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Glutathione depletion blocks conversion of OH-B12 to methyl-B12: new evidence

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by richvank, Aug 9, 2011.

  1. richvank

    richvank Senior Member

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    Hi, Drex.

    The dosages of hydroxo B12, methylfolate and folinic acid in the SMP can be increased if tolerable. For most PWME's, I think the dosages of the folates will probably be adequate. Some people do need higher B12 dosages, depending on their genomic polymorphisms. I realize that Freddd recommends avoiding folinic acid and going to higher dosage for methylfolate. However, as I've mentioned in the past, I think his genomic polymorphisms are unusual. Folinic acid is helpful for most PWME's, and going to higher dosages of methylfolate may block the glycine N-methyltransferase reaction, raising the ratio of SAMe to SAH too much. This could raise the rates of the methyltransferase reactions, and it's not clear to me what the consequences of that could be. I do agree that making sure the cofactor nutrients are at adequate levels in the body is important.

    Best regards,

    Rich
  2. richvank

    richvank Senior Member

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    Hi, Denise.

    Hopefully Drex's experience with the trehalose will be applicable to you, also.

    Swallowing B12 in a capsule will not get enough into the bloodstream to treat a partial methylation cycle block. Sublingual or injected B12 will get enough into the blood.

    We have not come to agreement on which form or forms of B12 are best to start with. Which is best seems to vary among different people, for genetic reasons. I have suggested starting with hydroxo B12, and this seems to help most people who try it. Hydroxo B12 does not work for Freddd, and in fact sets back his recovery. He finds that a combination of adenosyl B12 and methyl B12 at fairly high dosages is what he does best on.

    The urine amino acids test is helpful, but involves some uncertainties that can be resolved by taking the plasma amino acids test.
    The protocol I have suggested does not include SAMe. The multi in this protocol does have some TMG in it.

    Some people experience benefit from taking SAMe, but until the partial block of methionine synthase is lifted, taking extra SAMe will add to the flow into transsulfuration pathway, and some people experience sulfite problems if this flow gets too large, such as headaches or breathing problems. Sometimes these problems can be helped by taking molybdenum.

    Best regards,

    Rich
  3. drex13

    drex13 Senior Member

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    I have tried to do the Mb12 and metafolin tablets (Solgar) two different times, with the same result, with regards to digestive issues. I used them now because I ran out of the methylfolate drops. Methylfolate and folinic acid are two different things, the folinic are tablets that you can cut up into the right dosage, mine are made by Source Naturals , called Mega Folinic. I have not tried the MB12 drops yet, but have used the Hb12 and methylfolate drops (Methylmate B) with no issues. I buy the drops from Holistic Heal. (Yasko site). I take the SMP dosages, but have no other co-factors in place. Just stared adding them last night. I have been using the Hb12 and Methylmate B for about 6 weeks now.

    I just discovered that it looks like Source Naturals used to sell Metafolin in tablet form that contained no sweeteners, but it looks like they replaced that with the Folinic Acid. Wonder why ?
  4. Rockt

    Rockt Senior Member

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    Some people experience benefit from taking SAMe, but until the partial block of methionine synthase is lifted, taking extra SAMe will add to the flow into transsulfuration pathway, and some people experience sulfite problems if this flow gets too large, such as headaches or breathing problems.


    Rich, I was wondering how often you've seen adverse reactions to Sam-e? I started taking it Tuesday, (1 200mg tablet on an empty stomach/day), and my already crampy calves are worse and my entire legs feel weak and a little rubbery, (like I just did heavy leg presses). Could this be from the Sam-e, or maybe just coincidence? No headaches or breathing difficulties. In fact, I might have experienced a little increase in mental functioning, or at least a bit of a calming of my normally over-active brain.

    Also, I was wonderiing if you have a theory as to why PWME are so sensitive to ordinary supplements, that normal people can take pretty much without noticing anything? In my own case, B com, vit. E. and zinc seem to give me trouble. When I start to feel worse, I back off on these supplements and gradually feel better.

