this question:

    • GSH depletion in CFS was first suggested by Droge and Holm [6].
    • Cheney [7,8] reported that his CFS clinical patients were almost universally low in GSH.
    • Richards et al. [9] found that patients could be divided statistically into two distinct groups, one having significantly elevated erythrocyte GSH relative to a healthy control group, and the other having significantly lower values.
    • Fulle et al. [10] found elevated total (reduced plus oxidized) glutathione in muscle biopsy specimens from PWCs relative to healthy controls, but they did not report values for reduced glutathione alone.
    • Manuel y Keenoy et al. [11] found that a subgroup of fatigued patients with low magnesium, which did not improve with supplementation, had significantly lower GSH.
    • Manuel y Keenoy et al. [12] did not find a significant difference between CFS patients and fatigued controls in terms of whole-blood GSH, but they did not compare with a healthy control group.
    • Kennedy et al. [13] found significantly lower red blood cell GSH in PWCs compared to healthy controls (p=0.05).
    • Kurup and Kurup [14] found significantly lower red blood cell GSH in myalgic encephalomyelitis patients compared to healthy controls (p<0.01).


    These factors and conditions can be divided into three groups:

    • The first group is made up of those that (1) lower the rate of GSH synthesis or the rate of reduction of GSSG to GSH, or (2) raise the rate of export of GSH from cells, or (3) lead to loss of GSH from the scavenging pathway. This group includes the following: genetic defects [15], elevated adrenaline secretion [16-20] due to various types of stress, deficient diet [1] or fasting [21], surgical trauma [21,22], burns [23], and morphine [24].

    • The second group is comprised of ¬toxins that conjugate GSH and remove it from the body [25], such as organophosphate pesticides, halogenated solvents, tung oil (used on furniture), acetaminophen and some types of inhalation anesthesia.

    • The third group is comprised of conditions that raise the production rates of reactive oxygen species high enough to produce oxidative stress, causing cells to export GSSG. These include strenuous or extended exercise [26], infections (producing leukocyte activation) [21], toxins that produce oxidizing free radicals during Phase I detoxication by cytochrome P450 enzymes [21], ionizing radiation [27], iron overload [28], and ischemia--reperfusion events (such as stroke, cardiac arrest, subarachnoid hemorrhage, and head trauma) [29].


    • For purposes of this presentation, stressors are defined in the broad sense as events, circumstances or conditions that place demands on a person and tend to move his or her body out of allostatic balance. Allostasis is similar to homeostasis, but allows for changes in the set-point over time to match life circumstances [30]. Stressors can be classified as physical, chemical, biological, or psychological/emotional.

    • Stress is the state that results from the presentation of such demands. Selye [31] defined stress as "the state manifested by a specific syndrome which consists of all the nonspecifically-induced changes within a biologic system." Although Selye emphasized the nonspecifically-induced responses, the body also exhibits specific responses that depend on the type of stress [32].

    • Stress can be of a beneficial or a destructive nature. Distress is the destructive type of stress [31].

    • The perceived stress that people experience depends not only on the stressors to which they are subjected, but also on "their appraisals of the situation and cognitive and emotional responses to it." [33]

    • A person's history of both the occurrence of stressors and of the degree of perceived stress can be evaluated by structured interviews, and this has been done in a number of studies of CFS risk factors [34-45].


    YES. The types of stressors found to have higher occurrence in one or more CFS risk factor studies [34-45] include the following:
    • Physical: Aerobic exercise (especially of long duration), physical trauma (especially motor vehicle accidents) and surgery (including anesthesia).
    • Chemical: Exposure to toxins such as organophosphate pesticides, solvents and ciguatoxin.
    • Biological: Infections, immunizations, blood transfusions, insect bites, allergic reactions, and eating or sleeping less.
    • Emotional/Psychological:
    Stressful life events, including death of a spouse, close family member or close friend; recent marriage; troubled or failing marriage, separation, or divorce; serious illness in immediate family; job loss, starting new job, or increased responsibility at work; and residential move. Difficulties, including ongoing problems with relationships, persistent work problems or financial problems, mental or physical violence, overwork, extreme sustained activity, or "busyness."
    Dilemmas "A dilemma is a situation in which a person is challenged to choose between two equally undesirable alternatives."[45] Choosing inaction in response to a dilemma leads to further negative consequences.
    Problems in childhood, including significant depression or anxiety, alcohol or other drug abuse, and/or physical violence in parents or other close family members; physical, sexual or verbal abuse, low self-esteem and chronic tension or fighting in the family.


    YES. Three studies [34, 37, 38] found that CFS patients rated their level of perceived stress prior to onset higher than did healthy, normal controls for a similar period of time.


    NO. In view of the strong correspondence between the results of the CFS risk factor studies and the known GSH depletors, it is not surprising. It appears that the CFS patients who were studied had undergone a variety of factors and conditions that are known to deplete glutathione, and had also experienced high levels of perceived stress as a result.


