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B-12 - The Hidden Story

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Cort, Jul 26, 2009.

  1. Freddd

    Freddd Senior Member

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    Hi Klutzo,

    My cholesterol is one of the things that I have tested annually. It has fallen slightly since starting all these things and the HDL:LDL has remained basically unchanged. I can see no effects at all really as the slight fall was only 5 points and that is well within normal annual variation.

    My approach as been to stop and start things several times to find what is repeatable. After adding something I often retry things that didn't make a difference before. There are some things nobody is going to feel so it is difficult to advise on that. And sometimes the effect is quite indirect, ie finding that chondroitin/glucosimine/msm makes a difference but only when you have TMG on board. Combinations can be everything in this.
     
  2. Freddd

    Freddd Senior Member

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    Somebody, also from Utah, asked if I knew of a specific doc. I have lost track of where that post is but I am not familiar with that doc.
     
  3. Freddd

    Freddd Senior Member

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    Hi Mike,

    I was ill for decades, and the longer I was ill the worse the actual damage got. Methylb12 does indeed cause major startup symptoms in the severely deficient such as long term CFS/ME/FMS. It affects virtually every one of as many as 200-300 symptoms all at once and can certainly look like a worsening when in fact it leads to actual healing and recovery. The majority see significant results, the most significant being seen in those that have the most intense startup effects who are usually the sickest.

    When carefully studied ME looks like the purest case of the CNS/CSF (central nervous system, cerebral spinal fluid) deficiency of methylb12 specifically of any of these disorders. I'm very pleased to say that I USED to have it, for 30+ years, but am now fully recovered. As there are 4 overlapping primary deficiency syndromes it gets a little complicated. There are the body mb12, body adb12, CNS/CSF mb12 and CNS/CSF adb12 all with somewhat different characteristics complicated by methyfolate deficiency. Studies have documented the cobalamin deficiencies found in the CNS/CSF of FMS/CFS patients.

    People without methylb12 deficiency symptoms have no reaction to mb12 at all. People without adenosylb12 deficiency symptoms have no reaction to adb12 at all. Some people have reactions to both. They are both absolutely essential to the proper funtioning of the body, there are no substitutes or workarounds. Using inactive cobalamin pseudo vitamins such as hydroxyb12 and cyanob12 reduces reaction by severely reducing effectiveness limited to what the body can convert, which can range from zero to a couple of 10s of mcg per day. And not everybody who can concewrt it converts both forms. That appears to be how ME gets started, an inability to either convert dietary adb12 from meat into mb12 or a failure to transport it into the cerbral spinal fluid. It's sad to see so much misunderstanding about these things.

    So on the other hand, there is a subgroup of patients who see significant results. USUALLY those who have been ill less than 5 years.

    This is just blatantly ridiculous and untrue. Almost every benefiting significantly has been ill for more than 5 years, often decades. Everybody who has any reaction to it will benefit in the long run.
     
  4. richvank

    richvank Senior Member

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    Tests to detect overdriven methylation

    Hi, David, DrD, freddd, and the group.

    The best test panel for this is the Vitamin Diagnostics methylation pathways panel. It costs $300 and requires a doctor's or chiropracter's order. As I mentioned, the lab is in the process of moving, and probably won't be back up to normal operation until late January. Their phone number is (732) 721-1234, and they are in New Jersey. This test evaluates SAMe and SAH in the methylation cycle. If SAMe is high, that would suggest that the methylation cycle is overdriven. This panel also evaluates several forms of folate as well as reduced and oxidized glutathione. If the methylation cycle is overdriven, I think it is likely also that tetrahydrofolate will be high, and reduced glutathione will be low.

    An indirect way to evaluate this would be to get a Doctor's Data Lab plasma amino acids panel. If the methylation cycle is overdriven, I would expect to see high methionine, high sarcosine, low homocystine, low cystathionine, low cystine and low taurine. A Doctor's Data Lab urine amino acids test could also be run, and I think it would show similar results if the methylation cycle is overdriven.