    Thanks.
  5. richvank

    richvank Senior Member

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    Hi, Rockt.

    When I first suggested the simplified treatment approach in January, 2007, it included SAMe. However, several people who tried it experienced symptoms from it, so I took it out. I don't remember how many reported this, but it was quite a few, enough that it seemed better not to include it in the basic protocol.

    I don't know if your leg-related symptoms are caused by SAMe. I guess the way to find out is to discontinue it, without changing anything else at the same time, and see if you experience improvement.

    My hypothesis for why PWME's respond negatively to taking various supplements is that their metabolism is blocked by the vicious circle mechanism involving glutathione depletion, B12 functional deficiency, partial block in the methylation cycle, and folate draining from the cells. In this situation, taking various supplements can accentuate the blockages and produce increased oxidative stress. It's important to address the root of the blockage in the metabolism, which is at the enzyme methionine synthase, and that requires a combination of active folate and high-dose B12 of the right forms, either sublingually or by injection. There does need to be enough of the cofactor nutrients, including the ones you mentioned, to support the methylation cycle and related pathways, but taking more of them than the amounts needed when there is this fundamental blockage will not help.

    Best regards,

    Rich
  6. richvank

    richvank Senior Member

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    Hi, drex.

    I don't have any inside information on this, but note that the process for making Metafolin is patented by Merck in Germany. The companies that sell Metafolin have to be licensed by Merck. Perhaps Source Naturals no longer had a license,or decided not to pay the license fees, or perhaps Merck decided not to continue their license after PamLabs, under license from Merck, started supplying Metafolin as part of their prescription "medical foods," including Deplin, CerefolinNAC and Metanx, to minimize competition with these new products. MethylMate B uses 5L-methyl THF that is made by Gnosis. They must have a different process that does not infringe on Merck's patent. There is also 5-MTHF on the market, which I think is a racemic mixture of active and inactive forms of methylfolate. No doubt financial factors were involved somewhere along the line.

    Rich
  7. Sasha

    Sasha Fine, thank you

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    Hi Rich - as you know, I've been trying Freddd's b12 protocol but have come a cropper with what appears to be some sort of electrolyte deficiency caused by the relatively large amounts of b12 I had been taking on the protocol (about 2mg ab12 plus 7.5mg mb12 daily). I haven't been able to clearly identify the deficiency or consistently alleviate it so in the last couple of days I've stopped the protocol and am going to let my system settle back to normal before I have another go (either with a gentler version of Freddd's protocol or possibly with yours).

    You suggested in another thread that I try a lower dose of b12 such as the 2mg/day that people work up to on your protocol. I already have ab12 and mb12 to hand and since you are now suggesting that people consider having a go with mb12 rather than hb12, wondered if you had a view on a good ratio of ab12:mb12? Or whether you'd suggest mb12 alone?

    When I started Freddd's protocol, I began with ab12 for a week and felt an immediate (within minutes) increase in energy and on that day, and every day for the rest of that week, was able to be much more active than I have been for over a year. That makes me think that ab12 does me good! Adding in mb12 seemed to cause my electrolyte problems (extreme exhaustion and muscle soreness) which possibly masked any improved wellbeing that mb12 might have otherwise given me.

    Another question: I notice that the multivit/min supplement on your protocol excludes iron and copper. I take iron supplements due to long-term borderline anaemia (due to heavy periods). Does iron interfere with some element of the protocol?
  8. richvank

    richvank Senior Member

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    ***Hi. Sasha.

    ***I adopted Dr. Amy Yasko's multi when I suggested the simplified treatment approach. She has omitted both copper and iron, because both can contribute to oxidative stress under certain circumstances via the socalled Fenton reactions. However, both copper and iron are essential minerals, and women of reproductive age of course have a higher demand for iron than do children with autism, which is what the multi is used for primarily. I encourage people to do some testing to see which essential nutrients might be deficient, and to supplement accordingly.

