Hi, all.
I just want to note that methyl B12 has only one known function in the human body, which is to serve as a coenzyme for methionine synthase in the methylation cycle. Adenosyl B12 also has only one known function, and it is to serve as a coenzyme for methylmalonyl-CoA mutase. All the effects of vitamin B12 have been found to derive from these two functions.
Normally, the various forms of B12 in the diet or in supplements at RDA-level dosages go through the normal absorption, transport and intracellular processing and are converted to the amounts of these two coenzymes that are needed by the cells.
When very large dosages of methyl B12 compared to RDA levels are taken sublingually or by injection, the normal absorption, transport and processing of vitamin B12 into these two coenzymes are bypassed. Under these conditions, I think it may be possible to get too much methyl B12 into the cells, and that this could overdrive methionine synthase, so that cystathionine beta synthase will not receive sufficient homocysteine to feed the transsulfuration pathway sufficiently for the production of cysteine, glutathione, taurine, sulfate and other sulfur-containing metabolites. In addition, the methylation capacity might rise too high, which could affect DNA methylation and therefore gene expression. I think this is relatively uncharted territory, and going there may produce some deleterious effects.
Therefore, I think it would be wise to do some testing periodically while on high-dose B12 supplementation. The best test panel is the Vitamin Diagnostics methylation pathways panel. Unfortunately, because of a lab move, the availability of this test will probably be hampered until about the end of January. I think the next best would be a plasma amino acids panel, such as is offered by Doctor's Data Lab. The condition of the methylation cycle and the transsulfuration pathway can be inferred from this panel, though the interpretation is not as direct as with the Vitamin Diagnostics panel.
I again want to note that I think that the response to high-dose B12 treatment will differ for those who have inborn errors of metabolism involving the intracellular B12 processing enzymes and those who do not. It is not normal for a person's body not to be able to use hydroxocobalamin, and it is also not normal for glutathione to interfere with the utilization of B12. In fact, its normal role is to protect B12. The presence of these abnormalities suggests that there is an inborn error of metabolism involving the B12 processing enzymes.
In the past, I have noted that the simplified treatment approach, which utilizes hydroxocobalamin, has been found to help at least two-thirds of the people with CFS who have tried it. It is not clear that the treatment failure in the other nearly one-third is due to their inability to utilize hydroxocobalamin, as freddd has suggested. Rather, it looks as though deficiencies in cofactors or in amino acids are responsible in many cases, based on lab test results I've studied so far.
Best regards,
Rich
Hi Rich,
I just want to note that methyl B12 has only one known function in the human body, which is to serve as a coenzyme for methionine synthase in the methylation cycle
You use your words most carefully and I appreciate that. However, I think many may infer far more meaning from your careful choice of words than you would be willing to state. For instance, the "one known function" certainly appears to be a main function, critical to the maintenance and healing of every tissue in the body. The "upregulation of neural tissue healing" in the central nervous system noted by the Japanese in high dose research appears to be another function. It promotes the healing of myelin lesions among otyher things. The functioning of damaged neural tissue is enhanced when mb12 enters the CSF in sufficient quantity, which ability appears impaired in CFS/FMS/ME patients. The improvment in functioning remains as long as the mb12 level remains relatively high. For instance it is some combination of the effects of mb12 on the central nervous sytem that keeps me at 30mg/day injected. Otherwise a single 5mg sublingual is probably fully sufficient. At 5mg sublingual daily my central neurology deteriorates and I would be in a wheelchair without feeling or control over my lower legs, feet and toes and continual muscle contractures requiring Dilantin and Valium to control.
So MAYBE that is all a result of the single function you mention being performed more completely or maybe it isn't.
Adenosyl B12 also has only one known function, and it is to serve as a coenzyme for methylmalonyl-CoA mutase
Large dose Adb12 also gets into the CSF and does its single function in the neurons. As regards Adb12 I agree fully that it has a single function and it does it quite well. It's amazing the changes that occur when the neuronal mitochondria start working well with adb12 within the CNS. And while I know of no research to document it, there are plenty of persons who can demonstrate it. The effect is quite real. There are 4 clearcut response patterns; body mb12, body adb12, CNS mb12 and CNS adb12.
and it is also not normal for glutathione to interfere with the utilization of B12. In fact, its normal role is to protect B12.
