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Glutathione & Precursors - Detox or Induced Methylb12 and Methylfolate Deficiencies?

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Freddd, Sep 12, 2009.

  1. Athene

    Athene Never give up

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    Hi SaraM,
    I'm taking Kirkman Labs reduced glutathione tablets. The dose is from one to 5 tablets a day, and I taking 2 a day at the moment.
  2. mtnwoman

    mtnwoman

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    Hmm.. this thread looks quiet... maybe I'm posting at the wrong place, but I had a question for Freddd: Does he recommend a pharmacy for the methyl B12 shots? and does he recommend a dosage per syringe?

    Thanks,, this has been a fascinating read. I come from the lyme borrelious camp (many overlaps with ME/CFS imo...)
  3. Freddd

    Freddd Senior Member

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    Hi Mtnwoman,

    I've used University Pharmacy in SLC for the methylb12 injections. They are quite aware of the light sensitivity issue. They have a web site. The main active b12 discussion is at http://www.forums.aboutmecfs.org/showthread.php?188-B-12-The-Hidden-Story&p=97055#post97055.

    I would want to preface the discussion of doses with a suggestion, and that is to titrate up on the sublinguals. DrD over on that other thread has ordered some custom mb12 sublinguals with zero additives in addition to the base, no flavorings or anything that he has found quite effective. With sublinguals, if the effect gets too intense, you can always chew and swallow, pretty much putting an end to the absorbtion of the mb12. For a very deficienct person a single 1000mcg mb12 sublingual of any of the 5 star brands can knock your socks off. At best that results in about 150-250mcg being absorbed. If you inject 5mg there is no way to abort it part way through absorbtion if you are having a difficult time with it.

    I have suggested a 50mg trial dose of sublinguals as one continuous dose over several hours to test the effects of a 7.5-12.5mg injection and see if it is needed. Not everybody has any more effect from that then from 15-20mgs that they have titrated too. The hypothesis is that a dose of that size is only needed fro some people who have a difficult time getting the mb12 into the cerebral spinal fluid.

    I appear to have such a difficulty. I have had demilenation damage to my spinal nerves called subacute combined degeneration. In order to reverse the numbness in my feet, regain position sense and motor control I need to take 30mg per day as 4x7.5mg or 3x10mg. I titrated to this dose over time via effect. At once or twice a day I was able to feel the doses starting up and wearing off and corresponding improvement and disimprovement of my feet. At the dose I'm taking the improvement is more or less continuous without any onset or fallback up to several times per day.

    The other thing that is very important before testing the injections is to be taking the Metafolin which is important and the other basic and critical cofactors or at least having tested them for increasing or enabling effectiveness. Otherwise you might not get the effect from the mb12 that you would otherwise have. Good luck.
  4. Athene

    Athene Never give up

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    I just want to add to SaraM and anyone else relevant,

    I tried out my glutathione and built up gradually as Freddd advised. I reached the point where it was making me feel very ill. It took two months to reach this point, building up the dose. This is exactly what Freddd predicted.

    Either it does not agee with me at all or, as Fredd said, I am good with some, but the dose is critical. It definitely made me feel better for several weeks at the beginning.

    For the time being I am holding off and I may resume at a later stage, but build the dose up very slowly. Fredd warned me about all this and I thought that two months was slow enough to tell how I was doing, but clearly it wasn't. Next time I will stay on a very low dose for longer and build up VERY slowly.

    My recomendation to everyone is to follow Freddd's advice very carefully. this guy SERIOUSLY KNOWS WHAT HE IS TALKING ABOUT!!!
  5. Freddd

    Freddd Senior Member

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    Hi Athene,

    I think the that if any dose can actually be benficial of glutathione, it will only be a very small dose. A one year setback and resumption of neurological deterioration is a high price to pay. It took daily 4800mcg doses of Metafolin and large dose of mb12 and adb12 to get out of the induced deficiency state for me and similar doses for others. Even at that it took a year to retake all the improvements I had lost from the glutathione. It was cerrainly the worst setback I ever had and I wouldn't wish it on anybody.

    If you do find a beneficial dose don't build it higher. That only speeds up the induced deficiencies.

    I don't know why some feel better the first little while. I did feel better in certain ways for a short while without realizing what some of the changes that occurred from the first day meant at the time. It was only after any improvments had faded and the severe deficiency states set in that I realized the problem.

    Even outright poisons have been used to make people feel better. That doesn't make them good for the person. It is said that Hitler's doctor was giving him a strychnine tonic.

    http://en.wikipedia.org/wiki/Strychnine
    Although it is best known as a poison, small doses of strychnine were once used in medications as a stimulant, as a laxative, and as a treatment for other stomach ailments. A 1934 drug guide for nurses described it as "among the most valuable and widely prescribed drugs".[2] Strychnine's stimulant effects also led to its use historically for enhancing performance in sports.[3] Because of its high toxicity and tendency to cause convulsions, the use of strychnine in medicine was eventually abandoned once safer alternatives became available.
  6. Freddd

    Freddd Senior Member

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    I would like to request that those who have had good or bad responses to glutathione list the symptoms of those responses, what symptoms went away whast improved, what got worse, what came back from having been gone and which forms of folate and b12 you are taking. Thankyou.
  7. velha508

    velha508

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    This is exactly what I found. I've followed Fred's protocol for over a year with GREAT success! I have tried, glutamine and rice protein on multiple occasions (also trying to work on leaky, allergic gut and to fix low amino acids possibly related to poor digestion).

    I never had an immediate reaction, it always took time, but eventually the changes would start, the most noticable to me were - ear ringing and increased visibility of mB12 in my urine (red urine), which I thankfully knew to watch out for because of Fred's observations. Each time these were dose dependent, if I took a little glutamine I could take it for weeks before the change started, if I took a lot it happened more quickly.

