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The 3 Ps A Closer Look at the Middle One

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by stressman, Jan 24, 2011.

  1. stressman

    stressman

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    Hello everyone, Im new here so Ill briefly introduce myself. Im a retired aeronautical structural stress engineer (hence my nom de plume).

    My daughter was diagnosed two years ago with ME/CFS and Ive devoted the intervening time to studying the condition. Ive studied all the big names associated with the disease, but did not discover the work of the good Rich van Konynenburg until a couple of months back, sadly. Quite a revelation!

    This posting is a draft submission for peer review. I have not included any references at this stage.

    So here we are, the three Ps, predisposition, precipitation and perpetuation, the first and last of which are well understood and described.

    So what leads to the final precipitation of the condition? Ive dug out some very interesting stuff on the conditions that obtain prior to precipitation in a quest to answer my ongoing question as to why PWCs all have (very similar) gut dysbiosis. Stress seemed to be the most common link, so my Google Stress gut flora gave me the answer, though not the expected one. All hits were about IBS, not CFS. Well, well It turns out that stress destabilises glutathione, the HPA axis and of course, cortisol. This plays havoc with the gut flora. Question answered. However, it also indicated that PWIBS (sorry about the jargon) suffer the same physiological conditions as obtain in post-precipitation (i.e. chronic) ME/CFS.

    So far then: Many PWCs also have IBS but not all PWIBSs have precipitated into the CFS state although the pathologies are very similar if not identical. It must be a matter of degree, then, if both conditions display loss of toxic protection from glutathione depletion, and H2S poisoning from the gut flora.

    So- If we turn the degree up a couple of notches until CFS precipitates, what changed? Well, the toxic load of course. From then on, as is well documented, the condition is self-perpetuating.

    Its said that what turns it on will turn it off. Efforts to supplement d-ribose to turn on ATP production meet with very limited success. The much more successful efforts to re-start the methylation cycle nevertheless do not produce a universal cure. Should we not therefore start by addressing the toxic load? That is, after all, where I believe we came in.

    If Ive screwed up somewhere on this, start shooting now!

    If I havent, then I suggest that selenium, NAC, MSM and ALA are the necessary starting agents though please DONT TRY THIS AT HOME! Dosages and phasing (if necessary) need to be determined by one much more knowledgeable than I.
  2. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    I have taken NAC and ALA for years, mainly as they help the liver to detox from medications i use and so far i have had no liver problems show up in blood tests. My opinion on cfs is that its some sort of immune defiency thats why some feel better treating with antivirals, some with antibiotics but no one ever cured because of the underlying immune defiency. It might all come down to a retroviruses causing the immune defiency, just like HIV people get sick from all the co-infections like ebv, mycoplasma, gut problems etc. I think treating the energy production like ATP is worth a shot but i dont think its the cause and i have found that increasing energy artificially eventually just causes a crash, even using energizing antidepressants eventually make us crash too. if used occassionally they stand a chance as we then have time to recover. I think the mythlation thing is just another part of our system thats broken down, fixing it can help but we arent at the cause. Everything we have is treating symptoms and living within our energy envelope at the moment. Our big hope is xmrv/MLV being the cause. Thast my opion and i could be wrong, but i say try everything and see what happens.

    cheers!!!
  3. ukxmrv

    ukxmrv Senior Member

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    Hi Stressman,

    My history is that I had an acute onset of ME with upper respitory tract symptoms (infected tonsils, high temp, gland etc). At the time there was no stress and I was a young student living a happy life. No stomach problems at all. These stomach problems only happened after about a year of being repeated sick with the throat infections etc and being given antibiotics.

    If you go back and read about the epidemics of ME it's a good starting place to see who got the disease and in what sort of groups. There is no sign of extra stress or H2S being a major factor there. It is more like a viral illness or something that struck them out of the blue like a virus, bacteria, environmental problem? The epidemics went with polio.

    Research on PWCFS shows low cortisol. It's one of the paradoxes of a stress related argument. Did people have high cortisol to start with, developed the disease and then changed to low cortisol. We don't know but can't ignore the fact of cortisol being low in PWCFS.

    You may wish to cut out the epidemics and start on a subgroup instead. People who were under stress and had stomach issues and then were diagnosed with CFS. It's still a subgroup and that may only be applicable to that group of people. I don't know about the rest of us. I'm following the XMRV angle as it fits in more with my own illness onset and I tested XMRV+.

    Your theory could fit in as a perpetuating factor in the pathogenisis of the disease. If acute onset, well, happy people with great stomachs can remain ill for decades (as my case), then it could be that something causes x, then y etc, etc and we don't get better.

    Rich VKB should be declared an international treasure. He is a member of this group and the best person to run through your theory with.
  4. velha508

    velha508

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    Stressman,

    An individual may need to support methylation, overall general nutrition (vitamins and minerals andd prescription amino acids if plasma levels are low), and ALL mitochondrial co-factors (alpha lipoic acid, carnitine fumarate, d-ribose, CoQ10, etc.) all at once in order to start improving. A comprehensive of these protocols is found at this link:


    Active B12 basics thread (PROTOCOL, DO NOT POST QUESTIONS HERE):

    http://forums.wrongdiagnosis.com/showthread.php?p=191131&posted=1#post191131


    B12 discussion thread (POST ANY QUESTIONS HERE):

    http://forums.wrongdiagnosis.com/showthread.php?t=9948&page=1087


    Though I had slowly been becoming worse over approximately 8-10 years, I was lucky enough to find Rich's theory almost immediately after I fell seriously ill (primarily homebound) with CFS in the summer of 2009. I was equally lucky to find Fred's protocol posted on the wrongdiagnosis forum as many aspects of it were essential to my recovery (adenosylcobalamin and carnitine fumarate). Your daughter is lucky to have a father like you who is capable and willing to help as the protocol is somewhat difficult to follow if you are brain fogged with CFS.

    Many, many people have posted their start-up periods and recoveries on the wrongdiagnosis forum and thus you can follow peoples success, or lack thereof, by reading through the history. My impression has been that all that follow the advice given get substantially better.

    Due to the poor digestion aspect it was impossible for me to begin to get well without prescription amino acids. I could not use protein mixes due to the conflict in the protocol - I tested this and found, the same as others who tested, that GSH or precursors were detrimental to recovery. Please give it a read and post any questions you might have over there. Fred has been absent of late, but hopefully will be participating more soon as he has the most experience with the protocol and is very good at answering questions and concerns. He is recovered from CFS.

    Velha



    blah
  5. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    i think gut infections, candida etc are co-infections, clearing these gut issues up helps with absorption of nutrients etc but not the golden egg. I think the point of stress is a tough one, because if u ask anyone non cfsers as well they all have stresses going on that could easily have been a precusor to cfs. The most common onset is infection, i think the slow onset people probably caught something and shrugged it off as just a cold and then it kept returning off and on until one day it floors them.

    My opinion of cortisol is that it may have been initially high and then with prolonged stress due to infection etc it causes adrenal fatigue where dhea and cortisol levels drop, this is whats happening to me, pregnenolone is a hormone that helps with making dhea and cortisol as well as other hormones, also adequate cortisol is needed for thyroid to work properly, one indicator is low body temp, my temp is always low but has increased to almost normal since being on pregnenolone, this is something people who are on thyroid meds who arent responding need to look into. is it the golden egg, well know, but it helps. Its believed that cortisol lowers our immunity but this generalisation isnt quite right, we need the right amount of cortisol and dhea for a healthy immune system.
  6. stressman

    stressman

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    Thanks for your replies everyone, every bit learned is a bit nearer the truth.

    Heapsreal - what doses of ALA and NAC did you start on, and what is your dosage now? I've had very good detox results myself with MSM, incidentally.

    Ukxmrv - my daughter went through both wild highs and lows of cortisol last year with resulting hypo- and hyperglycaemia. Don't know what that means as I sit here. Interestingly, I included selenium in the above as it is a reverse transcriptase inhibitor (Dr Atkins).

