METHYLATION folks...

Discussion in 'Fibromyalgia Main Forum' started by Leaknits, May 27, 2008.

  1. Leaknits

    Leaknits New Member

    Please forgive me for being so stupid. I don't understand the explanations of the process, have mostly no clue what the substances being discussed are and, as always, have no money tree growing in the back yard.

    I have to depend on Lake County CA drs who will accept MediCare/MedicAid and have yet to find one who knows what to do for cfs/me. Current dr, when I said "myalgic encephalopathy" in his presence, didn't know what it is. I know because he said "What's THAT?"
    That's not all. He doesn't know what Methylation is, either.

    This is the man who, during the I Need A New Dr appt when I interviewed him as to whether he had any cfs patients, seems to have lied when he said "Yes."
    He also lied about not having the I'm God And You Aren't (IGAYA) attitude.

    He won't talk with me about treatment, just writes up another order for yet more pills. At this moment there are seven prescribed drugs in my cupboard:
    Soma 500mg Instructions: Take one at bedtime.
    Percocet 5-325 Instructions: Take 4 per day as needed for pain.
    Restoril 30mg Instructions: Take one at bedtime.
    Somnote 500mg Instructions: Take one at bedtime.
    Benadryl 50mg Instructions: Take four per day as needed for sinus.
    Valium 15mg Instructions: Take one & a half per day.
    Maxzide 75-50 (no mg or mcg words)
    Instructions: Take one & a half per day.

    Two of those above, Soma and Somnote, were issued together despite my protests; I don't know which one is causing some very odd effects.

    He refuses to treat the swollen lymphs. Won't even talk about it. So I have PAIN in 4 lymphs.
    When I ask him to look at my raw throat with sinus guck sliding down it, all he says is "Wow your spit is really thick." Duh. Appts are all set for as early in the morning as possible, so I haven't gulped down half a gallon of water by the time he sees me.
    He claims I don't have a fever because my temp is lower than the supposed "normal" of 98.6. My gosh if my temp went that high I'd be in bigger trouble than I already am.

    When I try to talk with him about insomnia, pain, agitation, anxiety he goes into an attitude of "Aha! Another Lake County junkie, here to get Drugs with a capital "D."

    Getting to a new dr, which I'd love to do, is not possible. This guy is the bottom of the barrel. I feel free to say that since I check regularly with local medical authority (quote: I am calling to ask if there is a dr in Lake County who understands and can treat Chronic Fatigue); the most recent attempt netted three names.
    I called each one. Apparently the drs don't tell the phone answerers much since each call resulted in "No, dr doesn't have any Chronic Fatigue patients."

    Seems to me if these people really did know anything about what to do with/for this d'd, they'd have at least a couple patients who have the illness.

    When I win the lottery I'll go to wherever the methylation process is used. Then maybe I'll get to understand what it is. Having slogged through tons of posts about it, all I got was more exhausted, confused, frustrated.

    I do know there are lots of people here on the board who are concerned and want to help. To them I say Thank You Very Much. It's a pity I can't find an expert in any dr's office.

    In addition to hopefully getting my stupidity forgiven, I also hope venting is forgiven.

    Lea.
  2. deliarose

    deliarose New Member

    Simplified Treatment Approach update 7-18-07 03/08/08 02:36 PM

    July 18, 2007


    Simplified Treatment Approach Based on the Glutathione Depletion-Methylation Cycle Block Pathogenesis Hypothesis for Chronic Fatigue Syndrome (CFS)


    by
    Rich Van Konynenburg, Ph.D.



    I first want to note that I am a researcher, not a clinician, and that what I have to say here should not be interpreted as medical advice.

    In January, 2007, in an effort to shed light on the validity of the Glutathione Depletion-Methylation Cycle Block (GD-MCB) Pathogenesis Hypothesis for Chronic Fatigue Syndrome (CFS), and to help clinicians to develop a practical treatment based on this Hypothesis, I suggested a simplified treatment approach. This approach is designed to lift the hypothesized methylation cycle block and to restore glutathione levels to normal. It was derived from a complete treatment program developed by Dr. Amy Yasko, N.D., Ph.D., for autism and other disorders that are also thought to involve methylation cycle block and glutathione depletion.

    A fairly large number of people with chronic fatigue syndrome (PWCs) have since voluntarily chosen to try this treatment approach, many with the help of their physicians. It now appears to be working well for many of these PWCs, but some serious adverse effects have also been reported in a few cases. Controlled testing of this treatment approach has not yet been done, but early results from these volunteers suggest that this would not only be worthwhile in view of indications of the efficacy of this approach, but also necessary to ensure its safe application.

    I would like to describe the history of the Glutathione Depletion-Methylation Cycle Block (GD-MCB) Hypothesis and the simplified treatment approach that is based upon it, and point out what I think the early treatment results mean with regard to this Hypothesis. But before I do so, I want to emphasize the following cautionary statements:

    While in the past I have stated that PWCs should cooperate with their physicians in trying the simplified treatment approach, as a result of experiences with this treatment approach that have been reported to me recently, I have concluded that it must be entered upon only under the supervision of a licensed physician, to make sure that if there are individual issues that arise, they can be taken care of immediately. The treatment approach itself consists only of nonprescription nutritional supplements that are normally found naturally in the body and are necessary for normal biochemistry to take place. It would thus appear to be fairly benign on its surface. However, it is now clear to me that restarting the methylation cycle after it has been blocked for extended periods, particularly in those PWCs whose general health has become quite debilitated, or those who have certain respiratory, cardiac, endocrine or autoimmune conditions, can present some serious challenges and hazards. I suspect that there is still much more to be learned about possible adverse effects of applying this treatment approach among the very heterogeneous CFS population, and this work properly lies in the province of clinicians. I believe that I have now carried this work as far as a nonclinical researcher can appropriately carry it. I am hopeful that clinicians will apply and test this treatment approach in order to learn how it may be safely, effectively, and practically utilized to treat PWCs, and it appears that this is now beginning to occur.

    As some readers will probably be aware, I presented a poster paper describing the above-mentioned Hypothesis at the most recent IACFS conference in Florida last January. It can be found on the internet on Cort Johnson’s website:

    http://phoenix-cfs.org/GSH%20Methylation%20Van%20Konynenburg.htm

    This Hypothesis has not yet been published in the peer-reviewed literature. My emphasis up to now has instead been upon addressing questions that remained to be answered before this Hypothesis could be considered for clinical testing and application in the form of a practical treatment approach.

