Some of the reason's people don't get well treating methylation in Rich Van Konynenburg's words

Discussion in 'Fibromyalgia Main Forum' started by ljimbo42, Mar 31, 2015.

  1. ljimbo42

    ljimbo42 Active Member

    This paragraph was at the end of one of Rich Van Konynenburg's paper's on his Glutathione Depletion Methylation Cycle Block hypothesis as the cause of CFS. He explains how toxic molds, viruses, Lyme disease and heavy metal toxicity may need to be addressed as well as methylation in order to recover from cfs/fm. I find the part about toxic heavy metals particularly interesting, because poor methylation can cause them to build up and then the heavy metals block the very enzymes needed to bring the methylation cycle back up to normal functioning!

    This is the quote from Rich-
    Last edited: Mar 31, 2015
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  2. IanH

    IanH Active Member

    I had many a discussion with Rich about this. However the evidence for the methylation cycle being at the root of ME/CFS is waning. There is no doubt that some problems within the cycle do exist but this is all an effect of the illness. Toxins will exacerbate the problem and there is no doubt that mycotoxins will cause most with ME and serious FM a real problem.

    My view is (I will explain it in simple terms) that ME is a neuro-inflammatory disorder, and there is plenty of evidence for this. In such an inflammatory state, mitochondrial function is undoubtedly impaired and sensitivity to toxins is increased. Hence even a "normal" toxic load will cause people with ME a problem. This is why people with ME must be "pristine" in their lifestyle. Removing excess toxins may be helpful but we must be careful about drawing conclusions about these substances as a cause. When people get tested for these toxins they invariably find they have a "load". Unfortunately we don't know what a "normal" load is of many of these metallo-toxins. If you go down this track of thinking that a heavy metal is a cause you will find it in your system.

    As an aside:
    I have this discussion in relation to MCS (multiple chemical sensitivity) , in my opinion a form of ME. Many with MCS believe that they are being poisoned by chemicals. In a way this is true but that applies to all of us, we are all being poisoned every day. Most people's systems deal with this and they don't suffer noticably. If you have MCS you become super sensitive to even slight rises in many "normal" toxins. However the variation is great. So great that Psychiatrists have a field day with these unfortunate sufferers. And, believe me, many suffer far more than people with straight ME or FM because they try avoid everything!

    Disturbances in gut microbiota from dietary imbalance. inhaled toxins, over-exertion, "over-stressed", loud noise,
    plus systemic toxins cause symptom worsening.

    Of course you can treat all the symptoms with processes like chelation, dietary changes, environmental changes etc but these will not remove the disease. Improvement is often noticed but I know so many people who been through these treatment processes will little or no result.

    Intravenous treatment with glutathione has little effect. The argument being that it is not in the cells but this is unlikely to be true.

    However if you view the illness as a brain inflammatory disease (ME is a true name) then any of these symptoms follow.

    The recent papers by Hornig and also by Yamato are well worth thinking about. Hornig showed that ME occurs in two distinct phases. Phase I about three years of severe inflammatory infectious response. Phase II a consolidated chronic phase of AIDS (non HIV). Yamato has shown that the shift from the acute inflammation to the chronic state may well be due to a chemokine deficiency. This chemokine is IL-1ra. (Interleukin-1 receptor antagonist) This normally blocks all the IL-1b receptors from any IL-1b. If there is insufficient IL-1ra then any amount of IL-1b will cause a neuro-inflammatory response in the microglia.

    In different people (different brains) this means lots of different variations in symptoms. You can imagine slight inflammation in different parts of the brain causing different symptoms, pain for some, fatigue for others (most), gut problems for other, lots of sensitivities for others, visual disturbances for some, tinnitus for others and so on.

    Now you could argue that all these problems could be caused by mitochondrial dysfunction as has been the case for autism (Rich's original source). Indeed it could explain them but its the variations in symptoms which makes me think this is not the central factor at all. It is a factor but a secondary one as it is in many inflammatory disorders. In addition some try to argue it arises from gut dysbiosis, but many people with ME do not have much gut dysbiosis at all but suffer from ME or FM nonetheless. FM clearly has a central sensitization, easily explained by microglial activation of the dorsal horn and this explains neuropathy too, as explained by Yamato.
    Last edited: Mar 31, 2015
  3. RadioFM

    RadioFM Active Member

    I have been saying from the beginning, we need to protect the Mitochondrial from the dysfunctional immune system.

