Methylation

Freddd · Aug 20, 2009

Hi Rich,

So how the cycle works then is that mercury takes the methyl from the methylb12, the former methylb12 becomes remethylated in the usual scheme of things from SAM-e and methylfolate, if available, or is just disabled, and then has that methy group taken my mercury again, acting as the intermediate carrier? Or is it immediately latched onto by TCIII and escorted to the liver for recycling? In any case hydroxyb12 is converted to methylb12 to be active, just a trickle of it.

A side note, there are mercury alerts even for bluegills in some Utah waters the situation has gotten so bad. I don't eat fish from Utah waters because even the ones that are not alerted have substantial mercury.

Freddd · Aug 21, 2009

Part 1 of reply to Rich's statement

Hi Rich,

I want to acknowledge that I realize that I have a lot to learn about all of this, and I want to say that my goal is to try to find the truth, and to use it to help as many people as I can to recover from CFS. I'm not motivated to try to defend a hypothesis for the sake of trying to be "right." So I hope you will view what I say in that light.

I agree in spades, doubled and redoubled. I'm glad you posted. I think that you consider this to be as important as I do. This kind of discussion can help clear up misconceptions in all directions. As I’m working backwards, from “what works” to a hypothesis of “why it works” and you are working from a hypothesis of “why it ought to work” to “what works” at the intersection hopefully we can find truth of a sort. A hypothesis has a long journey to make to theory and proven theory through much refinement. I was having a good time going after crocked docs and HMO/insurance companies and showing plan trustees how to get the most bang for a buck and writing HMO software and had plenty to do before this made me pay attention to it. I’m not a researcher. We, including me as a member consultant with a consulting group, were exhibitors, presenters and attendees at a number of conferences each year. Being on a design team for the healthcare X-prize is more up my line. I‘m a data analyst and software designer forced to take this on for personal and familial survival.

Agreement is most powerful when gotten at from opposite directions. I am willing to cooperate in every way to get to the bottom of this and get the necessary studies done one way or another. I have a deep and personal interest in all this as the many false assumptions and things “everybody knows” that are not true almost killed me and my children. I have done very considerable reading the past 7 years. As a systems analyst I do much research for a project of the type needed for that project. Let's consider this IEM for starters. I have never been diagnosed with anything that appears correct though I have had lots of hypothetical diagnosis and decades of worthless at best or damaging treatment based on these incorrect hypotheses, aside from FMS/CFS and polyneuropathy. More than 100 practitioners, most MDs, many specialists amongst them, have been singularly poor at diagnosing my problems. Most of them had the immediate response of "b12 deficiency" until they saw that I was taking 1mg of cyanocobalamin daily. Then they all immediately said "impossible" and continued to misdiagnose me. We both know that is a certain kind of institutional blindness or ignorance. Certainly my responses to the active b12s have given lie to the idiopathic neuropathies and at least a dozen or so other incorrect diagnoses over time. It’s true enough that I had IBS, but only as part of b12 deficiency caused FMS.

I have not been able to find published data on the prevalence of the cobalamin processing-related IEMs. I've read that cblC is the most common of them, and that it is "rare." I'm not sure how rare. One source, dated in 2006, reported that there were a total of 250 known cases.

My point here is that only a very small fraction of people with CFS can possibly have the IEM that you inherited.

It might be genuinely rare or might only be rarely recognized. The reading I have done is very suggestive that rarely recognized is probably a more correct description. The IEM is only recognized when the infant involved doesn't have a source of the active b12s, such as with soy based infant formulas. They don’t go around testing everybody for each of the handful of known IEMs. The true incidence is totally unknown. As one paper put it “unrecognized in the adult form”. Breast feeding infants won’t be recognized. Anybody eating meat and not having an absorbtion problem won’t be recognized. They truly do not know and via not knowing infer a rarity that may not exist. In any case a folate deficiency and/or inability to adequately convert folic acid, which affects 50% of population, must also be included as its lack can even prevent active b12s from being effective. In addition, totally unrecognized are the folks with CNS/CSF deficiencies of one or both active cobalamins such as folks with CFS/FMS and Alzheimer’s and who knows what else. The actual incidence of that CNS/CSF deficiency for either active b12 is not known either. Additionally, with deficiency symptoms being responsive to active b12s at serum levels over 1500pg/ml before treatment and despite uMMA and Hcy test results being negative, there is no definitive way to test for active b12 deficiencies except trials. In my consulting experience in group health over more than 20 years I would describe those kinds of cracks in the definitions as “large enough to drive a fleet of armored trucks through”.

the prevalence of CFS as defined by the Fukuda et al. definition has been estimated at about 0.4% of the population by Jason et al., which would amount to over a million people in the U.S. alone.