    I fully explored the protocol to try to find my best response and thus I experimented with a lot of things. I found that all of Fred's observations (including acne like bumps from hydroxyB12) were the same for me. The one difference I found is that I am not nearly as sensitive, and if a small amount of a vitamin or cofactor made no difference it did not mean a large amount would not - for example, I had no response to 500 mg of carnitine fumarate, but a great response to 5g/day. I continue to require 4-5 g of carnitine per day in order to maintain spectacular energy.


    Velha
  8. mtnwoman

    mtnwoman

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    I hope Fred is around to comment.

    My neuropathy is steadily getting worse in the past few months. I have lyme and co-infections (finally diagnosed in 2005 after no diagnosis for 9 years). I have been on intermittent antibiotics x 5 years.

    The only thing different since the worsening neuropathy has been the addition of Jarrow methylcobalmin 5mg SL at bedtime and about 4mg 3x/week of SLC Univ Pharm meB12 sq injections. Also have added Metafolin 1-2 once/twice a day.

    I take a bunch of other supps: MultiVit, B complex (both with meB12 and methylfolate); E, C, fish oil, zinc, Molyb, Vit K, magnes.
    I have also added more calcium citrate and Vit K2 MK7 in the past two months as I have been diagnosed w/ osteoporosis.

    Could the meB12 be methylating mercury?
    thank you!
  9. Freddd

    Freddd Senior Member

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    Hi Mtnwoman,

    Could the meB12 be methylating mercury?

    Let's look at the effect of mercury in the body. According to papers I have read about 80% of mercury toxicity symptoms are identical with those of methylb12 deficiency. Hypothetically this is because the mercury IS stealing the methyl group from the mb12 inactivating it. The single methyl group available in mb12 is 1.3% of it's mass. It takes 7mg of mb12 to react 100% with mercury to methylate 1mg of mercury. It takes approximately 30mg of methyl-mercury to show up as early mild toxic methyl-mercury symptoms. That would require 210mg of 100% reactive mb12 as a single dose, 2100mg at 10% methylation rate and 21,000mg at 1%. The actual rate appears below 1% as research consistently has shown that 99% of an injected dose is excreted unchanged within 24 hours. At a 1% per day liver excretion rate methyl-mercury it has a serum halflife of about 71 days and reaches equilibrium in serum at a couple of mgs of methyl-mercury in about a year according to models I have built based on measured excretion rates from accidental dosing with methyl-mercury using the doses in the range here that we talk about at the 1-10% rate to be generous with safety margin.

    I had continued neurological deterioration until I hit that threshold above 6mg per injection and by 7.5mg. 5 mg every day did no better than 1 mg but 7.5-10mg every day did MUCH better and reversed the continued deterioration. If the problem is getting the b12 into the csf/cns there appears to be a minimum threshold dose for effectiveness. Also, for me the effective time period for a 10mg injection is 8-10 hours.

    I also found Linus Pauling to be accurate on the vitamin C and for decades required 16 grams of vitamin C per day to keep various unidentified infections under control. After the mb12 etc I only take 6 grams a day now.

    The hallmark test for mb12 on central neuropathies is 50-60mg of sublingual in a continuous 3-4 hour dose made of of 10mg of Enzymatic Therapy and the rest 5mg Jarrow. This will produce a differential effect over an ineffective dose, for me immediately, but probably for anybody done 3 days in a row. If this doesn't make for noticeable change of ANY sort then there is something else going on (too?). I currently find that taking 3x800mcg Metafolin with each injection to make for maximum effectiveness. 4mg 3x a week has, based on the experience of quite a few people now, essentially zero chance of reversing the CNS (brain and cord) neurological deterioration. It just isn't enough or often enough. Assuming the mb12 and adb12 have been effective on a wide variety of other symptoms this is the possibility I would bet on, but no guarantee.o
    How have your other symptoms done? Can you list all the things that have improved, by how much and all those things that have stayed the same or gotten worse. This might give a clue. Some have even found that 5000 units of D3 was the key to healing after the mb12 was in place.

    Keep communicating. The neurological deterioration reversal is the most difficult thing to achieve and it is very fussy. Good luck.
  10. Mij

    Mij Senior Member

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    Dear Freddd,

    I will keep my message short not to overload the current conversations. I don't suffer from many of symptoms you described but have had ME for 20yrs. Since you are knowledgeable about b12 and folates I'm wondering if you could give me some insight as to why my MCV is always in 95-97 range and my MMA is in the upper normal range. I don't have any reaction whatsoever with mB12 by Jarrow or hydroxy B12 injections, I've taken it in combo with different folates over the years. Currently I am taking Thorne #12 B-complex which contains the adenB12 + mB12 and 5 Methyl- tetrahydrofolate but will switch to the protocol you rec'd for better absorption.

    My question(to save myself confusion, more expensive testing and shooting in the dark with supplements) is this, if I were to take your rec'd protocol and feel no obvious difference in my symptoms, would a lowered MCV result be a good indication that something is working?

    I need to have some sort of indicator that I'm moving in the right direction because at this point the most debilitating part of my illness is stamina, PEM and the whole automonic dysfunction. More energy would certainly be a good sign but how long on these supplements that you rec'd do I continue to take them if nothing is changing.

    Thanks!
    Mij
  11. Freddd

    Freddd Senior Member

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    Hi Mij,

    I think that switching to the Country Life, Jarrow AND Enzymatic Therapy, which is a little different than the Jarrow and long with the Metafolin, preferably without the NAC which is one prescription form could make a difference based on the experience of a lot of people. This also asuumes the basics.



    have had ME for 20yrs.

    Could you list your symptoms from the large list as well as any you can add, ME isn't as well represented on the list because it is more subtle and less diagnosed, especially in the USA.

    I had many symptoms that I could identify such as so much tightness in my neck that it was forced into reverse curvature, very painfully so.

