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Methylation protocol and glutathione

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by topaz, Jun 20, 2011.

  1. topaz

    topaz Senior Member

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    There appears to be a huge weight of evidence that glutathione deficiency exists in PWC's.

    Many (sites and practitioners) recommend supplementing with glutathione supporting supplements.

    However, am I correct in understanding that on either Freddd's or Rich's protocols, glutathione supplement is not recommended because correcting methylation will in turn increase glutathione levels (ie without direct intervention)?

    Is glutathione supplementation ever suggested?
  2. richvank

    richvank Senior Member

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    Hi, Topaz.

    Yes, glutathione is depleted in most cases of ME/CFS, when it is properly measured (i.e. reduced glutathione in the blood plasma). There is a subset, however, that has normal glutathione levels. I have some evidence indicating that this subset has polymorphisms in the glutathione transferase and/or glutathione peroxidase enzymes, so that even though they have normal glutathione levels, they are not able to use glutathione as effectively as normal.

    I tried encouraging direct glutathione boosting in ME/CFS cases for about 5 years. It was helpful to most, but not tolerated by some. For those who benefited, the benefits continued only so long as they kept boosting. They were not permanent.

    Our clinical study showed (with lab testing) that lifting the partial methylation cycle block using the simplified protocol does cause glutathione to come up automatically. I don't think this has been tested with Freddd's protocol, but I expect that it would have the same effect eventually, so long as the methylation cycle was not overdriven. I have seen lab reports from three people now that indicate that taking a high dosage of methylcobalamin sublingually can overdrive the methylation cycle, so that there is insufficient flow into the transsulfuration pathway to support the synthesis of glutathione in cases of ME/CFS.

    I have suggested adding liposomal glutathione to the simplified protocol in cases in which there is severe excitotoxicity on this protocol (anxiety, insomnia, and a "wired" feeling). I have not had much feedback on whether this helps, though some have reported positive responses.

    Freddd is dead set against glutathione supplementation, based on his own experience and that of some others. He found it devastating.

    I think response to glutathione boosting varies among people who have ME/CFS. It may depend upon genetic polymorphisms, or upon whether or not there are deficiencies in some essential nutrients, especially niacin (B3) and its derivatative, NADPH. I'm just not sure of the reasons for the different responses yet.

    Best regards,

    Rich
  3. leela

    leela Slow But Hopeful

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    Rich,

    Is there any way to determine if there is an overdrive of the methylation system, besides lab reports? What would that look like symptomatically?

    Also, could you summarize briefly what the chief expected side effects of the SMP are?
    I admit it is difficult for me to sort out what is what because I am doing other protocols simultaneously. I just wonder what to look for when actively trying to jump start the methylation/glutathione cycle. I sometimes feel quite toxic and am tempted to slather on some TD Glutathione, but have refrained, due to wanting to get the methylation cycle running by itself.
  4. Freddd

    Freddd Senior Member

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    Hi Toapz,

    It damaged my nervous system. It was a major setback for EVERYBODY trying it who had success with mb12, adb12 and Metafolin. It is a disaster waiting to happen. Those who never get out of the methylfolate/mb12 deficiency state will never notice what a disaster it is because those things will remain causing continuing damage. If you take mb12 and Metafolin and turn methylation on it will be made by your body.
  5. sandralee

    sandralee

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    Hi Rich,

    I'm aware that you favour HB12 rather than MB12, but what would you consider the safe maximum daily dose of MB12 to be, if a person's polymorphisms and deficiencies are unknown? Also, what do you consider the upper limit for Metafolin to be, and is there a optimim ratio between MB12 and Metafolin?

    I will consider your answer to be personal opinion, and not take it as medical advice.

    I have stopped all supplementation and special diets at the moment (except for a trial of Histame) due to a marked deterioration in health, but I was considering adding B3 back in, as my B3 levels are extremely low. In fact, Dr Myhill said it was the lowest that she had ever seen. Is it safe to take B3 in the absence of any other B vitamins? I'm reluctant to start introducing a number of supplements at this stage, until I give Histame a good go.

    I seem to belong to the subset of PWCs, who find that the more supplements they take, the worse we feel.

    Thanks again Rich for your generosity and willingness to give your time to this forum.

    Best wishes,

    Sandra
  6. topaz

    topaz Senior Member

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    Thanks for the great responses.
  7. topaz

    topaz Senior Member

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    Sandralee

    Re: B3

    Generally speaking, it is best to take vitamin B's as a multi as they work synergystically.