    I agree with the great late Richard Van Konynenburg work that Mathylation is relevant topic and may need to be addressed for healing to happen.

    Methylation support may be needed especially if you have a B12 or MTHFR issue. I had symptoms of B12 deficiency for many years before I got sick with CFS.

    I feel having these Methylation insufficiencies may set the stage for CFS in some people. Rich may have been right about glutathione and methylation insufficiency in relation to developing these risk factors.

    Question: Could a Genetic or Epigenetic susceptibility be a risk factor in CFS/ME/FM/Autism?



    The complexities are many and Richvank interpretation is one of many possibilities.

    I feel most chronily ill people will benefit from low dose Methylation support. I do feel glutathione support can be beneficial in increasing detoxification. But, will not fix the problem.

    A nutritional intervention may help turn on epigenetic expression needed to repair the body

    I now supercharger my cells with the Ketogenic diet concept and have created a simplified approach to controlling inflammation and supporting Mitochondrial integrity. I will post links below for other forum member to see my approach to healing.

    The human body is very complex and the one cause one diseases model of medicine does not always work in the discussion of chronic diseases.

    The great minds of the world who have a open heart to see past there own opinions will look for the truth in all possibilities.

    I feel that doctors who are literate in Lyme disease have the mind set and understanding to look a multitude of contributions factors.

    Yes, healing is possible I am proof of that and there are others who have discovered these literate doctors who Never Give Up The Fight!

    Please review threads below:

    I no longer have gut problems thanks to the Keto Diet. It has help me normalize my breathing as well. I also sleep better and have energy all day with out the Hypoglycemia lows.
    Last edited: Apr 1, 2015
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  4. ljimbo42

    ljimbo42 Active Member

    @IanH - You make a lot of good points. I agree that MCS is manifestation of me/cfs. I think I might have a very mild form of it. Many odors and smells bother me enough that I will hold my breath until I can get out of the situation, or breathe very shallow if I can't hold my breath long enough. Diesel fumes from trucks will do it, as will just regular car exhaust, chemical smells, perfumes, laundry detergent etc.

    The problem I have with discounting methylation is my experience last may. I had been taking many supplements for methylation and mitochondrial support for months. I decided to go up on my dose of methylfolate rather quickly to see if I would feel better. So I went up 200-400mcg every 3-4 days until I reached 6,400mcg. The very next day my energy level tripled, it went from about 10% functioning to about 30%, literally overnight-no exageration! On may 17, 2014 I was functioning at 10% and the next day, may 18, 2014 I was functioning at 30%. The only change I made was the methylfolate. It was such a profound change that I wrote on my calendar!

    I hope you can see why I am absolutely certain I had a methylation block, it's not a theory to me. I understand that you don't believe it, but that doesn't change my experience. I have spent many hours reflecting on this experience and I am secure in my understanding of it. When it's all said and done if we don't trust ourselves, who can we trust. So for me it's not a question if I had a partial methylation block, for me the question is what came first. Did the dysbisis and leaky gut lead to a methylation block or did the methylation block help create the other symptoms of my cfs/fm.

    Rate now it makes much more sense to me that the methylation block came first. I think among other things it caused a weak th-1 and a th-2 dominance.

    The research is clear on glutathione being a potent force within the immune system. I have short cuts on my desktop to about 10 studies showing this.
    It also seems clear now, that cfs/fm is a th2 dominant illness. This study just came out yesterday from Horning and Lipkin.

    I know of at least 2 other studies that show th-2 dominance in cfs/fm, so that seems pretty well established as well. One of the most important questions I think people need to ask themselves is WHY is the th-2 arm of the immune system dominant, and what is causing it?
    Last edited: Apr 1, 2015
  5. ljimbo42

    ljimbo42 Active Member

    There in lies the rub. There are so many interpretations on what needs to be treated and how, that most people get lost and can't see the forest for the tree's, which is completely understandable and almost unavoidable. I certainly was completely lost, but now I've found some, not a lot, but some, solid ground to stand on.;)

    The one thing about my cfs/fm that I am most certain of is the breakthrough I had with methylation as I said in my post to Ian. You make very good points about a ketogenic diet, mitochondrial support and controlling inflammation. All I think are necessary and helpful.