    Velha508 - thanks for the links, shall comb through them tomorrow!

    Heapsreal - good luck with the preg, glad to hear it helps. Unfortunately we can't but it legally here in the UK, neither would any doctor prescribe it for fear of being struck off. There are ways, I suppose... ;-)

    ...there being no exit, they left by the same door as in they went.
  7. dannybex

    dannybex Senior Member

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    Hi Stressman,

    I would be extremely cautious with ALA (and also active b12's and active folates) if your daughter has any heavy metal toxicities, especially mercury, as they may cause (a lot) more harm than good unless started in very small doses, or in the case of ALA, taken every three hours as a chelator, as per the Andrew Cutler protocol. More info on Cutler, ALA and mercury can be easily found doing a google search.

    Best of luck,

    Dan
  8. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    Lipoic acid i take 250mg once a day and NAC 600mg twice a day, i use NOW brand from Iherb, there well priced. As for the pregnenolone i get it prescribed by a doc, i cant believe that in the UK docs cant prescribe that sort of thing, UK docs have their hands tied alot, i think aussie docs are in between UK and USA docs as far as what sort of testing and treatment they can use.

    good luck,
    cheers!!!
  9. LaurieL

    LaurieL Senior Member

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    Hi Stressman,

    I think if this were a result of stress alone, then many more would suffer the condition due to stress. Yes, stress is an associated factor but I believe it can be more detrimental in certain genotypes. I believe genotypes predispose an individual to certain exposure related events and I find the mechansims between Autism, CSF, Alzhiemers, MS, Celiacs, mold exposure patients, and Lyme patients all very similar ( Gut dysbiosis and abnormal protein conjugation). What connects these groups are the HLA DR, DQ genotypes. Also interesting, and of which I have been lately looking into, are that with these genotypes, certain immunodeficient states created by polymorphisms in Immunoglobulins also coincide with the HLA DR, DQ types found in the above patient groups.

    As far as "what turns it on, should turn it off" isn't necessarily true. I throw around the question to myself about not necessarily what "turned on" the process but what was turned off to allow the start of the disease. I am no expert, but when I look at the many pathways including methylation, what I have seen is that when one component of a pathway is deficient, a reactional deficiency occurs in other components of that pathway due to alternate pathways kicking in to relieve the original deficiency. When those alternate pathways kick in, then I am seeing that deficiencies in those pathways can ensue due to the very affect of the entire body process. And then progresses into other diseases, deficiencies, and affected pathways and so on. I call them positive feedback loops, and I know these are incredibly hard to convert once they are started due to the domino effect I have tried to convey. I believe this is the premise behind the many adjuncts used in the varied methylation protocols.

    As far as glutithione, I can't convey how many failures I have come across with either direct supplementation, injection, or precursor supplementation. The glutithione destabilization associated with IBS could be due to the dysbiosis of the intestine, bacterial translocation, and the inability of the intestine to absorb or utilize properly the B vitamins, and folate. And also the neurotransmitters and Vitamin K. It is my suspicion that by addressing the methylation cycle, that this will also address one of the components of the intestinal dysbiosis I myself have and have been miserably unable to resolve for a number of years in numerous therapies.

    Perhaps the total lack of resolution for some in the case of methylation, comes from other polymorphisms and/or acquired deficiencies in other pathways that will need to be addressed as well as the many possible co-infections, diseases, auto antibodies, inflammatory pathways, and cytokine reactions that result from the interuption or deficient state in the first place.

    Laurie
  10. stressman

    stressman

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    Well, what lovely people and how knowledgeable you all seem to be! Thanks for your help.

    I must clarify what I meant by stress. I include anything physical e.g. bacterial/viral/toxic/genetic/injury as well as psychological. Of course, the CFS condition, once pecipitated as such, is itself a massive stressor. My intention was to reduce toxic stress with my four listed items as a minimum, ALA being the only thing I've read about that will remove mercury (the absolute worst!) from the brain. There are others, of course, coriander (cilantro in the US), chlorella etc. And selenium, as noted above, is an RT inhibitor. Glycyrrhizin being another. I have a fascinating Chinese study listing some dozens of phyto-RT inhibitors. It's all in medical jargon so most of it could just as well have been written in Chinese!

    Here's an interesting thing on mercury:

    http://www.youtube.com/watch?v=IHqVDMr9ivo

    ...there being no exit, they left by the same door as in they went.
  11. ukxmrv

    ukxmrv Senior Member

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    The problem Stressman, is that you are selecting all the "usual" CFS things that patients have been trying for decades. I was taking selenium in the 80's. Most of the other things at various times. They have been common because "someone" thinks that they are useful or there is a theory. Some patients gets a little symptomatic help. Few report cures or even substantial benefits.

    If you were in the right area, we wouldn't need this group.

    We desperately need something new to help all of us who have been sick for so long with no response. There's nothing you have mentioned so far that fits the bill. When I read this discussion my heart sinks.

    We have discusssed the "stressors" argument until we could simply not face it again. Until XMRV no new data has come our way for years.

    Here's to hoping that you will find something! Good luck. We need all the help we can get. Please look again if you can.
  12. Mark

    Mark Acting CEO

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    Hi stressman, welcome to Phoenix Rising!

    And thanks for a very interesting 'draft submission'.

    An excellent point IMO. Hard to fix anything whilst swimming against the tide - getting out of that current seems like a good plan. :)

    The difficulty there, though, is identifying what are the key elements of that 'toxic load' for a given individual. For some, no doubt, the key toxins are to be found amongst the usual suspects - mercury, various suspect synthetic chemicals, chlorine in the water, mold/fungus...but there are oh so many things in that list - and likely there's a personal individual pattern of which sensitivities are greatest, and which are most significant in an individual's current environment...and who is going to tell that individual which things to focus on first? Or help them with the sometimes extreme and expensive measures that may be required? Not the NHS, that's for sure.

    For me, I would have to add to that list of the "toxic load": tomatoes, soy, chicken, eggs, wheat/gluten, carrots, nuts...


    That's a nice little list (but shouldn't B12 be on it?) - I certainly had all of that, at the same time, for a year or so, during the year when I made such good progress, and I do put my own significant recovery down to that combination of pre-requisites (thanks to Dr Myhill).

    Having come out of the other side of all that, though, the extreme vulnerability to mold, to various classes of synthetic chemicals, and to all of those foods, which still give me IBS...all of that remains, still. I manage my life now, such as it is, by avoiding all of those things as far as I can - with the occasional treat (I had a lovely full cooked breakfast this morning, for which I'll almost certainly pay above and beyond the familiar mild stomach cramps an hour or so after eating).

    I'd like to hope that my gut flora could be re-stablised and those factors too could be resolved, but no luck so far...

    So I'm not sure that even all of the above, together, is still going to be enough to actually "cure" the underlying condition, and I see that in terms of a permanent immune dysfunction/vulnerability, probably explained by XMRV infection of the immune system itself. But still, that protocol delivers powerful benefit for very many people, so it seems to be one of the best clinical models, if not the best, that we have at the moment.

    Thanks for a thought-provoking thread, and do stick around to explore all this some more: it's always so encouraging to find real patient advocates like yourself: your daughter's very lucky to have support like that. :)
  13. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    Your right ukxmrv, the circle keeps going around with alot of the same ideas, but us, that been here for awhile and seen these ideas resurface again and again are here to steer them in the right direction, which i think u are. Its sounds like he has done alot of research and is somewhat excited about treatment and improvement, stressman we dont want u to build your hopes up too high on something alot of other cfsers have tried with small results. Put your time and effort into immune defiencies, xmrv and co-infections, use vitamins and minerals but they are there to help with keeping general health, treat gut problems for better nutrient absorption but its just a very small piece of the puzzle. Please dont take this as us being smart arses, but trying to help u move in the right direction.

    cheers!!! dude
  14. richvank

    richvank Senior Member

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    Hi, stressman.