With the above mentioned cracks, there are probably at least 30-60 million or more active b12 responsive persons in the USA, enough to include all those with CFS/FMS/CFIDS/ME without even burping. One estimate of elderly alone based on very conservative criteria and definitions of deficiency in a Dutch study, the same one saying 6mcg is adequate, nothing as terribly loose as merely having responsive symptoms, are 20% of those over 65 and that may include down to age 50 or younger as it doesn’t appear out of nowhere at 65. It is also estimated, conservatively, that 40% of those diagnosed with Alzheimer’s based dementia have a b12 deficiency dementia instead, and again that’s a conservative definition and doesn’t include CNS/CSF deficiency, which is not generally recognized, unless there is also a bodily deficiency. So that your statement “My point here is that only a very small fraction of people with CFS can possibly have the IEM that you inherited” can be entirely true and have no bearing on the issue at all. It’s a false assumption that it matters or is definitive. People generally react to an abundance of methyl b12 and adenosylb12 similarly to the way I do to the extent that they have similar subsets of symptoms. The IEM does not appear to make a gnats whisker worth of difference. The hypersensitivity seems to be characteristic of the b12 deficiency itself, not the why of the b12 deficiency.

I had certain long term symptoms from childhood which later might have been characterized as ME, if such had even existed and been recognized. I was diagnosed, probably correctly, with “delayed myelination” as a child, delaying generally understandable speech until 1st grade. However, no chronic disease was recognized. It’s only in retrospect and understanding of the full set of symptoms that it can be seen. I had repeating tonsillitis and then after a tonsillectomy repeating strep and several pneumonias and bronchitis that would last for months after each cold and each strep and was sick a lot, missing 25-33% of every school year. I had sleep disorders from before age 2. I was also gifted physically when I wasn’t sick and was larger, faster, better coordinated than anybody else in my class. I was diagnosed hypothyroid when I was 8. My mother considered me a hypochondriac and did her best to sell the docs on that idea. She considered my being sick a way to get back at her and embarrass her. I absorbed b12 just fine so I was not "deficient" in any sense similar to PA. It can be inferred by the symptoms I had, based on the reading I have done and experience I have had and comparing notes with hundreds, that my childhood symptoms were largely those of a lack of methylb12, and a lack in the cerebral spinal fluid of methylb12 and at least as an adult, adenosylb12 as well.

the fatigue must be "of new or definite onset (has not been lifelong)".

That describes me to a “T”. I did not have any unusual fatigue until age 39, 2 months before my 40th birthday, at which time I had a sudden onset (overnight) total multi system crash including a crippling level of fatigue. Before that I was an energizer bunny. It certainly was sudden onset. If you are basing the argument that I must not have had CFS because I lacked “definite onset” then it’s based on another false assumption. I developed many symptoms of ME in my late teens. Following a car wreck in which I was t-boned by a guy running a red light and having 3 fractured vertebras, dorsal horn damage and a really messed up back and neck generally, I developed FMS in a pretty typical pattern in my 30s. Then I had sudden onset of CFS at 39 following what was diagnosed as an entero virus that never went away for 16 years, an Incline Village type onset. CFS/FMS is a result, not a cause. CFS/FMS/ME/CFIDS are each made up of wholly contained subsets of the various b12 deficiency symptoms. As that b12 symptom universe contains hundreds of symptoms affecting every system of the body, the combination of symptoms in any specific person varies tremendously making this deficiency look like all sorts of other things. Could It Be B12?: An Epidemic of Misdiagnoses by Sally Pacholok RN http://www.amazon.com/Could-Be-B12-Epidemic-Misdiagnoses/dp/1884956467

This book talks about the diagnostic problems as she also was not easily diagnosed. As she is using a definition of b12 deficiency based on hydroxycobalamin she is far less inclusive of symptoms than I am. That does not damage her basic hypothesis, just limits it.