    ***There have been various issues raised concerning the use of this multi. Some people are sensitive to one or more of its constituents, and are not able to take it. Some people need more iron or copper. The reason I included a multi is that I was trying to make a "one size fits all" protocol that people could use without having to do a lot of testing or having to take numerous individual supplements. That has turned out to be a difficult thing to do, because people are unique, having inherited different sets of genetic polymorphisms. The Yasko multi has additional ingredients that are designed to support the methylation cycle and related pathways, so I decided to use it. But I probably should come up with a sort of nonallergenic, basic multi that could be an alternative for people for whom this one does not work well.

    Best regards,

    Rich
  9. Sallysblooms

    Sallysblooms P.O.T.S. now SO MUCH BETTER!

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    Tried to delete. I misread about SAMe. I take it, but thought the amount above was high, misread it.
  10. Sasha

    Sasha Fine, thank you

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    Thanks, Rich, for another very prompt and very helpful reply. I'll give an equal ratio of ab12:mb12 a shot at 1mg:1mg.

    Thanks also for explaining the background to the iron & copper story with that supplement. It's also helpful to know about some of the issues with it - certainly there have been a few individual supplements in the basic vits/mins that Freddd recommends that have given me trouble (Vit C, Mg, Ca) and if they were all in a single multi I wouldn't have been able to take anything.

    I've been reading your & Dr Nathan's paper on the study of the 21 PWC who underwent your protocol. Very interesting! The next step, of course, would be an RCT or even a study with waiting list controls. Are you able to tell us if anything is in the pipeline?
  11. richvank

    richvank Senior Member

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    Hi, Sasha.

    It would be very nice to have an RCT, blinded, with placebos, on a larger group of patients. However, that takes the right institutional setting and money. Dr. Nathan and I were able to do the less formal clinical study in his private practice, with a relativelhy small amount of funding from an anonymous donor. I'm retired and not associated with any institution. I also don't have the appropriate credentials (formal education in the biomedical sciences) to apply for a grant, even if I were affiliated with an institution (I worked for the University of California for about 30 years, but in engineering and the applied physical sciences). My hope is that a biomedical researcher with appropriate credentials and institutional affiliation will get interested in the methylation treatment and decide to apply for a grant do a study with all the appropriate bells and whistles. Getting the grant would still be a challenge, I think.

    I'm planning to present a poster paper at the upcoming IACFS/ME conference in Ottawa, and maybe somebody there will get interested. I've submitted abstracts to the previous four of these conferences. The first was not accepted, and the other three were assigned to the poster sesssion, rather than an oral presentation, as was the one I submitted this time. That's viewed as sort of the "black hole" in this organization, unlike some other societies, which devote considerable time at the conference to the poster sessions.

    I've bent the ears of the leaders of this organization mercilessly, one on one, over the past few years about glutathione and methylation, but so far I would say that (with a few notable exceptions) they just don't "get it." The fact that no patented drugs are used in the protocol may have something to do with this. Physicians are not trained to use nutritional supplements for treatment, and their usual view of them is, "Well, they probably won't hurt you." So I've continued to work with the patient community, and as patients go to some of these leading ME specialist clinicians and tell them about their results, maybe the message will get through that way. People who actually have ME have been the most receptive to trying methylation treatment. Thanks for your interest.

    Best regards,

    Rich
  12. Sasha

    Sasha Fine, thank you

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    Hi Rich,

    That's frustrating that what would be a low-cost trial (given that patients could pay cost for the supplements) hasn't yet got support.