    • This system manifests both specifically- and nonspecifically-induced responses to stress [32]. The nonspecifically-induced responses address the combined load of all the various types of stress that are being experienced simultaneously.

    • The nonspecific responses are mediated by three parts of this sytem: (1) the hypothalamus-pituitary-adrenal (HPA) axis, which produces cortisol and other glucocorticoids, (2) the sympathetic-adrenomedullary system, which produces epinephrine (adrenaline), and (3) the sympathoneural system, which produces norepinephrine (noradrenaline) [32].

    • Rapid-onset CFS patients report that they had a normal response to stress prior to their onset of CFS. Therefore, it can be surmised that if they experienced a high load of combined long-term stress lasting a few months to several years prior to their onset, they were subject to high levels of both cortisol and adrenaline during this extended period of time.

    • Note that depleted rather than elevated cortisol levels are frequently observed clinically in CFS patients (Cleare [46]). However, the decrease in cortisol secretion occurs later in the pathogenesis: "…the bulk of the data assembled to date is compatible with the view that the disruption in adrenocortical function is a late finding, and that elucidating the status of the central nervous system components which drive the regulation of the HPA axis would be crucial to a more complete understanding of this final event." (Demitrack [47])


    • Elevation of cortisol is known to suppress the inflammatory response by several mechanisms, including decreasing the expression of cytokines and cell adhesion molecules, and decreasing the production of prostaglandins and leukotrienes [48]. This effect is beneficially used therapeutically in many cases, but it can also have a down side if an infection is present.

    • Elevation of cortisol is also known to suppress cell-mediated immunity and to cause a shift to the Th2 type of immune response. Several mechanisms are involved, including suppressing the secretion of IL-1 by macrophages, inhibiting the differentiation of monocytes to macrophages, inhibiting the proliferation of T lymphocytes, and increasing the production of endonucleases, which increases the rate of apoptosis of lymphocytes [33,48].

    • Long-term elevation of adrenaline can be expected to deplete GSH, because adrenaline decreases the rate of synthesis of glutathione by the liver (Estrela et al. [18]), increases its rate of export from the liver (Sies and Graf [16]; Haussinger et al. [17]; Estrela et al. [18]), and decreases the rate of reduction (recycling) of oxidized glutathione (Toleikis and Godin [19]).


    I propose that glutathione depletion is the trigger for reactivation of endogenous latent viruses in CFS (hypothesis).

    Here's the support for this hypothesis:
    • Most of the evidence points to reactivation of latent endogenous viruses at the onset of CFS, rather than new, primary infections (Komaroff and Buchwald [49])
    • Infections by members of the Herpes family of viruses, such as Epstein-Barr virus and HHV-6 are commonly found in CFS patients [49].
    • GSH depletion is associated with the activation of several types of viruses [50-53], including Herpes simplex type 1 (HSV-1) [54]. Raising the GSH concentration inhibits replication of HSV-1 by blocking the formation of disulfide bonds in glycoprotein B, a protein that is necessary for proliferation of the virus [54].
    • Glycoprotein B is also found in all other Herpes family viruses studied, including EBV and CMV [55], and very likely is present also in HHV-6 and performs the same vital function there (hypothesis).

    It thus appears very likely that GSH depletion is the trigger for the reactivation of the latent forms of all the Herpes family viruses. Since glutathione likely becomes depleted prior to the onset of CFS, and since infections by these viruses are commonly found in CFS, it seems likely that glutathione depletion initiates the viral infections at the onset of CFS (hypothesis).

    • The shift to the Th2 immune response, as observed in CFS [56], is a known effect of both elevated cortisol [57] and of depleted GSH [58, 59]. I suggest that elevated cortisol produces the shift initially, and that GSH depletion maintains it later, after the cortisol level drops due to later blunting of the HPA axis.
    • The following dysfunctions seen in CFS [60] are known effects of depleted GSH: lowered natural killer cell and cytotoxic T cell cytotoxicity; inability of T cells to proliferate, as seen in decreased mitogen-induced proliferative response of lymphocytes and decrease in delayed-type hypersensitivity [61].

    In addition, I hypothesize the following:
    • The observed chronic immune activation [60] and the observed continuous activation of the RNase-L pathway in CFS [60] result from the failure of cell-mediated immunity to defeat detected infections, owing to the above effects of GSH depletion.
    • The observed low molecular weight RNase-L [62] results from lack of inhibition of caspases because of thiol (GSH) depletion, and they cleave the RNase-L.

    [Please note that as a result of communication with Dr. Jo Nijs, I learned that caspases have not been found to be able to cleave RNase-L. I now believe that calpain is responsible for this. Elastase is compartmentalized inside cells and is separated from RNase-L, so I do not believe it is responsible for the cleavage inside living cells.--Rich Van K. 5/22/07]

    • The observed elevated numbers of immune complexes [60] result from the shift to the Th2 response, which produces elevated levels of antibodies.
    • The observed elevation in antinuclear antibodies [60] results from the observed higher rate of apoptosis [63-66], which is caused by GSH depletion [67].