I don't think that there is enough evidence to say that. A significant percentage of people who are paying attention and trying these things find that gutathione does in fact interfer with methylfolate, methylb12 and adenosylb12, but perhaps the interference with the active b12s is secondary to the active folate interference. Even if it is "ONLY" 1/3 of folks for which that happens that is still a very sizable minority.
its normal role is to protect B12.
In sufficient quantity methylb12 doesn't need protection. In fact it's normal role appears to be to detoxify these things that would destroy it and cause the excretion of these toxins. Mb12 needs protection only when it is present in insufficient quantities. In a sense then, protecting b12 is a vital nutrient starvation response to remove it from one of its normal roles when not enough is present and would only be seen in deficiency states. Mb12 removes cyanide from the body, it is disabled by mercury which in turn is excreted by the liver at about 1% per day after reacting witn mb12, it protects against botulism neurotoxin, it protects against tetanus neurotoxin, it protects neurons from glutamate toxicity, it protects neurons from cascading neuronal death, it detoxifes nitrous oxide and removes it from the body. It does these anti toxin things only when presnt in high enough quantioty to do it. In various studies the list of toxins against which it is protective or that it removes is growing regularly now that more research is being done on active b12s instead of the laboratory mistake, cyanocobalamin.
Research over and over notes that mb12 has unique properties not matched by any inactive b12 forms. Mb12 has a dose proportionate healing curve unlioke inactive cobalamins. I and a number of others have explored the characteristics of that curve and found it's characterisitcs at sublingual dose levels and with injections. My internist is simply amazed at what has occurred. I walked into his office 6.5 years ago, slowly dying, typically sick almost all the time with one thing after another each lasting way too long. Now I haven't been sick in 6.5 years. I have gone from 200 sick days a year to ZERO. That in itself is an interesting demonstration. I have gone from total disability to looking for a suitable job or consulting contracts.
When very large dosages of methyl B12 compared to RDA levels are taken sublingually or by injection, the normal absorption, transport and processing of vitamin B12 into these two coenzymes are bypassed. Under these conditions, I think it may be possible to get too much methyl B12 into the cells, and that this could overdrive methionine synthase
Or maybe not. Honestly I don't know either. I would be pleased to provide a blood sample for analytical work and I know many others that would be too. My opinion is that there is a "channel" capacity that can be fully filled but that it isn't overdriven. If it were being overdriven what would be the characteristics? How would this be expressed in symptoms? Diseases? Biochemistry? In the studies done with uremics and very large injections of mb12 they were looking for all sorts of toxic effects and were unable to find any effect at all. The uremics were chosen because they are the only folks who can accumualte tremdously huge serum levels. The rest of us excrete it via the urine at better than 99% per day. It is the proverbial most expensive urine. The most painful side effect of that is paying for it out of pocket. The ONLY reason I am willing to do so is to keep me out of a wheelchair and keep my brain working well. About 3 months of sublinguals only at normal doses and I would not be able to walk.
It is not normal for a person's body not to be able to use hydroxocobalamin, and it is also not normal for glutathione to interfere with the utilization of B12. In fact, its normal role is to protect B12. The presence of these abnormalities suggests that there is an inborn error of metabolism involving the B12 processing enzymes.
It is not clear that the treatment failure in the other nearly one-third is due to their inability to utilize hydroxocobalamin,
There is that word again "NORMAL". It implies to most people far more than a technically correct usage of the term means. Why should anybody be expected to be able to utilize an inactive form of the vitamin, a pseudo vitamin as it were, other than how it is naturally supplied in our foods? Converting it to active is nothing our bodies evolved for. It puts a bias into the biochemistry having to perform this unnatural conversion. This bias is so widepsread that it has become "normal" by the BIG LIE method of frequent repetition.
