Proposed relationship between Lapp-Cheney B12 treatment and methylation

Discussion in 'Fibromyalgia Main Forum' started by richvank, Jun 18, 2012.

  1. richvank

    richvank New Member

    Hi, all.

    I think I now understand better why Drs. Lapp and Cheney found in the 1990s that a high dosage of injected vitamin B12 (they initially used cyanocobalamin) gave their ME/CFS patients an increase in energy, stamina, or well-being within 12 to 24 hours, which lasted for two to three days, and why the dosage had to be so high compared to the RDA for B12 (2,000 to 2,500 micrograms per injection, compared to 2.4 micrograms per day). I also think I now understand better how this fits in with the methylation-type treatments, which can bring greater improvement on a more permanent basis, and also how Freddd’s approach meshes with the above two types of treatments.

    Here’s my suggested explanation:

    It is known that normally after vitamin B12 is absorbed by the gut, it is transported in the blood to the body’s cells, bound to the carrier transcobalamin. After entering the cells, the B12 normally passes through an intracellular processing pathway, which produces the appropriate amounts of the two active coenzyme forms of B12 needed by the cells, i.e. adenosylcobalamin and methylcobalamin.

    Adenosylcobalamin acts as a coenzyme in the mitochondrial methylmalonate pathway, which feeds certain substances into the Krebs cycle to be used as fuel for making ATP. These substances are isoleucine, valine, threonine, methionine, the side-chain of cholesterol, and odd-chain fatty acids.

    Methylcobalamin acts in the cytosol as a coenzyme for the methionine synthase reaction, which links the methylation cycle with the folate metabolism and also helps to govern the flow into the transsulfuration pathway, which feeds the synthesis of glutathione, among other reactions.

    One of the key parts of the intracellular processing pathway for vitamin B12 is called the CblC complementation group. This group normally binds cobalamin in order to carry on its processing. The strength of this binding, called the affinity, depends strongly on the presence of glutathione. A recent study by Jeong and Kim (2011, PMID: 21821010) using bovine CblC and cyanocobalamin, found that glutathione, which is normally present in the cells, raised this affinity by a factor of over one hundred.

    In ME/CFS, we have found that glutathione becomes depleted. That being the case, we can expect the affinity of CblC for cobalamin to drop considerably. The effect of this would be to lower the rate of production of both adenosylcobalamin and methylcobalamin. The effect of lowering adenosylcobalamin is to decrease the fuel supply to the Krebs cycle and hence to lower the rate of production of ATP. The effect of lowering methylcobalamin is to partially block the methionine synthase reaction, lowering the methylation capacity, and draining the methylation cycle and disrupting the sulfur metabolism in general. The methyl trap mechanism then continues to convert other forms of folate into methylfolate, and this is partly catabolized by reaction with peroxynitrite which forms as a result of the glutathione depletion. The folates thus become depleted, and a chronic vicious circle mechanism is set up.

    Now, consider what happens when a high dosage of B12 is injected, as in the treatment discovered by Lapp and Cheney. When the dosage is high enough, the low affinity of the CblC complementation group for cobalamin is overcome, so that the rates of production of adenosylcobalamin and methylcobalamin are able to come up, perhaps even to normal levels. I suggest that this affinity problem is the reason for the need for such a high dosage of B12 to obtain a therapeutic effect.

    The added adenosylcobalamin would support the methylmalonate pathway, and more fuel would be supplied to the Krebs cycle, which would raise the rate of production of ATP. I suggest that this is what causes ME/CFS patients to experience a boost in energy, stamina or well-being on the high-dose injected B12 treatment. This is particularly significant in ME/CFS, because carbohydrate and fat metabolism is hindered due to the effect of glutathione depletion on the aconitase reaction, early in the Krebs cycle. Note also that deficiencies in some of the B-complex vitamins can interfere with obtaining this benefit, because they are also needed by the methylmalonate pathway.

    However, I suggest that even though methylcobalamin production would also rise, the partial block of the methionine synthase reaction would remain if B12 alone is given, and this is the reason for the limited benefit of that treatment. The reason why B12 treatment alone will not correct the partial block in methionine synthase is that there is insufficient methylfolate available to feed this reaction. The reason for that, as Prof. Martin Pall has pointed out, is that the level of methylfolate has been lowered by reaction with peroxynitrite. Peroxynitrite has risen because of the state of oxidative stress that ensues when glutathione is depleted.

    If methylfolate is added in addition to adding high-dosage B12, the partial block of methionine synthase can be lifted, which can then break the vicious circle mechanism that holds glutathione down. Over time, as glutathione rises, the affinity of CblC for cobalamin will also rise, and supplementation of high-dosage B12 will no longer be necessary. Likewise, peroxynitrite will drop as glutathione is restored, so that supplementation of methylfolate will no longer be necessary, either.

    [The next section discusses a protocol developed by a guy who calls himself "Freddd," who posts to the Phoenix Rising ME/CFS internet group, and who advocates a protocol that includes high-dose adenosyl B12, high-dose methyl B12, and high-dose methylfolate. I don't know what fraction of the ME/CFS population has the polymorpthism that Freddd apparently has. He and I have discussed this at length on the public forum, so there is not a patient privacy issue in his case.]