    Sorry I wasn't able to get to the other issues today that have been raised on this thread. I will try to do so in the future. There is a lot going on in my life at present, including family and household stuff as well as chronic fatigue related stuff. I'm not planning to dodge the issues. I need time to study in order to give decent responses, and that's hard to find right now. I also need to get to the medical library to pick up copies of some of the recent papers. There's a lot going on in B12 research, and it's relevant to the issues we are trying to resolve here. So please bear with me.

    Best regards,

    Rich
     
  5. Marylib

    Marylib Senior Member

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    For Rich

    Thanks so much for your input. I wish you and your family all the best.
     
  6. markmc20001

    markmc20001 Guest

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    After working with my doctor with various vitamins and meds, experimenting with glutathione, and currently going full on with freddd's B12 protocol, I am still feeling like I may have shot at improvement/ maybe remission someday if I can get the right ammount of vitamins at the right time to get my methylation cycle and glutahhione working right.

    I have read your glutathione depletion and methylation hypothesis and feel that your hypothesis may be a key part of my problem, if not the main problem. Thanks for all your research and contributions on these forums where we can follow your progress, thoughts, and careful science behind why this might help.

    Of course, I think I can speak for many, that freddd's contribution has irraplacable here for us willing too "experiment" with what has helped him and many others.

    best regards,
    Mark
     
  7. Freddd

    Freddd Senior Member

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    Hi Rich,

    I have a question about what some of this would mean.

    I would expect to see high methionine, high sarcosine, low homocystine, low cystathionine, low cystine and low taurine.

    So what are the consequences of low homocycteine? Is "LOW" there a statistical statement or does it represent an actual need to have homocysteine aty a certain minimum level. Would it be correct to assume that high methionine would actually go hand in hand with low homocysteine in this situation? What is the norming population? If it includes people taking cyanob12, folic acid, hydroxyb12 or that exhibits b12 and folate deficiency symptoms at any level then the norming would be based on a biased chemistry of people in chronic deficiency states. It's this very question of who is included in the norming population that is most troubling. The serum cobalamin "normal" is not sufficient to prevent b12 responsive deficiencies symptoms and hence is a very biased statistic based on a chronically deficient population. The "normal" folate levels also doesn't prevent methylfolate responsive deficiency symptoms. So if these "normal" levels you mention inculde people with "normal" amounts of active b12 and active folate deficiency symptoms, are they actually meaningful or do they just define what is normal for people with chronic defriciencies?
     
  8. dmholmes

    dmholmes Senior Member

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    I'll have the plasma amino acids done soon since the VD lab is unavailable. Mine should be a good test since we have the results before starting active B12s (Rich worked on my case and has a full history). My SAMe was low normal, SAH high, tetrahydrofolate normal, oxidized glutathione high, reduced glutathione low.
     
  9. richvank

    richvank Senior Member

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    Hi, freddd.

    I actually meant homocystine, not homocysteine. Homocystine is the oxidized form of homocysteine, and that's the one that's included on these panels. Homocysteine is measured by conventional medical labs, and I would expect it to be low, also, if methionine synthase is overdriven, but if a person just does the plasma or urine amino acids profile, we only have homocystine to look at. Because PWCs are in a state of oxidative stress, there is usually some observable homocystine if they have a normal level of homocysteine. But if homocysteine is low, then there isn't much precursor to make homocystine, and that's why I suggest that homocystine will be low if methionine synthase is overdriven.

    Yes, I do think that low homocysteine would go together with high methionine if the methionine synthase reaction is driven too fast. This would be a result of a high relative reaction rate converting homocysteine to methionine compared to the net rate in the balance of the methylation cycle that convert methionine ultimately back to homocysteine.

    What is the consequence of low homocysteine? I think it will mean that there will not be enough flow down the transsulfuration pathway, so the other sulfur metabolites will tend to be low also. That will mean, for example, that glutathione will remain low, and that will tend to preserve the state of oxidative stress and will tend to continue the dysfunction of the detox system, the immune system, and many other aspects of the biochemistry that depend on glutathione. I know that you are not a big fan of glutathione because of the bad experience you have had in supplementing it, which I think must result from the genetic issue we have discussed, but it is actually very vital in keeping us alive.

    Your point about how to define "low" is a good one. As you note, lab reference ranges must refer to some population, and what is that population. Not only is the nominal healthy population in our society today not as healthy as it should be, but some of the labs actually don't even attempt to construct their reference ranges using nominally healthy people. They just calculate a mean and plus or minus two standard deviations from a cohort selected from people who send them samples.