    MCV is always in 95-97 range and my MMA is in the upper normal range

    All the years I was taking Cyanocbl and folic acid and I remember noticing the MCV it was at 99.6-99.8. When I took mb12 it stayed there. When I took SAM-e, it stayed there. I was already taking all the basics. When I started with first 400mcg of Metafolin and then increased to 800mcg daily it went down to about 96 in 2 years. My period with increased folate need from the glutathione (precursor) 6 week trial, which still continues, saw my MCV increase to 101.6 while at the same time I needed 4800mcg of Metafolin just to keep my lips from developing angular cheilitis. I have recently increased this as 4800mcg was just too delicate. If i missed a dose for any reason I often would have a start at developing it. Increasing the Metafolin recently caused a large decrease of b12 visible in my urine, has made me more unlikely to have cheilitis to start getting going and hopefully is bringing my MCV down. MCV moes slowly becasue of the 90+ day lifetime of the red cells and because they can sit in the marrow quite a while, which in fact is what causes them to keep getting bigger without the b12/folate to mature them. For me mb12 made no difference in that but Metafolin did and glutathione demonstrated it's adverse effects by causing the increase in MCV by somehow decreasing the folate effectivness to which there are 3 clues; increased MCV, angular cheilitis and very much increased b12 visible in urine continuing every day until enough Metafolin is taken lowing it back immediately in the same way it did the first time I took it.

    So you may have something else in your body causing a problem like glutathione did for me or you may lack some factor and I think that I am still missing a factor X on the MCV puzzle.


    Now for the MMA. Let me put this in context a little. It could mean that that is just the amount your body produces. However, we have a clue in your other items that you have certain kinds of b12/folate deficiency symptoms. such as ME. ME appears to me in the matrix I am laying out to be a CSF/CNS deficiency of at least one or both of the active b12s. So as other research has shown CSF containing MMA because of malfunctioning mitochondria is associated with a variety of diseases such as Parkinson's and others while deficient levels of unspecified cobalamin are found in CSF/FMS plus others and I would presume ME based on the evidence. The research is just really getting going on that.

    So assuming you are one of us with CFS/FMS research indicated CSF/CNS deficiencies MMA could be getting generated in the CSF and shows up in the blood because that is possibly where it goes when removed form the CSF. This hypothesis can be tested with separate day doses of 50mg mb12 sublingual and 51mg sublingual doses done as single continuous dose lasting 3-4 hours as you put all the tablets under your lip you can manage and make them last. According to my hypothesis based on the reports of myself and many others this is a large enough dose to penetrate the CSF/CNS by diffusion.

    For the energy you need to modify your program as suggested then add l-carnitine fumarate as the more effect form for energy. The necessary dose appears to run from 250mg to 5 grams a day depending upon the person. It could be some other things as well so we add the other critical cofactors, because it can be combinations of things. Keep in touch and we can work through this systematically.
  12. richvank

    richvank Senior Member

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    Hi, Freddd.

    I've been giving some more thought to the question of why glutathione supplementation was so disastrous for you, when ordinarily it is such an important and beneficial substance in the body, and in fact, as I think you know, the depletion of glutathione is what I have hypothesized as being the initial biochemical cause of the development of ME/CFS.

    How about this:

    It's known, and is in published research, that glutathione will react rapidly with other forms of B12 to form glutathionylcobalamin. This form has been detected as normally present inside cells, and this is part of the basis for thinking that glutathione acts as a protector of B12 at an intermediate stage of its metabolism inside the cells.

    In your case, you are putting in the two coenzyme forms of B12 sublingually, and are apparently depending on them to diffuse into your cells, independently of the normal transcobalamin transport and importation processes.

    What if glutathione reacts with these coenzyme forms before they enter the cells, and what if your cells are not able to convert glutathionylcobalamin back into the coenzyme forms? I think that would explain your observations, in the light of your report that you do have an inborn error of metabolism in the intracellular B12 processing enzymes. This may also be true of others whose cells are not able to make this conversion.

    Best regards,

    Rich
  13. Freddd

    Freddd Senior Member

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    Hi Rich,

    I do agree that the conversion of active b12s to glutathionylcobalamin is apparently occurring at a great rate and I certainly can convert it back to active at anything like the rate I need. I can't get enough b12 to my cells without diffusion.

    For me mb12 made no difference in that but Metafolin did and glutathione demonstrated it's adverse effects by causing the increase in MCV by somehow decreasing the folate effectivness to which there are 3 clues; increased MCV, angular cheilitis and very much increased b12 visible in urine continuing every day until enough Metafolin is taken lowing it back immediately in the same way it did the first time I took it.

    This is quoted from a couple of posts above. The question is why does it affect these folate specific items in me and those undergoing "glutathione detox reaction" which is moderately common. More and more people on this set of forums are posting their negative reactions to glutahione. In a more thorough piece I am preparing for you I am putting together I am including descriptions of "glutathione detox reaction" and comparing it directly to those symptoms and signs listed specifically for folate deficiency of which I have a number. This more complete list might very well point at what the biochemistry is for someone who knows and could see possible connections.

    So why does Metafolin reduce urine output of b12 substantially? So why does glutathione increase excretion of b12 in the urine very substantially and maintains it? Why does glutathione cause angular cheilitis in a few days? Why does glutathione increase MCV and MCH and possibly other blood measures. Why does glutathione increase inflammation throughout the body. Why does glutathione increase asthma? Why does glutathione increase allergic responses and MCS. Why does Gltuathione increase the peeling and raggedness of skin around the nails and finger tips. I can duplicate all of these merely by not taking enough Metafolin each day. Though by merely not taking it the things don't start so hard or fast. I do get dietary folate and folic acid so it normally never gets as intensely bad as it got on glutathione and afterwards. Why does the "anti-folate" effect of glutathione start within 2 hours of first dose and last for at least 2 years afterwards for some people. The b12 deficiencies came on much slower.
  14. richvank

    richvank Senior Member

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    Hi, Freddd.