    I agree with that statement, but sometimes it can very difficult to balance holding onto what is true for oneself and yet stay open to new idea's and possibilities. It is something for me, and most I believe, that is a ongoing challenge. Congrats on your healing, you must have put in a lot of hard work to get where you are!
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  6. IanH

    IanH Active Member

    I try to avoid self analysis as a means of identifying a cause of illness. Also I was not very successful at convincing people that ME was a mitochondrial disease.

    I do not disagree that methylation is a problem, I said so but it is unlikely to be a primary cause of the disease. I was the first person in NZ to suggest that ME was in fact a mitochondrial disorder, back in 2004, shortly afterward I wrote to the UMDF recommending that ME be considered a mitochondrial disorder. I was also the first person
    on these forums to recommend a treatment protocol for mitochondrial treatment in ME. And I continue to recommend a mitochondrial support protocol in the treatment of ME and FM. So far I have placed 143 people on the mitochondrial support protocol or a cut-down version of it.

    However I do not see much empirical support for the idea that the mitochondrial insufficiency is due to a methylation cycle issue, rather the reverse, that mitochondrial insufficiency is the cause of some methylation cycle retardation. I made this point quite clear to Rich and he knew I had a valid/supported point.

    Also, taking 6.5 mg methylfolate and improvement in symptoms does not confirm a methylation block.
    There are other explanations to the effect of higher dose MTHF eg.

    MTHF at the dose you use is an indirect regulator of trimonoamine neurotransmitter synthesis and monoamine concentrations in the brain, it increases serotonin and reduces glutamate.

    and there are other explanations too but . ..

    The point I am making is that just because you got a good response from high dose MTHF does NOT confirm a partial methylation block. Again this was a point I made to Rich.

    Think about how neuro-inflammation affects systemic functions.

    Firstly your question and the Th1/Th2 balance in ME. (or infectious fatigue in general).

    "WHY is the th-2 arm of the immune system dominant, what is causing it?"

    Quite a bit of research has pointed to neuro-inflammation being the cause but until Hornig and Yamato published their research this has been vague. Not so now.

    Yamato and Hornig research are pointing to the answer.

    There are two factors:

    If you have a failure (exhaustion) of the normal anti-pathogen response (Th1) ie a drop in IFN-gamma and TNF-a etc then Th2 will dominate.

    Th1 cells, which produce interferon (IFN)-gamma, interleukin (IL)-2 and tumor necrosis factor (TNF)-beta, evoke cell-mediated immunity and phagocyte-dependent inflammation.

    Hornig showed that this process is "exhausted" in Phase II ME resulting in a balance shifted to Th2. Note that in the early phase I of ME no such shift occurs.

    IL-1a and IL-1b play a major role in the shift from Th1 to Th2. This has been shown in many animal studies. IL-1 (-/-) mice do not shift from Th1 to Th2 under many assaults expected to trigger the shift but do so when Il-1b(a) is added to their blood. What Yamato has shown is that if IL-1ra is downregulated then even small amounts of IL-1b(a) will be enough to throw the balance from Th1 to Th2 because there is little or no IL-1ra to block it.

    So the immune balance in phase II ME is shifted towards Th2 and is explained by a faulty IL-1ra. Next they need to look at the miRNA and see what is going on there then follow that up to see if there is a genetic link. BY that I mean a dysfunctional epi-genetic link. I suspect there will be. If that bears out, the question is what is causing this and the consequent neuro-inflammation. I doubt it has much to do with methylation cycle components- although it will be implicated. However I can see how mitochondrial function will be affected and in turn how methylation cycle processes might be affected by mitochondrial depolarization which is known to occur in neuro-inflammatory diseases, ME included.

    Incidentally but importantly, one of the known pathologies associated with the gene polymorphisms of IL-1ra is microvascular dysfunction, a problem known to be present in ME and in FM. This is also associated with peripheral neuropathy in diabetes and I am suggesting also in ME because the neuropathy in diabetes is almost indistiguishable from the neuropathy in ME and FM.