    Welcome aboard! As someone who has an engineering and materials science background myself, I welcome your efforts to extend your thinking beyond the effects of stress on the deformation and failure of airframe materials to the effects of a broader spectrum of stresses on homo sapiens! :)-)

    You mentioned having encountered my work on ME/CFS and of being aware that efforts to restart the methylation cycle have not resulted in a universal cure.

    This is true. Quite a few PWME's/PWC's do report significant improvement from methylation-type treatments (of which there are several variants now in use by various practitioners who are treating autism, ME/CFS and Lyme disease, as well as some of the adult neurological diseases and hyperhomocysteinemia). In the clinical study conducted by Dr. Nathan and myself, about two-thirds of the patients reported significant benefit from the treatment. In the self-selected informal polls (on Phoenix Rising, CFSFMExperimental and CureTogether.com) it is running about half. (I suspect that some of the reports of worsening resulted from the detoxication symptoms that seem to be part and parcel of this type of treatment, because of the jump-start they give to the body's detoxication system.)

    I've heard of a small number of what appear to be complete recoveries (defined here as the ability to return to full-time work and to handle various types of stress without relapse). These appear to be people who also did some other treatments concurrently or beforehand, though, such as avoidance of and treatment for mold, treatment for Lyme disease, antiviral treatment, bowel treatments, and/or detox of heavy metals.

    My current view is still that the partial methylation cycle block is the fundamental abnormality in the pathophysiology of ME/CFS. However, it appears that after this partial block has formed, glutathione has become depleted, B12 function has been blocked, and folates have drained significantly from the cells into the blood, there are then a variety of other
    things that are allowed to happen. It is as though the body's enemies take advantage of the opportunity to attack when its defenses are down. The defenses of which I speak are the immune system, the detoxication system, and the antioxidant enzyme system. After these subsequent assaults, in the words of the King James version, "the last state of that man is worse than the first." This ends up causing significant additional misery for the PWME/PWC: In the words of a character in Bertolt Brecht's "Threepenny Opera," "OHH, the VARIETY of my CEASELESS TORMENT!!"

    I agree with your suggestion about the need to remove toxins. While I suspect that it is true that a buildup of toxins occurs prior to the onset of ME/CFS in some cases, I also suspect that a larger buildup occurs subsequent to the development of the partial methylation cycle block because of the resulting dysfunction of the detoxication system. Similarly, I think the resulting dysfunction of the immune system explains Prof. Garth Nicolson's observation that the longer PWME's/PWC's are ill, the more pathogens they accumulate.

    It is known, for example, that some of the enzymes in the methylation cycle, transsulfuration pathway and glutathione system are vulnerable to being blocked by mercury, if its levels become high enough. If this occurs, it would seem that it would likely not be possible to resurrect normal function of this part of the metabolism solely by helping methionine synthase, which is what the methylation treatments seek to do.

    In a similar way, some entrenched pathogens and biotoxins appear to have ways of holding down glutathione for their own protection, and it seems likely that they will need to be dealt with directly before methylation treatments can restore glutathione levels.

    And of course, now enters the (still disputed, but likely valid, in my opinion) discovery that retroviruses are associated with ME/CFS. If so, as Dr. Mikovits mentioned in her recent Santa Rosa talk, this is another factor that will somehow be associated with oxidative stress, glutathione depletion, and a methylation deficit, either as a cause or an effect, or maybe both.

    You may have encountered my papers at www.cfsresearch.org, a site which will be available only until January 31, when it is scheduled to be shut down. After that, the Phoenix Rising site will be the main repository for my papers, thanks to Cort: http://www.aboutmecfs.org/Trt/TrtGSHIntro.aspx

    In case you haven't seen some of my subsequent posts that deal with augmentation of the methylation treatments and other aspects of the biochemistry, I will post them below. I would welcome any comments you would like to share concerning these thoughts or anything else involved with the goings-on in ME/CFS.

    Best regards,

    Rich


    First post:

    I want to express some thoughts on the methylation treatment for what they are worth, and would welcome your opinions and experiences related to these comments.

    First, as many of you know, back in 1999 I first became aware of glutathione depletion in CFS from talks given by Dr. Cheney. I did quite a bit of studying to see what glutathione was all about, and I convinced myself that many or most of the aspects of CFS could be explained by glutathione depletion.

    Over the next five years or so, I encouraged people who had CFS to try to raise their glutathione levels in various ways. Many of them reported that this was beneficial to them, though if they stopped boosting glutathione, their situation relapsed to what it was before. So it was only a temporary fix. And there were others who were made worse temporarily by boosting glutathione, and could not tolerate it.

    I became convinced by the fall of 2004 that there must be a vicious circle mechanism that was holding down glutathione, but I didn't know what it was.

    Then in December of 2004, S. Jill James et al. published an autism research paper in which they found that glutathione was also depleted in autism, and that this depletion was linked to a dysfunction in the methylation cycle, which is located upstream in the sulfur metabolism from glutathione synthesis. In addition, they found that treating to lift the methylation cycle partial block also caused glutathione to come up automatically.

    I realized at that point that the same thing must be going on in CFS.
    So I began encouraging people with CFS to do treatments to lift a partial methylation cycle block. Over the course of the next few years, we accumulated evidence that this mechanism is in fact present in most people with CFS, and that these types of treatments were significantly helpful to about two thirds of the PWCs who tried them.
    A small number of people have reported to be essentially completely recovered as a result of this treatment. However, most have experienced significant benefit, but are not completely recovered, and some have been doing these types of treatments for over three years now.

    About a third of the people have reported either that they could not tolerate the treatments, or that they have not experienced any benefit from them.

    Among those who have not been able to tolerate the treatments, it appears that excitotoxicity has been one of the main problems. This leads to insomnia, anxiety, hypersensitivity of the senses, and a constantly "wired" feeling.

    In recent months I have been trying to understand how to improve this situation, and I want to share some more thoughts on that.

    First, for the people who can tolerate the treatments but do not experience benefits from them, I suspect that the likely causes are that the methylation cycle and related pathways do not have all the nutrients they need to come back up to normal operation. These include amino acids (especially methionine, serine, glycine, glutamine, and cysteine), vitamins (especially the other B vitamins and vitamin C), and certain minerals (especially zinc, copper, magnesium, manganese, selenium and molybdenum). These deficiencies could be at least partly caused by dysfunction of the digestive system, and I think that there is a lot of potential in working to fix the gut problems. I think the biofilm treatments and Dr. de Meirleir's most recent gut work are things we should pay attention to here. I think the KPU or HPU that Dr. Klinghardt has emphasized comes in here, too, in some cases, depleting zinc, B6 and other nutrients.

    For people who experience severe excitotoxicity and thus cannot tolerate the treatments, I suspect that this is caused by a temporary further depletion of glutathione as more of the homocysteine is converted back to methionine, and less is available for making cysteine and glutathione.

    I recently read Dr. Amy Yasko's article on excitotoxicity in the publications section of her website. She has some interesting ideas there, and I think that her discussion of the metabolism of glutamate in the brain shows where the main cause of excitotoxicity on this type of treatment lies. Normally, glutamate is secreted by neurons into their synapse with other neurons, serving as an excitatory neurotransmitter. The astrocytes are then supposed to import the glutamate, convert it to glutamine, and send it back to the neurons to be converted to glutamate and to be used again as a neurotransmitter. But this importation and conversion requires energy in the form of ATP, and I think that's where the problem arises. If glutathione becomes more depleted, the mitochondria of the astrocytes will be less able to produce ATP at normal rates, because of the oxidative stress that will arise, partially blocking the Krebs cycle and the respiratory chain. So I think there is a good basis for suspecting that the temporary glutathione depletion that occurs when this treatment is used is what is responsible for the rise in excitotoxicity.