    • When the immune system detects the viral infection, it becomes activated.
    • In attempting to proliferate, the lymphocytes draw upon the already depleted supplies of GSH and its precursor, cysteine (or cystine).
    • Being in the blood, the lymphocytes have earlier access to GSH and cysteine than do the skeletal muscles.
    • Competition in CFS between the immune system and the skeletal muscles for these substances has already been hypothesized by Bounous and Molson [68], and I agree with their hypothesis.
    • The skeletal muscles become more depleted in GSH.
    • This produces a rise in their concentrations of peroxynitrite. (Peroxynitrite forms from superoxide and nitric oxide. Superoxide becomes elevated because the depletion of GSH causes a rise in hydrogen peroxide, and this exerts product inhibition on the superoxide dismutase reaction, causing superoxide levels to rise.)
    • As Pall [69] has stated, "Peroxynitrite reacts with and inactivates several of the enzymes in mitochondria so that mitochondrial and energy metabolism dysfunction is one of the most important consequences of elevated peroxynitrite."
    • The resulting partial blockades in the Krebs cycles and the respiratory chains in the red, slow-twitch skeletal muscle cells decrease their rate of production of ATP. Since ATP is what powers muscle contractions, the lack of it produces physical fatigue. It becomes chronic because GSH remains depleted.


    YES. Oxidative stress is now well-established in CFS.
    The following researchers have presented evidence for oxidative stress in CFS:
    • Ali [70,71]
    • Cheney [7,8]
    • Richards et al. [9,72]
    • Fulle et al. [10]
    • Manuel y Keenoy et al. [11,12]
    • Vecchiet et al. [73]
    • Kennedy et al. [13]
    • Smirnova and Pall [74]


    • Long-term cortisol elevation is known to damage the hippocampus, and GSH depletion is involved [75].
    • Additional depletion of GSH would likely exacerbate the effects of elevated cortisol on the hippocampus.
    • The hippocampus is involved with memory, sleep, and control of the HPA axis.
    • Deficits in all these areas are seen in CFS.
    • Examination of the hippocampus in CFS by magnetic resonance spectroscopy suggested significantly lower metabolism in the right hippocampus [76].
    • It seems likely that elevated cortisol and depleted GSH account for at least some of the CFS brain function deficits.


    YES. While there are no published controlled studies of mercury level testing in CFS patients, several clinicians who specialize in treating CFS have reported that many of their patients have high mercury levels:

    • Ali [77]
    • Godfrey [78]
    • Conley [79]
    • Poesnecker [80]
    • Teitelbaum [81]
    • Corsello [82]
    • Goldberg [83]

    In addition, immune testing has shown significantly elevated hypersensitivity to mercury in many CFS patients (Stejskal et al., [84]; Sterzl et al., [85]; and Marcusson, [86]). This suggests that the immune system has responded to elevated mercury levels.

    (Note that there have been epidemiological studies that showed no evidence that dental amalgams are associated with CFS as a causal factor [87,88]. However, this does not constitute evidence that amalgams do not give rise to elevated mercury levels after CFS onset in people who have amalgams and who may have developed CFS as a result of other causes.)



    • It is known that thyroid cells normally produce hydrogen peroxide to oxidize iodide ions as part of the pathway for producing thyroid hormones. Normally, this oxidation occurs outside the cell membrane, and the interior of the cell is protected from the hydrogen peroxide by intracellular GSH [89].

    • It has been shown by Duthoit et al., [90] that if hydrogen peroxide is allowed to enter thyroid cells, it will attack and cleave thyroglobulin, producing C-terminal fragments that can diffuse into other cells and are recognized by autoantibodies from patients with autoimmune thyroid disease. This suggests that hydrogen peroxide entry into thyroid cells may be the cause of this disease.

    • It has been shown by Wikland et al. [91], using fine needle aspiration cytology, that about 40% of patients suffering from chronic fatigue show evidence of chronic autoimmune thyroiditis, even though TSH levels were in the normal range in many of them.

    HYPOTHESIS: It seems likely that GSH depletion accounts for the high prevalence of autoimmune (Hashimoto's) thyroiditis in CFS.


    [Please note that I presented another hypothesis for this at the 2007 IACFS conference as a poster paper. It is included later in this thread.--Rich Van K., 5/22/07]

    • It has been found recently that the monthly menstrual cycle in women presents an additional demand on GSH that does not occur in men. 17-beta estradiol is elevated in women from the late follicular phase through the early luteal phase of the cycle. This hormone stimulates the activity of the enzyme glutathione peroxidase [92].

    • Perhaps this occurs to protect against elevated production of reactive oxygen species generated during the rapid growth of the endometrium.

    • The resulting reactions depress the endometrial GSH level during the time the estradiol level is high [92].