    Having said that, I have taken B3 before on its own as Niacin does have its own particular benefits. I think its ok to take B3 on its own (but better to take multi-B) but if you want, you can add inositol and biotin which are said to assist B3.

    I usually supplement with additional B3 on top of my multi B. Personally, I prefer the natural nicotinic acid form of niacin. This is known as "flushing" niacin because it gives you a tingle and often a facial and upper body "flush". This passes in less than 20 minutes usaully. It is recommended to start with 100mg once a day and build up to say around 500mg to gradually increase your tolerance to the "flushing". Just dont take it before you're due to go out!

    The "flush" was not popular so a non-flushing niacin was formed which has now become the norm.

    The flushing form of niacin is believed to have significant cholesterol lowing effects, however cholesterol is not a problem I personally need to target.

    Google the difference between nicotinic acid and niacinamide and you can make up your own mind about the benefits.

    I'd be interested to hear others views on this.

    Good luck
  8. Adster

    Adster Senior Member

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    I too would be interested in hearing more about this, and if there are obvious symptoms of this particular issue. Thanks Rich! :)
  9. sandralee

    sandralee

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    Hi Topaz,

    Thanks for the reply.

    I was prescribed slow release niacinamide by Dr Myhill, and up until recently I was taking it daily. I've just discovered though (if I can believe what is on the net) that it is contraindicated for low blood pressure. I'm over the moon if I can get my blood pressure above 90/60.

    Unfortunately nicotinic acid is also not appropriate as is it a vasodilator, which would exacerbate my existing low blood volume and hence low blood pressure.

    Best wishes,

    Sandra
  10. Richard Lee

    Richard Lee

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    Hi Rich

    Is it the use of MeB12 instead of (say) HydroxoB12 that most concerns you, or the size of the dosage, or its sublingual intake, or all three combined?

    I believe that Dr Neubrander got good results with autistic children using subcutaneous MeB12 shots every day or every second or third day. Do you regard that as more or less risky than daily sublinguals?
  11. minkeygirl

    minkeygirl Senior Member

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    Could someone explain to me what the methylation protocol is? Please dumb it down. Thank you.
  12. Dreambirdie

    Dreambirdie work in progress

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    Interesting that the mB12 can overdrive methylation...

    In my experiments with all the B12's, I have not been able to take more than a smidge of mB12 without glutathione, because it makes me extremely *WIRED and TOXIC.* Now that I am using the TD glutathione, I can handle a full 500 mcg (a lot for me) and a full tab of Folapro without the excito-toxicity symptoms being an issue.

    I have not taken any hB12 for several months, as I ran out. I will soon reorder and see how that goes with and without the glutathione.

    Thanks Rich, for all your great feedback, input and information.
  13. Dreambirdie

    Dreambirdie work in progress

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    The discussion about it is mostly on this thread: http://forums.phoenixrising.me/show...fied-Methylation-Protocol-Revised-as-of-Today

    SIMPLIFIED TREATMENT APPROACH
    FOR LIFTING THE METHYLATION CYCLE BLOCK
    IN CHRONIC FATIGUE SYNDROM (March 30, 2011 Revision)
    Rich Van Konynenburg. Ph.D.
    (Based on the full treatment program
    developed by Amy Yasko, Ph.D., N.D.
    which is used primarily in treating autism [1])

    SUPPLEMENTS

    1. General Vitamin Neurological Health Formula [2]: Start with one-quarter tablet and increase dosage as tolerated to 2 tablets daily
    2. Hydroxy B12 Mega Drops [3]: 2 drops under the tongue daily
    3. MethylMate B [4]: 3 drops under the tongue daily
    4. Folinic acid [5]: one-quarter capsule daily
    5. Phosphatidyl Serine Complex [6]: 1 softgel capsule daily (or lecithin, see below)

    All these supplements can be obtained from http://www.holisticheal.com.
    The fourth supplement comes in capsules that contain 800 mcg. It will be necessary to open the capsules, dump the powder onto a flat surface, and separate it into quarters using a knife to obtain the daily dose. The powder 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. In general, they can be taken at any time of day, with or without food.
    Phosphatidyl serine can lower cortisol levels. Patients who already have lower than normal cortisol may wish to substitute lecithin [7] (at one softgel daily) for supplement number 5 above. Lecithin is also available from http://www.holisticheal.com.
    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.