    If this is true, then it would seem that boosting glutathione while doing the methylation cycle treatments would help this situation. There are lots of ways to try to do this. I know that some people have been nebulizing glutathione, and some have been using liposomal forms of glutathione. There are other ways as well. For people who can tolerate glutathione boosting, this may help to calm the excitotoxicity when doing methylation cycle treatments.

    For people who have experienced some benefits, but have then plateaued and have not had much improvement for a long time, I suspect that the problem is that there are factors that are preventing glutathione from coming up, or are preventing the methylation cycle from coming up, or both. So far, the people in this situation who have repeated the methylation pathways panel offered by Health Diagnostics and Research Institute (formerly Vitamin Diagnostics) have reported that their results on this panel have still not normalized. That's why I suspect that something is preventing recovery of this part of the metabolism in these people.

    So what is it? I think the major suspects are things known to deplete glutathione. These include mold toxins, Borrelia bacteria (Lyme disease), and heavy metals, such as mercury. We don't know yet about how important XMRV is in CFS, but this may also be a possibility.

    If these factors are indeed holding down glutathione, then I suspect that they will need to be dealt with directly before the methylation cycle treatments will be successful in restoring the methylation cycle and the folate and glutathione levels.

    I have just heard from Lisa (slayadragon) that when she and another person have dealt with other issues, including mold toxins, they have then found that the methylation treatments have been much more effective in helping them to detox. Again, I think this suggests that other impediments to raising glutathione may need to be dealt with first.

    Along this same line, the women who were treated in the study that Dr. Neil Nathan and I carried out had already been treated for a variety of other issues before starting the methylation treatments. These issues included mold illness, Lyme disease, and heavy metal toxicity.

    In addition, the people who have reported essentially complete recovery from these treatments have also reported that they did a number of other treatments beforehand, some of them being antiviral treatments.

    So I think there are bits and pieces of evidence that support this line of thinking.

    One other thing that occurs to me is that this may be a major difference between CFS in adults and autism in children. The children with autism are of course much younger, in general. This being the case, they have had much less time to accumulate toxins and infections than have the adults. They also don't have amalgam fillings in their baby teeth. The really young ones have probably not had as much possible exposure to tick bites as the adults. The point is that the adults (especially those who have been ill with CFS for many years) may have many more impediments to the success of these treatments than the young children with autism, and they may need more additional treatments to address them specifically.

    I would be interested in your thoughts about these things. Does this seem to make sense in the light of your experiences?



    Second post:

    1. I think it is well established now that many and probably most
    cases of both autism and CFS have a partial methylation cycle block at
    the root of their biochemical abnormalities.

    I realize that many and perhaps most of the people in the research and
    clinical communities involved in these two disorders are not (yet!) on
    board with this concept, but I believe that careful study of the
    available research results and attention to the results of treatment
    based on this concept do bear it out.

    2. While a knowledge of the normal biochemistry of the methylation
    cycle and related pathways points in a general way toward the types of
    treatment that are likely to be effective, it does not uniquely
    identify the optimum treatment for either autism or CFS.

    For one thing, we humans all differ in terms of our particular sets of
    genomic polymorphisms, so that the same treatment is likely not
    optimum for all people who have autism or CFS.

    For another thing, a person who has one of these disorders does not
    have normally functioning physiology and biochemistry. The best path
    back to normal will probably have to be determined experimentally by
    each person, because normal biochemistry is not enough to tell us the
    best path back to normal. Because of this, I don't think that anyone
    can claim that a particular protocol is the "best" for use by everyone
    who has autism or CFS.

    3. What we can say on the basis of biochemical testing is that in
    autism and CFS there is a partial block of the enzyme methionine
    synthase, which is found in every cell of the body.

    We also know that this enzyme requires the reactants homocysteine and
    5-methyl tetrahydrofolate, that it requires methylcobalamin (a
    biochemically active form of vitamin B12) as a coenzyme, and that the
    reaction it catalyzes produces methionine and tetrahydrofolate.

    We also know that in the liver and kidneys there is an alternate
    pathway that converts homocysteine to methionine, which is called the
    BHMT (betaine homocysteine methyltransferase) pathway.

    Both these reactions produce methionine, and another reaction in the
    methylation cycle converts methionine to S-adenosylmethionine, which
    is the main source of methyl groups for methylation reactions in the
    body, of which there is a large number.

    While the BHMT reaction does convert homocysteine to methionine, it
    does not involve the folate metabolism, and thus does not convert 5-
    methyl tetrahydrofolate to tetrahydrofolate, as the methionine
    synthase reaction does.

    Since the folate metabolism is important for other aspects of the
    overall biochemistry (including the synthesis of DNA and RNA to make
    new cells), and since the methionine synthase pathway is the only
    pathway that closes the methylation cycle in organs, tissues and cells
    beside the liver and kidneys, it is not sufficient to support only the
    BHMT pathway.

    4. Based on this, the main goal of treatment of autism and CFS must be
    to restore methionine synthase to normal operation. Since there is
    usually not a shortage of homocysteine, the substances that need to be
    raised in their levels in the body to stimulate the activity of
    methionine synthase are 5-methyl tetrahydrofolate and methylcobalamin.

    5. In addition to stimulating methionine synthase, there are other
    things that are needed by the methylation cycle and associated
    biochemical pathways for their operation.

    Other cofactors that are needed are other B vitamins (which are
    included in B-complex vitamin supplements) and some minerals
    (including zinc, magnesium, manganese, copper and selenium). In
    addition, certain amino acids are needed to feed this part of the
    biochemistry. These include methionine, serine, cysteine, glutamine
    and glycine.

    Whether or not these additional substances will need to be
    supplemented in treating a particular person will depend on the
    nutritional status of that person.

    6. Some of the toxic heavy metals, including mercury, are capable of
    blocking the activity of various enzymes in this part of the
    biochemistry. If the levels of these toxic metals are too high, they
    may prevent operation of the methylation cycle or associated
    biochemical pathways unless treatment is specifically used to lower
    their levels. Whether this is necessary for a particular person will
    depend on that person's body burdens of toxic metals.

    7. Getting back to the substances the levels of which need to raised
    to stimulate the activity of methionine synthase, there are various
    ways in which the levels of 5-methyl tetrahydrofolate and
    methylcobalamin can be raised. Possibilities to consider start from
    supplying the most common commercial supplemental forms of folate and
    B12, which are folic acid and cyanocobalamin. These are the least
    expensive and have the longest shelf lives.

    8. Folic acid is not a natural form of folate, and must be chemically
    reduced in the body before it can be used. People vary by a factor of
    five in their ability to do this, so that some people cannot utilize
    folic acid very well as a source of usable folate.

    One solution is to raise the dosage, so that more of the folic acid
    will be reacted by the DHFR enzyme to produce tetrahydrofolate, which
    can be converted by the cells to other forms of folate, including 5-
    methyl tetrahydrofolate.

    However, four sequential biochemical reactions are needed to convert
    folic acid to 5-methyl tetrahydrofolate, including two DHFR reactions,
    the SHMT reaction, and the MTHFR reaction. If a person has genomic
    polymorphisms in any of these enzymes that slow their respective
    reactions, this will interfere with the formation of 5-methyl THF from
    folic acid.

    If the folic acid dosage is increased in order to raise the amount of
    5-methyl THF that is produced in the bodies of these people, the level
    of unreacted folic acid in their blood streams will rise. There have
    been some suggestions that this can increase the risk of cancer, but
    this is not well established at this time.

    I do not advocate using folic acid as the main source of folate in
    treatment to lift the methylation cycle block because it is an
    unnatural form of folate, because many people cannot use it readily
    because of their genomics, and because there is at least some evidence
    suggesting that high dosages of it can raise the risk of cancer. Also,
    I have seen in test results that many people with CFS have "normal"
    levels of folic acid in their blood, while their levels of 5-methyl
    THF are low.