    HYPOTHESIS: I propose that this additional estradiol-driven demand for GSH in women exacerbates the GSH depletion that occurs as a result of other causes, and that this makes women more vulnerable to developing CFS, accounting for the higher observed prevalence of CFS in women than in men.


    • Diet high in sulfur-containing amino acids (as in animal-based protein, such as milk, eggs and meat) and antioxidants (as in fresh fruits and vegetables) [93].
    • Diet high in GSH, e.g. fresh fruits and vegetables and meats [94].
    • Curcumin [95].
    • N-acetylcysteine together with glutamic acid (or glutamine) and glycine [96], or NAC together with dietary protein [97].
    • Non-denatured whey protein [98]
    • Oral reduced glutathione [4]
    • Intravenous reduced glutathione [99]
    • Intramuscular reduced glutathione [100]
    • Transdermal reduced glutathione skin cream or lotion [101]
    • Sublingual reduced glutathione troches [102]
    • Reduced glutathione rectal suppositories [103]
    • Reduced glutathione aerosol [104]
    • Reduced glutathione nasal spray [105]



    Patricia Salvato, M.D. [100] has used intramuscular injections of GSH combined with ATP clinically for several years. In 1998 she reported on a study of 276 CFS patients, using 100 mg of GSH and 1 mg of ATP weekly. After 6 months of treatment, 82% experienced improvement in fatigue, 71% experienced improvement in memory and concentration, and 62% experienced improvement in levels of pain.

    Paul Cheney, M.D. reported in 1999 [7,8] on his clinical use of oral undenatured whey protein in CFS patients. The dosage varied with different patients, up to 40 grams per day. He reported that several of his patients improved on this treatment, and some who had had active infections with herpes family viruses, mycoplasma, or chlamydia were cleared of them by this treatment.

    John S. Foster, M.D. and his colleagues reported in 2002 [99] on their use of GSH in an intravenous fast push (over 2 to 3 minutes). Dosage ranged up to 2,500 mg, 1 or 2 times weekly, as part of a detoxification protocol used on a variety of patients, including some with CFS. They reported that the treatment "has been promising in addressing neurodegenerative and neurotoxic disorders."


    Glutathione depletion indeed appears to be an important aspect of the pathogenesis of chronic fatigue syndrome for at least a substantial fraction of patients.

    Is repletion of glutathione likely to be the complete answer for treating CFS?

    No. GSH depletion occurs near the beginning of the complex pathogenesis of CFS. There are likely to be many interactions and vicious circles as the pathogenesis develops into the pathophysiology, and there may also be damage that is difficult to correct. The mediators of such damage would likely be infections, toxins and reactive oxygen species, all of which are able to build up because of the depletion of GSH. It is likely that a multifaceted treatment protocol will be necessary.

    There are also some cautions that should be exercised:
    • When GSH repletion is begun in patients who have been GSH-depleted for extended periods of time, their immune and detoxication systems can begin to function at higher levels of performance. If their bodies have accumulated elevated levels of toxins (especially mercury) and infections, glutathione repletion can cause significant Herxheimer-type reactions as pathogens are killed and toxins are mobilized. Care should be taken to proceed slowly and cautiously in such cases in order to avoid moving toxins into the central nervous system or exacerbating symptoms to a level that is intolerable to the patient.
    • Plasma cysteine level should be monitored periodically when repleting glutathione, to ensure that it does not rise to levels that could be neurotoxic [106].


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  8. richvank

    richvank New Member



    Richard A Van Konynenburg, Ph.D.
    (Independent Researcher and Consultant)

    8th International IACFS Conference on
    Chronic Fatigue Syndrome, Fibromyalgia
    and other Related Illnesses

    Ft. Lauderdale, Florida, U.S.A.
    January 10-14, 2007

    Epidemiological studies have found that the prevalence of CFS is significantly higher in women than in men.

    Jason et al. (1) found a ratio of 1.8 (women to men) in a community-based study in Chicago, IL, USA, that included over 28,000 adults.

    Reyes et al. (2) found a ratio of 4.5 (women to men) in a study in Wichita, KN, USA, that included nearly 24,000 households.

    Other studies in San Francisco, CA, USA (3), the U.K. (4), Australia (5), Sweden (6), Iceland (7) and the Netherlands (8) have also found significantly higher prevalence of CFS or CFS-like illness in women.

    Children have been found to have a lower rate of incidence of CFS than adults, and there does not appear to be an effect of gender on the incidence of CFS in childhood:

    Carter and Marshall (1995) (9)

    Jordan et al. (2000) (10)

    Chalder et al. (2003) (11)

    Means et al. (2004) (12)

    Jones et al. (2004) (13)

    Farmer et al. (2004) (14)

    ter Wolbeek et al. (2006) (15)

    This suggests that the transition to a higher relative rate of incidence of CFS in females occurs during adolescence, and thus that it may be related to increases in production of the female sex hormones, which occur at that time.


    1. Many people with CFS have polymorphisms in the genes that code for the detox enzymes that metabolize the estrogens, and in particular the dominant estrogen, estradiol.