    So what I do to make a judgment of whether something is low or not in the amino acids panels is not only to use the lab reference ranges, but to compare with what I have seen in other cases in which I know that the methylation cycle is not overdriven, because I have simultaneous direct measurements of SAMe and SAH from the VD panel. So I'm looking at relative values, not trying to define what an ideal value would be. That's the best I can do with the data available.

    The VD reference ranges are based on a population of at least 120 nominally healthy medical students between the ages of 20 and 40, nonsmokers, not known to have any chronic diseases. Granted, they may not have optimum nutrition, but we can use their numbers as a reference for people who are clearly ill, and my experience, as reported in the poster paper Dr. Nathan and I presented at the most recent IACFS/ME conference, which is available on Cort's site as well as in the files section of the Yahoo cfs_yasko site, is that the ill people have significantly different values than this reference group, and when they are effectively treated, their numbers move into the normal ranges. The people also report significant improvements in their symptoms. So we don't have an ideal situation, but I think we have a test situation that works, and that's about the best one can hope for. I guess what I'm saying is that one has to use experience and judgment, but that it is possible to make sense out of these numbers and get an indication of what's going on in an individual's body, based on them.

    We may find that nobody's methylation cycle is overdriven, and if so, that will be great. We may also find that the sarcosine pathway can cope with very large inputs of methyl B12 and still keep the ratio of SAMe to SAH at a safe level. But I'm concerned about pushing the methylation capacity too high, because it affects so many things, and in particular gene expression, which is fundamental to what goes on in all the cells at a deep level. I just think it pays to be cautious when giving supplements at pharmacological doses, which the body may not be set up to completely cope with, as opposed to the usual physiological doses that come in from the diet. I'm also concerned about diverting too much flow away from the transsulfuration pathway, because that would rob the rest of the sulfur metabolism of its input, which would affect many other biochemical systems.

    Best regards,

    Rich
     
  10. richvank

    richvank Senior Member

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    To David re: plasma amino acids test

    Hi, David.

    O.K., I think it will be interesting to see the results of this panel. We should not only be able to tell whether your methylation cycle is overdriven or not, but we should also be able to see the status of your amino acids in general.

    In studying cases of people who have not responded to the Simplified Treatment Approach, I am finding some who just don't have high enough levels of the amino acids that are needed to feed this part of the metabolism, i.e. methionine, serine, glutamine (or glutamate), cysteine and glycine.

    I think this results partly from problems with digestion of protein and absorption of amino acids by the gut, and partly from a higher than normal rate of burning of amino acids for fuel to make ATP by the cells.

    It looks as though in CFS that the cells are not able to use carbs and fats as well as normal for this purpose because of a partial block early in the Krebs cycle resulting from oxidative stress in response to glutathione depletion, so they shift to burning more amino acids. This would be analagous to a person burning their furniture in the fireplace to keep warm. It works, but it has certain disadvantages in the long run! :eek:

    Rich
     
  11. dmholmes

    dmholmes Senior Member

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    Makes sense, and in my case a big increase in exercise likely burned out my amino acids.
     
  12. velha508

    velha508

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    Hi Athene,

    I have/had numbness in the middle toes of each of my feet. I have been supplementing with Freddd's protocol since Sept. The numbness in my feet wasn't touched until I went to 2x7.5mg mB12 injections per day. However, it wasn't progressing at sublingual doses. After a few days at the 2x per day dose I could feel reversal starting - also, my capability to sweat returned at this doseage also (I've experimented with this and found this works for me)...

    Others I've read about have seen feeling return at lower, sublingual only doses, also the amount and type of co-factors could contribute, there is discussion of this on the wrongdiagnosis forum. Hope yours starts reversing soon!

