Glutathione Depletion—Methylation Cycle Block Hypothesis: The Simple Approach

by | Jun 27, 2009 | Chronic Fatigue Syndrome / ME, TREATMENTS | 4 comments

developed by: Richard A. Van Konynenburg, Ph.D

Methylation Cycle - SimpleRichard A. Van Konynenburg, Ph.D 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. Due to subsequent requests from clinicians for a description of a treatment approach based on this hypothesis, Van Konynenburg came up with a Simple Approach Part I, Part II and a more Customized Approach, based on what he perceives to be the most successful treatment approaches currently used in autism, which he believes shares the same basic pathogenetic mechanism with CFS. In most cases, it will be necessary for the physician to use the Customized Approach and tailor the treatment program to the individual patient. He has since updated his approach and added some cautions. Please note that some people who have tried this approach have had adverse effects, sometimes of a serious nature.

Van Konynenburg believes that the fundamental biochemical issue in a large subset of the CFS patients is that the methylation cycle is blocked. The main goal of this treatment approach is to remove this block and restore the methylation cycle. He also believes that glutathione depletion is directly responsible for many of the features of CFS, but that it is usually not possible to normalize the glutathione levels on a permanent basis by direct approaches of glutathione supplementation. Rather, the methylation cycle block must be corrected first, to break the vicious circle that is holding down the glutathione levels. In addition to this, about one-third of CFS patients, because of particular genetic polymorphisms, cannot tolerate supplementation with glutathione or other substances intended to help them directly to build glutathione.

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., he suggests two treatment approaches for CFS. The first is a simplified approach better suited to patients who have been ill a relatively short time and are not disabled. 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 the customized program should be followed. 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 (Ref. 2 in his 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. Van Konynenburg believes that the second approach is the treatment that will be necessary for most CFS patients, especially those who are more debilitated/disabled, as well as those with certain genetic polymorphisms.

Protocol: The simplified approach includes taking the following oral supplements daily, all of which are available from Dr. Yasko’s supplement website at

  • 1/4 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).
  • 1/4 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 1/4 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 hydroxocobalamin is specified rather than methylcobalamin as the main supplemental form of vitamin B12, 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.

This simplified approach also includes 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.

Treatment Course: Once treatment begins, the patient may feel worse initially. It is best to determine whether this is occurring because the treatment is working and the patient’s body is beginning to detox and kill viruses, or whether it is occurring because the patient does in fact have upregulation polymorphisms in their CBS (cystathionine beta synthase) enzyme, in which case you will have to move on to the more complicated complete treatment regimen.

Which of these is the case can be determined by taking spot urine samples for a urine toxic metals test and a urine amino acids test from Doctor’s Data Laboratories. These can be ordered through Dr. Yasko (at if you would like to receive her interpretation of the results, or they can be ordered directly from Doctor’s Data Laboratories (

If the toxic metals are elevated on the urine toxic metals test, this will indicate that the patient has begun to detox, which is desirable. If taurine and ammonia are elevated on the urine amino acids test, this will suggest that the patient does have CBS upregulation polymorphisms, in which case you will have to stop this treatment and move to the more complicated approach described below.

It would be best to do this treatment for a week or two before doing the urine tests, so that meaningful results can be obtained on these tests, unless the patient cannot tolerate it. If the latter is the case, then you will have to go on to the more complicated Customized Approach.

A yahoogroup has been started for those wanting to explore Dr. Amy Yasko’s protocol and Rich Van Konynenburg’s treatment plans in depth: Please note, this is a treatment group and not a support group.

see also: Dr. Amy Yasko’s Nutrigenomics Protocol

source(s): Suggestions for Treatment of Chronic Fatigue Syndrome (CFS): The Simple Approach based on the Glutathione Depletion—Methylation Cycle Block Hypothesis for the Pathogenesis of CFS by Richard A. Van Konynenburg, Ph.D.

  • Earthwalker

    Earthwalker is the username that PT founder Julie Genser created for her online interactions so many years ago when first creating Planet Thrive.

    Julie's (Earthwalker's) life was derailed over twenty years ago when she had a very large organic mercury exposure after she naively used a mouth thermometer to measure the temperature of just-boiled milk while making her very first pizza at home. The mercury instantly expanded into a gas form and exploded out the back of the thermometer right into her face. Unaware that mercury was the third most neurotoxic element on Earth, Julie had no idea she had just received a very high dose of a poisonous substance.

    A series of subsequent toxic exposures over the next few years -- to smoke from two fires (including 9/11), toxic mold, lyme disease, and chemical injuries -- caused catastrophic damage to her health. While figuring out how to survive day-to-day, and often minute-to-minute, she created Planet Thrive to help others avoid some of the misdiagnoses and struggles she had experienced.