    Nevertheless, high enough dosages of folic acid will likely work as
    the source of folate for many people who have partial blocks of
    methionine synthase, and I realize that this form of folate has been
    advocated and used with some success by Dr. Vinitsky. I think that the
    reason he uses such large dosages is that they are needed to overcome
    the problems I have discussed. I view this as a rather inefficient
    approach to raising 5-methyl THF, though if and when it works, I can't
    argue with success.

    9. If folinic acid is used, this will bypass the need for the DHFR
    reaction, which is slow in many people. Folinic acid is a natural form
    of folate, found in natural foods. It can be converted by the cells to
    the various coenzyme forms of folate, including 5-methyl THF.

    Three sequential reactions are needed to convert folinic acid to 5-
    methyl THF, including the MTHFR reaction. If genomic polymorphisms are
    present that will slow these reactions, the conversion to 5-methyl THF
    will be hindered. This can be compensated to some degree by raising
    the dosage of folinic acid. In spite of some claims, formaldehyde is
    not involved in the folinic acid reactions. Dr. Jon Pangborn has been
    a proponent of using folinic acid in the treatment of autism, and it
    is used to a considerable extent by the DAN! (Defeat Autism Now!)
    doctors. Dr. Amy Yasko has included folinic acid in her treatment as
    well.

    I think that one advantage of including folinic acid in the treatment
    of CFS is that it can be used by the cells to supply other forms of
    folate, especially initially, before the methionine synthase reaction
    is producing enough tetrahydrofolate to supply these needs. Thus, this
    should be able to help support the synthesis of DNA and RNA for making
    new cells, such as in the gut and the bone marrow, before the
    methylation cycle block has been fully lifted.

    10. The most direct approach to raising the level of 5-methyl THF is
    to take it directly. The correct chiral form for use by the body is
    sold as Metafolin or FolaPro or Deplin and comes from a manufacturing
    process that has been patented by Merck-Germany.

    There are other 5-methyl THF products that are made in different ways,
    and some of them may be racemic mixtures, which include forms that are
    not usable by the body, but I don't know about this in detail.
    Metafolin is the Merck trademark, which has been licensed to some
    suppliers. FolaPro is a Metagenics trademark, but the form of folate
    in it is the same as in Metafolin.
    Deplin is a "medical food" produced by PamLab under license from Merck-
    Germany. It has gone through FDA-approved testing as a treatment for
    depression. The dosage in Deplin is 7.5 milligrams (7,500 micrograms),
    which is much larger than the dosages in which Metafolin and FolaPro
    are sold (800 micrograms). Note also that I (following the lead of Dr.
    Yasko) have recommended a dosage that is one-quarter of that, or 200
    micrograms, in addition to a smaller amount of 5-methyl THF in the
    Actifolate combined-folate supplement. So the dosage in Deplin is
    quite large compared to what I have suggested for use in treating CFS.

    Dr. Amy Yasko has been a proponent of using 5-methyl THF in the
    treatment of autism and other neurological disorders, and I have
    adopted it in the Simplified Treatment Approach for treating CFS,
    also.

    Dr. Jon Pangborn has argued against its use on the grounds that it is
    a "dead-end" form of folate that can be used only by the methionine
    synthase reaction. However, this is the reaction that needs to be
    stimulated in autism and CFS.

    In addition, it has been reported by Antoniades et al. that 5-methyl
    THF also reacts with peroxynitrite, which may be an additional
    advantage in CFS, and Prof. Martin Pall argues that this is the main
    role of 5-methyl THF in the treatment of CFS and related disorders, on
    the basis of his NO-ONOO theory.

    In my view, Dr. Yasko has the right approach, in using both folinic
    acid and 5-methyl THF. She also uses some folic acid, and I included
    that when I adopted the combined supplements she was using, though I
    don't think it is a necessary part of the treatment, and may be better
    omitted.

    11. There is also the question of which route should be used to
    supplement folate. Most people seem to be able to absorb folate if it
    is taken orally, and that is what I have recommended, but sublingual
    and injection routes may be necessary for some, if their digestive
    problems are severe.

    12. Moving on to the possible supplemental forms of vitamin B12 that
    can be used, they are cyanocobalamin, hydroxocobalamin (which is in
    equilibrium with aquocobalamin in the body)adenosylcobalamin (also
    known as dibencozide) and methylcobalamin.

    13. Cyanocobalamin is the least expensive and has the longest shelf
    life. However, in the cell, thecyanide group must be removed from the
    molecule before it can be converted to methylcobalamin, and this
    cyanide must be disposed of so that it does not rise to toxic levels,
    which can be life-threatening.

    The body has four ways of detoxing cyanide, and for low dosages (in
    the micrograms per day range), these usually do the job, except
    perhaps in people who have the rare Leber's hereditary optic
    neuropathy.

    However, in the larger dosages used for treating autism and CFS
    (several milligrams per day), detoxing the cyanide can be a concern,
    and I know of one case of CFS in which use of large dosages of
    cyanocobalamin led to cyanide toxicity.

    So I don't recommend using cyanocobalamin in milligram-level dosages
    by itself. If there is enough hydroxocobalamin used with it, that can
    help to protect against cyanide toxicity, but I still think it is
    better not to take large dosages of cyanocobalamin.

    14. Hydroxocobalamin must be converted by the cells into
    methylcobalamin before it can be used by methionine synthase.

    Unless a person has an inborn error of metabolism that involves the
    intracellular cobalamin processing enzymes, which is rare, their cells
    should be able to do this conversion, and this has the advantage that
    the cells can control how much methylcobalamin they make and retain so
    that they do not overdrive the methylation cycle.

    The cells can normally also convert this form to adenosylcobalamin,
    the other coenzyme form of B12 that they use (in the mitochondria).

    Hydroxocobalamin is the form of B12 that I favor for treating CFS. Dr.
    Amy Yasko also uses this form for treating some cases of autism,
    depending on the person's particular COMT and VDR polymorphisms.

    "Freddd," who posts to the aboutMECFS forum and the wrongdiagnosis
    forum, does not advocate use of hydroxocobalamin on the grounds that
    it is an "inactive" form of B12. It's true that it is not one of the
    coenzyme forms of B12, and must be converted to become one of these
    forms, but in all but a very few people, it is "active," in sense that
    the cells are equipped to use it effectively. Freddd himself has
    reported that he has a genetic mutation in his intracellular cobalamin
    processing enzymes.

    15. Methylcobalamin can be supplemented directly. At relatively low
    dosages, the cells will initially remove the methyl group from the
    molecule, and then will reform methylcobalamin and adenosylcobalamin
    as needed.

    At very high dosages (several milligrams per day) taken either
    sublingually or by injection, some methylcobalamin is apparently able
    to diffuse into cells and bypass the normal cobalamin processing
    enzymes, to supply itself to the methionine synthase enzyme directly.

    This is the approach advocated by freddd, and it seems to be helping
    some people with CFS. However, I have three concerns about this
    approach.

    One is that methylcobalamin is chemically able to react with inorganic
    mercury to produce methylmercury, which can readily enter the brain,
    where mercury acts as a potent neurotoxin. Many PWCs have high body
    burdens of inorganic mercury as a result of inhaling mercury vapor
    from amalgam fillings over extended periods in which their glutathione
    was depleted, so that they could not detox it well.

    I don't have proof that methylation of mercury occurs in CFS patients,
    though two or three anecdotal reports have suggested that it might,
    and guinea pig experiments have found that this can occur in them.

    Second, many PWCs have fairly high body burdens of a variety of
    toxins, and high dosages may cause rapid mobilization of these toxins,
    producing symptoms that are intolerable.

    Third, I have seen a couple of cases in which such high dosages of
    methylcobalamin, together with high dosages of 5-methyl THF, have
    apparently overdriven the methylation cycle, which I believe will
    prevent glutathione from coming up to normal as soon as it otherwise
    would.

    So while I think that methylcobalamin can be helpful, particularly in
    cases in which the person is low in methyl groups, I recommend caution
    with using multi-milligram dosages of methylcobalamin by sublingual or
    injection routes.