Rich, if you were to examine the definitions of b12 deficiency and symptoms list by country you would see that the lists are highly correlated with the form of inactive b12 used primarily in that country for vitamins and/or therapy. Also, a country such as India with a large percentage of vegetarian population has a different list. There is a pattern of symptom inclusion and exclusion that is apparent. A combined list from many countries has 3 times as many items as that of any single country. I could not find an English list from Japan which sets very different standards of b12 deficiency, below 550pg/ml, and uses methylb12. They are also the leading edge researchers on methylb12. Most docs think “ALCOHOLIC” these days when they see an MCV over 100 (formerly >92-96) instead of ringing the b12/folate deficiency alarm. Knowing that explains why so many docs accused me of being an alcoholic through the years when I hardly drank at all.

There are plenty of symptoms that are not included in that universe so there are lots of things that don’t look like b12 deficiency but there are lots of things that do. Just because a name like IBS or FMS gets pinned on something causality is not defined. The only way to test definitively whether one of these indefinite symptoms is of b12 deficiency origin is to do a trial.

However, for those who do not have these IEMs, which as I've indicated above would include the vast majority of those who have CFS, other forms of B12 are useful. In fact, recent research (PMID: 19447654) indicates that whatever the form of cobalamin, when it enters a cell in the normal way, the first thing that happens is that the beta ligand (whether cyano- hydroxo-, aquo-, methyl-, or adenosyl-) is removed from the cobalamin molecule by the cblC enzyme, before the cobalamin goes on to be converted to either methylcobalamin or adenosylcobalamin. So in the case of a person who does not have these IEMs, any form of cobalamin can be used to produce the two active coenzyme forms. These researchers did find, however, that the initial form of the cobalamin did have an effect on the relative amounts of methyl- and adenosylcobalamin that were formed. Based on this, I do not think it is valid to state that hydroxocobalamin cannot be used in the treatment of CFS.

Let’s consider a classic b12 deficiency disease, Pernicious Anemia which technically is an Intrinsic Factor deficiency rather than the actual resulting macrocytotic anemia. People receiving the classic treatment, several “loading doses” of inactive b12 injections and then 1 cyanocobalamin injection per month or 1 hydroxycobalamin injection each 3 months. That usually succeeds in a statistically significant percentage of people having their MCV brought down into “range” and keeping their serum cobalamin level above 300pg/ml. Even with that these are not “well” people. They remain ill, virtual zombies, for decades, barely kept alive by this trickle of b12. Due to some peculiarity of thinking the rest of their many symptoms are not considered b12 deficiency symptoms that can be healed and they are left twisting in the wind the rest of their lives. If the inactive b12 therapies as accepted by most of the world’s doctors actually worked these people would be healed. They are not. That should be a clue.

Freddd · Aug 21, 2009

Part 2 of reply to Rich's statement

As hydroxycobalamin only affects a subset of b12 deficiency symptoms it is not a good test since if it doesnt affect all of the symptoms one still has to then test with both active b12s. I know the literature says absolutely nothing about this. That is a defect of the literature. After the mistake in 1948 there has been far too much effort to justify the mistake and continue it rather than showing all the reasons that inactive cobalamins are inadequate. Yes they have a longer shelf life. So does mercury or a chunk of steel or lead. I do not have all the theory down. Much of the theory based on inactive cobalamins to justify their use is just plain wrong. For inactive cobalamins to work at all every step of a complicated and intricate process has to work correctly, there has to be an additional source of methyl groups and then it only provides partial results at best. The assumptions that they are all working correctly in everybody just is not valid. Rich, why do you use methylfolate? Folic acid ought to work. After all the theory is said and done it comes down to because it bypasses all the assumptions about why folic acid ought to work and works a lot better for more people a higher percentage of the time. The exact same reasoning applies to the active b12s. They bypass all the assumptions and work a lot better for a more people more often. One can reasonably expect that a population of ill people may select for various malfunctions of the biological system. Bypassing all the assumptions about what ought to work and using the directly active substances ought to produce superior results. They do. That is a directly testable hypothesis.