    My view is that the triggering process in ME involves:

    genetic polymorphisms (some of which have been identified by Jonathan Kerr, eg see:, IL-1ra gene SNP being one of them.
    environmental toxins affecting those SNPs (most SNPs in disease are affected by one or more environmental factors)
    A neuro-inflammatory assault (virus or trauma), which causes a depletion of IFN-gamma and or TNF-alpha. Then under the above circumstances (SNP plus environmental toxins or poor env toxin management as in case of vitamin D deficiency, ) a complete shift to Th2 which is intractible. BINGO - ME.

    Also The FoxI1 transcription factor and the STAT3 transcription factor are the main transcription factors of the gene, both of which have been implicated in neuro-inflammatory conditions. I include vitamin D3 because it has some control over FoxI1.

    Now, what is the connection between IL-1b and mitochondrial dysfunction? Michael Maes, a well known researcher in ME has shown that IL-1b persistence causes mitochondrial insufficiency and membrane depolarization. This is exactly what we get when IL-1ra is deficient.

    Other factors such as gut dysbiosis, general infections, stress etc. affect symptoms.
  7. ljimbo42

    ljimbo42 Active Member

    @IanH- So my theory is that low glutathione, from genetic SNP's, toxins, and stresses from many sources, impair methylation and lower glutathione. Here are some of the reasons. It appears that low glutathione can create low interferon-gamma among other imbalances and the th-2 dominance found in cfs/fm. As I am sure you know IL-12 is involved in the production of INF-gamma.

    Here is another study that shows that glutathione enhances IL-12 and therefore gamma interferon.

    Here is a study that shows elevated levels of glutathione could increase IL-2 production-

    There are many studies showing that depleted glutathione can cause th-2 dominance. I can post more of them if you want me to.

    The problem with that statement is that I cut back to about 1200-1600mcg methylafolate a day months ago, but the breakthrough I had continues unabated. It wasn't just an improvement, it was a profound shift in my body. Tripling one's energy isn't just an improvement when it happens literally overnight, it's amazing!

    So the high dose methylfolate in and of itself is not the cause for the huge jump in energy. I believe it was a partial methylation block, just as Rich Van Konynenburg discribed in his theory and now that I have opened up the cycle, a low dose of methylfolate (and methylcobalamin) is enough to keep it open.

    I think it takes a long time to undo the all the dysfunctions it causes treating methylation alone, and by a long time I mean years, without other types of targeted intervention. I think you are aware of Freddd from Phoenix Rising and his recovery from cfs. He is now functioning at 90-100% through methylation treatment.

    I think he said it took him about 7 years to undo all the dysfunctions. He also said when he reached a high dose methylfolate, he felt his body "turn on". That I think was a partial methylation block breakthrough, just like mine. There is a woman who when she reached 5,000mcg methylafolate treating methylation, she said she felt a definite "shift" in her body and now feels "wonderful" and no longer needs her daily naps to get through the day.

    Treating methylation transformed her life so profoundly she started her own company, only selling methylation supplements! So clearly, I am not alone with my experience. I think many people have had this breakthrough treating methylation and have misinterpreted it as something else.

    So there is a lot of evidence that low glutathione can cause a th-1 to th-2 shift and all the symptoms that come with it. I will bet that in time, Rich's views on the partial methylation block, for the most part, will be proven true.
    Last edited: Apr 2, 2015
  8. joanierav

    joanierav Member

    i am thinking of starting the methylation treatment. what is the easiest , supplement i could/should try first. something that i will not herx with. i am too sick to handle herxing.

    thank you, joanierav
  9. joanierav

    joanierav Member

    do you think taking the high dose of methylfolate without doing the whole treatment first would work for me?

    im so glad you found help with the folate. that is great news jimbo.

  10. ljimbo42

    ljimbo42 Active Member

    @joanierav- A high dose of methylfolate would most likely make you very ill, I strongly recommend not doing that. Treating methylation is so complicated and difficult that I am very hesitant to recommend anything, espescially where you are so ill. Die-off and other adverse reactions are going to happen and if your body is not strong enough to handle it, it could make you very sick.