    Dr. James Neubrander has advocated use of subcutaneously injected
    methylcobalamin at a dosage of about 60 micrograms per kilogram of
    body weight every three days for the treatment of autism, and it is
    widely used by the DAN! doctors. Subcutaneous injection gives a slower
    release to the blood stream.

    16. Adenosylcobalamin (dibencozide) can also be used. This is the
    other coenzyme form of B12 used by the cells. In small dosages taken
    orally, this passes to the cells and the adenosyl group is first
    removed, and then both methyl- and adenosylcobalamin are made as
    needed by the cells.

    If taken in larger dosages (several milligrams per day) by the
    sublingual or injection routes, some adenosylcobalamin is apparently
    able to diffuse into the cells and be used directly.

    Dr. Amy Yasko recommends use of this form in addition to others by
    some people with autism and other disorders.

    Freddd advocates use of large dosages of this form sublingually.

    I haven't recommended use of this form, but it may be helpful in CFS.

    17. The question of what dosages of folate and B12 forms should be
    used to treat CFS is one that is not easy to resolve, and I think it
    varies with the individual PWCs.

    I have suggested some dosages based on Dr. Yasko's use in autism. Some
    people have found them to be too high, at least initially, and have
    had to start with lower dosages in order to be able to tolerate what
    appear to be detox and/or die-off related symptoms. Others have found
    that they need larger dosages.

    Freddd has advocated continuing with larger dosages and "pushing
    through" what he calls the "start-up" symptoms. I have advocated what
    I think is the cautious approach of backing off on the dosages until
    the symptoms are tolerable, and working up from there, as tolerated.
    Freddd's view is that that only delays the recovery.
    I don't have proof of which of these approaches is the best.

    18. I want to acknowledge Trina's help in choosing the initial
    supplements for the Simplified Treatment Approach back in January,
    2007.

    19. I think there is still a lot more to be learned about how best to
    treat CFS. Basic treatment directed at lifting the methylation cycle
    block clearly seems to me to be an important aspect, but it does not
    appear to do the whole job for many PWCs. For those who receive
    limited help or no help at all from this treatment, I suggest
    considering the issues discussed in sections 5 and 6 above. If this
    still doesn't bring recovery, then I would suggest considering direct
    efforts to treat problems of the digestive system as well as exploring
    whether there are comorbid conditions, such as tick-borne diseases or
    mold illness, if this has not already been done.
    As always, I recommend working closely with a physician when doing
    treatment to lift a partial methylation cycle block.


    Third post:

    In my opinion, the gut and the brain are the two organs whose dysfunctions are the most complex in CFS, because so many things are going on that impact these organs. In both cases, I think that the vicious circle involving partial methylation cycle block, draining of folates from cells, and glutathione depletion is at the basis of the problems. Here are the factors I've identified that may be affecting the digestive system in CFS:

    1. Low stomach acid production. I think this could be caused either by deficiency in certain nutrients that are needed by the parietal cells in the stomach (such as zinc) or by mitochondrial dysfunction in these cells as a result of glutathione depletion, or both.

    2. Low production of digestive enzymes by the pancreas. The pancreas has been shown to be particularly sensitive to methylation deficits. Also, the pancreas requires a signal in the form of secretin, which does not get sent well if the food coming into the duodenum lacks enough acid.

    3. Low production of bile and bile acids. A major part of the volume of the bile depends on glutathione in the liver. A major part of the bile acids contain taurine, which can be depleted in some cases in which there is a methylation cycle block, which impacts the entire sulfur metabolism. Also, the excretion of bile by the gall bladder requires a signal from cholecystokinin, and this is also not sent well if there is a lack of acid in the food mixture coming into the duodenum from the stomach.

    4. Slow emptying of the stomach. This has been found in an Australian CFS study. I suggest that it is due to the above factors. Normally, the stomach emptying is controlled by the rate at which the food can be processed in the gut. If digestion is not going well, the food will be held up in the stomach.

    5. Low production of acetylcholine. Acetylcholine is the neurotransmitter of the parasympathetic nervous system, which promotes gut motility. Choline is necessary for making this neurotransmitter. Some normally comes in from the diet, and some is made in the body by the conversion of phosphatidylethanolamine to phosphatidylcholine. This is one of the two main users of methylation in the body, so it is impacted by the partial methylation cycle block.

    In my opinion there has been a misinterpretation of past research in CFS involving choline. It has been mistakenly thought that choline is elevated in CFS, rather than being deficient, because of misinterpretation of the results of magnetic resonance spectroscopy studies of the brain in CFS.

    All but one of these studies evaluated the ratio of choline to creatine, and found it to be higher than normal. The error was to assume that creatine remains the same in CFS patients as in healthy normals, and thus to infer that choline must be higher than normal.

    However, creatine also requires methylation for its synthesis in the body (and may be the main user of methylation), so a methylation cycle block should be expected to lower its production as well. If creatine is lowered more than choline is lowered in CFS, the choline to creatine ratio would be higher than normal, but both choline and creatine would be lower than normal.

    In one study, the ratio of choline to water in a part of the brain was evaluated, and was found to be higher than normal. However, CFS patients generally suffer from diabetes insipidus (not to be confused with diabetes mellitus) and thus their bodies lose water excessively to the urine. If the drop in water in the brain exceeds the drop in choline, the ratio of choline to water will be higher than normal, but both water and choline will be lower than normal.

    The only study that attempted absolute measurements of choline and creatine found both of them to be lower in CFS than normal, but with the methods used, the result was not found to be statistically significant. I'm hopeful that future studies in this area will be able to measure the absolute levels of these metabolites more precisely.

    Vance Spence's group at the University of Dundee in Scotland published four papers involving acetylcholine response in CFS. They found that CFS patients had a much stronger response when acetylcholine was given through the skin than did normals. I believe this was caused by acetylcholine depletion in the CFS patients, which would have caused their population of acetylcholine receptors to rise in compensation, so that when the acetylcholine was given, they would have had a greater response to it. The authors did not consider that acetylcholine might be low in these patients, because they accepted the published conclusions from the MRS studies, which I believe were based on a misinterpretation.

    There is also a Japanese paper in which it was reported that three patients were given a drug (pyridostigmine) which inhibits cholinesterase, the enzyme that normally breaks down acetylcholine. This would have had the effect of raising the level of acetylcholine. These patients were reported to have benefited from this treatment, and this has been a puzzle, because it was believed (incorrectly in my opinion) that acetylcholine is not low in CFS.

    6. Abnormality in serotonin production. Serotonin also influences gut motility, and production and metabolism of serotonin is also impacted by methylation. Some studies have suggested that serotonergic effects are higher than normal in CFS.

    7. Difficulty in making new enterocytes. The enterocytes that line the gut are normally replaced rapidly, compared to most other types of cells in the body. This requires DNA and RNA, and synthesis of these requires help from the folate metabolism, which is dysfunctional in CFS because of the partial methylation cycle block.

    8. Inability to take out toxins from the gut at normal rates. Glutathione is important in detoxing the gut, and it is depleted.

    9. Intestinal yeast infections and bacterial dysbiosis are very common in CFS. I suggest that they result from a combination of lack of stomach acid to kill the pathogens that come in with food, poor digestion of food because of low stomach acid, low bile and low digestive enzymes, which leaves food for the unhelpful bacteria, and poor gut motility (especially lack of cleansing peristaltic waves) because of the neurotransmitter problems discussed above, which leaves food in the small bowel, and leads to SIBO (small intestinal bacterial overgrowth).

    10. Lowered level of secretory IgA. This results from dysfunction of the HPA axis, which I believe results in turn from glutathione depletion in the hypothalamus/pituitary.

    11. The combination of the presence of the dysbiotic bacteria and the lack of enough secretory IgA and glutathione makes the gut vulnerable to developing permeability (leaky gut). This allows large molecules to enter the blood from the gut, and the immune system responds, producing food sensitivities.