    The history of the development of this Hypothesis is as follows:

    In 1999, I first learned from two public talks presented by Dr. Paul Cheney that many PWCs are depleted in glutathione, and that taking steps to build glutathione can be helpful to many. Dr. Derek Enlander has since reported to me that he began injecting glutathione as part of a complex into CFS patients as early as 1991. I also found that Dr. Patricia Salvato had reported in early 1998 on her use of intramuscular injection of glutathione in 276 patients. Over the years, quite a few CFS doctors have incorporated means of building glutathione into their protocols, either by administration of glutathione itself by various routes, or by oral supplementation with glutathione precursors, such as whey protein products.


    What is glutathione, and what does it do?

    Glutathione is technically a tripeptide, which can be thought of as being like a very small protein, as it is made up of only three amino acids (while proteins are made up of many more). It is present naturally in every cell of the body, as well as in the blood, the bile and the fluid lining the lungs. The liver is normally the main producer of glutathione in the body. Glutathione plays many important roles in the body. Probably the best known are its protection against oxidative stress produced by oxidizing free radicals and other reactive oxygen species, its support for the immune system, and its role in removing a variety of toxic substances from the body.


    When glutathione becomes somewhat depleted, as it does in many cases of CFS, its normal functions are simply not performed well. Many of the symptoms of CFS as well as observed abnormal results on specialized lab tests can be traced directly to glutathione depletion, as I described in an earlier AACFS poster paper in 2004. It can be found on Cort Johnson’s website:

    http://phoenix-cfs.org/GluAACFS04.htm

    As I noted in that paper, while direct efforts to build glutathione are helpful to many PWCs, for most they provide only temporary improvement and do not result in permanent restoration of glutathione levels or a cure for CFS. I suspected that a vicious circle mechanism must be involved in holding down the glutathione levels in CFS.

    Then, later in 2004, an important paper was published involving research into autism by S. Jill James and her coworkers: “Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism”
    (Am J Clin Nutr. 2004 Dec;80(6):1611-7). The study they reported showed that glutathione is depleted also in autism, and that this depletion is associated with a block in what is known as the methylation cycle (or methionine cycle).


    Before discussing this further, I want to address the question “What is the methylation cycle, and what does it do?”

    The methylation cycle is part of the basic biochemistry of the body, and is believed to operate in every cell. This cycle includes the amino acid methionine as well as S-adenosylmethionine (SAMe, used as a supplement by some PWCs), S-adenosylhomocysteine, and homocysteine. Some homocysteine is converted back to methionine, thus completing the cycle. There are two parallel pathways from homocysteine to methionine. They are the methionine synthase pathway and the BHMT (betaine homocysteine methionine transferase) pathway. The methylation cycle is directly linked to the folate metabolism and to the transsulfuration pathway.

    The methylation cycle performs many vital roles in the body. First, by means of SAMe, it supplies methyl (CH3) groups to many different biochemical reactions. Some of them produce substances such as coenzyme Q-10 and carnitine, which have been found to be depleted in many PWCs. Methylation also plays an important role in “silencing” certain DNA to prevent its expression, and in producing myelin for the brain and nervous system.

    The methylation cycle also controls the body’s response to oxidative stress, by governing how much homocysteine is diverted into the transsulfuration pathway, which contributes to determining the rate of synthesis of glutathione.

    A third important role of the methylation cycle is to control the overall sulfur metabolism of the body. In this role, besides controlling glutathione synthesis, it exerts control over synthesis of several other important substances, including cysteine, taurine and sulfate.

    When the methylation cycle is blocked at the enzyme methionine synthase, these important roles are not carried out properly. In addition, a methylation cycle block necessarily involves a block in the folate metabolism, to which it is intimately linked, and this interferes with synthesis of new DNA and RNA, among other important effects.

    Two of the most significant effects of a methylation cycle block are that neither the immune system nor the detox system can operate properly. If the methylation cycle remains blocked for an extended period of time, infections and toxins can be expected to build up in the body.


    After I read the paper by S. Jill James and her coworkers (referred to above), I began to suspect that the genetic factors and biochemical mechanism they had found in autism are the same or similar to those important in CFS. A block earlier than glutathione in the sulfur metabolism, at the methylation cycle, could explain the persistent glutathione depletion in CFS. It began to dawn on me that other aspects of CFS that did not appear to be explained by glutathione depletion per se could be explained by a methylation cycle block.

    It was difficult for me initially to believe that there was a connection between autism and CFS, given the profoundly different symptoms and different affected population groups (primarily boys in autism, compared to primarily adult women in CFS). However, I knew of others who had publicly suggested such a connection in the past (Dr. Michael Goldberg in the U.S. and Prof. Malcolm Hooper in the UK), and this new study seemed to provide more detailed evidence of this connection at the genetic and biochemical levels.

    I began to look into autism in more detail, and I attended the Long Beach conference of the Defeat Autism Now! (DAN!) project in October of 2005. The more I learned about autism, the more I became convinced that we are dealing in CFS with many of the same issues at the genetic and biochemical levels. The book by Drs. Jon Pangborn and Sidney Baker entitled “Autism: Effective Biomedical Treatments” (Autism Research Institute, September, 2005) provides excellent explanations of the biochemistry of autism, and the parallels with CFS can be seen there.

    I want to emphasize that I did not develop the Glutathione Depletion--Methylation Cycle Block Hypothesis out of thin air. The autism researchers had already provided a convincing basis for this model in that disorder. S. Jill James and coworkers did much of the clinical work that underlies it. Richard Deth and his coworkers had worked out much of the theory of the methylation cycle block and had applied it to autism. Professors James and Deth had been presenting talks on their work at autism conferences. The physicians in the DAN! project (as well as Dr. Amy Yasko, though I had not yet learned of her work when I began to understand the importance of the methylation cycle block) had already been treating autism cases by measures intended to lift the methylation cycle block. What I did was to apply the results of their work to CFS, and to present a detailed biochemical and symptomological case to support the proposition that this model also applies to CFS.


    What is the essence of the Glutathione Depletion-Methylation Cycle Block Hypothesis for the Pathogenesis of CFS?

    This hypothesis proposes first that in order to develop CFS, a person must have inherited genetic variations (also called SNPs or single-nucleotide polymorphisms) in a combination of certain genes that code for enzymes and other proteins associated with the methylation cycle and related pathways.