    2. These polymorphisms can be expected to occur equally in males and females, since these genes are autosomal (i.e. they are located on non-sex chromosomes). However, these polymorphisms would be particularly important in women who are in their potentially reproductive years, because of the higher production of estradiol in these women.

    3. One result of the presence of these polymorphisms would be to increase the levels of semiquinones and quinones (16).

    4. Semiquinones and quinones react back and forth between each other in a process that generates superoxide ions and is called redox cycling (17).

    Hypothesis (continued)

    5. This redox cycling would produce an additional contribution to oxidative stress in these women that does not occur in men. Men’s bodies produce much lower amounts of estradiol (by the action of aromatase on testosterone), and the metabolism of the remainder of the testosterone occurs by different pathways that do not involve redox cycling (18).

    6. According to the Glutathione Depletion—Methylation Cycle Block Hypothesis for the pathogenesis of CFS (19), oxidative stress depletes glutathione, which leads to the onset of CFS.

    7. Therefore, women in their potentially reproductive years who have the relevant polymorphisms would have an additional factor biasing them toward onset of CFS that men do not have, and this would produce a higher prevalence of CFS in women than in men.

    (Note that this redox cycling mechanism is well established and has been under study for several years because of its possible involvement in carcinogenesis (16, 17).

    Rates of Production of Estradiol in
    Males and Females


    BOYS: 0.04 micrograms per day

    GIRLS: 0.3 micrograms per day

    MEN: 50 micrograms per day (22)

    WOMEN (by menstrual cycle stage) (22):

    Early follicular 36 micrograms per day
    Preovulatory 380 micrograms per day
    Midluteal 250 micrograms per day

    Normal Metabolism of Estradiol by Detox Enzymes (23,24)

    (See diagram)

    The metabolism of estradiol (and of the estrogens in general) is complex, including a large number of alternative pathways and metabolites.

    Most of the metabolism of estradiol occurs in the liver, while smaller amounts occur in other organs, including breast, uterus, brain, kidneys and ovaries.

    Some estradiol is converted to estrone, and some is acted upon by various CYP450 enzymes to form multiple hydroxylated metabolites. Estradiol itself, estrone and these hydroxylated metabolites can be conjugated by other detox enzymes to form sulfates, glucuronides, or fatty acid esters. The various sulfate and glucuronide conjugates are the main metabolites that are excreted in urine and stools. Only the major pathways of estradiol metabolism are discussed in detail in the following.

    The main hydroxylation reactions in the liver involve the CYP450 enzymes CYP3A and CYP1A2, and their chief product is 2-hydroxyestradiol, which is a catechol estradiol.

    Normal Metabolism of Estradiol by Detox Enzymes (continued) (23,24)

    (See diagram)

    A smaller fraction of the total estradiol is metabolized by the enzyme CYP1B1, located in organs other than the liver. This reaction primarily produces 4-hydroxyestradiol, another catechol estradiol.

    Most of the catechol estradiols are O-methylated by the enzyme catechol-O-methyltransferase (COMT) to form 2- and 4-methoxyestradiols, which are excreted.

    Some of the catechol estradiol molecules escape the COMT reaction and instead are further oxidized by CYP1B1 to form semiquinones, which in turn are oxidized to form quinones. Normally, these are conjugated to glutathione by the glutathione transferase (GST) superfamily of enzymes and are excreted.

    What would happen to estradiol metabolism if there were polymorphisms in the detox enzymes?

    (See diagram)

    CYP3A4 AND CYP1A2: Known polymorphisms that lower the activity of these enzymes would decrease the fraction of estradiol that is metabolized by them in the liver. This would have the effect of increasing the fraction of estradiol that is metabolized in other organs by CYP1B1.

    CYP1B1: Known polymorphisms that raise its activity would cause a greater rate of production of 4-hydroxyestradiol, and would also cause more of this to be oxidized to form semiquinones and quinones (16).

    COMT: Known polymorphisms that lower its activity would decrease the fraction of 4-hydroxyestradiol that is methylated, leaving more to be oxidized to semiquinones and quinones.

    GST enzymes: Known polymorphisms that lower the activity of members of this superfamily of enzymes would decrease the rate of removal of semiquinones and quinones, leaving more of them to carry on redox cycling and to contribute to oxidative stress (25).

    Have any of the detox enzymes that metabolize estradiol been found to have these polymorphisms at higher frequencies in people with CFS?

    Of these enzymes, so far the only one that has been reported to have been studied in CFS is COMT.

    Goertzel et al. (26) found that they could distinguish CFS cases from controls with an accuracy of 75% by using combinations of polymorphisms of only five genes. They reported that of the nine genes containing a total of 28 polymorphisms that they considered, the gene for COMT was among the three most important genes for distinguishing CFS cases from controls. They considered six COMT polymorphisms in their study. (This result is remarkable in view of the facts that the entire human genome contains about 25,000 genes and several million polymorphisms, and this demonstrates the importance of elevated frequencies of COMT polymorphisms in CFS.)