    She has clawed her way over many health mountains to get to where she is today. She is excited to bring the latest iteration of Planet Thrive to the chronic illness community.

    In 2019, Julie published her very first cookbook e-book called Low Lectin Lunches (+ Dinners, Too!) after discovering how a low lectin, gluten free diet was helping manage her chronic fascia/muscle pain.


  1. earthwalker

    I emailed Rich Van Konynenburg to see how he felt about using this protocol for MCS and this was his response:

    The treatment is premised on the presence of glutathione depletion and a partial block in the methylation cycle. My hypothesis for MCS is that glutathione is depleted in the sustentacular cells of the olfactory epithelium in the “ceiling” of the nasal cavity. In cases where this is true, I think this treatment will help, because it restores glutathione levels. I think this is the mechanism involved when MCS is associated with CFS.

    There may be another subset of MCS that does not involve glutathione depletion. For example, in cases in which the MCS began with a large exposure of some chemical, I think the mechanism might be different, such as involving damage to the olfactory epithelium which is not repaired.

    Did your MCS start with a large acute exposure to some chemical?

    One way to tell for sure whether your glutathione is depleted is to take the Vitamin Diagnostics, Inc., methylation pathways panel. Here is the contact information:

    Methylation Pathways Panel
    This panel will indicate whether a person has a partial methylation cycle block and/or glutathione depletion. I recommend that this panel be run before deciding whether to consider treatment for lifting the methylation cycle block. I am not associated with the lab that offers this panel.

    The panel costs $300 and requires an order from a physician or a chiropractor. The best way to order the panel is by fax, on your clinician’s letterhead.

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

    Lab Director: Tapan Audhya, Ph.D.
    (usually at the lab on Tues. and Wed. from 1 to 3 p.m., Eastern time)

    Dr. Audhya is willing to help clinicians with interpretation of the panel by phone, or you can interpret the panel results using the following information:

    Interpretation of the Vitamin Diagnostics Methylation Pathways Panel by Rich Van Konynenburg, Ph.D.

    Several people have asked for help in interpreting the results of their Vitamin Diagnostics, Inc., methylation pathway panels. Here are my suggestions for doing so. They are based on my study of the biochemistry involved, on my own experience with interpreting more than 120 of these panel results to date, and on discussion of some of the issues with Tapan Audhya, Ph.D., who is the director of the Vitamin Diagnostics lab.

    The panel consists of measurement of two forms of glutathione (reduced and oxidized), adenosine, S-adenosylmethionine (SAM) , S-adenosylhomocysteine (SAH), and seven folic acid derivatives or vitamers.

    According to Dr. Audhya, the reference ranges for each of these metabolites was derived from measurements on at least 120 healthy male and female volunteer medical students from ages 20 to 40, non- smoking, and with no known chronic diseases. The reference ranges extend to plus and minus two standard deviations from the mean of these measurements.

    Glutathione: This is a measurement of the concentration of the reduced (active) form of glutathione (abbreviated GSH) in the blood plasma. From what I’ve seen, most people with chronic fatigue syndrome (PWCs) have values below the reference range. This means that they are suffering from glutathione depletion. As they undergo the simplified treatment approach to lift the methylation cycle block, this value usually rises into the normal range over a period of months. I believe that this is very important, because if glutathione is low, vitamin B12 is likely unprotected and reacts with toxins that build up in the absence of sufficient glutathione to take them out. Vitamin B12 is thus “hijacked,” and not enough of it is able to convert to methylcobalamin, which is what the methylation cycle needs in order to function normally. Also, many of the abnormalities and symptoms in CFS can be traced to glutathione depletion.

    Glutathione (oxidized): This is a measurement of the concentration of the oxidized form of glutathione (abbreviated GSSG) in the blood plasma. In many (but not all) PWCs, it is elevated above the normal range, and this represents oxidative stress.

    Adenosine: This is a measure of the concentration of adenosine in the blood plasma. Adenosine is a product of the reaction that converts SAH to homocysteine. In some PWCs it is high, in some it is low, and in some it is in the reference range. I don’t yet understand what controls the adenosine level, and I suspect there is more than one factor involved. In most PWCs who started with abnormal values, the adenosine level appears to be moving into the reference range with methylation cycle treatment, but more data are needed.

    S-adenosymethionine (RBC) (SAM): This is a measure of the concentration of SAM in the red blood cells. Most PWCs have values below the reference range, and treatment raises the value. S-adenosylmethionine is the main supplier of methyl groups in the body, and many biochemical reactions depend on it for their methyl groups. A low value for SAM represents low methylation capacity, and in CFS, it appears to result from a partial block at the enzyme methionine synthase. Many of the abnormalities in CFS can be tied to lack of sufficient methyation capacity.