    The hypothesis further proposes that the person must also be subjected to some combination of a variety of long-term physical, chemical, biological or psychological/emotional stressors that lowers glutathione levels to the point that a block occurs in the enzyme methionine synthase in the methylation cycle, in response to the oxidative stress that is inherent in glutathione depletion. The formation of this block is aided by the presence of the inherited genetic polymorphisms. This lowering of glutathione levels also simultaneously removes the normal protection that glutathione provides to vitamin B12 and allows the accumulation in the body of toxins that can interfere with the utilization of vitamin B12, mercury perhaps being the dominant one.

    This hypothesis further proposes that the result of the above is that the level of methylcobalamin is held too low to support the methionine synthase reaction, and it therefore becomes chronically blocked. This produces a vicious circle mechanism that causes CFS to become a chronic condition.

    Finally, this hypothesis proposes that all the features of CFS can be shown to originate from this root cause. While I have not yet demonstrated this for every feature of CFS, the first paper cited in this article explains a large number of them in detail on this basis. Previous treatments for CFS have dealt with downstream issues in the pathogenesis, but they have not completely addressed this root cause, and, in my opinion, that is why we have not seen many completely cured CFS cases up to now. Note that when I refer to cured cases, I do not mean that the genetic predisposition has been removed, but that the PWCs are healthy from the symptomatic point of view.


    As I became more convinced of the parallels between autism and CFS, I began to point out this connection to some clinicians directly and to others via the internet, as well as to PWCs in internet groups, and I began encouraging them to consider the treatments that were being used by the Defeat Autism Now! project to treat autism, focusing on unblocking the methylation cycle. A small number of PWCs tried this approach, and while some initial benefits were observed from this, it did not seem to be an effective approach over the long term, at least in the way I was suggesting that it be applied.
    I then learned of the work of Dr. Amy Yasko, N.D., Ph.D. in autism. I studied her materials, including the book written by her and Dr. Garry Gordon entitled “The Puzzle of Autism,” joined her discussion forum at
    http://www.ch3nutrigenomics.com
    and eventually attended her teaching seminar in Boston in October of 2006. After considering all of this, I concluded that it was likely that her treatment approach could help many PWCs, so I decided to emphasize it. An important feature of her work is her effort to tie the genetics of individuals to the biochemistry and to do tailored treatment based on genetics, again directed toward correcting the methylation cycle block, but also incorporating support for a variety of body systems and organs. I also learned that Dr. Yasko had had some experience in using her approach in cases of CFS as well as a variety of adult neurological disorders, but that she was currently focusing primarily on autism.

    I wrote a short article pointing out the connection I was seeing between autism and CFS and pointing to these treatments, and it was published in the October 2006 issue of the Townsend Letter. This can be found at the following url:

    http://findarticles.com/p/articles/mi_m0ISW/is_279/ai_n16865315

    Quite a few PWCs acted on my suggestion to try Dr. Yasko’s full treatment approach, and they are currently continuing with it. Many of them participate in the Yahoo cfs_yasko internet group, a group that was specifically formed for them, which can be found at

    http://health.groups.yahoo.com/group/CFS_Yasko/

    Most of them are currently in the first step of this treatment approach, and they are generally reporting that this treatment is producing considerable detoxification of their bodies, as monitored by urine testing. The full Yasko treatment approach involves detailed genetic and biochemical testing, and is rather expensive and complex. While some PWCs are in a position to pursue this treatment and appear to be doing so successfully, it seemed to me that there are many others for whom this approach is beyond reach, either for economic or cognitive reasons or both. Practicing physicians have generally also found this treatment to be somewhat cumbersome to incorporate into their practices because of the complexity and the considerable time and expense required to tailor the treatment to each individual patient.

    In response to these issues and to requests from clinicians for a written description of practical CFS treatment based on this hypothesis, I wrote an article that outlined the full Yasko treatment approach, but also described a simplified treatment approach that incorporated nutritional supplements that form the core of Dr. Yasko's so-called "step 2." This is the step in her treatment program that involves actually lifting the block in the methylation cycle. This article can be found on Cort Johnson’s website:

    http://phoenix-cfs.org/GSH%20Methylation%20Treatment%20Konynenburg.htm

    When I proposed this approach, I did not know what fraction of the PWC population would be able to tolerate the resulting die-off of pathogens and mobilization of toxins that would result from the consequent ramp-up of the immune system and the detox system after they had been dysfunctional for such long times during the long illness duration of many PWCs. As can be seen in the above-cited article, I was not very optimistic. However, I still thought it was worth a try, since the existing full Yasko approach did not seem to have the characteristics necessary for wide use in the CFS community, and it appeared that lifting the methylation cycle block was the key to recovery for many PWCs. With the help of a woman (name omitted to protect her privacy) who is currently receiving the full Yasko treatment herself, I selected a basic set of seven supplements from Dr. Yasko's step 2, as discussed in the above-mentioned article.

    After this article was presented on the internet, another woman (name omitted to protect privacy) decided to try this simplified treatment approach. As a result of benefits that occurred almost immediately, she reported her experience on the ImmuneSupport.com CFS discussion board. In response to her reports, others began to try this approach. This began in February of 2007, and the number of people on this treatment has continued to grow, the longest duration of treatment now being somewhat more than four months, ranging down to some as short as a few days.

    As experience has been gained, I have shortened the initial list of seven supplements in the suggested simplified treatment approach to five, as described below. The cost of the basic five supplements is somewhat more that two dollars per day.

    After suggesting this treatment approach, I initially attempted to maintain a list of those who were trying it, based on reports I received from physicians and individual PWCs. However, when the number of people I was aware of grew past 60, I no longer felt that I could maintain a complete count. Many have been reporting their progress periodically to the ImmuneSupport board, and a new Yahoo group also has been established recently for PWCs trying this approach, at the following url:

    http://health.groups.yahoo.com/group/simplified_protocol_support/


    I will now describe the current version of the simplified treatment approach based on the Glutathione Depletion--Methylation Cycle Block Hypothesis.

    All the supplements used in this approach can be obtained from the http://www.holisticheal.com site, or all but the Complete Vitamin and Neurological Health Formula can be obtained elsewhere. Please note that I have no financial interest in any of the supplements that I have suggested in the simplified treatment approach.

    As I mentioned above, 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 it is wise to start with smaller dosages than those given below, and it is also wise to start with one supplement at a time and work up to the total of five supplements, to test carefully for adverse effects. It will take somewhat longer to reach the suggested combination and dosages by this route, but early experience has shown that this is prudent.