    Thank you for this very thought-provoking post!

    Here's what I suggest might have gone on when you added the glutathione or glutathione precursors:

    I suggest that the glutathione reacted with the methylB12 to produce glutathionylcobalamin. I suggest that your cells were not able to convert glutathionylcobalamin back to methylcobalamin because of a genetic mutation in the intracellular B12 processing enzymes, which you have reported having. This caused your cells to become deficient in methylcobalamin, which is a necessary cofactor for the enzyme methionine synthase, which links the methylation cycle with the folate cycle. This caused a partial block in both. In the folate metabolism, the result of this is a buildup of methylfolate, because it is not being utilized as a reactant in the methionine synthase reaction at a rate as high as normal. Because methylfolate does not have a glutamate tail, as other forms of folate in the cells do, it does not carry a negative charge, and thus is able to leak through the plasma membranes of the cells, into the blood plasma. The cells therefore become deficient in folates as well as methylcobalamin. This is called the "methyl trap" mechanism in folate research.

    Since one of the roles of folate is to assist in the pathways for synthesizing purines and thymidine, and hence in the pathways for making new DNA and RNA, the deficit in intracellular folate in the cells in the bone marrow results in difficulty in making new red blood cells, which require DNA in the initial phase of their synthesis. The result is that fewer of them are made, so the available hemoglobin is put into fewer red cells, causing them to become larger than normal. This is the origin of the macrocytic anemia that is produced by either low folate, or low B12, which causes low folate by the methyl trap mechanism.

    I suggest that when the cells have become low in folate as a result of the methyl trap mechanism (in the case we are discussing, this was initially brought on by methylcobalamin deficiency as a result of reaction of glutathione with methylcobalamin, and inability to retrieve the cobalamin from the glutathione binding) then if methylcobalamin is again added, the cells will not be able to utilize it properly, because methionine synthase will be partially blocked due to lack of enough methylfolate in the cells. The result is that the excess methylB12 will be excreted in the urine.

    When methylfolate is then added in amounts large enough to restore the methionine synthase reaction, the cells will then be able to utilize methylcobalamin more efficiently again, so less of it will be excreted in the urine.

    I don't think I can answer all the other good questions you posed, but I suspect that the above mechanism gives rise to the other symptoms you discussed as well. Some of them appear to involve the immune system. When folate goes low in the cells (which I suggest occurs as a result of the methyl trap mechanism in response to "trapping" of B12 by glutathione, in an irretrievable way in your case) this also particulrly affects the immune system and the gut, both of which depend on making new cells rapidly, and thus both of which need a generous supply of new DNA (This, by the way, is the reason why cancer chemotherapy agents that deplete folate particularly cause depletion of the red and white blood cells and unpleasant symptoms involving the gut). A partial block in the methylation cycle, which also results from this process, as discussed above, may also have effects on the immune system. It could be that glutathione actually becomes depleted in this process as well, even though adding it initially is what caused the problems in your case. Glutathione depletion definitely impacts the immune system, especially the cell-mediated immune response and controlling inflammation, which involves production of oxidizing species by the immune system.

    The reason why glutathione becomes depleted is that a partial block in the methylation cycle appears to cause draining of sulfur-containing metabolites down the transsulfuration pathway, through sulfoxidation, and into excretion in the form of sulfate in the urine. This depletes the sulfur metabolism, and this in turn lowers glutathione. However, in your case, even though this occurs later in the process, a vicious circle mechanism has been set up, and the only way to break it is to add both methyfolate and methylcobalamin together, which you did, and it worked. This vicious circle mechanism, by the way, is the reason why the methylation treatments for ME/CFS all contain both B12 and folate together. Taking one of these two individually will not break the cycle. Both are needed. This is the real breakthrough that you discovered experimentally on your own, and that was also discovered in autism research by S. Jill James and coworkers, published in late 2004. The same is true in both ME/CFS and autism.

    Anyway, I suggest that glutathione did not impact folate directly in your case, but rather indirectly, by lowering the availability of methylcobalamin, therefore shutting down methionine synthase, therefore provoking the methyl trap mechanism, which drained folate out of the cells, and thus resulted in symptoms of folate deficiency.

    The remaining puzzle, to me, is why this process affects quite a few other people as well, according to what you have reported. Do they also have genetic mutations in their intracellular B12 processing enzymes? How common are these, actually? I don't know the answers to these questions.

    Hope this helps.

    Rich
    Lotus97 likes this.
  15. Freddd

    Freddd Senior Member

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    Hi Rich,

    I find this very thought provoking.

    Thank you for this very thought-provoking post!

    We each bring a different direction of thinking at this. So, what you are saying in terms of the "model" I'm using is that I have described a "methyl-trap". This really sounds like a BINGO to me. I have seen the term but had never found a really satisfying description of the experience of it.