    [1] Yasko, Amy, Autism, Pathways to Recovery, Neurological Research Institute, 2009, available from http://www.holisticheal.com or Amazon.
    [2] General Vitamin Neurological Health Formula is formulated and supplied by Holistic Health Consultants LLC.
    [3] Hydroxy B12 Mega Drops is a liquid form of hydroxocobalamin (B12), supplied by Holistic Health Consultants. 2 drops is a dosage of 2,000 mcg.
    [4] MethylMate B is a liquid form of (6s)-methyltetrahydrofolate supplied by Holistic Health Consultants, based on Extrafolate S, a trademark of Gnosis S.P.A. 3 drops is a dosage of 210 mcg.
    [5] Folinic acid is 5-formyltetrahydrofolate. one-quarter capsule is a dosage of 200 mcg.
    [5] Phosphatidyl Serine Complex is a product of Vitamin Discount Center. 1 softgel is a dosage of 500 mg.
    [7] Lecithin is a combination of phospholipids without phosphatidylserine. One softgel is a dosage of 1,200 mg.
  14. dannybex

    dannybex Senior Member

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    That's GREAT DB -- very encouraging! I got some nebulized glutathione a few weeks back, but then had a bad (really bad) reaction, but am 99% certain that was due to high-salicylate/phenols (very high!) in a meal, as I was "okay" until about 1 hour after that meal.

    Hopefully we can all find what works for us with this complex, complicated condition. You, and many others like Sushi and Jenbooks and Sallysblooms are testaments to the fact that glutathione is indeed helpful for some folks.
  15. Freddd

    Freddd Senior Member

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    As regards "overdriven methylation", it is a big question mark. So far symptoms caused by this hypothetical situation are not demonstrable. The tests used to detect it are likely standardized on a chronically mb12/Methylfolate population and may merely indicate a statistical range of deficiency characteristics.

    Further in the entire b12 treatment arena treating to test results produces notoriously poor results largely because what the tests define as "normal" is normally chronically deficient based on pseudo b12 and pseudo folate. In studies done with people chosen by symptoms rather than test results, 2/3 of the responders would have been excluded by having "normal" or "high" b12 and "normal" or "low" uMMA and Hcy. "Normal" MCV now would have been classified macrocytotic 5-10 years ago but as the lab I called said "If we alerted all the high MCV we would be ignored because high MCV has become normal". So the abnormal has become the statistical "normal" now because of chronic b12/folate deficiencies in a large percentage of the population.


    And finally, methylb12 has dose proportionate healing characteristics over a large range. The rate of increase appears to decrease by the log of the amount as with many substances. It is discontinuous; there is a body curve and a CNS curve with a discontinuity between them. If I have to make a choice between not having the hypothetical and so far undetectable symptoms of overdriven methylation and continued CNS degeneration or stopping the CNS degeneration and being able to walk and control my bowels and have a functioning mind I'll choose the latter.
  16. Dreambirdie

    Dreambirdie work in progress

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    Hi Dan--

    It's an ongoing roller coaster. I had a very bad night, probably because I overdid it, which is what happens when I feel better.

    Good luck to you ~~ DB
  17. dannybex

    dannybex Senior Member

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    And to you to DB! Hope you're having 'better' days again very soon.

    I'm still on that same rollercoaster at times...although at least not from overdoing it from feeling better. It's so hard to be patient isn't it, especially when we hit bottom, but I guess that's the name of the game. Slow but sure wins the race.

    At least I hope so. :)
  18. Freddd

    Freddd Senior Member

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    Hi Richard Lee,

    I can't answer certain questions for Rich. I have 6 years of experience with injectable mb12 and 8 years with sublinguals. I will tell you that I consider injectable mb12 to be on the average considerably inferior and less reliable compared to the 5 star sublingual mb12 brands. I did a series of tests on injectable mb12 batches from multiple source batches of crystal. In addition to the same qualitative variations I found in sublinguals I also found additional variable degradation from injectable solution light exposure at the pharmacies during and after preparation themselves.