    12. In some cases, celiac disease or non-celiac gluten sensitivity develops, affected by genetics.

    13. The dysbiotic bacteria form biofilms that protect them.

    14. Dr. de Meirleir and colleagues have found that dysbiotic bacteria produce hydrogen sulfide and D-lactate, which enter the systemic circulation and cause deleterious biochemical effects. His view is that the develoment of the gut-related problems are the fundamental cause of ME/CFS, rather than effects of the partial methylation cycle block. He has noted that "friendly" bacteria normally produce some of the nutrients needed by the methylation cycle, such as folate and B12. The interrelationship of the gut problems and the partial methylation cycle block is in my opinion a Gordian knot that we have not yet completely unraveled. I note that Dr. Amy Yasko emphasizes treatment of the gut issues as one of the early parts of her overall methylation-based treatment of autism. Perhaps a combination approach is also needed in ME/CFS.

    There are probably more factors that I haven't discussed here, and there are also many consequences of the gut problems that I haven't discussed, but in view of the above, it is not surprising that there are digestive system problems in CFS. I think that the root cause of these problems is the partial methylation cycle block, and that treatment must be given to lift this block, while at the same time direct efforts to correct the downstream problems in the gut must also be made.


    Fourth post:

    To the best of my current understanding, all the cobalamin forms except glutathionylcobalamin can be hijacked by toxins. There are still some parts of B12 metabolism that have not been sorted out completely by the researchers in this field, but here's a synopsis of what is believed to be known at this point:

    When various forms of B12 are taken orally via food or ordinary oral supplements (not sublingually, transdermally, liposomally or by injection) in a normally operating digestive system, all the forms of B12 are separated from protein by acid in the stomach, and are bound to haptocorrin. In the early part of the small intestine, the haptocorrin is broken down, and the B12 forms are bound to intrinsic factor, which is produced by the parietal cells of the stomach. In the last part of the small intestine (the terminal ileum) there are receptors for intrinsic factor, and it is drawn into the cells lining the intestine (enterocytes), together with the forms of B12 that are bound to it. The enterocytes transfer the B12 forms to transcobalamin, which is carried in the blood to the various cells of the body. The cells have receptors for transcobalamin, and they draw it into lysosomes inside the cells. In the lysosomes, the transcobalamin is broken down, and the forms of B12 are freed. They are passed from the lysosomes into the cytosol, and their beta ligands are removed. These include hydroxo-, methyl-. and adenosyl-. At this point the B12 is just cobalamin. The cobalamin is then passed either to methionine synthase in the cytosol or into the mitochondria. The fraction that is passed to methionine synthase is methylated by SAMe to become methylcobalamin and it supports the methylation cycle. The fraction that passes into the mitochondria is converted to adenosylcobalamin, and it supports methylmalonyl-CoA mutase.

    It has been proposed that during its metabolism in the cytosol of the cells, B12 is normally chaperoned by proteins over its entire pathway to formation of the B12 coenzyme forms. There is evidence that glutathione is involved in this chaperoning process, by formation of glutathionylcobalamin, which protects cobalamin from reacting with toxins during its transition from the initial form that was absorbed to its final coenzyme form, either methylcobalamin or adenosylcobalamin. But the details of this process are still not totally elucidated. I have hypothesized that this need for chaperoning is the reason why depletion of glutathione leads to loss of B12 function, and thus a partial block of the methylation cycle as well as a partial block of the methylmalonate reaction, which causes methylmalonate to rise in the urine organic acid tests.

    Note that all forms of B12 that are taken by the ordinary oral route are normally treated the same way. Their individual ligands are removed, and then the two coenzyme forms of B12 are produced as needed by the cells. Because of this, the intake form of B12 are all vulnerable to hijacking, if there is not enough glutathione to protect the intermediate cobalamin.

    Now, what about taking high dosages of forms of B12 by the artificial routes (sublingual, transdermal, liposomal, or injection)? If the dosages are high compared to usual RDA-type B12 dosages, which are in the few micrograms range, that is, if they are up to several milligrams, 1000 times higher than RDA-type levels, then the capacity of transcobalamin to bind the B12 in the blood will be overwhelmed. The transcobalamin will be saturated, and it will carry its bound B12 to the cells in the normal way. The B12 in excess of this will be carried in the blood in an unbound state. As far as I know, the behavior of this unbound B12 has not been researched, but based on the experiences of many people, it appears that some of it is able to diffuse across cell membranes and enter cells without benefit of the transcobalamin receptors. Whatever does not enter the cells in this way is extracted from the blood by the kidneys and passes into the urine.

    Again, the behavior of unbound B12 forms after they diffuse into the cytosol of the cells has not been researched. However, based on experiences reported, at least some of both methylcobalamin and adenosylcobalamin appear to be able to perform their normal coenzyme functions after entering the cells in this manner. If the dosages are high enough, they can apparently overwhelm the hijacking by toxins sufficiently so that some survives to perform their normal functions. In the case of hydroxocobalamin given by these artificial routes, some apparently enters the cells, and it must be converted to methylcobalamin and adenosylcobalamin inside the cells, even though it did not come in via the transcobalamin mechanism, because the experimental evidence is that it does support the normal coenzyme functions of B12.

    If a person has normal cobalamin processing enzymes in their cells, it seems to me that after sufficient detoxication has taken place and glutathione levels have been restored, the hijacking of B12 by toxins will decrease, and the amount of B12 supplementation needed should also decrease. It may take considerable time to get the toxin load down, though, especially if the person has been ill for a long time, and the toxins have built up considerably while the detox system was dysfunctional.

    On the other hand, there are people who have genetic mutations in one or more of the intracellular B12 processing enzymes. These are called inborn errors of metabolism. In these cases, the cells may not be able to utilize B12 and make its own coenzyme forms in the normal way. If this is the situation, then the person may have to continue to take high-dosage B12, either methylcobalamin or adenosylcobalamin or both, depending on the mutations present. freddd has reported that this is his situation. Based on his experience that taking glutathione or its precursors caused a major setback in his B12 function, it would seem that his inborn error of metabolism must involve a step downstream of the formation of glutathionylcobalamin. Apparently, once glutathione combines with cobalamin, his cells are not able to use it to make the coenzyme forms. I don't think this is the situation with most people who have ME/CFS. Therefore, I think that with time, most will be able to drop back on their B12 dosages. There are a small number who have reported what appears to be complete recovery, and as far as I know, they haven't continued taking high dosages of B12, but I don't really have much data on this. I would very much appreciate hearing from people about their experiences with this.

    I should also note that there are people who have various other problems in B12 handling. Some have low stomach acid, so that they are not able to liberate B12 from protein in the stomach. Some have pernicious anemia, so that they don't have enough intrinsic factor, and thus can't absorb B12 from the gut. Some have had an intestinal disease such as Crohn's or celiac, or they have had part of their intestine removed surgically, so they also cannot absorb B12 well from the gut. Some have a transcobalamin deficiency, so that they can't bind B12 and transport it properly in the blood. Some may lack transcobalamin receptors on their cells, and so on.

    Just for completeness, let me note that the cells apparently export extra B12 that they don't need back to the blood, bound to haptocorrin. This actually constitutes most of the B12 that is normally found in the blood at any time. This B12 is eventually imported by the liver. Some is stored in the liver, and some is excreted in the bile, passing back to the intestine, where is again available to be bound to intrinsic factor and reabsorbed. This part of the B12 metabolism has not been completely researched, but apparently it is a salvage pathway that avoids wasting B12 and provides it at times when not much is coming in from the diet.
  15. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    wow! rich, thats close to one of your longest posts ever. Can u really dumb it down and just say what to take in your supplement protocol without explaining everything eg methyl b12 and folinic acid and dosages, just pure nuts and bolts like a shopping list. Then i will go back through and reread your post. Im the kind of guy who reads the a book from back to front, picks out bit and pieces of interest and then reads it from front to back, and do this several times to cement it all.