    Have you read the three Wheatley papers? With this additional information assuming I have described it accurately how would your interpretation of these speculative papers change?
    Cobalamin in inflammation III — glutathionylcobalamin and ...

    by C Wheatley - 2007 - Cited by 2 - Related articles
    Jan 10, 2008 ... And that it is the Co that is involved in the oxidation of arginine and ...... The reaction of nitric oxide with glutathionylcobalamin. ...
    www.ncbi.nlm.nih.govJournal ListTaylor & Francis iOpenAccess - Similar




    1. Methyl-trap can be caused by glutathione
    2. It causes folate to leave the cells by having a near total lack of methyb12.
    3. Glutathione disables methylb12 and appears to disable adb12 that is outside mitochondria.
    4. Methyl-trap symptoms are "unnaturally hard" folate deficiency symptoms with just plain different from b12 deficiency symptoms and some overlapping with each form of b12 as they build up over time.
    5. "Glutathione detox reaction" has exactly all those methyl-trap/methylfolate-deficiency symptoms with the b12 deficiency symptoms building up over time
    6. FMS/CFS forum causes a selection from population of people with certain symptoms profiles and from studies, selecting for people with low cerebral spinal fluid cobalamin levels
    7. FMS/CFS forum selects for people with methylation block
    8. FMS/CFS forum selects for people with methyl-trap by symptoms that match up with the whole FMS/CSF/ME spectrum





    INFERENCES


    1. A cellular shortage can exist of methylb12 and adenosylb12 regardless of "cobalamin" level in serum (what about CSF/CNS?) or likely even high HTC2 levels induced by glutathione converting the mb12 and adb12 to glutathionylcobalamin which is not directly active before the active form can get utilized in the cell thereby causing a "glutathione-trap".
    2. Methyl-trap can begin causing symptoms within hours of a large enough dose of glutathione



    The remaining puzzle, to me, is why this process affects quite a few other people as well, according to what you have reported. Do they also have genetic mutations in their intracellular B12 processing enzymes? How common are these, actually? I don't know the answers to these questions.

    I want to address this but give you a little more info assembled right here.

    First let's consider what genetic variations I might have. It assumes that the problem of having enough cobalamin in the CSF/CNS is a composite of at least 2 separate possibly genetic situations. There was a study done of diabetic neuropathy and it's response to intrathecal injections of mb12 of 5mg if I remember correctly. The symptoms had sizable functional improvements as long as the CSF cobalamin level remained high. It remained high in various subjects ranging from less than 3 months to more than 12 months. In the high dose studies (around 50mg mb12) the Japanese have done results indicate functional improvements continue for the duration of the dosing. The hypothesis is that there is a problem transporting cobalamin through the BBB that is overcome by a high serum level. Currently they have an IV dosing study at 50mg again going on presumably to see what the serum level range that is needed to actually penetrate the CNS/CSF. A 5 star 1mg sublingual might peak the serum level at 10,000-20,000pg/ml. I have to maintain an estimated (by model) level of about 200,000pg/ml to maintain spinal cord functioning along with a certain "quality" of mb12.

    In addition the pragmatic test which I suggest people use is that 50mg sublingual dose of 7.5-10mg SC injection after body equilibrium and tailing off of start-up responses to see if they have benefit from CNS penetrating doses. If they are interested in finding the exact penetration dose they can work up to it as I did. It did not happen below 6mg for me, and there is one "it works" at 7.5mg which does not improve in any way except duration up to 25mg sc injection. For some people adb12 gets the "it works" response, in others it is the mb12 that gets it, and in some each of the two forms gets it.

    As far as body responses, many people have separate response to each of the two active b12s. This is very easily demonstrated.


    why this process affects quite a few other people as well, according to what you have reported. Do they also have genetic mutations in their intracellular B12 processing enzymes?

    From the evidence of research the people with FMS/CFS have problems maintaining a high enough level of either or both cobalamins in their brain independent of blood serum level due to hypothesized problems crossing the BBB and/or being cleared out too quickly (could glutathione be involved there somehow?) So if one looks at people with some combination of the 4 active b12 deficiencies, methylation block and/or methyl-trap and/or CFS/FMS one is looking at the a population with mb12, adb12 and methylfolate deficiencies plus other factors. It may be exactly these other factors and combinations of factors along with genetic factors that distinguish which disease form breaks through the "non-specific" symptoms barrier first.


    So I appear to have:

    1. Inability to get enough cobalamin into my CSF/CNS
    2. I appear to not be able to retain cobalamin in my CSF/CNS
    3. I have very impaired capability, but not completely incapable, of utilizing Cycbl, it affected 2 symptoms out of 175 noticeably, perhaps more below the level of notice. I appear to have some of the required enzyme(s) but not much.
    4. I have very impaired capability, but not completely incapable, of utilizing Hycbl, extent not known. It appears to affect somewhat more symptoms, but still very few. I appear to have some of the required enzyme(s) but not much.
    5. I have some degree of conversion of mb12 to adb12, only partial lack of enzyme.
    6. I have some degree of conversion of adb12 to mb12, only partial lack of enzyme
    7. I have such inadequate conversion of folic acid to methylfolate that I have outright deficiency symptoms of folate deficiency while taking folic acid and eating a pretty decent diet with dark green leafies etc.
    We know, and can demonstrate, that folic acid conversion is inadequate for 50% of population or more genetically because even the best converters may not covert enough to escape from methylation block and methyl-trap. Maybe "folate-trap" woiuld be a better name for it.

    We know from much research that 33% of persons have zero response on the measures taken, to hycbl and/or cycbl and the rest often have very minimal response both as to range of symptoms affected and degree of affect. As far as folic acid and cyanocbl for me they were able to maintain my MCV <100, influenced the degree of pain my "beef-red burning" tongue felt and maybe a few other things less noticeable. I would not have been one of those 33% for whom cycbl/folic acid would have been ineffective for MCV. I would have been a success story even while severely disabled by other active b12/folate deficiency symptoms and signs. It's not what I call success but researchers tracking MCV would have called it a success. For me it just sucked.

    It is easily demonstrated that for the other 2/3s b12 equilibrium is never reached taking cycbl and/or hycbl because the suitable methylb12 and/or adb12 will virtually always, with necessary cofactors such as Metafolin, produce more results when looking at number of symptoms affected and depth of response. I know that these are supposedly people without my minuscule keyholes for converting inactive cobalamins to active ones. However, my keyholes are only smaller, not non-existent. It is not a completely shut off thing. One might hypothesize that once certain types of damage are done and the normal body load of b12 is depleted, the keyhole that the person has is too small to replenish the body deficiency. Only 1-5mcgs are circulating in the blood serum normally making the body load being normally 1000-5000 times as much as is in circulation. It would appear that he reason adb12 is effective even after saturation with mb12 is because it can restore all the mitochondria without adequate adb12 in a couple of doses by diffusion and it can take decades by trying to get enough adb12 to the mitochondria trying to push it through the several keyholes, involving a keyhole even in the conversion of mb12 to adb12 and the reverse.

