1. Patients launch $1.27 million crowdfunding campaign for ME/CFS gut microbiome study.
    Check out the website, Facebook and Twitter. Join in donate and spread the word!
No Longer Naive in the Ways of The Beast
After having lived for years with ME/CFS, Jody Smith learned there's more to this beast of an illness than she realized, and that what might help one person may not help others ...
Discuss the article on the Forums.

Why is the dosage of vitamin B12 so high for ME/CFS treatment?

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by richvank, Mar 4, 2012.

  1. richvank

    richvank Senior Member

    Messages:
    2,717
    Likes:
    738
    Hi, all.

    The above question has been around for quite a few years, and we haven't had a good answer for it. I think it is now possible to answer it, based on some recent research in Korea.

    Here's some background: In the 1990's, Drs. Charles Lapp and Paul Cheney initiated treatment of their CFS patients by injection of vitamin B12, after observing that many patients had elevated homocysteine or methylmalonate in urine testing. They found that there was a threshold of response at between 2,000 and 2,500 micrograms per injection to produce an improvement in energy, stamina or wellbeing that lasted for two or three days. Lower dosages did not appear to produce improvements. This was puzzling, because the recommended daily allowance (RDA) for vitamin B12 in adults is only 2.4 micrograms per day. Why did the dosage need to be so high to produce improvement in symptoms?

    As many of you know, the sublingual hydroxocobalamin dosage in the Simplified Methylation Protocol today is comparable to the injected dosages that Drs. Lapp and Cheney found to be necessary, still very high compared to the RDA dosage, and this question has remained. (I note that high dosages of B12 are also used in autism, which shares much of the same pathophysiology with ME/CFS.)

    O.K., in 2011 a paper was published by two researchers in Korea, Jeong and Kim. The abstract is pasted below.
    The research they report was actually done on a bovine (cow) B12-processing complementation group and cyanocobalamin. However, the human complementation group is very similar, and I suspect that the results will also be similar for other forms of B12 than cyanocobalamin.

    They studied the CblC complementation group. This is part of the B12 processing pathway that is found inside all cells. When a form of B12 comes into a cell from the blood by the usual transcobalamin route, it is bound to CblC, and its beta ligand (cyano-, methyl-, or adenosyl-) is removed. Then it is sent on to be converted back to methylcobalamin or adenosylcobalamin as needed by the cell.

    In order for this processing to happen, the CblC complementation group must first bind the B12 form. The strength of binding is called the affinity (Kd), and it is measured in concentration units. The higher the affinity, the lower the Kd. It turns out that the bare CblC complex has a relatively low affinity for B12, compared to the concentration of B12 in the cells, and this would be unfavorable for the necessary binding, and would tend to lower the reaction rate.

    What these researchers found is that normally glutathione binds to CblC, and in doing so, it increases the affinity of CblC for B12. And it does so by a whopping amount--over a factor of a hundred!!

    Turning this around, if glutathione becomes depleted, as in ME/CFS and autism, the affinity of CblC for B12 is going to drop substantially. I suggest that the glutathione depletion, combined with its major effect on this affinity, is the reason the B12 dosage must be so high in treating ME/CFS and autism.

    Best regards,

    Rich


    Biochem Biophys Res Commun. 2011 Aug 26;412(2):360-5. Epub 2011 Jul 29.

    Glutathione increases the binding affinity of a bovine B?? trafficking chaperone bCblC for vitamin B??.

    Jeong J, Kim J.

    School of Biotechnology, Yeungnam University, 214-1 Dae-dong, Gyeongsan-si, Gyeongsangbuk-do 712-749, Republic of Korea.

    Abstract

    Intracellular B(12) metabolism involves a B(12) trafficking chaperone CblC that is well conserved in mammals including human. The protein CblC is known to bind cyanocobalamin (CNCbl, vitamin B(12)) inducing the base-off transition and convert it into an intermediate that can be used in enzyme cofactor synthesis. The binding affinity of human CblC for CNCbl was determined to be K(d)=?6-16 ?M, which is relatively low considering sub-micromolar B(12) concentrations (0.03-0.7 ?M) in normal cells. In the current study, we discovered that the base-off transition of CNCbl upon binding to bCblC, a bovine homolog of human CblC, is facilitated in the presence of reduced form of glutathione (GSH). In addition, GSH dramatically increases the binding affinity for CNCbl lowering the K(d) from 27.1 0.2 to 0.24 0.09 ?M. The effect of GSH is due to conformational change of bCblC upon binding with GSH, which was indicated by limited proteolysis and urea-induced equilibrium denaturation of the protein. The results of this study suggest that GSH positively modulates bCblC by increasing the binding affinity for CNCbl, which would enhance functional efficiency of the protein.

    Copyright 2011. Published by Elsevier Inc.