    It also takes a long time, it not a quick fix at all. I have made some progress but I still have a long way to go. I would suggest talking to a functional medicine doctor if at all possible, one knowledgeable in methylation treatment.

    I am sorry I couldn't be more helpful. There is a lot of info on methylation at I think they have a list of functional medicine doctors there that are knowledgeable in treating methyaltion also.

    Even if you can't see a functional medicine doctor,maybe you can have phone conversations with one that will help guide you. Some functional medicine doctors are doing that now. Best of luck to you!
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  11. IanH

    IanH Active Member

    "low glutathione, from genetic SNP's, toxins, and stresses from many sources, impair methylation and lower glutathione"

    Yes I have considered this myself and it remains a possibility. Problem with the theory is that clinical practice and research data from other brain disorders does not support it very well. It is an old idea from autism (where Rich got the ideas from).

    There are many SNPs related to the glutathione pathway and these have been well investigated in Autism, not much in ME/CFS. Treatment of autism with glutathione or it's precursors such MTHF, NAC, B12, SAMe etc have not proven very effective. The treatment is also ineffective for Schizophrenia, a related illness. Despite raising glutathione levels with treatment (Kern et al) key symptoms are mostly unchanged.

    In Parkinsons as in most neuroinflammatory disease there is a glutathione depletion but here the relationship between neuro-inflammation and glutathione depletion is more evident. In PD there are polymorphisms of the genes for IL-1b and TNF-alpha but no polymorphisms of any relevance in the glutathione pathway. So in PD the thought is that neuro-inflammation is causing mitochondrial dysfunction and hence a depletion of glutathione.

    However in Alzheimers there are glutathione pathway SNPs.

    It is generally agreed in Psychiatry and Neurology that the glutathione depletion is not a primary cause of most main symptoms.

    Generally Glutathione depletion exacerbates peroxynitrite induced pathology so exacerbating symptoms.

    In ME it is more difficult to assess symptoms because of placebo effects and complete lack of research. (except the above study by Gerwyn Morris:

    However you can hang on to your hypothesis regarding ME because of lack of data. Scientifically I have little faith in Rich's idea that glutathione depletion is a major causal factor in ME/CFS (actually Amy Yasko's idea). Why would ME/CFS be any different from these other diseases.
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  12. ljimbo42

    ljimbo42 Active Member

    @IanH - That is a good question. I haven't researched connections between Parkinson's, Alzheimer's and cfs/me. Do you know if there is a th-2 dominance in these other diseases? If so, could you give me some info to follow? I did a little research today, but had little time and did not find much.
  13. IanH

    IanH Active Member

    Ok I will get some refs for you.

    I note you have quite a bit of MCS. Have you been tested for MCAD ie. Mast Cell Activation Disease.
    MCAD is a testable neuro-inflammatory condition which causes many of the symptoms similar to ME/CFS

    Probably the best place to read up it is the World Journal of Haematology (Hematology)

    Just search for "A concise, practical guide to diagnostic assessment for mast
    cell activation disease" World Journal Of Hematology.

    I think they have a diagnostic guide.

    There is an older paper here:

    note re: successful treatment using the "methylation cycle support" Yes I am aware of FREDD and others who have claimed that the methylation cycle treatment protocol helped them - and I am sure it did.

    The protocol is almost the same as the mitochondrial support so just because a treatment for a "deficient" system is successful is not a confirmation of the hypothesis. IE a treatment can not be used as a diagnostic tool. I made this point to Rich.
  14. joanierav

    joanierav Member

    jimbo. thank you for responding. good luck to you on your journey.

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  15. ljimbo42

    ljimbo42 Active Member

    @IanH - I have not been tested for MCAD. I do have many of the symptoms though, flushing, itching, severe nasal allergies and others. Is MCAD something often seen in people with cfs/fm or is it usually something separate?

    It sure sounds an awful lot like cfs/me. Histamine, which I think is causing some of the symptoms I mentioned, is metabolized through methylation. So it seems methylation could play some kind of a role in these symptoms. Couldn't a TH-2 dominance also create many of the same symptoms?
  16. ljimbo42

    ljimbo42 Active Member

    @IanH - I found this study interesting on dna methylation and Alzheimer's and thought you might want to read it- here are a couple of paragraphs, with the link to the study at the bottom of my post.