    As I also mentioned above, this treatment approach should be attempted only under the supervision of a licensed physician, so that any individual issues that arise can be properly dealt with. It's important to "listen to one’s body" when doing this treatment. If the detox becomes too intense to tolerate, or if significant adverse effects appear, as described below, the supplements should be discontinued, and the situation should be evaluated immediately by a licensed physician. This treatment will produce die-off and detox symptoms as the immune system and detox system come back to normal operation and begin ridding the body of accumulated infections and toxins. This appears to be inevitable, if health is to be restored. It may require considerable judgment and clinical experience on the part of the physician to distinguish between inevitable die-off and detox symptoms and possible adverse effects.

    While die-off and detox symptoms are occurring, there will also likely be improvement in CFS symptoms over time. The intensity of the expected die-off and detox symptoms can be decreased by lowering the dosages of the supplements. These symptoms probably result from the body’s limited rates of excretion of toxins. If toxins are mobilized more rapidly than they can be excreted, their levels will rise in the blood, and it is likely that this will produce more severe die-off and detox symptoms. By lowering the dosages, and thus slowing the rate of mobilization of toxins, their levels in the blood can be lowered, thus ameliorating the symptoms.

    The temptation to try to get better faster by increasing the dosages suggested by Dr. Yasko must be resisted. In particular, the suggested dosages for the FolaPro and the Intrinsi/B12/folate supplements should not be exceeded. 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 improvements in energy level and cognition occur, it is tempting for PWCs to overdo activities, which, early in the treatment, can still result in “crashing.” It is wise to resist this temptation as well, because complete recovery will not occur overnight with this treatment approach.

    I am not aware of negative interactions between the five basic supplements and prescription medications used by physicians in treating CFS. However, this treatment approach should not be attempted without considering together with a licensed physician possible interactions between the supplements included in it and any prescription medications that are being taken. This is particularly important if addition of SAMe to the basic five supplements is contemplated.

    When this treatment approach is used together with prescription medications, a licensed physician must be consulted before discontinuing any prescription medications. Some of them can cause very serious withdrawal symptoms if stopped too abruptly.

    If this treatment approach is begun by a PWC who is taking a thyroid hormone supplement for a hypothyroid condition, the PWC and the supervising physician should be alert to the possibility that HYPERthyroid symptoms, such as palpitations and sweats, can occur, even very soon after starting this treatment. The physician should be consulted about possibly adjusting or eliminating the thyroid hormone supplementation if this occurs.


    Here are the five supplements, as found in Dr. Yasko’s book “The Puzzle of Autism,” (p. 49) and as described in detail on her website http://www.holisticheal.com :

    1. One-quarter 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).

    2. One-quarter tablet Intrinsic B12/folate (This includes 200 micrograms of folate as a combination of folic acid, 5-methyl tetrahydrofolate, and 5-formyl tetrahydrofolate, also known as 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)

    3. Up to two tablets (It’s best to start with one-quarter tablet and work up as tolerated) Complete Vitamin and Ultra-Antioxidant Neurological Health Formula 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.)

    4. One softgel capsule Phosphatidyl Serine Complex (This includes the phospholipids and some fatty acids)

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


    The first two supplement tablets are difficult to break into quarters. One of the PWCs who is following the simplified treatment approach has suggested that an alternative approach is to crush them into powders, mix the powders together, and divide the powders into quarters using a knife or single-edged razor blade 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 this is not an issue, they can be taken at any time of the day, with or without food.

    Since some questions have been asked about which components of this treatment approach are essential, and since some PWCs appear to be taking augmented versions of the simplified GD-MCB treatment approach that I wrote about in my January treatment paper (cited above), I want to offer some comments to help PWCs and their physicians to evaluate which supplements to include in treatment.

    FolaPro--This is included because many PWCs have a genetic polymorphism in their MTHFR (methylene tetrahydrofolate reductase) enzyme that affects the production of 5-methyltetrahydrofolate (which is identical to the product FolaPro). This form of folate is the one used by the methionine synthase enzyme, which is the enzyme that appears to be blocked in many cases of CFS. If PWCs were to have their genetics characterized, as in the full Yasko approach, they would know for sure whether they needed this supplement, but in the simplified approach I suggest simply giving it to everyone. This should not present problems, because the total folate dose, including the FolaPro and the folates in the Intrinsi/B12/folate supplement, amounts to 400 micrograms per day, which is within the upper limit for folate supplementation for adults and for children four years of age and older, as recommended by the Institute for Medicine of the U.S. National Academy of Sciences.

    Intrinsi/B12/folate--This supplement contains three forms of folate--FolaPro, folinic acid (identical to the drug leucovorin) and folic acid (the most common commercial folate supplement). It also has some cyanocobalamin (the most common commercial vitamin B12 supplement) and some intrinsic factor (identical to that normally secreted by the stomach to enable vitamin B12 absorption by the gut) as well as some other things. The folinic acid 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, until this is corrected. This enzyme normally converts 5-methytetrahydrofolate to tetrahydrofolate, which is needed in other reactions. This supplement also has some intrinsic factor and some cyano-B12 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. Vitamin B12 is needed by the enzyme 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 Neurological Health Formula--This is Dr. Amy Yasko's basic high-potency general nutritional supplement. This is a general foundation for the biochemistry of the body. I suspect that this supplement is better for PWCs trying the simplified treatment approach than other high-potency general nutritional 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 in magnesium and low in calcium, and has no iron or copper. As far as I know, there are no other supplements with all these characteristics. I therefore believe that this supplement is important for use in the treatment approach. The TMG helps to stimulate the BHMT pathway in the methylation cycle, and that helps to build SAMe, which is needed by the parallel methionine synthase pathway. The nucleotides will help to supply RNA and DNA for making new cells until the folate cycle is operating normally again.

    Phosphatidylserine complex—This contains various phosphatidyls and fatty acids, which will help to 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 stimulate the BHMT pathway.

    Perque B12--This is sublingual hydroxocobalamin. The dosage is fairly large, in order to overcome the blocking of B12 by toxins such as mercury in CFS. As I mentioned above, B12 is needed to stimulate the activity of methionine synthase. Methylcobalamin is actually the form needed, but some people cannot tolerate supplementing 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 is known to be able to methylate mercury. (Note that methylcobalamin is the substance used by bacteria to perform methylation on environmental mercury, and the resulting methylmercury is concentrated in the food chain up to the large predatory fish and enters the human diet.) Methylmercury can readily cross the blood-brain barrier. Methylation of mercury by methylcobalamin has been reported in the literature to occur within the bodies of guinea pigs in laboratory experiments. Perque B12 is sublingual to compensate for poor B12 absorption in the gut of many people.