    PMID: 21821010
  2. snowathlete

    snowathlete

    Messages:
    2,019
    Likes:
    2,054
    UK
    Thank you Rich for taking the time to inform us of this. Its interesting. Does this not suggest that we would benefit from a large intake of Glutathione along with the B12 then? Is there a way to get alot of Glutathione into the cells at the same time?
  3. chilove

    chilove Senior Member

    Messages:
    243
    Likes:
    41
    Very helpful Rich. Thanks so much!
  4. richvank

    richvank Senior Member

    Messages:
    2,717
    Likes:
    738
    Hi, Snow.

    I think that's an excellent question. Historically, from about 1999 to 2004, I encouraged PWMEs to try to boost glutathione in various ways. Doing that alone did give some people symptomatic improvements, but they were temporary. Others could not tolerate it, and we did lots of guessing about why. When I caught on to the methylation cycle problem in late 2004 from the autism researchers, I shifted to encouraging PWMEs to boost their methylation cycles and stopped promoting glutathione boosting, and that has worked out better in terms of results.

    However, this treatment has been difficult for some people to take, especially initially, and I think that one of the problems is that it probably lowers glutathione even further initially, because more of the homocysteine gets converted to methionine, and less is available to go into making cysteine and glutathione. So I have started suggesting that people might try adding either some liposomal glutathione or some acetylglutathione, because I think they are most able to get glutathione into the cells. I haven't had much feedback on whether this has worked for people or not, and I don't know how many have tried it.

    Now, the question you're asking is what about getting a lot of glutathione into the cells while also putting in B12. I don't know how that would work out. One concern I have is that I think it's important not to ramp up the methylation cycle, the B12 function, the folate metabolism, and glutathione too fast in a person who has been ill for an extended time. These things will make major changes to the metabolism, and I think it's best to take it slow enough so that things can adjust as you go. I do think that for one thing, it could mobilize toxins a lot faster than they could be excreted, and that could make a person pretty miserable.

    I also think that there could be a problem in recycling the glutathione fast enough when it becomes oxidized in a body that is under a lot of oxidative stress. This could shift the ratio of glutathione to oxidized glutathione too much, and that could affect the biochemical reactions in a big way.

    So I don't have a very good answer for you. Don't have experience to go on, and the system is too complicated for me to figure it out on the basis of theory. Sorry about that.

    Rich
  5. Sallysblooms

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

    Messages:
    1,767
    Likes:
    327
    Southern USA
    I think the supplements that raise GSH and also Liposomal GSH have been very good for me. I do many things, B12, SAMe etc also, but many supplements were needed for my improvement.
  6. madietodd

    madietodd Senior Member

    Messages:
    2,405
    Likes:
    1,580
    East Coast, USA
    Very interesting, Rich!

    I'm still trying to puzzle out why the SMP didn't work for me, and at the moment I'm looking at potassium. Looking over old tests, I see that I've always been at the bottom of normal. I bought a potassium meter, and discovered that when methylation gets going and I don't supplement potassium, my levels go below 3.5 and I feel awful.

    I got a huge boost in the first few days of the SMP, but then nothing held. It's possible that there's also a folate issue involved, but I'm wondering now if potassium might have suddenly become my limiting factor.

    Do you know if potassium is a necessary co-factor anywhere in your protocol?

    Madie
  7. Dreambirdie

    Dreambirdie work in progress

    Messages:
    4,964
    Likes:
    3,020
    N. California
    Hi Rich--

    I was using Lee Silsby's transdermal glutathione with good results for my MCS symptoms for about 9 months, but recently I have been breaking out in a rash that lasts up to 2 weeks the day following application. VERY FRUSTRATING! I had them send me the alternate cream for hypersensitive people, but that gave me a rash as well.

    I began to wonder if the rash could POSSIBLY be from toxins exiting my body through my skin... (could that be possible?) With that in mind I decided to take long baths to try to soak out the culprit, the day after I applied the cream, but it's not working out. It's becoming clear that I will need to switch over to either the liposomal glutathione or acetylglutathione. Which one is more effective and what brand would you recommend?

    Thanks in advance.
  8. richvank

    richvank Senior Member

    Messages:
    2,717
    Likes:
    738
    Hi, Madie.

    I've learned about the potassium depletion issue from Freddd. It hadn't occurred to me before, but I think it does make sense. A PWME will have a deficit of cells, because they haven't been able to replace them as fast as they have died, owing to their low folate status. When the folates come up as a result of methylation treatment, the cells are going to be able to divide and reproduce themselves faster, because they will be able to make new DNA faster, and that will present a demand for potassium for the new cells, which is known to be low already in PWMEs, based on the work of Burnet et al in Australia a few years ago. I still think there is a rate issue involved--if the folates are brought up faster, as with Freddd's higher-dose protocol, there should be a bigger demand for potassium. If this is done more slowly, dietary sources of potassium are more likely to be able to keep up with the demand. But how fast is fast, and how slow is slow? No doubt it will depend on a particular PWME's diet, also, and whether they have very much potassium coming in.

