A Simplified Treatment Approach Based on the Glutathione Depletion - Methylation Cycle Block Pathogenesis Hypothesis for Chronic Fatigue Syndrome (CFS)
by Rich Van Konynenburg, Ph.D.
The Simplified Glutathione Depletion-Meythlation Cycle Block Treatment Approach.
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.)
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." 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 withsmaller 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.
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. 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.
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." It is wise to resist this temptation as well, because complete recovery will not occur overnight with this treatment approach.
Drug Interactions. 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.
Thyroid. 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.
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 :
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)
Treatment Tips. 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.
Treatment Components Explained
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.
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.
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.
Responses Thus Far. 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.
Improvements. 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
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
8. Lifting of brain fog, increase in cognitive ability, return of
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
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.
Negative Effects. 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
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
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
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 [I] 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 ophthalmologyworkup 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.
Many Questions. 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.
Conclusions. 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
July 18, 2007
A Yahoo discussion group is now devoted to these topics. You can find it at http://health.groups.yahoo.com/group/CFS_Yasko/