    There are also two other supplements that were included 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 PWCs can't tolerate much of this, and some need more. If PWCs can't tolerate this, they should leave it out, because stimulating the BHMT pathway, using TMG and choline in the other supplements, will probably make enough SAMe for them naturally. For people who can tolerate SAMe, a dosage of 400 mg per day is suggested.

    Methylation Support RNA 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 if people can afford it. Dr. Amy Yasko has since advised me that if a PWC desires to take only one of her RNA Products, she would suggest choosing either the Health Foundation RNA Formula or the Stress Foundation RNA Formula, rather than the Methylation Support RNA Formula, as being most helpful to take the edge off the detox.

    The above suggested list of supplements may not be optimum, and future clinical studies may produce an improved protocol. I think that the forms of folate and B12 are probably essential, because they target what I believe is the root issue in the abnormal biochemistry of CFS. I think the Complete supplement is important to support the general biochemistry and to correct deficiencies that might be present in essential nutrients, as well as to support the methylation cycle and the rest of the sulfur metabolism. I think that some way of stimulating the BHMT pathway is important, also, to bring up SAMe, and the phosphatidyl serine complex provides this, as does the TMG included in the Complete supplement.

    With regard to possible interactions between the supplements in the simplified treatment approach and other supplements that PWCs may be taking, I am aware of two: (1) 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, as mentioned above, 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. (2) I would also not recommend taking additional trimethylglycine (TMG, also called betaine) or additional forms of choline, such as phosphatidylcholine or lecithin, since that may stimulate the BHMT pathway too much at the expense of the methionine synthase pathway. The betaine-HCl used to augment stomach acid is something that may have to be omitted while doing this treatment, too, since it will contribute to this stimulation.

    Adding glutathione support will help some people, as will adding molybdenum.
    As more things are added, though, one is moving toward the full Yasko approach, which is more complicated and expensive. If this is done, I recommend that it be done with the guidance of Dr. Yasko and under the supervision of a personal physician. The simplified treatment approach appears to work well by itself for many PWCs, but others may find that the die-off and detox (or even adverse effects) from this approach used by itself are too severe. In those cases, the PWCs could consult “The Puzzle of Autism,” sold on Amazon.com, to consider together with their doctors what else discussed there might help them. If the simplified approach seems to help to some degree, and it captures one’s attention for that reason, but it still either does not accomplish all that is desired, or it is not tolerated, then perhaps the next step would be to consider the full Yasko treatment. At least then there would be stronger motivation to look into it. Otherwise, it can appear very daunting to many PWCs.

    The reported responses to this treatment approach have mainly involved a combination of two categories of effects: (1) improvements in some of the common CFS symptoms (some of them quite rapid and profound), and (2) intensification or initial appearance of a variety of symptoms that appear to result from increased detoxification and immune system attack on infections. The former are most welcome, and they are what continue to motivate the people on this treatment, in the face of the detox and die-off symptoms, which are unpleasant but appear to be inevitable, given the large body burdens of toxins and infections that many PWCs have accumulated during their illness, lacking adequate detox capability and cell-mediated immune response during that time.

    In addition to these main responses, a few PWCs have reported adverse effects, some of them quite serious. These are discussed below. A few of those who have started the treatment have stopped it for various reasons, including adverse effects. Some have taken breaks from the treatment and have then returned to it or are planning to do so.

    While this informal testing of the simplified treatment approach currently is not being carried out in a controlled fashion, and while not all the PWCs trying it are using the complete suggested complement of supplements, it is nevertheless possible to state that the treatment appears to be working for quite a few PWCs, though not all.

    The following symptoms of CFS have been reported to have been corrected by various PWCs on this treatment. Note that these are gathered from reports from many PWCs, so that not all have been reported by a single person.

    1. Improvement in sleep (though a few have reported increased difficulty in sleeping initially).
    2. Ending of the need for and intolerance of continued thyroid hormone supplementation.
    3. Termination of excessive urination and night-time urination.
    4. Restoration of normal body temperature from lower values.
    5. Restoration of normal blood pressure from lower values.
    6. Initiation of attack by immune system on longstanding infections.
    7. Increased energy and ability to carry on higher levels of activity without post-exertional fatigue or malaise. Termination of “crashing.”
    8. Lifting of brain fog, increase in cognitive ability, return of memory.
    9. Relief from hypoglycemia symptoms
    10. Improvement in alcohol tolerance
    11. Decrease in pain (though some have experienced increases in pain temporarily, as well as increased headaches, presumably as a result of detoxing).
    12. Notice of and remarking by friends and therapists on improvements in the PWC's condition.
    13. Necessity to adjust relationship with spouse, because not as much caregiving is needed. Need to work out more balanced responsibilities in relationship in view of improved health and improved desire and ability to be assertive.
    14. Return of ability to read and retain what has been read.
    15. Return of ability to take a shower standing up.
    16. Return of ability to sit up for long times.
    17. Return of ability to drive for long distances.
    18. Improved tolerance for heat.
    18. Feeling unusually calm.
    19. Feeling "more normal and part of the world."
    20. Ability to stop steroid hormone support without experiencing problems from doing it.
    21. Lowered sensation of being under stress.
    22. Loss of excess weight.