    Now for the last piece of info. Of the nine people purposely or accidently trying glutathione 100% were already on one active b12 program or another and most on Metafolin as well. This made for a very pronounced effect from the glutathione which ranged in form from glutathione IV infusions to to MAXGL to undenatured whey to various intentional and accidental combinations of precursors. It didn't matter HOW the person got there, they all worked in generating glutathione and since the people were using active b12s and folate there was a big drop and a big rebound timed with the glutathione. The other group were those who developed "glutathione detox reaction" over longer periods of time but were able to immediately start reversing it by taking the right supplements. Everybody doing it had some mb12, adb12 and folate startup responses post glutathione with the first larger doses of each item they took, which for those having gone through it before, were a real relief.

    My experience has been that many people have a subset of the symptoms I have or a lesser degree of intensity for the same symptoms. They tend to respond with less distinct responses but some respond with more intense and more distinct reponses so I am not at the extreme on everything. With the evidence that I have at least seven different things potentially going on surrounding folate and cobalamin I would say that there is every probability that some of these same things will be found in this entire population, such as CSF/CNS cobalamin deficiency, folic acid to mfolate conversion and who knows what else. From the symptoms most here have dozens of symptoms of folate and mb12 and adb12, both body and CNS symptoms, indicating every expectation of similar responses. I think that my keyhole size reduction merely limits the interconversion. I wasn't discovered as a child because I did not have such a complete blockage to b12 conversion as to have failure to thrive or other fatal infant deficiency syndromes. So perhaps these partial problems are far more common than the complete system failure you have in mind. It all adds up to my being hypersensitive as to quantity and type of b12 for CNS and body, hypersensitive to qualitative issues of mb12 and everything is amplified by ongoing lifelong folate deficiency symptoms until I took Metafolin. Based on my experience with hundreds of people giving feedback the separate responses to adb12 and mb12 are normal and expected, at least until adb12 equilibrium is reached.

    So what do you think of all this? The symptoms matrix I am modeling in Excel right now is nerely done for this whole set of symptoms and distinguishing which ones respond for CNS versus body, adb12 vs mb12 vs folate. And The methyl-trap appears to produce a very clear, but not complete picture of folate deficiency.


    We are both out to solve these problems. We come at it from very different directions and when we can agree, such as your descriptions of both methylation block and methyl-trap and how they match up to the symptoms data I think indicates a correct description of results though not necessarily a correct description of causes, especially small details. Those are the things researchers will be hashing out on this for the next hundred years. That is not a span of time us sick people have. I have never regained as much feeling in my feet as I had before the glutathione. If I hadn't foind the mb12 when I did, I would be dead now. If I hadn't found how to reverse the neurological defects in the CNS when I did I'd be wearing diapers in a wheelchair if I were still alive. I estimate that there are another 100,000,000 people in the USA alone having identifiable symptoms of mb12/adb12/mfolate deficiencies including those having the symptoms 20 years before Parkinson's and MS develop. I am playing to keep mb12 and adb12 from being banned by law except by prescription. Then these problems would never be solved as we as a society shoot ourselves in every part of the body you can name. These are the stakes I'm playing for. What are the stakes you are playing for?

    These problems cost me everything important in my life and I'm starting over at 62. I identified the problem I had with cyanocbl by 1980 and took in papers to docs describing such and identifying the real b12 forms. They told me I was wrong and called me names and kicked my out of practices. It got me labeled as "conversion disorder" (Its All In Your Head late 19th century fashion), "hypochondriac", "liar" as in "you have too many symptoms to be believable" and got me kicked out of multiple practices for insisting cyanocbl wasn't the "real b12" and that I really had things going wrong with me, real physical symptoms.

    In the reviewing of group health plans we also did patient satisfaction surveys. Playing "BLAME THE PATIENT" and "CALL THE PATIENT NAMES IF YOU DON'T UNDERSTAND THE PROBLEM" is guaranteed to get a bad satisfaction rating as well as being bad medicine.

    Misunderstood research is the ground on which these docs were standing to do such things. All those biochemical tests based on a population chronically deficient in adb12, mb12 and methylfolate just achieves a norm that fails to recognize the real problems and because of a lack of establishing a supplemental standard basis on which to base nutritional and vitamin research by changing things against that standardized background, the very real differences are not seen. I feel it is very important to achieve a full understanding of the active b12s and folates because so many people are at risk without it. If the Nobel prize had been awarded for methylb12 and adenosylb12 in 1948 we wouldn't even be having this discussion and the entire USA/UK medical scene would be different with millions much healthier. My life would have been better without CFS/FMS and the other 100 symptoms of various aspects of b12 and folate deficiencies.
  16. dannybex

    dannybex Senior Member

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    Heavy Metals and the active folates...

    I just wanted to throw heavy metals into the mix. If you have hidden heavy metal toxicities, the Metafolin may be causing the problem...

    I got a lot worse back in Oct-November after some of the methylation supplements were overprescribed by my doctor. I was prescribed 2 kinds of b12, and 3 different types of the active folates (from the simplified list).

    The end result was severe anxiety, cramping, cold extremities, neuropathies, etc., all of which were a result of heavy metals (mainly mercury and arsenic) being dumped too quickly. I had to stop the methylation supps, and haven't restarted them yet, although I hope to soon...maybe in the next month. As both Freddd and Rich say, one needs these nutrients not only for detoxification, but for rebuilding the body.