That "1/3" who fail to utilize hydoxcobalamin is an interesting number. It is solidly in the range established by hundreds of research studies of the percentage of people who have no response to hydroxycobalamin in the area being researched. The range there is 20% to 40% for most studies and as high as 60% in some special situations dealing with inborn processing errors.
So 2/3 have some response to hydroxycobalamin. Statistically that puts it into the plus-minus 1 standard deviation on a normal distribution curve. However, the response is incomplete. It only affects about 1/3 of the symptoms and signs that a combination of mb12 and adb12 do. This can be easily demonstrated.
In a single challange sublingual dose trial, with 5 star rated sublinguals only, I performed over several years with about 1000 people in all, about half of them symptomatic and about half of them without any symptoms that one might expect to be affected. I'm sorry to say I did this on the run without keeping good records and it needs to be repeated with good record keeping. About 95% of those with symptoms had a response within one hour to either mb12, adb12 or both. In the next trial I will obviously have to include hydroxycobalamin and cyanocobalamin in a double blind situation. However, nobody actually expects "just a vitamin" to do anything they would actually notice. Those without symptoms, in good health and all, had a basically zero rate of response. The only ones of those that started up in the symtom free group and had a response were those who after a response said, "Oh. I had forgotten about those symptoms they started so long ago and the doctors never thought they were important" or something similar. They turned out to be symptomatic after all and had a response. It turns out that many of the nonspecific symtoms that doctors routinely ignore and train patients to routinely ignore are in fact low level b12 deficiency symptoms.
The creeping MCV (and corresponding MCH) values in the USA also indicate that a change is happening. Normal values used to be <92-93 depending upon the lab. My internist was shocked to see that I had suddenly healed by doing nothing at all when my alertable 99.8 MCV when the lab was alerting >96 had become non allertable when they changed to >100. It seems that MCV=99.8 has become "normal" since it is now within 2 standard deviations of mean which they explained to me. It seems that so many people were now allertable that the docs were ignoring it. How to LIE with statistics. Normal has a techincal meaning but that is not how most people understand it.
With more people than ever taking vitamins containing inactive b12 and inactive folate and inactive b6, more and more people are becoming borderline macrocytotic.
It is not clear that the treatment failure in the other nearly one-third is due to their inability to utilize hydroxocobalamin, as freddd has suggested. Rather, it looks as though deficiencies in cofactors or in amino acids are responsible in many cases, based on lab test results I've studied so far.
With the active b12s it is very clear when a failure to respond is due to lack of cofators. It appears something like this.
About 5% have total failure to respond due to lack of one or more cofactors, most frequently methylfolate, but including SAM-e, l-carnitine fumarate, magnesium, Zinc and Vitamin D3. Much more common is a limited response.
About 90% have a limited response to some degree or another due to lack of cofactors. Again, the most common needed cofactor is that usually supplied by another pseudo vitamin, folic acid. There is a pattern here. It is the pattern of the "depleted methylator" or "methylation block" being an artifact of inactive pseudo vitamins and lack of the real vitamins. I had it. Lots of people have/had it. Dr Myhill states that the way to unblock it is with Methylb12. What percentage of people develope "methylation block" if they are taking methylb12 and methylfolate all along? Do any develop it under those conditions?
These estimates are based on real world responses, not hypotheses based on lab reports. Lab reports are incredibly non predictive about who will respond to mb12, adb12 or methylfolate. If my treatment were based on lab reports I would be dead or most certainly in a wheelchair by now. The statistics based treatment with these items is ruining health, destroying lives and killing some people.
"NORMAL" is enshrined with values based on chronic deficiency states and poor to borderline funtioning based on 60 years of research and statistics based on inactive pseudo vitamins.
Just this year the new explosion of Ricketts exposed that very problem of low vitamin D. And they were not off by just a little, like a factor of 2. Rather many are suggesting a change of an entire order of magnitude, to 2000-4000 units from 200-400 units.
Again, I think you place far to much importance on my IMEs, whether they are as rare as thought or not. I almost certainly never would have had my CFS crash without being a vegetarian and trusting cyanob12 as a supplement, because I had no choice.