    The following reported symptoms, also gathered from various PWCs trying this simplified treatment approach, are those that I suspect result from die-off and detox:

    1. Headaches, “heavy head,” “heavy-feeling headaches”
    2. Alternated periods of mental “fuzziness” and greater mental clarity
    3. Feeling “muggy-headed” or “blah” or sick in the morning
    4. Transient malaise, flu-like symptoms
    5. Transiently increased fatigue, waxing and waning fatigue, feeling more tired and sluggish, weakness
    6. Dizziness
    7. Irritability
    8. Sensation of “brain firing: bing, bong, bing, bong,” “brain moving very fast”
    9. Depression, feeling overwhelmed, strong emotions
    10. Greater need for “healing naps.”
    11. Swollen or painful lymph nodes
    12. Mild fevers
    13. Runny nose, low grade “sniffles,” sneezing, coughing
    14. Sore throat
    15. Rashes
    16. Itching
    17. Increased perspiration, unusual smelling perspiration
    18. “Metallic” taste in mouth
    19. Transient nausea, “sick to stomach”
    20. Abdominal cramping/pain
    21. Increased bowel movements
    22. Diarrhea, loose stools, urgency
    23. Unusual color of stools, e.g. green
    24. Temporarily increased urination
    25. Transiently increased thirst
    26. Clear urine
    27. Unusual smelling urine
    28. Transient increased muscle pain


    Finally, the responses reported below are more serious, and I would classify them as adverse effects of the treatment. This list includes all the adverse effects of which I am aware at the time of writing this article, but I suspect that as more PWCs try this treatment with the assistance of their physicians, this list will grow. I am describing these as they have been reported on the ImmuneSupport CFS discussion board by the PWCs who experienced them. Though this information may be incomplete, and cause—effect relationships are difficult to determine exactly from the available information, I’m hopeful that it will be helpful to clinicians and other PWCs:

    1. One person had had a history of severe pesticide exposure and also autonomous multi-nodular goiter, which she described as follows: “Gradually the right lobe grew to over 4 cm x 4cm, and had to have right lobe out. . . This same surgeon made the decision to leave the left lobe in, as I had always had trouble with thyroid med back then too. So, they restarted my Synthroid and I stayed on that for [a] few more years. I ALWAYS had shortness of breath and became VERY tachycardic upon ANY activity. . .” This person started the simplified treatment approach on March 21, 2007 (actually using higher dosages than suggested for FolaPro and Intrinsi/B12/folate). On May 19, she went to an emergency room with tachycardia, chest pain, trouble breathing, trouble sleeping, elevated blood pressure and fever of 100.7 F. She was admitted to the hospital and released the next day. No evidence was found for heart attack. This person later reported the following: “I followed up with my PCP and had CT scan of neck and chest and my goiter is causing tracheal compression, again, and breathing is VERY hard. . . My area hospitals can't do this surgery because my goiter grows substernal, deep in my chest.” This person has expressed a desire to continue the simplified treatment approach, but is currently exploring the possibility of first having additional surgery on the multinodular goiter.

    2. A second person had a history of lung problems due to both carbon monoxide exposure and exposure to molds, as well as heart-related symptoms. She started part of the simplified treatment approach on May 27, 2007. After having been nearly homebound for ten years, she was able to begin riding a bicycle. However, in early July, 2007, she went to an emergency room twice with severe breathing problems (shortness of breath), a fever of 99.8 to 100.1 F. that eventually lasted for sixteen days, and severe chest and left arm pain. No evidence was found for heart attack. She was diagnosed with an enlarged left atrium and diastolic dysfunction. She has currently discontinued the simplified treatment approach and is under the care of cardiologists.

    3. A third person had a history of autoimmune disease, including Sjogren’s syndrome. After her fourth dosage of combined FolaPro and Intrinsi/B12/folate, she experienced “a moderately severe autoimmune flare, with numerous joint and soft tissue issues, fatigue, pain, etc.” She also experienced a severe flare of Sjogren’s syndrome, with “very dry mouth, dry eyes, and severe eye pain.” Six days after discontinuing the supplements, she had a thorough ophthalmology workup and was diagnosed with autoimmune scleritis. She has been given topical steroids and has reported that her eyes are greatly improved.

    4. At least two persons experienced a temporary termination of peristalsis of the gut and consequent constipation after beginning the simplified treatment approach. In these two cases, induction of diarrhea cleared material from the gut, but did not restore the peristalsis. In both cases, peristalsis restarted twelve days after terminating the folate-containing supplements. One of these persons had a history of treatment with psychotropic drugs, including Klonopin. About 18 hours after starting to get relief from the constipation, she became very sick, with “vomiting, vise-like headache, and shaking.” She had many bowel movements over a ten-hour period, and then began to feel better. The other had a history of autoimmune diseases, including Sjogren’s syndrome and Autoimmune Ovaritis, as well as diastolic dysfunction.


    There are many questions remaining to be answered about this treatment approach, including the following:

    1. For which PWCs would this be an appropriate treatment approach?
    2. For what fraction of the entire PWC population will this treatment approach be beneficial?
    3. How can PWCs who are likely to experience adverse effects from this treatment approach be identified beforehand, so that these effects can be avoided?
    4. Are there PWCs who are too debilitated to be able to tolerate the detoxing and die-off processes that result from this treatment approach, and if so, will the full Yasko treatment approach be suitable for them?
    5. Will the simplified treatment approach actually lead to continuing improvements over longer times for those who find it beneficial, all the way to cured cases?
    6. Will the simplified treatment approach be effective in cases of "pure fibromyalgia" as it appears to be in many cases of CFS?
    7. How can this treatment approach be further improved?

    And many more.

    However, the results to date seem encouraging. I suspect that many PWCs can be helped by this treatment approach or something similar to it. I also believe that the appearance of improvement in such a wide range of CFS symptoms when this treatment approach is used provides evidence that a block in the methylation cycle does in fact lie at the root of the biochemical and physiological derangements found in many PWCs, or very near to it. The wide range of symptoms that appear to be associated with die-off and detox appear to give evidence that this treatment is in fact stimulating more normal operation of the immune and detox systems.

    I want to reiterate what I wrote near the beginning of this article: This treatment approach must be entered upon only under the supervision of a licensed physician, to make sure that if there are individual issues that arise, they can be taken care of immediately. The treatment approach itself consists only of nonprescription supplements that are normally found naturally in the body and are necessary for normal biochemistry to take place. It would thus appear to be fairly benign on its surface. However, it must be pointed out that restarting the methylation cycle after it has been blocked for extended periods, particularly in those PWCs whose general health has become quite debilitated, or those who have certain respiratory, cardiac, endocrine or autoimmune conditions, can present some serious challenges. I believe that there is still much more to be learned about the possible hazards of applying this treatment approach to the very heterogeneous CFS population, and this work properly lies in the province of clinicians. I am not a licensed physician, but a researcher. I believe that I have carried this work as far as a researcher can appropriately carry it. I am hopeful that clinicians will further test this treatment approach in order to learn how it may be safely, effectively, and practically utilized to treat PWCs, and it appears that this is now beginning to occur.

    I also hope that physicians or their patients who decide to try this treatment approach will let me know how it works for them, though I may not be able to answer all the emails I receive, as their volume is growing.