    Placebo controlled would be ideal, of course - though one of the issues with placebos for some treatments is that they are detectable (e.g. they don't taste of anything whereas the active drug tastes nasty, or they don't have immediate side effects whereas the active drug does). I wonder if a good design would be to have the control arm take the basic vits/mins (some of which probably taste nasty and have side effects) and lecithin just like the active b12 arm and have the control arm just taking a sublingual placebo for the b12. I wonder if Jarrow would produce a b12-less sublingual for a trial? Or people have talked on the forums about compounding pharmacies making things to their spec, so that might be another option.

    I wonder if it's worth approaching the ME research charities to ask if they can link you up with someone who could help. Or maybe if Dr Yasko could suggest contacts (I would have thought she'd have been trying to get a trial going for her autism work).

    A lot of clinicians find themselves in this position, I think - they have a protocol that they think benefits patients but don't have the clinical trial background or institutional affiliation to get a trial underway and need a research partner (and funding). And it reflects very poorly on our research funding at a structural level that there often isn't funding available for non-patented treatments that won't be a cash cow for someone.

    I wonder if it's even worth approaching the local university's department of epidemiology or public health to ask if there's anyone who would be interested in working on a trial and applying for grants (perhaps someone already working in a related area, which would be apparent from their website). There is research money available for nutritional funding, apparently, though an ME charity would probably be a better bet.

    Sorry, just thinking aloud - you've probably tried a lot of this stuff already. But your trial would be very low-cost in relation to a drug trial, especially if it was a preliminary controlled trial with relatively small numbers (e.g. 50 in each arm - someone would have to do a statistical power calculation based on your expected effect size in order to determine a suitable sample size). If you get an effect in a small trial, it would get attention and be easier to get funding for a bigger trial.

    I wonder if it's worth getting a bunch of the ME clinicians who do "get it" like Dr Myhill to either agree to join in the trial (i.e. propose a multi-centre trial) or just write a testimonial to the idea of doing a trial, in order to present it to the ME research charities.

    Sorry, just rambling off the back of my frustrations on this - it has long been a bugbear of mine that this kind of thing is hard to get funded while useless pharmaceutical trials get done all the time.
  13. Valentijn

    Valentijn Activity Level: 3

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    Very frustrating, as these nutritional supplements make a big difference. I wonder if naturopathic educational institutions (like Bastyr University) might be more interested in running studies, and if they'd qualify for funding.

    Maybe the anti-supplement doctors need things dumbed down for them, in a similar manner to treating using "real" drugs: "If symptoms X Y and Z, and/or lab results A B and C, treat with R S and T at these dosages." Even some of the more mainstream M.E. doctors might be happier with things spelled out, rather then presenting them with a complex microbiological theory, especially if they're very busy treating patients and don't have time to focus on understanding the processes occuring.

    That said, I have no idea how well doctors in general retain what they learned about this sort of stuff, or how well they're expected to understand the diseases they're treating.
  14. Sallysblooms

    Sallysblooms P.O.T.S. now SO MUCH BETTER!

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    :DYes, supplements do so much when you have good doctors to help with dose and brands, time of day, schedules etc.


    HA! Good point. I am so glad my doctors do know how to treat with supplements!!!!

    It actually isn't rocket science to understand how we lose many vitamins, hormone balance etc when ill or stressed. Even healthy people need to be careful. Using all of the scripts most doctors love ends up depleting many things in the body. Supplements are so important.
  15. suzanne

    suzanne Senior Member

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    Hi Rich,
    I found your comment on SAM-e really interesting. I had tried the Yasko protocol, after having my SNP's tested and started the noinated supplements. Mostly I was taking hydroxy B12 and actifolate. After 6 months i had o improvement and gave up- not being aware that i am an mdermetylator and really needed the methyl b12. 18 months down the track I have now started the methyl B12 (750 mg jarrows) and methyl folate (800mg)...I worked up to these doses and have been on them 3 weeks. i am noticing detox type exacerbation of symptoms such as ineased headaches and nausea, but I am alos noticing more energy at the same time- and my daily migraines (agh) have slowed down and I have not had one now or about 8 days (yah). So I would say that my genetic mutation Taq fok ++; mthfr +-; plus others must mean I need the methyl B12 - it is like chalk and cheese for me with the first time around. I am glad I found this site so that I could revisit as I was just getting more and more neurological stmpoms and BAD body itching. The body itching is starting to improve- but is a bit variable on different days. I can feel that the 750 mg methyl b12 is the maximum I can go to at hits point in time.