    Velha
     
  13. dmholmes

    dmholmes Senior Member

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    Yes, if their forum comes back up. :mad:
     
  14. Freddd

    Freddd Senior Member

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    Hi Athene,

    I understand your impatience. Maybe I can clarify. Numbness can be at a number of different levels. First there can be skin, then there can be muscle numbness. The go away separately and come back separately. Then thefre can be peripheral nerve problems or central nerve problems. Sometimes numbness will start retreating when all the needed cofactors are in place including all the basics and critical cofactors. Mb12, adb12, l-cartnitine-fumarate, omega3 oils at perhaps 2 grams a day total of the active components, zinc, magnesioum, methylfolate, magnesium are all absolutely essential. Then a titration upwards of mb12 to 15 or 20mg sublingual, then trying ther 50mg single dose mb12 and 51mg single dose adb12. Those, if they have any effect clue you into the hypothetical CNS/CSF deficiency. This central shortage of cobalmins can lead to deterioration in the cord or parts of the brain (subacute combined degeneration). For me, the numbness contionued to build despite years of sublinguals and injections to 5mg. It took one injection of 7.5mg sc mb12 daily to stop the increasing numbness and 4x7.5mg sc mb12 injections daily or 3x10mg sc mb12 daily to substantially reverse it. Velha reported the same 7.5mg which is approximately equivalent to 50mg sublingual to go other the threshold for CNS healing. It is in line with Japanese experiments and studies. There are a handful of people doing this that I know of and everybody I know of is having some degree of success but it depends on a minimum of 2 x 7.5mg SC injections daily. The range so far is 15-30mg/day in 2-4 injections. There is not a lot of data and this is very experimental. I'd be very interested to hear what Rich has to say about this protocol. I certainly don't recomend it for everybody, only those for whom lower amounts don't work. It is expensive. I also suggest that a person needs to work up to the 20mg daily and be at equilibrium there so as not to have overwhelming startup effects. Going to this all of a sudden without titrating is NOT suggested. I must admit that had I known about it I would have started sooner and with less damage. The more damage and longer lasting the more difficult to reverse and the longer it takes. Good luck. Kevin, over at http://forums.wrongdiagnosis.com/showthread.php?p=209358#post209358 (back up) also has a couple of years of experience at this. He was in a wheelchair and is now back at work as an EMT.
     
  15. Freddd

    Freddd Senior Member

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    Hi Rich,

    I know that you are not a big fan of glutathione because of the bad experience you have had in supplementing it, which I think must result from the genetic issue we have discussed,

    This is clearly a false assumption on your part. The reaction I had appears to be the main reaction had by persons taking active b12s and active folate who have significant results and then try the glutathione precursors. Many many people also have the same reaction and call it a GLTUTATHIONE DETOX REACTION. This name for the reaction is widely used. The symptoms are listed for glutathione detox reaction are those of acute folate deficiency with methylb12 secondarily with adb12 deficiency symptoms if taken for a longer period. None the less despite the name it is called once the precursors or glutathione is stopped the same things will quickly correct it; daily large enough doses of methylfolate, adb12 and methylb12. It has nothing at all to do with any IMEs I have unless they are very common and predominant.
     
  16. richvank

    richvank Senior Member

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    To freddd re: glutathione and high-dose methyl B12

    Hi, freddd.

    O.K., I'll take you word for that, for the sake of argument, though it would be nice to have some documented data.

    Assuming that what you say is true, how could this be explained at the biochemical level? Here's a hypothesis, for what it's worth:

    As we've discussed before, the normal mechanism of the overall B12 absorption, transport and metabolism is different for small (several microgram) dosages of the various forms of B12 taken orally, as compared with large dosages (several milligrams) of methyl B12 or adenosyl B12 taken sublingually or by injection. In the first case, transcobalamin carries the various forms of B12 to the cells, where it binds to a receptor, and the cell engulfs the transcobalamin--B12 complex by endocytosis, digests the transcobalamin, strips off the beta ligand from the B12 form, chemically reduces the cobalamin, and then probably protects it by forming glutathionylcobalamin before passing it either into the mitochondria to form adenosylcobalamin or to methionine synthase, where it is converted into methylcobalamin.

    In the high dosage case, the carrying capacity of transcobalamin is overwhelmed, and free methy- or adenosyl-B12 is transported in the blood plasma to the cells. Some of it enters the cells, but since it is not bound to transcobalamin, it most likely does not enter by endocytosis, and thus probably does not have its beta ligand removed or go through the normal processing. As a result, it survives in the cell as methyl- or adenosyl-cobalamin, respectively. and apparently is able to bind to methionine synthase and methylmalonyl CoA mutase, respectively, and perform as coenzymes to these enyzmes.