    Again in answering also for myself I would consider hydroxycbl to be far more predictable in it's ineffectiveness than mb12. With hydroxycbl there is almost no risk of actually recovering.
  19. Waverunner

    Waverunner Senior Member

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    In this study, caffeine seems to increase reduced glutathione in the rat brain:

    Pharmacol Biochem Behav. 2011 Jun 15. [Epub ahead of print]
    Chronic coffee and caffeine ingestion effects on the cognitive
    function and antioxidant system of rat brains.
    Abreu RV, Silva-Oliveira EM, Moraes MF, Pereira GS, Moraes-Santos T.
    Laboratrio de Nutrio Experimental (LNE), Faculdade de Farmcia,
    Universidade Federal de Minas Gerais, Av. Antnio Carlos, 6627,
    Pampulha, Belo Horizonte, Minas Gerais, 31270-901, Brazil; Ncleo de
    Neurocincias, Departamento de Fisiologia e Biofsica, Instituto de
    Cincias Biolgicas, Universidade Federal de Minas Gerais, Av. Antnio
    Carlos, 6627, Pampulha, Belo Horizonte, Minas Gerais, 31270-901,
    Brazil, 31270-901.
    Coffee is a popular beverage consumed worldwide and its effect on
    health protection has been well studied throughout literature. This
    study investigates the effect of chronic coffee and caffeine ingestion
    on cognitive behavior and the antioxidant system of rat brains. The
    paradigms of open field and object recognition were used to assess
    locomotor and exploratory activities, as well as learning and memory.
    The antioxidant system was evaluated by determining the activities of
    glutathione reductase (GR), glutathione peroxidase (GPx) and
    superoxide dismutase (SOD), as well as the lipid peroxidation and
    reduced glutathione content. Five groups of male rats were fed for
    approximately 80days with different diets: control diet (CD), fed a
    control diet; 3% coffee diet (3%Co) and 6% coffee diet (6%Co), both
    fed a diet containing brewed coffee; 0.04% caffeine diet (0.04%Ca) and
    0.08% caffeine diet (0.08%Ca), both fed a control diet supplemented
    with caffeine. The estimated caffeine intake was approximately 20 and
    40mg/kg per day, for the 3%Co-0.04%Ca and 6%Co-0.08%Ca treatments,
    respectively. At 90days of life, the animals were subjected to the
    behavioral tasks and then sacrificed. The results indicated that the
    intake of coffee, similar to caffeine, improved long-term memory when
    tested with object recognition; however, this was not accompanied by
    an increase in locomotor and exploratory activities. In addition,
    chronic coffee and caffeine ingestion reduced the lipid peroxidation
    of brain membranes and increased the concentration of reduced-
    glutathione. The activities of the GR and SOD were similarly
    increased, but no change in GPx activity could be observed. Thus,
    besides improving cognitive function, our data show that chronic
    coffee consumption modulates the endogenous antioxidant system in the
    brain. Therefore, chronic coffee ingestion, through the protection of
    the antioxidant system, may play an important role in preventing age-
    associated decline in the cognitive function.
    Copyright 2011. Published by Elsevier Inc.
    PMID: 21693129 [PubMed - as supplied by publisher]
  20. richvank

    richvank Senior Member

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    Hi, Richard.

    I don't know enough to give simple answers to your questions (above). I think that all three of the aspects you mentioned are potential issues.

    At this point, the only way I can tell whether the amounts an individual is taking are causing the overdriving problem I'm concerned about is to see certain types of lab test results on that person.

    My goal in commenting on treatment of the vicious circle mechanism that I believe is associated with the partial methylation cycle block in ME/CFS is to try to help people with ME/CFS to restore this part of the metabolism to normal operation, because I believe it's the core issue in this disorder.

    What I can do is to describe the situation in the biochemistry as I see it, based on what is known about this part of the metabolism as applied to the interpretation of test results that some people have sent me.

    In normal operation, the activity of the methionine synthase enzyme (which I believe, based on lab testing, is partially blocked in ME/CFS) is continuously varied to balance the body's needs for methyl groups, folate vitamers, and antioxidant protection. There are several feedback loops involved in this overall system that normally balance the response to these needs.

    When sufficiently large amounts of both methylfolate and methylcobalamin are supplied to a cell, these feedback loops are overridden. The result is that the activity of methionine synthase remains high, regardless of the body's needs. The effect of this is to cause both the methylation cycle and the folate cycle to run faster than normal, while the flow down the transsulfuration pathway to make cysteine (needed for the sythesis of glutathione) and also to make coenzyme A, taurine, sulfate and other sulfur-containing metabolites that are needed for a variety of purposes, is held lower than normal.

