Hi Rich
Is it the use of MeB12 instead of (say) HydroxoB12 that most concerns you, or the size of the dosage, or its sublingual intake, or all three combined?
I believe that Dr Neubrander got good results with autistic children using subcutaneous MeB12 shots every day or every second or third day. Do you regard that as more or less risky than daily sublinguals?
Hi, Richard.
I don't know enough to give simple answers to your questions (above). I think that all three of the aspects you mentioned are potential issues.
At this point, the only way I can tell whether the amounts an individual is taking are causing the overdriving problem I'm concerned about is to see certain types of lab test results on that person.
My goal in commenting on treatment of the vicious circle mechanism that I believe is associated with the partial methylation cycle block in ME/CFS is to try to help people with ME/CFS to restore this part of the metabolism to normal operation, because I believe it's the core issue in this disorder.
What I can do is to describe the situation in the biochemistry as I see it, based on what is known about this part of the metabolism as applied to the interpretation of test results that some people have sent me.
In normal operation, the activity of the methionine synthase enzyme (which I believe, based on lab testing, is partially blocked in ME/CFS) is continuously varied to balance the body's needs for methyl groups, folate vitamers, and antioxidant protection. There are several feedback loops involved in this overall system that normally balance the response to these needs.
When sufficiently large amounts of both methylfolate and methylcobalamin are supplied to a cell, these feedback loops are overridden. The result is that the activity of methionine synthase remains high, regardless of the body's needs. The effect of this is to cause both the methylation cycle and the folate cycle to run faster than normal, while the flow down the transsulfuration pathway to make cysteine (needed for the sythesis of glutathione) and also to make coenzyme A, taurine, sulfate and other sulfur-containing metabolites that are needed for a variety of purposes, is held lower than normal.
I don't know what the long-term consequences of this will be. What I see in the test results of people who are supplementing both methylfolate and methylcobalamin at dosages in the several milligrams per day range are indications that glutathione is not coming up, while the methylation cycle and folate metabolism are carrying out a "futile cycle" by passing methyl groups back and forth between them via sarcosine and methylfolate. As a minimum, it seems to me that this would slow their recovery.
If a person should also happen to have inherited a slow version of the enzyme glycine N-methyltransferase, which some people have, this overdriving of the methylation cycle could cause the SAMe level to rise high above normal, and that would affect gene expression as well as the rates of a large number of methyltransferase reactions. I can't predict the outcome of that.
Methylation is also involved in cancer, in silencing tumor suppressor genes, so elevating the availability of methyl groups above normal levels, such as might occur if the glycine N-methyl transferase activity is low for genetic reasons, could potentially have some effect on that as well.
It's known that cancer cells have a higher demand for B12 and folate and have higher numbers of receptors for them than normal cells do, presumably to support their more rapid multiplication, so that if there are incipient cancers present, high dosing of these two together could potentially accelerate tumor growth. One person reported activation of a long-dormant incipient skin cancer (actinic keratosis) on this type of treatment.
In theory, methylcobalamin can methylate inorganic mercury, making it fat-soluble and able to cross the blood-brain barrier. When sublingual methylcobalamin is held in contact with teeth that have amalgam fillings for long times, it would seem that the concentrations of both methylcobalamin and inorganic mercury could be high enough to achieve a significant reaction rate and significant production of methylmercury.
All this having been said, some PWCs do need to take the methyl form of B12 because of their particular inherited genetic polymorphisms. Dr. Amy Yasko bases the choice of which form to use on characterization of these polymorphisms. In suggesting the simplified approach, I decided to opt for hydroxocobalamin in the basic protocol, and it was found to work for most of the PWCs in our clinical trial. The idea was to enable people to do something that has a good chance of helping, without the cost and complexity of the full Yasko program. I did this with the knowledge that this protocol would not be optimum for everyone, but it is a place to start. When people observe effects from the simplified protocol, they become interested in the methylation issue, and then they are motivated to look into it further, perhaps get some testing if it is feasible for them to do so, and perhaps modify their treatment to something that is a better match for them.
If a PWC finds that the simplified protocol does not work for them after two or three months, I suggest doing some testing to find out why, and changing the treatment appropriately. I favor using the smallest dosage that will do the job, so that the body will be able to balance its needs by regulating this part of the metabolism as well as it can.
I also recommend working with a physician while on this type of treatment. If injections are feasible in a person's situation, that is certainly an option. As Freddd has pointed out, it's important that the injected solution be of good quality and properly prepared, as methylcobalamin does not have high chemical stability.
There is nothing sacred about the simplified protocol as far as I'm concerned. If an individual finds something that works better for them, my attitude is more power to them! I'm a researcher, not a clinician, and I see my role as trying to figure out what's going on in this disorder. Hopefully that will provide clues to treatment, but it isn't straightforward to determine the best treatment protocol simply on the basis of biochemical theory.
For one thing, people are all unique in terms of their genetics, and I have to object when treatment results for an individual or a group of individuals are extrapolated and claimed to apply to all cases. They may indeed apply to many others, but I have seen enough heterogeneity in the ME/CFS population that I don't believe in one-size-fits-all treatments, and sometimes there can be unpleasant surprises when this approach is taken.
I also believe that when judging the effects of a treatment, we need to define the treated population as tightly as we can. If we are looking at an undefined population that includes people with the whole variety of B12-related problems, and not only those who satisfy the (admittedly imprecise) criteria for ME/CFS, I think we have to question how applicable the results are to the ME/CFS population.
I again want to reiterate that I very much appreciate the contribution that Freddd has made to this field. I think we can learn a lot from his experience, and I certainly have myself. My concern is that we examine it in the light of Freddd's own situation, which he has shared with us, and apply it appropriately to other cases. There is still a great deal that we don't know about ME/CFS, the metabolism related to the methylation cycle, and how to apply appropriate treatment. I also very much appreciate reading reports of the experiences of people in these forums. These experiences are a big part of the "acid test" for me of whether my hypotheses make sense or not.
Best regards,
Rich