    Now, how could glutathione interfere in this second case? Here's what I hypothesize: Glutathione reacts with these active B12 forms, and converts them to glutathionylcobalamin. As I noted above, this is formed in the normal processing of B12, also, and apparently serves as a protection to the B12 at an intermediate step in its processing. So why does this cause a problem in the high-dosage supplementation case? As you know, I have been suggesting that in your case it's because you have a genetic mutation in one or more of your B12 processing enzymes, and based on what you have reported, I still think this is true in your particular case. But if this "glutathione blocking" also occurs in others who do not have such genetic mutations when they use the high dosage approach, then there must be another explanation. I suggest that perhaps glutathionylcobalamin is formed in the high-dosage case as a molecule in the cystosol of the cell that is not associated with a processing enzyme, and thus becomes unusable, whereas in the low-dosage case, the glutathionylcobalamin is associated with a chaperone molecule, so that it can be carried on through the normal processing.

    One reason I can't be definite about this suggestion is that I don't think the research on B12 metabolism has gone far enough yet to nail all of this down. I think there has been some more published by Ruma Banerjee's group in Michigan, and I hope to get up to speed on her latest work soon, to see if what I've suggested here is consistent with what they are finding.

    One of the things that makes it difficult to interpret results on people who have used the high-dosage active B12 treatment is that as you know, this treatment sort of leapfrogs over many steps of the normal absorption, transport and metabolism of B12, and as such it is effective in a variety of types of B12-related conditions, all the way from those who have frank B12 deficiency in their diets, to those who have absorption problems such as pernicious anemia-type conditions, to people who have genetic problems with transcobalamin, to those who have genetic defects in their B12-processing enzymes as you apparently do, based on your reports, to those who have a partial methylation cycle block, which we have documented by lab testing in CFS. So when the high-dosage treatment works for someone, we don't know what their actual abnormality is or was.
    That makes it difficult to transfer the experience with this heterogeneous group to others, or to understand the details of what went on.

    I'm happy that you have personally had success in restoring your health with this approach, and that you have been able to help many others with it. I am in the process of trying to understand what goes on at the biochemical level, in order to be able to optimize the treatment of CFS. I think your work provides some important clues, but as I described above, I still don't know enough to explain the results to my satisfaction or to be able to project from this experience with certainty. I intend to keep working on this, as more becomes known. In the meantime, I favor taking a cautious approach, because in my experience, when the basic science is not completely understood, there can be surprises when an empirical approach to treatment is taken, and not all of them are pleasant. This commonly occurs in the drug treatment of diseases, as you know, and leads to pulling drugs from the market after the unpleasant surprises occur in the public. That's why I advocate doing some testing periodically to see what the effects of the treatment are at the biochemical level, even though this treatment involves orthomolecular substances rather than drugs. These orthomolecular substances are being used at pharmacological dosages in this treatment, not at their usual physiological dosages. The effects may all be positive, and if so, that will be great. But I think it pays to take a look, particularly since the testing is readily available.

    In the Simplified Treatment Approach, the dosage of hydroxocobalamin is also phamacological, and I advocate periodic testing when that treatment is used as well.

    Best regards,

    Rich
     
  17. Freddd

    Freddd Senior Member

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    Hi Rich,

    Two modifications of of information to reconsider. First, why the pronounced folate antagonist appearance? The b12 deficiencies are not as pronounced as the folate deficiency, or perhaps the folate deficiency symptoms merelyu appear sooner. That begs the question of what could be the cause of the very pronounced folate deficiency? This appears to happen regardless of the dosage level of the active vitamins and they are not actually a required component. They merely allow the observation of the already gained benefits turning off suddenly and then turning back on suddenly. This can be easily duplicated over and over. It is independent of actual doses taken before hand. Some were taking a lot less b12 than others and almost nobody was taking anything ohter than a single 800mcg methylfolate beforehand. I'm sure I could assemble a panel that will produce those results to perform that experiment if you can provide the funding for before and after tests. Now that we know that it can be recovered from as quickly as it is induced it isn't so scary. The problem is money. If I had it I would fund it myself. The other group of people afflicted have nothing to do with active b12 and folate. They are generally the ones that widely report it as glutathione detox reaction. This class of people doesn't see this happen suddenly as the active effects turn off suddenly since they don't have this benefit in the first place. Not being aware of this they experience the appearance of this new class of symptoms and worsening of existing symptoms and can't assign it to the specific cause of returning deficiency since they had never relieved them in the first place. However, I have communincated with several folks who formerly have had glutathione detox reaction by their own description and then had it relieved by taking relatively large doses of methylfolate, adb12 and mb12. The name not withstanding that too is induced folate and active b12s deficiencies. While I had a severe long lasting instance, it isn't at all unique.