    A potassium level of 3.5 is pretty low. If your meter is accurate, I would say that you have really needed more potassium, and I'm very glad that you discovered this. Isn't it wonderful to be a guinea pig? :)-) I really wish that we had been able to have all this sorted out in advance, but it seems that we still have things to learn. Thanks for the help!

    Best regards,

    Rich
  9. richvank

    richvank Senior Member

    Messages:
    2,717
    Likes:
    738
    Hi, DB.

    I don't have a comparison of liposomal and acetylglutathione. I also don't have a comparison of brands of liposomal glutathione. I just talked with Dr. Tim Guilford at the OHM meeting a few days ago, and he continues to say that his lipoceutical glutathione is the best. A PWME at the conference tried a sample of it, and told me that she could feel the benefit of it right away.
    His brand is Readisorb. But I can't tell you whether another brand would have had the same effect or not. There's just no "consumers report" on this stuff. At the same conference was the Allergy Research Group booth, and they were promoting their acetylglutathione. As far as I know, both these types of glutathione can get into the cells. I don't know the relative prices.

    Best regards,

    Rich
  10. Dog Person

    Dog Person *****

    Messages:
    78
    Likes:
    64
    Do you know that riboflavin is key in the methylation pathway? You need a riboflavin enzyme to convert B6 to it's active form, and also to convert folic acid to it's active form tetrahydrofolic acid, both to be used in the methylation pathway. Without enough B2 and B6, you can not convert tryptophan to niacin. When the body is low in niacin, it will not keep adequate levels of B12 in the body. All this seems to fit with much of what you all write about. No one seeme to mention riboflavin. It also is what lets you produce and recycle glutathione. It also allows you to regulate the circidian sleep cycle and it allows you to make the carrier protein for iron so you don't congest up. If you have unbound iron, it gets put into fluids of the body to excrete like mucus, bile, tears, etc.

    If you have enough riboflavin - your urine will be fluorscent dark yellow.

    The trick to taking riboflavin is that the body can only absorb 25 mg/hour. If you take more at once, you just urinate out the rest and it is wasted. When you show symptoms of riboflavin deficiency, it is only when all the body's storage locations are completly used up. The major storage location is the liver. Current research does not have a quantitive amount that should be stored in your body. The good news is there are no known side effects and the National Reserach Council has not even set a safe upper limit due to it's high safety of use.
  11. richvank

    richvank Senior Member

    Messages:
    2,717
    Likes:
    738
    Hi, Dog Person.

    Right on! Riboflavin is vital! It's also important to get enough of the other B-complex vitamins. The B vitamins work together in the energy metabolism, and a deficiency of even one of them can put a monkey wrench into the works. The entire B-complex is included in the multi that is part of the simplified methylation protocol, and Freddd also includes a B complex in his protocol, so we agree that these vitamins are important. And....B2 does make for beautiful urine!! ;);)

    Best regards,

    Rich
  12. bertiedog

    bertiedog Senior Member

    Messages:
    415
    Likes:
    225
    Hi Rich

    You might be interested to know that very recently at the suggestion of a private doctor I saw I added 250 mg Essentials Lipoceutical Glutathione to my regime which also includes Patricia Kane's lipid protocol and Thorne's Basic Nutrients to continue to help methylation After day 6 I developed killer migraines which lasted 4 days. Having done a Google search for adding glutathione in a compromised body I found that it can turn into glutamate which as you know is a neuro toxin and this can cause migraines of the severest nature in certain people. Obviously I am one of these people and I would never try it again.

    I seem to remember that in the past using topical liposomes ofl glutathione also gave me very bad migraines but I cannot stress enough how this time the migraines were so severe I could understand how people contemplated suitcide the pain and feelings of depression were so severe. The last capsule I took was Friday and only yesterday did I feel a bit more normal.

    Its so annoying knowing that we need something that is essential to our body and yet we cannot tolerate it!
    Pam
  13. richvank

    richvank Senior Member

    Messages:
    2,717
    Likes:
    738
    Hi, Pam.

    I'm very sorry that this happened to you. Migraines are awful! Somehow we have to figure out beforehand which treatments will be helpful and which will be harmful for a given person, and we are not there yet. One of the wonderful things about us humans is that we are all unique, but that unfortunately works against us when we are trying to treat these pesky disorders! Thanks for posting your experience, and I hope things get back to "normal" for you soon. Also, I'm sorry I hadn't responded to your earlier email. I'm quite behind!