    Two studies (27,28) have found the COMT Val 158 Met polymorphism to have significantly higher frequencies in people with fibromyalgia than in controls. (This may be relevant because of the high comorbidity between CFS and fibromyalgia.)

    What about polymorphisms in the CYP and GST enzymes in CFS? Have they been observed at elevated frequencies?

    Although no studies have yet been published about the frequencies of polymorphisms in the CYP enzymes or the glutathione transferases in CFS relative to controls, the author has received anecdotal reports from several people with CFS who have had these polymorphisms characterized, and trends in the data suggest high frequencies for these polymorphisms in CFS, also.


    This hypothesis is consistent with known biochemistry, and in combination with the Glutathione Depletion—Methylation Cycle Block Hypothesis for the pathogenesis of chronic fatigue syndrome (19), it provides a plausible explanation for the observed higher prevalence of CFS in women, a feature that has heretofore not been explained.

    This hypothesis is also consistent with available evidence concerning the elevated frequencies of polymorphisms in catechol-O-methyltransferase (COMT) in CFS.

    Controlled study in people with CFS of the frequencies of polymorphisms in the other enzymes involved in the metabolism of estradiol appears to be warranted. Such study would test this hypothesis. It would also shed light on the pathogenesis of CFS, and perhaps on the pathogeneses of other disorders important in women’s health.


    1. Jason, L.A., Richman, J.A., Rademaker, A.W. et al., A community-based study of chronic fatigue syndrome, Arch. Intern. Med. 159 (18), 2129-2137 (1999).

    2. Reyes, M., Nisenbaum, R., Hoaglin, D. et al., Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas, Arch. Intern. Med. 163, 1530-6 (2003).

    3. Steele, L., Dobbins, J.G., Fukuda, K. et al., The epidemiology of chronic fatigue syndrome in San Francisco, Am. J. Med. 105 (3A), 83S-90S (1998).

    4. Gallagher, A.M., Thomas, J.M., Hamilton, W.T. and White, P.D., Incidence of fatigue symptoms and diagnoses presenting in UK family care from 1990 to 2001, J. Royal. Soc. Med. 97, 571-5 (2004).

    5. Lloyd, A.R., Hickie, I., Boughton, C.R. et al., Prevalence of chronic fatigue syndrome in an Australian population, Med. J. Australia 153, 522-8 (1990).

    6. Evengard, B., Jacks, A., Pedersen, N. and Sullivan, P.F., The epidemiology of chronic fatigue in the Swedish Twin Registry, Psych. Med. 35, 1317-26 (2005).

    7. Lindal, E., Stefansson, J.G., and Bergmann, S., The prevalence of chronic fatigue syndrome in Iceland—a national comparison by gender drawing on four different criteria, Nordic J. of Psychiatry 56 (4), 273-7 (2002).

    8. Bazelmans, E., Vercoulen, J.H., Galama, J.M. et al., Prevalence of chronic fatigue syndrome and primary fibromyalgia syndrome in the Netherlands, Ned. Tijdschr. Geneeskd. 141 (31), 1520-3 (1997).

    9. Carter, B.D. and Marshall, G.S., New developments: diagnosis and management of chronic fatigue in children and adolescents, Current Problems in Pediatrics 25, 281-93 (1995).

    10. Jordan, K.M., Ayers, P.M., Jahn, S.C. et al., Prevalence of fatigue syndrome-like illness in children and adolescents, J. Chronic Fatigue Syndrome 6 (1), 3-21 (2000).

    11. Chalder, T., Goodman, R., Wessely, S. et al., Epidemiology of chronic fatigue syndrome and self reported myalgic encephalomyelitis in 5-15 year olds; cross sectional study, BMJ 327, 654-5 (2003).

    12. Mears, C.J., Taylor, R.R., Jordan, K.M. and Binns, H.J., Sociodemographic and symptom correlates of fatigue in an adolescent primary care sample, J. Adolesc. Health 35, 528.e21-528.e26 (2004).

    13. Jones, J.F., Nisenbaum, R., Solomon, L. et al., Chronic fatigue syndrome and other fatiguing illnesses in adolescents: a population-based study, J. Adolesc. Health 35 (1), 34-40 (2004).

    14. Farmer, A., Fowler, T., Scourfield, J., and Thapar, A., Prevalence of chronic disabling fatigue in children and adolescents, Brit. J. Psychiat. 184, 477-81 (2004).

    15. ter Wolbeek, M., van Doornen, L.J., Kavelaars, A., and Heijnen, C.J., Severe fatigue in adolescents: a common phenomenon?, Pediatrics 117 (6), e1078-86 (2006).

    16. Sissung, T.M., Price, D.K., Sparreboom, A. and Figg, W.D., Pharmacogenetics and regulation of human cytochrome P450 1B1: implications in hormone-mediated tumor metabolism and a novel target for therapeutic intervention, Mol. Cancer. Res. 4 (3), 135-50 (2006).