    I will however, after the lab is back up and running, do the draw and have the methylation test panel and send the results to you for interpretation. I do have curiosity. At the gross symptoms level, what would be symptomatic of overdriven methylation in theory? Only 200mg of SAM-e makes any noticable difference at my present dose of 30mg/day sc injected of methylb12. That is completely unchanged from 5mg/day sc injected or even 5mg/day sublingual (1mg sc injected) . The only apparant difference of that large dose is of certain CNS neurological effects.
     
  18. richvank

    richvank Senior Member

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    Hi, freddd.

    I'm not sure I totally understand what you have written (above), but I think you mean that it appears that when the people with the conditions you are dealing with supplement with glutathione precursors, the effect is to counter their folate function and cause it to appear that they are deficient in folate, because their resulting symptoms can be reversed by taking more folate. Is that right?

    And I think you also mean that supplementing with glutathione precursors in these people can also counter the active B12 coenzymes, and cause it to appear that they are deficient in B12. Is that right?

    I'll make some comments, though I'm not sure that they will be responsive, because I'm not sure I understand what you are saying.

    In CFS, as it appears to me, anything that brings about a partial block in the methionine synthase enzyme in a genomically susceptible person will bring about a vicious circle interaction between this block and depletion of glutathione, so that both remain present chronically. I think this most often occurs by the initial depletion of glutathione by various causes, which leaves B12 unprotected in the cells and allows it to react with toxins. There is then insufficient production of methylcobalamin, and that causes the partial block of methionine synthase.

    When methionine synthase becomes partially blocked, 5-methyl THF initially builds up in the cells, because the methionine synthase reaction, which normally converts it to THF, is partially blocked. Because 5-methyl THF does not have a glutamate tail, as do other folate forms, it is able to leak out of the cells, into the blood plasma. That is called the "methyl trap" mechanism. The result of it is that the cells become depleted in all forms of folate, as other forms are channeled into producing 5-methyl THF, and it leaves the cells.

    So the combination of low methyl B12 and low 5-methyl THF in the cells is the reason that both B12 and folate must be supplied to overcome the partial block. It is observed that when this is done, glutathione rises back up to normal automatically, which verifies that there is a vicious circle mechanism that links the partial methylation cycle block to the depletion of glutathione.

    Before I learned about the partial methylation cycle block from the autism researchers in late 2004, I used to encourage people to try to raise their glutathione by direct methods, such as supplying glutathione precursors. Some PWCs (perhaps most) reported that this gave them some benefit temporarily, but they had to keep doing it or they would return to their initial state. A few people could not tolerate direct boosting of glutathione. Perhaps they correspond to the people you have described.

    What was going on in the people who could not tolerate this treatment? I'm not sure. Perhaps they were mobilizing toxins, in which case it would properly be called a detox effect. Perhaps cysteine was being boosted too high, since cysteine is known to be a neurotoxin if it goes too high. For the people who were using NAC as one of the glutathione precursors, perhaps they were moving mercury into their brains, since according to the work of Aposhian et al. in rats, NAC can move mercury into the brain. Perhaps this supplementation was causing the generation of too much sulfite, and the sulfite oxidase enzyme was overloaded, allowing sulfite to rise to toxic levels.
    Perhaps these people had sulfate-reducing enzymes in their gut, and this supplementation was eventually leading to too much hydrogen sulfide production by these bacteria. I think there are many possibilities, and it may have been different for different people.

