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July 18, 2007

Simplified Treatment Approach Based on the Glutathione Depletion-Methylation Cycle

Block Pathogenesis Hypothesis for Chronic Fatigue Syndrome (CFS)

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.

[History section deleted. Full version of this document can be found at CFS_Yasko in the Files section, fi-
lename “simp. trtmnt. appr. 7-18-07.doc”. - mm]

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 site, or all but the Complete Vitamin and Neurological
Health Formula can be obtained elsewhere. Please note that I have no financial in-
terest in any of the supplements that I have suggested in the simplified treatment ap-

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 sup-
plement at a time and work up to the total of five supplements, to test carefully for ad-
verse 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 prop-
erly 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 de-
scribed 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 opera-
tion 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 de-
tox 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 In-
trinsi/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 pre-
scription medications used by physicians in treating CFS. However, this treatment ap-
proach should not be attempted without considering together with a licensed physician
possible interactions between the supplements included in it and any prescription med-
ications that are being taken. This is particularly important if addition of SAMe to the ba-
sic 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 supple-
ment 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 consul-
ted about possibly adjusting or eliminating the thyroid hormone supplementation if this

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 :
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 vit-
amin B12 as cyanocobalamin, 22.5 milligrams of calcium, 17.25 milligrams of phosphor-
us, and 5 milligrams of intrinsic factor)

[NOTE: Because Metagenics changed the formulation of Intrinsi/B12/folate, as of April,

2009, I am recommending that Actifolate be substituted for it, at the same dosage—Rich

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 addition-
al 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 ap-
proach 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 re-
ported 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 ap-
proach 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 sup-
plement, 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. Na-
tional 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 cy-
ano-B12 to help those who have a type of pernicious anemia that results from low pro-
duction 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 try-
ing the simplified treatment approach than other high-potency general nutritional supple-
ments, 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

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 path-

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 genet-
ic reasons, and I'm also concerned that people with high body burdens of mercuric mer-
cury could move mercury into the brain if they take too much methylcobalamin. Methyl-
cobalamin 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 con-
centrated 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 Founda-
tion 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 stud-
ies 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 gener-
al 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 be-
taine-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 sim-
plified 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, 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 cap-
tures one’s attention for that reason, but it still either does not accomplish all that is de-
sired, 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. Other-
wise, 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 ini-
2. Ending of the need for and intolerance of continued thyroid hormone supplementa-
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-exer-
tional 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
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 im-
proved 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 simpli-
fied 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 treat-
ment 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 de-
cision 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 AL-
WAYS 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 hospit-
al 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 treat-
ment 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 expos-
ure 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 en-
larged left atrium and diastolic dysfunction. She has currently discontinued the simpli-
fied 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, fa-
tigue, 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 supple-
ments, 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

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 shak-
ing.” 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, in-
cluding 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 benefi-
3. How can PWCs who are likely to experience adverse effects from this treatment ap-
proach 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 treat-
ment 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 ap-
pearance 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 ap-
proach 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 imme-
diately. 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 het-
erogeneous 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