    In Freddd’s case, I suspect that there is an inherited polymorphism in the CblC complementation group. While normally glutathione supports this group and helps it to process B12, in Freddd’s case this does not work. Glutathione binds cobalamin and his CblC complemention group is unable to retrieve it and convert it into the two coenzyme forms of B12. Freddd has found that if he uses large dosages of both adenosylcobalamin and methylcobalamin (applied sublingually or by injection) and if he avoids glutathione or precursors to form glutathione he can overcome this problem. Apparently these two coenzyme forms of B12 are able to diffuse directly into the cells and bypass the normal B12 processing pathway, so that both the mitochondria and the methionine synthase reaction are supplied directly with the cofactors they need. In addition, he supplies methylfolate in high dosage as well, which overcomes the deficiency in this reactant.
    I suspect that the reason why Freddd has observed an independent benefit by adding adenosylcobalamin is the same as the reason why the Lapp and Cheney treatment brought benefit to their patients, i.e. it causes a boost in fueling the mitochondria.

    I think this explains the results reported by Drs. Lapp and Cheney, the reason for the increased benefit of adding methylfolate as in the methylation-type protocols, and the basis for the success of Freddd’s approach.

    Best regards,

  2. Forebearance

    Forebearance Member

    Thank you so much, Rich!
  3. mbofov

    mbofov Active Member

    I am a bit tired right now so can't really process what you have written, but I'm very interested and plan to revisit it when I have a bit more energy.

    Best wishes,

  4. Mikie

    Mikie Moderator

    You are so helpful to us and we appreciate it. Hope you are doing well.

    Love, Mikie
  5. joanierav

    joanierav Member

    hi rich , thanks again for all your help. your posts are always so informative. yrs ago there was a man, i cant remember his name but it was something like schar or schlar. he would give adenosine phosphate injections for herpes type infections. i dont even know if im saying it or spelling it correctly, it was 20 yrs ago, he was in north jersey. its vague in my memory

    i suffered greatly when first dx with cfs, with oral herpes simplex. but by the time i found him, he had already retired.

    is this the same as what you are talking about? because ive heard that patients benefited greatly from his injections.
    love, joanie
  6. sarahcatherine

    sarahcatherine New Member

    I saw Dr. Lapp a few months ago. I have had extremely good results from the B 2 injections. With the increase in energy and stamina, I have been able to start physical therapy for my patella problems, work out regularly, fix healthy meals, and drop over 10 pounds (of the 40 that I gained since my fibro/cfs started).

    Anyway, I really appreciated this post. I want to learn as much as I possibly can about how everything in my body works. It makes me appreciate my Bio 110 and 111 classes that I slacked off in during college!
  7. ulala

    ulala New Member

    in NYC used to give me IV pushes of some kind of Vit. B12. After I had these pushes I felt completely normal for almost 3 days. Of course it's hard to find someone to give B12 in the vein and I think what she was giving was a very expensive form of B12. Do you know what that could be?

    I get B12 IM shots and they don't do anyting for me. Thanks so much for bringing this up!
  8. richvank

    richvank New Member

    Hi, all.

    Thanks for your comments about B12 and how it works in ME/CFS.

    I seem to recall the ATP injections from some years ago, too, but the B12 injections are a different thing.

    I don't know what form of B12 Dr. Levine was using. I would guess that it was hydroxocobalamin, but not sure. Quite a few of the docs who specialize in treating ME/CFS do inject hydroxocobalamin. I think that if PWMEs will take some oral methylfolate together with the B12 shots, they will experience more benefit, for the reason I wrote. I have told several of the docs about this, but not sure how many have tried it.

    Best regards,

  9. ulala

    ulala New Member

    that hospitals use in cases of an emergency that is given IV. I have a feeling that's what Dr. Levine was using.

    Is leucovorin the same as methylfolate? I think leucovorin is an active form of folic acid?
  10. Mikie

    Mikie Moderator

    My Snowbird neighbor, who is in his 70's, got his labwork back and he was low in B12. I told him about my methylcobalamin sublingual tablets and he asked his doc if he could take it. She's up north and told him he could and it would probably help but that she wanted to put him on injections when he got home. His B12 level was normal when he had his labwork done before he left for home and the doc was so impressed. No injections. He loves taking the tablets because they are cherry flavored. It's his favorite med/supp :)

    So, your help has extended beyond PWC. Thanks!

    Love, Mikie
  11. richvank

    richvank New Member

    Hi, ulala.

    Leucovorin is folinic acid (5-formyl tetrahydrofolate). It's different from methylfolate. Folinic acid is a chemically reduced, naturally occurring form of folate, unlike folic acid, which is a synthetic, oxidized form. The body has to chemically reduce folic acid before it can be used, and some people are not able to do that very rapidly, so folinic is more available to their bodies. Folinic acid does not have a direct role in the metabolism, as other forms of folate do. It is thought to be a buffer or storage form of folate in the cells. Folinic acid is included in the simplified methylation treatment, because it is able to supply other forms of folate until the methionine synthase reaction gets going faster, which methylfolate cannot do.

    Best regards,

  12. richvank

    richvank New Member

    Hi, Mikie.

    That's great to hear! I'm glad that you were able to help him out. I suspect that there are many people in his age range (I should say MY age range, since I just turned 70 in April!) who are low in B12 and don't know it. Sublingual B12 could help a lot of them, if they only knew about it, and it's more convenient than going in for shots, although maybe that gives the doc a chance to check other things!

    Best regards,

  13. Mikie

    Mikie Moderator

    We are about the same age. In FL, that makes us kids :)

    These people never went to docs for years and years. Then, when they did go, they had all kinds of things wrong which might have been avoided had they gone in earlier.

    I'm just glad the vitamin b-12 worked for him. I gave you full credit for it. Thanks for all you do. You never know how many are touched by your good work.

    Love, Mikie