    So even though I had almost the worst possible reaction to the simplified protocol, I'm grateful for it in a weird way -- it proved once and for all that I have carried a serious burden of stored heavy metals, and need to slowly chelate them out. I've restarted the Cutler protocol to do this as safely as possible.

    By the way, Cutler says that methylb12 does not methylate mercury. I don't have the exact quote here, but he said something like if it did, we wouldn't have problems that some of us do. The mercury in fish is in the methylated form, that's why they can handle it with no problem. Again, not an exact quote, but something along those lines.

    Best regards,

    Dan
  17. Freddd

    Freddd Senior Member

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    Hi Dan,

    Arsenic is an interesting thing. If you after find yourself in an old building with late 19th century or earlier green wallpaper or maybe in an area with "treated" lumber, treated with arsenic to preserve it, and you smell the inappropriate odor of garlic, what you are smelling is one of a number of toxic methylarsinine a very volatile substance created by methylb12 producing fungi or bacteria growing on "Paris green" wall paper or other arsenic containing items. When a person has a body burden of arsenic and they take methylb12, the arsenic is mobilized and exhaled from the lungs giving the person garlic breath in the absence of garlic or DMSO.

    http://en.wikipedia.org/wiki/Trimethylarsine
    Poisoning events due to a gas produced by certain micobes was assumed to be associated with the arsenic in paint. In 1893 the Italian physician Bartolomeo Gosio published his results on "Gosio gas" that was subsequently shown to contain trimethylarsine.[4] Under wet conditions, the mold Scopulariopsis brevicaulis produces significant amounts of methyl arsines via methylation[5] of arsenic-containing inorganic pigments, especially Paris green and Scheele's Green, which were once used in indoor wallpapers. Newer studies show that trimethylearsine has a low toxicity and could therefore not account for the death and the severe health problems observed in the 19th century.[6] [7]

    So methylb12 speeds up the removal of arsenic from the body. As it detoxifies a single atom of arsenic several methyl groups are needed and so multiple mb12 molecules are disabled. Removing 1mg of arsenic from the body via methylb12 disables more than 53 mgs of mb12, approximately 11 times the body's total quantity. Removing cyanide with mb12 or hycbl also requires mass amounts such as multiple IV doses of 35 grams.

    You should know that ONLY methylb12 is a methylator. Adenosylb12 goes into the mitochondria and generates ATP for energy. Hycbl and cyanocbl both have to be converted to both mb12 and adenosylb12 or they are inactive as a vitamin. So when they are used they compete for methyl groups donated from other sources.

    severe anxiety, cramping, cold extremities, neuropathies,

    Those are nonspecific reactions as they can be caused by other things. Cramping of one sort can be caused by too much potassium or calcium. Another distinctive form of cramping is caused by low potassium which is often caused by successfully starting a methylation program as cell formation goes into high gear. Severe anxiety often can result, for people who tend to have anxiety, from the sucessful mehtylation startup as the nerves start working better and differently from the shutdown state. Some feel it as energized, some as euphoria, some as nervousness and some as anxiety.


    Neuropathies, I can tell you from massive experience, can intensify considerably with a large increase in paresthesias as to intensity, frequency and type making it appear that the neuropathies are worse. Also nerves that have ceased to function can send jolting pain all the way down the body as they come back to life. The neuropathic areas become very painful as they are returning to life and functioning. Often the intensified symptoms are run through backwards from the order they came on but a hundred times faster and more intense.

    Cold extremities are often experienced as the neurology is undergoing changes, again from my own years of experiences. So I see nothing at all that actually shouts out "heavy metals" but instead says "start-up responses".

    Why do you distinguish these as "heavy metal" inspired symptoms?. Methylb12 promptly removes tiny amounts of arsenic from the body removing the burden slowly but eventually.

    Can you describe the cramping as fully as possible for instance, also the neuropathy changes though those when those are changing distinguishing worsening from getting better is very difficult and takes time. These might help distinguish more of what is going on. Good luck.
  18. richvank

    richvank Senior Member

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    Hi, Dan.

    Here's a repost from another thread that addresses methylB12 and mercury.

    Rich


    My concern about methylB12 is related only to its possible potential for methylating inorganic mercury that may be in the body, primarily from exposure to mercury vapor, as is released continuously from amalgam fillings in the teeth. Methyl mercury is readily able to cross the blood-brain barrier and enter the brain, where it apparently then reacts with enzymes containing selenium (and to a lesser extent, sulfur) and acts as a neurotoxin, with a residence time in the brain measured in years.

    I do not have proof that this will actually occur in humans with the inventories of inorganic mercury that are actually present and the dosages of methyl B12 that are used in treating ME/CFS.

    My concern comes from the fact that there are published papers indicating that methyl B12 is able to react and donate a methyl group to inorganic mercury, and in fact, it is one of the only substances in biological systems that is able to do this. The reason is that inorganic mercury exists as a doubly positive mercuric ion (Hg++). In order for a substance to donate a methyl group to it, the substance must be negatively charged. methyl B12 forms a carbanion, which is able to do this.

    It is known that the way methylmercury enters fish is that bacteria in aquatic environments use methyl B12 and other similar substances to methylate mercury, and then are eaten and travel up the food chain to the larger fish. Apparently the bacteria methylate the mercury as a means of exporting it to their outer surfaces and so protecting themselves from its toxicity. It can have some toxic effects on fish (see first abstract below) and when people eat fish containing methylmercury, it can be toxic to them, especially if their bodies are low in selenium (see second abstract below). Methylmercury dumped as waste into the ocean in a fishing area was responsible for the Minimata disease disaster in Japan in the late 1950s, and methylmercury used to treat grain seed that was unfortunately later eaten by people caused a disaster in Iraq as well.

