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 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:
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. (Go To Part I: Theory and History)
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Treatment Tip. 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." ...
Detoxification and Die-off. 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. ...
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.
Slow and Steady. 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." ...
The Five Supplements
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
- One-quarter tablet (200 micrograms) Actifolate (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).
- 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).
- Up to two tablets (It's best to start with one-quarter tablet and work up as tolerated) General Vitamin 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, sometrimethylglycine, some nucleotides, and several supplements to support the sulfur metabolism.)
- One softgel capsule Phosphatidyl Serine Complex (Vitamin Discount Center)(This includes the phospholipids and some fatty acids)
- Activated B12 Guard (Perque)(2,000 micrograms hydroxocobalamin with some mannitol, sucanat, magnesium and cherry extract)
SIMPLIFIED TREATMENT APPROACH
All these supplements can be obtained from http://www.holisticheal.com, or all but the third one can be obtained from other sources.
The first two supplement tablets are difficult to break into quarters. We recommend that you obtain (from any pharmacy) a good-quality pill splitter to assist with this process. They can, alternatively, be crushed into powders, which are then separated on a flat surface using a knife or single-edged razor blade, and the powders can be mixed together. They can be taken orally with water, with or without food.
These supplements can make some patients sleepy, so in those cases they take them at bedtime. They can be taken at any time of day, with or without food.
GO SLOWLY. As the methylation cycle block is lifted, toxins are released and processed by the body, and this can lead to an exacerbation of symptoms. IF THIS HAPPENS, try smaller doses, every other day. SLOWLY work up to the full dosages.
Although this treatment approach consists only of nonprescription nutritional supplements, a few patients have reported adverse effects while on it. Therefore, it is necessary that patients be supervised by physicians while receiving this treatment.
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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.
Intrinsic/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.
Interactions With Other Supplements
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.
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Responses Thus Far
The reported responses to this treatment approach have mainly involved a combination of two categories of effects:
[the rest is probably good to click to the site to read if you are going to engage this abbreviated protocol or want to understand it more completely]
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