    17. Liehr, J.G. and Roy, D., Free radical generation by redox cycling of estrogens, Free Radical Biol. & Med. 8, 415-23 (1990).

    18. Bhagavan, N.V., Medical Biochemistry, fourth edition, Harcourt/Academic Press, Burlington, MA (2002) pp. 785-6.

    19. Van Konynenburg, R.A., Glutathione depletion—methylation cycle block hypothesis for the pathogenesis of chronic fatigue syndrome, poster paper, this Conference.
    20. Klein, K.O., Baron, J., Colli, M.J. et al., Estrogen levels in childhood determined by an ultrasensitive recombinant cell bioassay, J. Clin. Invest. 94, 2475-80 (1994).

    21. Andersson, A.M. and Skakkebaek, N.E., Exposure to exogenous estrogens in food: possible impact on human development and health, Eur. J. Endocrin. 140, 477-85 (1999).

    22. Yen, S.S.C., Jaffe, R.B. and Barbieri, R.L., Reproductive endocrinology, 4th ed. Saunders (1999), as cited in Ganong, W.F., Review of medical physiology, twenty-second edition, New York, Lange Medical Books/McGraw-Hill (2005), p. 441.

    23. Tsuchiya, Y., Nakajima, M. and Yokoi, T., Cytochrome P450-mediated metabolism of estrogens and its regulation in human, Cancer Letts. 227, 115-24 (2005).

    24. Raftogianis, R., Creveling, C., Weinshilboum, R., and Weisz, J., Chapter 6: Estrogen metabolism by conjugation, J. Nat. Cancer Inst. Monographs No. 27, 113-24 (2000).

    25. Hachey, D.L, Dawling, S., Roodi, N. and Parl, F.F., Sequential action of phase I and II enzymes cytochrome P450 1B1 and glutathione S-transferase P1 in mammary estrogen metabolism, Cancer Res. 63, 8492-9 (2003).

    26. Goertzel, B.N., Pennachin, C., Coelho, L. de S., et al., Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome, Pharmacogenomics 7 (3), 475-83 (2006).

    27. Gursoy, S., Erdal, E., Herken, H. et al., Significance of catechol-O-methyltransferase gene polymorphism in fibromyalgia, Rheumatol. Intl. 23, 104-7 (2003).

    28. Garcia-Fructuoso, F.J., Beyer, K., and Lao-Villadoniga, J.I., Analysis of Val 159 Met genotype polymorphisms in the COMT locus and correlation with IL-6 and IL-10 expression in fibromyalgia syndrome, J. Clin. Res. 9, 1-10 (2006).
  9. monalisa3

    monalisa3 New Member

    Wow! A lot to read through. Excellent info! I have read through some of it and am fascinated, mainly because Ihave been researching heavy metal toxicity (mercury) a few months now. This glutathione depletion theory seems VERY intersting though I don't know enough about it yet. I know you have probably been asked before about a connection to FM also. I realise you are a researcher in CFS and you can't really comment on FM connection to this theory but it seems to me like FM could fit here somewhere.

    Keep up the great work!
  10. Diva55

    Diva55 New Member

    Hi Monalisa3
    There is a thread which Rich posted a while back about FM & Methylation Block. He asked if people with "Pure FM" would consider trying the protocol.

    Many people with FM have an overlap with CFS - I certainly do! So even if the protocol does not get to the "pure" elements of FM it might help with the overlap CFS elements.

    Well that's just my take on it. It's all very experimental even with CFS.

    I have the supplements but am waiting awhile to start them as I need to clear a space to allow for any initial reactions to them.

    Rich: Great info you have posted - my doctor will be bombarded with more info!

  11. richvank

    richvank New Member

    Hi, monalisa.

    So far I've heard from only one person with "pure FM" who has tried the simplified treatment approach based on the methylathion cycle block hypothesis. She reported that her sleep became worse, and she stopped the treatment. It would be helpful to have more "pure FM" cases, but it's really up to the PWFs if they want to try it. It might help, but since I don't understand the pathogenesis of FM, I can't make a scientific case for it. For CFS, on the other hand, I think the science is in place to support this treatment, and the early results of the use of this treatment are encouraging. For people who satisfy the diagnostic criteria for both CFS and FM, I think this treatment is definitely worth a try.

  12. monalisa3

    monalisa3 New Member

    I have been following some people's progress who are on the protocol from time to time. Though slow, it certainly seems encouraging. It would seem to me that you are on the right track with all of this. I have a question for you and apologies if it's been asked before (you probably get sick of the same questions). It's just hard to search through all the posts on this topic as there are too many. Anyway, the question is, how and why does one's methylation get blocked and glutathione get depleted in the first place??? I really need to understand this.

    Thanks in advance
    [This Message was Edited on 05/24/2007]
  13. richvank

    richvank New Member

    Hi, Monalisa.