    Rich Van Konynenburg, Ph.D.
    Independent Researcher and Consultant
    richvank@aol.com





  3. deliarose

    deliarose New Member

    Treatment for CFS based on GD-MCB Hypothesis 03/08/08 02:35 PM

    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)

    richvank@aol.com


    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: http://phoenix-cfs.org/GSH%20Methylation%20Van%20Konynenburg.htm
    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 http://www.holisticheal.com:

    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 http://www.testing4health.com) if you would like to receive her interpretation of the results, or they can be ordered directly from Doctor’s Data Laboratories (http://www.doctorsdata.com). 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 http://www.amazon.com 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 http://www.genovations.com). 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 http://www.immuno-sci-lab.com (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 http://www.gdx.net/home/assessments/detox/reports/. 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 http://www.testing4health.com. 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 http://www.autismanswer.com. 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
    richvank@aol.com

  4. deliarose

    deliarose New Member

    Book on detoxification, helpful in methylation block treatment 03/05/08 12:00 PM

    Hi, all.

    As I think many of you know, treatment to lift the methylation cycle block in CFS is producing continuing improvement in quite a few people (about two-thirds of those who go onto the simplified treatment, according to the physicians who are using it).

    However, as you know better than I do, it's taking a LONG time to bring recovery! Based on the reports from many of you, it appears to me that perhaps the main rate-limiter is the rate at which toxins can actually be excreted from the body, which occurs primarily in the stools, urine and sweat.

    This seems to result from the detox system being unable to operate normally while a person has CFS, because of dysfunction of the sulfur metabolism, caused by the methylation cycle block and the glutathione depletion. A large inventory of toxins therefore accumulates over time, and when the detox system is restarted by the treatment, it has a large backlog of toxins that have to be removed before a person can become healthy again. This seems to be a slow process relative to the size of the backlog.

    I've been studying what can be done to increase the rate of excretion of toxins. While I have to refrain from giving individual treatment advice on the internet, because I'm not licensed and because everyone's case is unique, I can suggest sources of information that I think can be helpful.

    Recently I got a copy of the book "7-Day Detox Miracle," revised 2nd edition, by Peter Bennett, N.D., and Stephen Barrie, N.D., with Sara Faye (Prima Publishing, 2001).

    I think this book is one of the best I've seen on the overall detox process. Although it has a very catchy title, I don't mean to imply that their approach as applied to CFS will produce recovery in seven days, or that it will be miraculous, but I do think they give a good discussion of things that might be helpful in conjunction with methylation cycle block treatment, so I want to call this book to your attention.

    As you can see, the authors are naturopaths. The second author was the founder of Great Smokies Diagnostic Lab, now Genova Diagnostics. I have no financial interest in this book or lab, and I recommend that you consider the detox advice given there together with your doctor before deciding whether it would be appropriate in your case, and also that you be monitored by your doctor while on treatment.

    Rich
  5. deliarose

    deliarose New Member

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


    Rich
  6. deliarose

    deliarose New Member

    This is excerpted from above. It's just the 5 supps that constitute the treatment.

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

    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.
  7. Forebearance

    Forebearance Member

    It's fine with me if you vent!

    I wish you had a better doctor. Maybe you could ask for a different kind. Like for example, ask for a doctor who treats environmental illness or a doctor who treats Lyme disease. Just a thought. Or an infectious disease doc if you think viruses are your main problem.

    Gosh, you don't take all that stuff just because your doctor prescribed it, do you? yikes. I guess I'm not used to drugs. Or used to trusting doctors.

    The simplified methylation protocol is just five inexpensive pills. You basically try them and see if they agree with you and if they cause you to feel like you are 'detoxing'.

    I know it's hard to grasp the biochemistry. All those terms are foreign to non-biochemists. I had to learn them. It took some time.

    People who don't have CFS could take those five pills and probably nothing would happen. They are just nutrients. People with CFS should be cautious in trying them, of course. You could possibly have a big reaction.

    Good luck!
    Love,
    Forebearance

    [This Message was Edited on 05/27/2008]
  8. Leaknits

    Leaknits New Member

    My goodness, Deliarose! I can certainly see you've done your homework about this methylation issue; as soon as I can find a dr who knows his left hand from his right I'll give him (I'm presuming him, please forgive me ladies who also are drs) a print-out of your suggestions.

    Not this guy I'm seeing now, though. No way. Among other things he has no idea what serotonin and norepinephrine are. Looking at that lil fact, I'll just have to bumble along as is for a while until a Good Dr is found.

    Thank you incredibly much; I know what it can cost a CFS/ME body to do all that work in your reply!

    Good news: just yesterday when the delivery lady from the pharmacy I use dropped by with (FINALLY!)abx for the lymphs and sinuses and on-fire throat, it DUH occurred to me to ask her if she had any ideas re a New Doc Search.
    Got two names and called both offices, left messages. Hoping for positive replies and, also, that one or both will be open to working with me re the d'ME and methylation. I do have some pretty serious cardiac and respiratory issues so will have to remind dr about those. Don't want to make myself more sick and stay that way in the attempt to get rid of this bleeping thing.

    No dr here has ever been able to tell me whether the length of time a person has had CFS/ME/Fibro has any effect on the length of time it might take to notice results of any treatment.
    Of course my current guy absolutely knows I can't react in one day to a change in meds. He's wrong, but he still thinks he knows that. I've said it before: he must not have been in class on the day that Rule One, Everybody's Different was discussed.

    Again, Ms D, thank you and here's hug,
    Lea.
  9. Leaknits

    Leaknits New Member

    FOREBEARANCE said:
    It's fine with me if you vent!

    I wish you had a better doctor. Maybe you could ask for a different kind. Like for example, ask for a doctor who treats environmental illness or a doctor who treats Lyme disease. Just a thought. Or an infectious disease doc if you think viruses are your main problem.

    Gosh, you don't take all that stuff just because your doctor prescribed it, do you? yikes. I guess I'm not used to drugs. Or used to trusting doctors.

    The simplified methylation protocol is just five inexpensive pills. You basically try them and see if they agree with you and if they cause you to feel like you are 'detoxing'.

    I know it's hard to grasp the biochemistry. All those terms are foreign to non-biochemists. I had to learn them. It took some time.

    People who don't have CFS could take those five pills and probably nothing would happen. They are just nutrients. People with CFS should be cautious in trying them, of course. You could possibly have a big reaction.
    **********************************************
    Hi, Forebearance!
    Thank you for replying and also for understanding that I don't understand a LOT of this protocol...but I bet you and many other people here at the message board know more about it than does the dr I'm seeing now.