    I am interested in the SAM-e comment you ade- re sulfites and headaches. My dr tested me a while back and said that based on high histamine results I was an undermethylator- so, he put me on 800mg SAM-e (titrated slowly) B6 200mg, P5P 40mg, zinc 75 mg and vit E 400iu. I seemed to not noticce any difference to these cofactors.

    I am now wondering if the SAM-e may be too much whilst I am trying to get the methylation cycle going...do you think I should cut this out- chronic daily headaches is a number one symtom of mine and the headaches have gotten worse since i starte the ethyl b12- sorry for the lon story. Any thoughts about cutting out the SAM-e as a trial. i guess I can always addit back in down the track when (if) the headaches settle. i would hate to think that i am causing/ adding to my headache woes.

    regards, and thanks for your informed input, Suzanne
  16. richvank

    richvank Senior Member

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    Hi, Suzanne.

    It does sound as though stopping the SAMe supplementation would be a good thing to try in your case.

    Rich
  17. hixxy

    hixxy Woof woof

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    Rich: Have you found any further information regarding this problem of impaired synthesis of methylcobalamin by GSH depletion? Do we know if glutathione actually a cofactor in the enzyme? I don't suppose you've decided on a cut-off for reduced glutathione levels at which you'd recommend methylb12 instead of hydroxob12?

    I suspect I fall into this group, but given my 2 homozygous COMT polymorphisms this is a bit horrble. I find methylation treatment doesn't cause anything remote to detox symptoms until I give myself a small amount of methylb12.

    hixxy
  18. richvank

    richvank Senior Member

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    Hi, hixxy.

    Yes, a recent paper from Korean researchers has reported that glutathione increases the affinity of the CblC complementation group for cobalamin by a factor of over 100. The CblC complementation group is part of the intracellular B12 processing pathway. When glutathione becomes depleted, its affinity for cobalamin drops, and that inhibits the flow of B12 through the processing pathway to make both methyl B12 and adenosyl B12.

    No, I don't have a quantitative value for the cutoff, but if you find that you need methyl B12 to get a good effect, I think that you need it. You wrote that it is a bit horrible because of your COMT SNPs. Do you mean that you experience neurotransmitter-related symptoms when you use methyl B12? Please explain.

    Best regards,

    Rich
  19. hixxy

    hixxy Woof woof

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    Increased overstimulation and immediate and drastic worsening of MCS. This is on tiny tiny little bits. Doing hydroxob12 shots does absolutely nothing. Almost seems like I'm injecting saline. Methylb12's effect is drastic though. I'm going to discuss with my doctor still continuing the hydroxob12, but adding teeny weeny bits of methylb12. Maybe eventually the glutathione will rise enough that I can switch to hydroxob12 only as I should have plenty of methyl groups.
  20. determined

    determined Senior Member

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    Hi hixxy,
    I think mB12 (or maybe the combined effect of mB12 and methylfolate) has increased my MCS too. I have basically stayed at my starting dose because of this. As things stand, the trade-off has been worth it. I am still able to work part time.

    I think you mentiioned somewhere else, hixxy, that you feel your gut is the big problem regarding MCS? I agree with this.

    I know you are feeling low lately; you are on my mind and I am hoping that you can rest up a bit, then go back at it. When I was diagnosed with cancer years ago, many people mentioned "resilience" as being most important in the battle. Multiply that by 10 or so, and that's what is required with this illness. Be gentle with yourself - it is perfectly rational to feel the full burden every now and again and wonder if you can bear it.

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