    S-adenosylhomocysteine (RBC) (SAH): This is a measure of the concentration of SAH in the red blood cells. In CFS, its value ranges from below the reference range, to within the reference range, to above the reference range. Values appear to be converging toward the reference range with treatment. SAH is the product of reactions in which SAM donates methyl groups to other molecules.

    Sum of SAM and SAH: When the sum of SAM and SAH is below 268 micromoles per deciliter, it appears to suggest the presence of upregulating polymorphisms in the cystathione beta synthase (CBS) enzyme, though this may not be true in every case.

    Ratio of SAM to SAH: A ratio less than about 4.5 also represents low methylation capacity. Both the concentration of SAM and the ratio of concentrations of SAM to SAH are important in determining the methylation capacity.

    5-CH3-THF: This is a measure of the concentration of 5-methyl tetrahydrofolate in the blood plasma. It is normally the most abundant form of folate in the blood plasma. It is the form that serves as a reactant for the enzyme methionine synthase, and is thus the most important form for the methylation cycle. Many PWCs have a low value, consistent with a partial block in the methylation cycle.

    The simplified treatment approach includes FolaPro, which is commercially produced 5-CH3-THF, so that when this treatment is used, this value rises in nearly every PWC. If the concentration of 5-CH3-THF is within the reference range, but either SAM or the ratio of SAM to SAH is below the reference values, it suggests that there is a partial methylation cycle block and that it is caused by unavailability of sufficient bioactive B12, rather than unavailability of sufficient folate. I have seen this frequently, and I think it demonstrates that the “hijacking” of B12 is the root cause of most cases of partial methylation cycle block. Usually glutathione is low in these cases, which is consistent with lack of protection for B12, as well as with toxin buildup.

    10-Formyl-THF: This is a measure of the concentration of 10-formyl tetrahydrofolate in the blood plasma. It is usually on the low side in PWCs. This form of folate is involved in reactions to form purines, which form part of RNA and DNA as well as ATP.

    5-Formyl-THF: This is a measure of the concentration of 5-formyl tetrahydrofolate (also called folinic acid) in the blood plasma. Most but not all PWCs have a value on the low side. This form is not used directly as a substrate in one-carbon transfer reactions, but it can be converted into other forms of folate. It is one of the supplements in the simplified treatment approach, which helps to build up various other forms of folate.

    THF: This is a measure of the concentration of tetrahydrofolate in the blood plasma. In PWCs it is lower than the mean normal value of 3.7 nanomoles per liter in most but not all PWCs. This is the fundamental chemically reduced form of folate from which several other reduced folate forms are made. The supplement folic acid is converted into THF by two sequential reactions catalyzed by dihydrofolate reductase (DHFR). THF is also a product of the reaction of the methionine synthase enzyme, and it is a reactant in the reaction that converts formiminoglutamate (figlu) into glutamate. If figlu is high in the Genova Diagnostics Metabolic Analysis Profile, it indicates that THF is low.

    Folic acid: This is a measure of the concentration of folic acid in the blood plasma. Low values suggest folic acid deficiency in the current diet. High values are sometimes associated with inability to convert folic acid into other forms of folate, such as because of polymorphisms in the DHFR enzyme. They may also be due to high supplementation of folic acid.

    Folinic acid (WB): This is a measure of the concentration of folinic acid in the whole blood. See comments on 5-formyl-THF above. It usually tracks with the plasma 5-formyl-THF concentration.

    Folic acid (RBC): This is a measure of the concentration of folic acid in the red blood cells. The red blood cells import folic acid when they are initially being formed, but during most of their approximately four-month life, they do not normally import, export, or use it. They simply serve as reservoirs for it, giving it up when they are broken down. Many PWCs have low values. This can be caused by a low folic acid status in the diet over the previous few months, since the population of RBCs at any time has ages ranging from zero to about four months. However, in CFS it can also be caused by damage to the cell membranes, which allows folic acid to leak out of the cells. Dr. Audhya reports that treatment with omega-3 fatty acids can raise this value over time.

  2. Mia

    My doctor uses a very similar approach to restart the methylation system, his name is Dr. Vinitsky.

  3. earthwalker

    Please note: Vitamin Diagnostics has moved to the following address!

    Vitamin Diagnostics
    540 Bordentown Avenue, Suite 2300
    South Amboy, NJ 08879
    Tel: +1 732-721-1234
    Fax: +1 732-525-3288

  4. earthwalker

    Thanks Mia. What state does Dr. V practice in?

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