    Wow. EXCELLENT suggestion re the environmental or Lyme or infectious disease drs. See, I'd never have thought of doing that. But I will. I promise. Ticks we have a'plenty of here so it's possible a Lyme dr could tell if the ONE tick bite I ever got in my life about 20-something years ago caused or expanded the d'd.

    Actually I believe I've had this rotten mess for decades but have no way to prove it since I don't know whether the years' long gaps in my memory are due to childhood abuse or this crummy disease.
    I do remember, though, coming home from school...in grade school, yet...and falling on my bed to sleep till dinner. School grades were horrible because I couldn't understand the subjects nor hold onto info and the teachers didn't have time to deal with that.

    Time for a dumb question: how would I know if my woes are viral, therefore should check out an infectious disease dr? As nearly as I can tell I've never given this d'd to anyone.

    No and No again, I don't take all that stuff just because dr prescribed it. I've asked him "Okay, you are giving me such and such...should I phase out of one or more of what you've ordered up already?," and he has always said "No."

    Some days I don't NEED four painmaskers, for instance, so I don't take pain med when I don't hurt so badly I want to scream.
    I don't think his idea that I need Soma is right, either; I've had some real whizzers of reactions to muscle relaxers. Under the influence of one called Baclofen, I wouldn't speak. I could, I just wouldn't. Weird. When I told dr wonderful about that, he had not one word to say except "Come back next month." Guess he forgot I have already reacted oddly to one of that type of med...the Soma bottle is still unopened. His "But this one is DIFFERENT" didn't convince me, same as the same statement from him regarding Cymbalta when he was trying to convince me it would ease pain.

    It doesn't. It also doesn't do jack for depression for me, see Rule One...Everybody's different. No, wait, that's not exactly true. The Cymbalta did have an effect on depression. It got worse. FLUSH!...

    I react oddly to multi-vitamins, too. Bought a bottle of Centrum Silver, since I'm six decades and a few months old. Took ONE. Wired? Wow. I tell you, there's just nothing like being exhausted and yearning for sleep and a VITAMIN won't allow it. I now cut those things into quarters; here's hoping whoever invented the pill-splitter got a medal.

    I sort of "check in" with myself to see if I need a valium for nerves or a benadryl for sinuses. If myself says "no," I listen. Wish dr did. Listen, that is.

    The Restoril and/or Somnote (Chloral Hydrate) might be doing something to help...I slept for 5 whole uninterrupted hours last night!! Much different from the 2 or 3 hr "naps," too widely separated from each other.

    Like you, Forebearance, (Great name, by the way) I am not "used to" drugs, nor do I really trust a dr who won't look at me, scolds me because I have this _______ thing which makes me react strangely to his pills and potions, and won't tell me anything including the "Why" of one of his latest suggestions. He just likes to enter the cubbyhole where I wait for him, flop into his chair, and say "So. What's going on?" I swear he's done that every time I've been in the office and he does it to all of his patients. I call that sort of odd, but that's just my opinion.

    Thanks again for letting me vent!
    Lea.
  10. deliarose

    deliarose New Member

    I feel your pain and frustration.

    There are a handful of alternative/functional medicine docs who are working with Rich's or Amy Yasko's protocol.

    They are few and far between and often out-of-network, so more $$. The few names that come to mind: Karen Vrchota in Minnesota, Neal xxx in Missouri, Nancy Mullan in Burbank,CA.

    Lots of Vrchota patients on this board for what it's worth.

    I think the methylation panel is a good starting point, even if you have to spend the whole 300 bucks out of pocket. If the lab comes back abnormal, it may help persuade a regular doc that there is something wrong with your folate metabolism and B12 absorption/metabolism.

    I got a friendly naturopath to order it, and then my regular mainstream PCP agreed to do the blood draw in his office. They had one of those machines that centrifuges the blood. It then had to be shipped fedex overnite on ice back to Vitamin Diagnostics.

    Of all the tests I've had done in 10 years, I think that was the most useful.

    However, unless mistaken, a lot of the people on this board who are doing some variation of Rich's 5 (barrowinnovations,(karen), Munch, Forebearance, lbconstable, Lisa Petrison/slayadragon, Krista, Morningsunshine, elliespad) didn't bother with the test and just tried the supplements empirically.

    Having said that, I notice you are on a lot of meds and have serious respiratory and cardiac issues, so obviously you need to proceed cautiously and preferably under the supervision of a doc.

    But from what I can gather, most of us who are doing some kind of treatment to improve methylation function, whether it's Rich's 5 or Yasko's longer form protocol are not gettign any support from mainstream MDs. They are just not interested.

    Some of us are juggling mainstream docs for regular labs, meds with either alt docs or yasko herself for the methylation part of our treatment.

    It's an exercise in gymnastics! But it has been so worth it for me. I am about 30 percent better in 15 months and I feel hopeful about continued improvement. I should say it has been a slog though and I've spent a lot of money on supplements!

    There is also a CFS yasko yahoo health group that you may wanna check out and also yasko's group at www.ch3nutrigenomics.com.

    If you have a family member who can help with research or funds, now is the time to reach out to them1!

    Also, one of the members of CFS yasko may be willing to mentor you....if you need guidance. Unfortunately, I am swamped at teh present time, and cannot offer my services.

    d.

  11. deliarose

    deliarose New Member

    Lyme and CFS 05/03/08 07:56 AM

    Hi, all.

    For what it's worth, my current hypothesis is that Lyme disease is one of the routes into CFS, for people who are genetically predisposed by having inherited one of several possible combinations of genetic polymorphisms. The Borrelia bacteria that cause Lyme disease have been found to deplete glutathione, and this is reported in the peer-reviewed published literature. According to the Glutathione Depletion--Methylation Cycle Block hypothesis that I have proposed for the root causes and pathogenesis of CFS, glutathione depletion is what usually brings about a partial block in the methylation cycle, and that becomes chronic and results in CFS. So there appears to be a plausible link between Lyme disease and CFS in this mechanism.

    We don't have much experience yet in the treatment of the Lyme--CFS combination, but some patients are currently being treated with the simplified treatment approach to lift the methylation cycle block, combined with antibiotics for the Lyme disease. Anyone contemplating this should do so with the advice and supervision of a licensed physician.

    Rich