    There have been experiments in guinea pigs in which it was found that methylation of mercury occurred in their bodies. It is not clear whether this methylation occurred within their own metabolism, or whether it was carried out by bacteria in their gut.

    As far as I'm concerned, this is an issue that has not yet been resolved. I'm aware that people with certain polymorphisms will benefit more in terms of helping their methylation cycle by taking methyl B12 rather than hydroxo B12. I know that there are people who are taking dosages of methyl B12 of several milligrams per day, sublingually, and some are reporting benefits. I don't know what their body burdens of inorganic mercury might be. Unfortunately, there is no good way of evaluating it, short of doing autopsies, which isn't very helpful for people who want to keep living for a while!

    It may be that supplementing with selenium will give sufficient protection from methylmercury toxicity. This approach is actually used by marine animals and birds, who eat seaweed, containing selenium, together with fish containing methylmercury. Some whales have been found to have large deposits of selenium-mercury compound in their livers. This is very chemically stable, and makes them both non-bioavailable. It should be noted, however, that selenium is toxic in large amounts as well, and the Institute of Medicine has placed a recommended upper limit on selenium supplementation of 400 micrograms per day. Some have argued that this limit is too conservative. The safe upper limit for an individual probably depends on a number of factors, the body burden of mercury being one of them, but it is difficult to determine what it should be on an individual basis. The Institute of Medicine attempts to set a limit with a safety factor that will apply to the general population.

    I wish I could give you a more definitive answer to your question, but that's as much as I know. It's possible that I am being overly cautious in raising this issue, but I really do not want people to be harmed.

    Best regards,

    Rich


    J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2009 Oct;27(4):212-25.
    Reproductive, developmental, and neurobehavioral effects of methylmercury in fishes.

    Weis JS.

    Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA. jweis@andromeda.rutgers.edu
    Abstract

    In the decades since the Minamata tragedy in Japan, there has been a considerable body of research performed on effects of methylmercury in fishes. The studies have revealed that some of the most sensitive responses seen in fishes are reminiscent of the symptoms experienced by the Minamata victims. This article reviews the literature, with a focus on mercury's effects on fish reproduction (hormone levels, gametogenesis, fertilization success), embryonic development (morphological abnormalities, rate), the development of behavior, and neurobehavioral effects in adults. Both experimental exposures and epidemiological approaches are included. There have been many studies demonstrating delayed effects of mercury exposure in that exposures during one life history stage can produce effects much later during different life history stages. For example, exposure of maturing gametes can result in abnormal embryos, even though the embryos were not themselves exposed to the toxicant. Exposures during sensitive embryonic periods can produce long-lasting effects that can be seen in adult stages. The existence of these manifold delayed effects renders the practice of short-term toxicity testing particularly unhelpful for understanding the effects of this (and other) toxicants.

    PMID: 19953396 [PubMed - indexed for MEDLINE]



    Toxicology. 2010 Nov 28;278(1):112-23. Epub 2010 Jun 16.
    Dietary selenium's protective effects against methylmercury toxicity.

    Ralston NV, Raymond LJ.

    Energy & Environmental Research Center, University of North Dakota, 15 North 23rd Street, Grand Forks, ND 58202, USA. nralston@undeerc.org
    Abstract

    Dietary selenium (Se) status is inversely related to vulnerability to methylmercury (MeHg) toxicity. Mercury exposures that are uniformly neurotoxic and lethal among animals fed low dietary Se are far less serious among those with normal Se intakes and are without observable consequences in those fed Se-enriched diets. Although these effects have been known since 1967, they have only lately become well understood. Recent studies have shown that Se-enriched diets not only prevent MeHg toxicity, but can also rapidly reverse some of its most severe symptoms. It is now understood that MeHg is a highly specific, irreversible inhibitor of Se-dependent enzymes (selenoenzymes). Selenoenzymes are required to prevent and reverse oxidative damage throughout the body, particularly in the brain and neuroendocrine tissues. Inhibition of selenoenzyme activities in these vulnerable tissues appears to be the proximal cause of the pathological effects known to accompany MeHg toxicity. Because Hg's binding affinities for Se are up to a million times higher than for sulfur, its second-best binding partner, MeHg inexorably sequesters Se, directly impairing selenoenzyme activities and their synthesis. This may explain why studies of maternal populations exposed to foods that contain Hg in molar excess of Se, such as shark or pilot whale meats, have found adverse child outcomes, but studies of populations exposed to MeHg by eating Se-rich ocean fish observe improved child IQs instead of harm. However, since the Se contents of freshwater fish are dependent on local soil Se status, fish with high MeHg from regions with poor Se availability may be cause for concern. Further studies of these relationships are needed to assist regulatory agencies in protecting and improving child health.
    Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

    PMID: 20561558 [PubMed - indexed for MEDLINE]
  19. Freddd

    Freddd Senior Member

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    Hi Rich,

    Because of my background with a father who was a dentist and was undoubtedly contaminated with it daily, playing with mercury, carefully, but still doing so as a child, a bunch of fillings after braces, I started selenium early on, as soon as it became available as a supplement some years before I started mb12. I take 200mcg a day which seems reasonable. Around here "locoweed" is a native plant. I figured that a supplement might help and likely wouldn't hurt.
  20. Freddd

    Freddd Senior Member

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    Hi Rich,

    One thing to add to my post to you a few up on the various possible genetic contribution to the problems of people here. The fact that I responded to cyanocbl and folic acid just enough to keep my MCV under 100 made it impossible to be diagnosed with b12 deficiency even with multitudinous symptoms because in the 1970-80-90 etc until present for many docotrs, the belief is that macrocytosis is the primary b12 deficiency response and that it can't be present without it. I hear that from people all the time, told that by their doctors. This is based on 50 years of research doing everything possible to "prove" cyanocbl and hycbl decrease macrocytosis and thereby are b12.

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