    Best regards,

    Rich
  14. Dog Person

    Dog Person *****

    Messages:
    78
    Likes:
    64
    You write that all the B vitamins work in tandem. This is true. However, you need to know which B vitamins you need more of and which ones activate the others and which ones are cofactors for. For example, if you are choline deficient, your body will not store manganese in the liver. So you are manganese deficient due to choline deficiency. However, if you take manganese, you will only become more choline deficient, due to it trying to help your liver store the manganese. So you take choline, but you require the active form of folic acid to activate choline in the transulfation pathway. (Ziesel). So by taking choline you become more folic acid deficient. Folic acid deficiency has been indicated as a cause of many migraines as well. So you see, it is very important you know all the interactions between the B's. You can not take all of them at the same time either, as some form insoluble complexes with others and you won't absorb them. Some can be absorbed with high doses by passive diffusion but others can not. In my opinion it is ever good to do a shotgun approach with B vitamins.

    As to Pam and her migraine. By taking what she "thinks" she needs has obviously thrown her nutritional balance off to a greater stress response. Research out of New York's migraine center shows that the vast majority of migraines are due to low magnesium. Taking magnesium will not fix the problem, you must determine what is causing the loss of magnesium from the body. What is causing the stress response and which nutrient or nutrients are specifically needed to remedy the problem.

    Research has shown that inappropriate use of micronutrients can lead to death.
  15. aquariusgirl

    aquariusgirl Senior Member

    Messages:
    946
    Likes:
    91
    Well, that's a downer.

    Seriously, got any constructive advice about how to supplement b vits? Test them all & supplement accordingly?
  16. richvank

    richvank Senior Member

    Messages:
    2,717
    Likes:
    738
    Hi, Dog Person.

    I would like to learn more about the issue you mentioned of insoluble complexes forming between the B vitamins. Can you give more details on that, with references?
    This is news to me. As you probably know, there are many B-complex supplements on the market, and also many general nutritional supplements that contain the full range of vitamins
    and essential minerals, and some contain a variety of other nutrients as well.

    I would also be interested in more details on death being caused by micronutrients. Are you referring to overdosing of some of the minerals? Can you give references to support this?

    Thank you.

    Rich
  17. Dog Person

    Dog Person *****

    Messages:
    78
    Likes:
    64
    http://www.prof-donaldmccormick.com/Nutrition Pg. 2.html
    "Also most of such micronutrients when chronically taken in excess, become toxic and, again, in some instances can be lethal. Hence, we need to consume those amounts, usually micro- to milligram quantities per day, that help us maintain growth, health, and normal reproductive function, but avoid such excesses as may be deleterious. Most of the peer-reviewed literature on this subject has been summarized in volumes that collate information within periodically updated chapters that are especially appropriate for nutritional professionals."

    Handbook of Vitamins, Third Edition Revised and Expanded, edited by Robert B. Rucker, John W. Suttie, Donald B. McCormick, Lawrence J. Machlin, copyright 2001 Pages 255-270

    "A number of metals and drugs form chelates or complexes with riboflavin and riboflavin-5-phosphate that may affect their bioavailability (30). Among the agents in this category are the metals copper, zinc and iron; the drugs caffeine, theophylline and saccharin; and the vitamins nicotinamide and ascorbic acid; as well as tryptophan and urea. The clinical significance of this binding is not known with certainty in most instances and deserves further study."
    30. D.B. McCormick, Riboflavin, in Present Knowledge in Nutrition, 6th ed. (M.L. Brown, ed), International Life Sciences Institute, Washington DC, 1990, p 146.
  18. Adster

    Adster Senior Member

    Messages:
    554
    Likes:
    217
    Australia
    Inappropriate use of lots of things can lead to death. Guns and knives, for example :D
    madietodd likes this.
  19. Dreambirdie

    Dreambirdie work in progress

    Messages:
    4,964
    Likes:
    3,020
    N. California
    And other people's bad advice. :D
  20. dannybex

    dannybex Senior Member

    Messages:
    2,161
    Likes:
    509
    Seattle
    Definitely very complex and complicated, and you make a good point regarding all the interactions. I don't have a link right now, but have read in many places that the standard "balanced" b-complex isn't balanced at all, one doesn't just 'pee out' what isn't used or needed -- there are other ramifications as they do indeed interact with each other and with minerals...

    I found that I couldn't tolerate b6 until I added sufficient riboflavin.

    And speaking of migraines, riboflavin (at kind of scary high doses) has been found to reduce the number of migraines:

    http://www.ncbi.nlm.nih.gov/pubmed/15257686

    A good general overview of riboflavin and it's benefits/interactions can be found here:

    http://www.ajcn.org/content/77/6/1352.full

See more popular forum discussions.

Share This Page