    In my hypothesis, glutathione gets depleted first, and that brings on a block in the methylation cycle. This block then prevents glutathione from coming back up. That is, there is a vicious circle, and that keeps the person ill.

    In order for this to happen in a person, they must have inherited a set of genetic variations (polymorphisms or SNPs) from their parents, which makes them vulnerable to developing CFS.

    Then, they must have some combination of long-term stressors in their life, which can be physical (such as a trauma or way too much exercise), chemical (toxins such as heavy metals, solvents, pesticides, etc.), biological (such as infections, blood transfusions or vaccinations) or psychological/emotional (such as ongoing conflicts or very stressful events, ongoing serious worries, etc.) These things combine together to raise cortisol and adrenaline, and to lower glutathione.

    When glutathione goes low enough, the methylation cycle slows down because the enzymes in it are sensitive to oxidative stress. Also, toxins build up, because there is not enough glutathione to take them out of the body as usual. An important toxin is mercury, which many people inhale from their fillings.

    When there is not enough glutathione, there is no protection for vitamin B12, from toxins such as mercury. It therefore reacts with toxins, and now there is not enough methyl B12 to operate the methionine synthase enzyme, which is in the methylation cycle. This solidifies the methylation cycle block and makes CFS chronic. Unless this block is removed, the person will not recover from CFS, in my hypothesis.

    If you want more details about these biochemical mechanisms, please read the papers I've posted in this thread. It's all spelled out there.

  14. Elisa

    Elisa Member

    Thank you so much for posting it all together - it is very helpful. I really commend you for all your hard work - it is quite a contribution and I am grateful.

    I really think you will help many people - if they can implement it and take it slowly. That way they won't scare themselves.

    As you mentioned - unblocking the cycle - calls the body to begin detoxyfing many toxins and pathogens and that can be hard on the body. So go very very slow...Just my two cents!

    I know it is doing someting for me - I bought a bike and rode twice today. I have been nearly homebound for almost 10 yrs. I am in heaven taking a spin on my bike - like a dream to me. I am thrilled. Just a wonderful gift...

    I am also working with a DAN doctor!

    [This Message was Edited on 05/24/2007]
  15. monalisa3

    monalisa3 New Member

    Thank you so much Rich for taking the time to explain it to me. It's very technical and am starting to get my head around it. Thank god I have been researching mercury/amalgam toxicity in the past few months and through the knowledge I have gained I can appreciate and understand your theory somewhat. Otherwise I'd have no idea.

  16. monalisa3

    monalisa3 New Member

    Let's say mercury from amalgam fillings is one form of toxin that depletes glutathione and blocks the methylation cycle, would you agree that a necessary first step might be to remove the fillings (turn off the running tap of toxins) or any other sources of toxins. Than attempt to fix biochemistry imbalances of the body such as gluathione depletion. Correcting the methylation block and thus restoring glutathione levels in the body can help us detox again.

    Hope this makes sense Rich. I was just thinking that it would be wise to remove the source of toxicity first (where possible ofcourse) and then try to correct the body's natural detoxing system. Really want your take on this as I have come to value your opinion. I truly think you are on to something very significant not just for CFS but also for FMS. Have given all this a lot of thought.

    [This Message was Edited on 05/26/2007]
  17. richvank

    richvank New Member

    Hi, Monalisa.

    In toxicology, what you have suggested is usually considered a very sound principle, and if you can remove a source of toxins without causing more exposure in the process of doing so, it is definitely the right thing to do.

    However, in the case of amalgams, the problem is that the process of removal causes a significant amount of exposure to mercury, even when precautions (such as a strong vacuum, a lot of water cooling, slow drilling, a dam, and an external breathing air line) are used.

    I have heard from several PWCs who experienced symptoms of mercury exposure (particularly neurological symptoms) after having this done.

    I think that the problem is that when glutathione is low, there is nothing to bind the mercury that does get into the body and take it out.

    I think that most of the exposure is to metallic mercury vapor. When drilling is done, the mercury is heated, and its vapor pressure rises exponentially. Then the person inhales it. From the lungs it passes into the blood, and the enzyme catalase converts metallic mercury to mercuric ions. At that point, if there is not enough glutathione, the mercuric ions bind to sulfur wherever they can find it, such as in enzymes and other proteins. Some gets into the brain.

    In view of this, my suggestion is to do the methylation cycle block treatment first, so that the glutathione level can come back up to normal. After that, it will be safe to remove the amalgams.

  18. Mikie

    Mikie Moderator

    Thank you for all your hard work. Having everything in one place is great. I have read your papers online separately but this is so much better.

    Again, thank you.

    Love, Mikie
  19. DirkP

    DirkP New Member

    ty Rich. this is _very much_ appreciated. dirk
  20. monalisa3

    monalisa3 New Member

    Thank you rich for your advise on amalgam removal. It certainly does make sense to build up your glutathione first so that the body can better cope with further mercury exposure during the removal process. That's a lot for me to think about now.

    Thank you so much again for taking the time to answer everything and to help.