    I appreciate all the work u have done, but u need a few different levels of explanation as the depth of the subject gets beyond my brain power and im sure others as well.

    cheers!!!
  16. LaurieL

    LaurieL Senior Member

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    OMG, Thank you!!!

    Rich,

    Absolutely two :thumbsup: :thumbsup: !!!

    On the other side of the coin, I am not as brain fogged as some are, and I have been busting my hump trying to come up with some detail. Chasing so many links, and trying to fit it together. I am one of those that want more than the nuts and bolts, so thank you very much. Knowledge is power, and I want to get to a resolution. All the detail you wanna throw this way, feel free. :D

    Laurie
  17. richvank

    richvank Senior Member

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    Hi, heapsreal.

    O.K., the protocol for the simplified treatment approach is pasted below.

    Best regards,

    Rich



    April 18, 2009


    SIMPLIFIED TREATMENT APPROACH
    FOR LIFTING THE METHYLATION CYCLE BLOCK
    IN CHRONIC FATIGUE SYNDROME (Revised)

    (Extracted from the full treatment program
    developed by Amy Yasko, Ph.D., N.D.
    which is used primarily in treating autism [1])

    SUPPLEMENTS

    1. FolaPro [2]: tablet (200mcg) daily
    2. Actifolate [3]: tablet daily
    3. General Vitamin Neurological Health Formula [4]: start with tablet and work up dosage as tolerated to 2 tablets daily
    4. Phosphatidyl Serine Complex [5]: 1 softgel capsule daily
    5. Activated B12 Guard [6]: 1 sublingual lozenge daily

    All these supplements can be obtained from http://www.holisticheal.com, or all but the third one can be obtained from other sources.
    The first two supplement tablets are difficult to break into quarters. We recommend that you obtain (from any pharmacy) a good-quality pill splitter to assist with this process. They can, alternatively, be crushed into powders, which are then separated on a flat surface using a knife or single-edged razor blade, and the powders can be mixed together. They 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. They can be taken at any time of day, with or without food.
    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, and Gordon, Garry, The Puzzle of Autism, Matrix Development Publishing, Payson, AZ, 2006, p. 49.
    [2] FolaPro is a registered trademark of Metagenics, Inc.
    [3] Actifolate is a registered trademark of Metagenics, Inc.
    [4] General Vitamin Neurological Health Formula is formulated and supplied by Holistic Health Consultants LLC.
    [5] Phosphatidyl Serine Complex is a product of Vitamin Discount Center.
    [6] Activated B12 Guard is a registered trademark of Perque LLC.
  18. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    Thanks rich,
    Now the actifolate has 3 different folates in it and one of them is the same as folapro, are both taken to get a higher dose of L-5-methyl tetra.
    These are used as they are better absorbed then normal folic acid supplements and to get the same blood levels much higher doses of folic acid are needed??

    Pho serine, are the other ingredients in the product neccessary, NOW brand just sells a better priced PS supplement but doesnt contain the other ingredients.

    If using hydroxy b12 injections what dosages are recommended. I understand cynocobalamin is not recommended, so other sublingual b12 equivilent doses??, methyl b12, dibencozide?

    The multi looks like a good product.

    Now would your protocol clash with any of my current supps, vit e 1000mg twice a day, NAC 600mg twice a day, lipoic acid 250mg(understand mercury thing), 5htp 200mg and non flush niacin 1000mg twice a day, pregnenolone 50mg T/D, melatonin,

    The only thing i havent used is the folates, i have had some help with hydroxy b12 injections in the past and use it now when i crash, the PS was good but price has held me back with all the other junk i have been on. I think i am getting close to licking this problem after viral treatments with the last of my problems being very cycling which is insomnia and fibro, horse or the cart thing. Have u seen sleep improvements when your protocol is followed, i have read where b12 helps with sleep but i havent found this but then i havent used folates with it either.

    I believe cfs does damage to our nervous system in some way and i know our body uses b12(and folates) for nerve regeneration etc, does this happen through the raising of glutathione or by another means. I think now that i have my viral load down that any ongoing damage being done to my nervous system is greatly reduced and now at a stage where it is able to regenerate and recover.

    cheers!!!
  19. richvank

    richvank Senior Member

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    ***Hi, heapsreal.

    ***My responses are at the asterisks below:


    Thanks rich,

    ***You're welcome.

    Now the actifolate has 3 different folates in it and one of them is the same as folapro, are both taken to get a higher dose of L-5-methyl tetra.

    ***Partly, because it does do that, but mainly to include folinic acid, which is also in Actifolate.

    These are used as they are better absorbed then normal folic acid supplements and to get the same blood levels much higher doses of folic acid are needed??

    ***Not so much the absorption, but rather folic acid has to be converted to these active forms, and some people can't do that very well for genetic reasons.

    Pho serine, are the other ingredients in the product neccessary, NOW brand just sells a better priced PS supplement but doesnt contain the other ingredients.

    ***The others are beneficial, too. Phos. choline is important because the methylation block lowers the body's production of choline, and also choline can be converted to betaine to drive the alternative BHMT pathway for methylation in the liver and kidneys. This will boost production of SAMe, which is necessary to methylate cobalamin to make methylcobalamin. Also, the phos. serine complex supports rebuilding of all the membranes, which have taken a beating from the oxidative stress.

    If using hydroxy b12 injections what dosages are recommended.

    ***Maybe starting with less than 2,000 micrograms per day, because the delivery to the blood will be more efficient. Not sure how much lower. Might have to experiment.

    I understand cynocobalamin is not recommended, so other sublingual b12 equivilent doses??, methyl b12, dibencozide?

    ***Probably similar. Freddd has more experience with those than I do.

    The multi looks like a good product.

    Now would your protocol clash with any of my current supps, vit e 1000mg twice a day, NAC 600mg twice a day, lipoic acid 250mg(understand mercury thing), 5htp 200mg and non flush niacin 1000mg twice a day, pregnenolone 50mg T/D, melatonin,

    ***I don't think so, but some people have difficulty with extra sulfur metabolites getting through the sulfite oxidase enzyme. Sometimes molybdenum helps.

    The only thing i havent used is the folates, i have had some help with hydroxy b12 injections in the past and use it now when i crash, the PS was good but price has held me back with all the other junk i have been on.

    ***I would suggest starting low and slow with the folates if your B12 status is already pretty good. They can give you a real kick in the pants, detox-wise!

    I think i am getting close to licking this problem after viral treatments with the last of my problems being very cycling which is insomnia and fibro, horse or the cart thing.

    ***Sounds good.

    Have u seen sleep improvements when your protocol is followed, i have read where b12 helps with sleep but i havent found this but then i havent used folates with it either.

    ***That can go either way. Some people find that taking the phos. serine complex at bedtime helps, presumably because it lowers cortisol, which is supposed to be low at night and disturbs sleep if it is high. The other issue is excitotoxity, which can occur (or get worse than it already was) on methylation treatments, and that causes insomnia as well as anxiety, a "wired" feeling, and other fun things.

    I believe cfs does damage to our nervous system in some way and i know our body uses b12(and folates) for nerve regeneration etc, does this happen through the raising of glutathione or by another means.

    ***I'm not sure what the whole story is there. I do think that raising glutathione is part of it, because it should reduce oxidative stress and thus allow the mitochondria to work better. The additional ATP production should help the nervous system a lot. Fixing methyation should also help to repair the myelin. There are at least three substances in myelin that require methylation for their synthesis. Methyation is also needed for the function of the dopamine D4 receptors, which are involved in attention, according to the work of Dick Deth's group.

    I think now that i have my viral load down that any ongoing damage being done to my nervous system is greatly reduced and now at a stage where it is able to regenerate and recover.

    ***That sounds very good. Hopefully the timing is right for methylation treatment in your case.

    cheers!!!


    ***Best regards,

    ***Rich
  20. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    cheers!!!!

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