    I don't know what the long-term consequences of this will be. What I see in the test results of people who are supplementing both methylfolate and methylcobalamin at dosages in the several milligrams per day range are indications that glutathione is not coming up, while the methylation cycle and folate metabolism are carrying out a "futile cycle" by passing methyl groups back and forth between them via sarcosine and methylfolate. As a minimum, it seems to me that this would slow their recovery.

    If a person should also happen to have inherited a slow version of the enzyme glycine N-methyltransferase, which some people have, this overdriving of the methylation cycle could cause the SAMe level to rise high above normal, and that would affect gene expression as well as the rates of a large number of methyltransferase reactions. I can't predict the outcome of that.

    Methylation is also involved in cancer, in silencing tumor suppressor genes, so elevating the availability of methyl groups above normal levels, such as might occur if the glycine N-methyl transferase activity is low for genetic reasons, could potentially have some effect on that as well.

    It's known that cancer cells have a higher demand for B12 and folate and have higher numbers of receptors for them than normal cells do, presumably to support their more rapid multiplication, so that if there are incipient cancers present, high dosing of these two together could potentially accelerate tumor growth. One person reported activation of a long-dormant incipient skin cancer (actinic keratosis) on this type of treatment.

    In theory, methylcobalamin can methylate inorganic mercury, making it fat-soluble and able to cross the blood-brain barrier. When sublingual methylcobalamin is held in contact with teeth that have amalgam fillings for long times, it would seem that the concentrations of both methylcobalamin and inorganic mercury could be high enough to achieve a significant reaction rate and significant production of methylmercury.

    All this having been said, some PWCs do need to take the methyl form of B12 because of their particular inherited genetic polymorphisms. Dr. Amy Yasko bases the choice of which form to use on characterization of these polymorphisms. In suggesting the simplified approach, I decided to opt for hydroxocobalamin in the basic protocol, and it was found to work for most of the PWCs in our clinical trial. The idea was to enable people to do something that has a good chance of helping, without the cost and complexity of the full Yasko program. I did this with the knowledge that this protocol would not be optimum for everyone, but it is a place to start. When people observe effects from the simplified protocol, they become interested in the methylation issue, and then they are motivated to look into it further, perhaps get some testing if it is feasible for them to do so, and perhaps modify their treatment to something that is a better match for them.

    If a PWC finds that the simplified protocol does not work for them after two or three months, I suggest doing some testing to find out why, and changing the treatment appropriately. I favor using the smallest dosage that will do the job, so that the body will be able to balance its needs by regulating this part of the metabolism as well as it can.

    I also recommend working with a physician while on this type of treatment. If injections are feasible in a person's situation, that is certainly an option. As Freddd has pointed out, it's important that the injected solution be of good quality and properly prepared, as methylcobalamin does not have high chemical stability.

    There is nothing sacred about the simplified protocol as far as I'm concerned. If an individual finds something that works better for them, my attitude is more power to them! I'm a researcher, not a clinician, and I see my role as trying to figure out what's going on in this disorder. Hopefully that will provide clues to treatment, but it isn't straightforward to determine the best treatment protocol simply on the basis of biochemical theory.

    For one thing, people are all unique in terms of their genetics, and I have to object when treatment results for an individual or a group of individuals are extrapolated and claimed to apply to all cases. They may indeed apply to many others, but I have seen enough heterogeneity in the ME/CFS population that I don't believe in one-size-fits-all treatments, and sometimes there can be unpleasant surprises when this approach is taken.

    I also believe that when judging the effects of a treatment, we need to define the treated population as tightly as we can. If we are looking at an undefined population that includes people with the whole variety of B12-related problems, and not only those who satisfy the (admittedly imprecise) criteria for ME/CFS, I think we have to question how applicable the results are to the ME/CFS population.

    I again want to reiterate that I very much appreciate the contribution that Freddd has made to this field. I think we can learn a lot from his experience, and I certainly have myself. My concern is that we examine it in the light of Freddd's own situation, which he has shared with us, and apply it appropriately to other cases. There is still a great deal that we don't know about ME/CFS, the metabolism related to the methylation cycle, and how to apply appropriate treatment. I also very much appreciate reading reports of the experiences of people in these forums. These experiences are a big part of the "acid test" for me of whether my hypotheses make sense or not.

    Best regards,

    Rich

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