    In your particular case, as I wrote before, I think that supplementing glutathione may have caused the conversion of methyl B12 and adenosyl B12 to glutathionylcobalamin, and your body was not able to convert it back, for genetic reasons. When you went low in methyl B12, the methyl trap mechanism then would have drained folate metabolites from your cells into the blood, which would have rendered the cells deficient in folate, as well as being deficient in active B12. Under these conditions, supplementation with active folate and active B12 would have restored the methionine synthase back to normal operation.

    As I also wrote before, in other people, who do not have genetic issues with the B12 processing enzymes, it may be that the glutathionylcobalamin could not be utilized because it was not associated with a chaperone molecule, as in the normal processing of B12 in the cells.

    As I understand it, you associate certain symptoms with low folate and other symptoms with low B12. I'm not sure how this works, because both are needed for the methionine synthase operation. It is true, though, that folates have a small number of other functions, the most notable being the synthesis of purines and thymidine, which are needed to make new RNA and DNA for new cells. The most rapidly proliferating cells would likely be the most sensitive to a folate depletion, such as those lining the gut and the blood cells, including both red and white cells. This is believed to be the origin of the macrocytic anemia that results when folate is low. Low B12 can also do this, because of the methyl trap mechanism, which produces low folate availability in the cells.

    And B12 does have the separate function of adenosyl B12, which assists in feeding certain substrates into the Krebs cycle to produce energy in the form of ATP.

    So I can sort of see how some symptoms might be associated with deficiency of one or the other, but it would seem that there would be a big overlap, because a lot of the symptoms would result from a partially blocked methylation cycle, and either low folate or low B12 can cause that.

    With regard to funding, I'm in the same boat you are. Our clinical study was funded by an anonymous donor, but this donor doesn't seem to be interested in doing it again. I'm hopeful that eventually someone who is properly connected and can obtain funding will get interested in the methylation block.
    There's no money in it for the drug companies, except perhaps the "medical food" supplier, because patented drugs are not involved, so the usual sources of biomedical research funding are just not there.

    I'm happy to hear that you are going to run a Vitamin Diagnostics methylation pathways panel on yourself. I think the results will be very interesting.

    I think that the fact that taking 200 mg of SAMe has a noticeable effect on you suggests that your methylation capacity is still below normal, even with the heavy supplementation of methyl B12. Again, I realize that I seem to keep harping on this, but I think this may be a result of the genetic issue. Those are very large dosages of B12, and ordinarily, I think they would give generous support to the methylation cycle, so that taking 200 mg of SAME would not produce a noticeable effect. So I'm guessing that your methylation cycle is still not overdriven. However, I can't be sure that this would be the case in people who don't have genetic issues with their B12 processing enzymes, but are supplementing at the same high levels you are.

    You asked what would be the symptoms of an overdriven methylation cycle.
    I can only try to project them theoretically from the biochemistry and my hypothesis, so I could be off the mark. However, if flow down the transsulfuration pathway is diminished because of fast conversion of homocysteine back to methionine, then I think that all the symptoms that flow from depleted glutathione, as well as depleted cysteine and taurine, would follow. These include most of the symptoms of chronic fatigue syndrome, according to my hypothesis.

    Best regards,

    Rich
     
  19. _Kim_

    _Kim_ Guest

    First, I'd like to thank both Freddd and Rich for allowing us to "hear" the conversation between the two of you. You could just as easily taken this offline, but instead, we are privileged by your openness.

    Second, I want to report that, after one month of doing Freddd's protocol, I have started to notice some changes. Four days ago, I added in SAMe (400mg). The cognitive and sensory symptoms have improved. The fatigue is, perhaps, a little less profound as well. The only co-factor left for me to add is d-ribose. I've ordered some from iherb to try.

    If the improvements continue, I'll be doing the happy dance for New Years.
     
  20. lebowski

    lebowski

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    this is like an open university i m following with great pleasure so thanks again ..

    rich so is there an explanation in ur mind ,
    how the folates ,fredd use when he (and the people he knows ) use to stop that def. symptoms (the 4.8 mg one i think ) when they r on glutathione ,
    can stop the detox of taking glutathione or precursors of it ?

    or did u ever observed such a thing .. a person taking glutathione and having detox , but than he adds very high dose methylfolate to it , his detox stops .. can high dose folate do it according to ur theory ?
     

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