Lets take this one step further. Consider whatever the form of cobalamin, when it enters a cell in the normal way. When the active b12s enter the cell directly by diffusion it is not entering the normal way and is not stripped (hypothesis). It enters rapidly and maintains its identity and can become immediately active, starting within about 5-10 minutes with a suitable sublingual tablet. It bypasses 100% of the assumptions about all of this. I cant prove the diffusion hypothesis but the workings of it can be demonstrated. It is quicker, takes less time, than the researched times of inactive cobalamins taking the normal way in. This can be demonstrated over and over by many of the hypersensitive persons. An effective active b12 sublingual tablet is faster than IM injection, faster than SC injection, faster than oral consumption, faster than inactive cobalamin. If it isnt diffusion, what is the mechanism that allows an active sublingual tablet to start having an effect, even a very intense effect, in 5-10 minutes in a suitably sensitive person? The whole testing method I outlined elsewhere for detection of such deficiencies with questionnaire and single dose trial depends upon this fast action. It doesnt catch everybody, maybe 60%. Ive given over 1000 people active b12 tablets face to face and watched their reactions. I know, we need a study proving this. I should have thought ahead and done it as a study. Its quick, has an easily stated small hypothesis and needs no expensive lab tests, just simple self observation. A sublingual hydroxycobalamin, cyanocobalamin or candy can be used as control. People without symptoms are virtually always without responses. They have no expectation at all of a vitamin providing a knock their socks off response, just the opposite in fact, so they tend to ignore small responses.

Whether hydroxycobalamin has no effect on me or only too little to stop neurological deterioration is unknown at this time and I am not inclined to test that. Cyanocobalamin was totally ineffective and even damaging. The return of multiple symptoms is as rapid taking hydroxycobalamin as taking nothing at all. However, taking 10 mcg of methylb12 would likely be no better, to keep it in perspective.

I have learned to recognize all four specific b12 deficiencies, body and cerebral spinal fluid affecting the central nervous system, CSF/CNS, of each methylb12 and adenosylb12. The CSF/CNS deficiencies can exist without the body deficiency that can cause the sudden onset of the severe and unusual fatigue. A methylb12 body deficiency doesnt cause the fatigue either. Research has clearly indicated that the cobalamin level (type or types unspecified) in the CSF of folks with CFS/FMS is depressed to about 25-50% of the control population, mechanism(s) unknown. Hydroxycobalamin is ineffective on even the best researched sectors such as PA, 20-40% of the time dependent upon study, when by every test the persons are clearly deficient. Whether all these people have one or more of the handful of known IEMs is unknown. For that matter they may be deficient of methylfolate instead. Their cells were never cultured to look for such a cause for non response in these many studies. It was perfectly acceptable that 20-40% were non-responders, just like to a drug. Even with studies using only methylcobalamin there are a percentage that are complete non responders to methylb12. I have not been successful finding studies using both active cobalamins to determine a percentage of non responders. Even so, many people with the CSF/CNS deficiencies would still be non responders as the doses used in most studies is inadequate to overcome that lack. Having read many studies, prepared statistics and given presentations at conferences I know that having a statistically significant response in a statistically significant percentage of participants compared to placebo, visible mostly on lab tests is a lot different than a knock your socks off widespread naked eye healing event. In detecting fraud we have to do a lot better than a statistically significant indication. That might tell us where to look but we have to come up with hard data. Lets be real.

My point here is that only a very small fraction of people with CFS can possibly have the IEM that you inherited.

That doesnt matter at all. It amounts to a straw man. Im not testing and not asking about any IEMs. I am basing things purely on symptoms and responses. It may be correct, and as I point out to anybody interested, is that I have a superset of characteristics and most folks only have some subset of my symptoms. Interestingly they respond in a very similar fashion however. Having a large positive response to a large amount of unbound active b12s is not limited to those with any of the IEMs concerning cobalamin as far as I can tell.

You have made the point that use of methylcobalamin and adenosylcobalamin should, however, suffice for treating any of these B12-related conditions, including the IEMs and CFS. I agree that this is true, but I have one concern with use of high dosages of methylcobalamin in CFS. It relates to the fact that many people who have CFS have had amalgam fillings in their teeth during many years of illness, during which glutathione has been depleted in their bodies. It is likely (and there is evidence to support this) that these people have significant body burdens of inorganic (mercuric) mercury. It has been shown that methylcobalamin has the capability of converting mercuric mercury into methylmercury, and it has also been shown that methylmercury is able to cross the blood-brain barrier readily, thus delivering a major neurotoxin into the brain.

80% of mercurys neurotoxicity is identical with methylb12 deficiency. Could it be that mercury, acting to disable methylb12 causes the very neurological symptoms of concern through the mechanism of disabling active b12? It certainly appears to be a possibility as methylb12 is disabled when it donates the methyl to mercury. Nitrous oxide disables b12 as well causing sudden onset of neurological symptoms. This is very well documented. I too have had amalgam fillings through the years. My father was a dentist. He was, unfortunately often contaminated with mercury such as when a 5 pound jar was dropped. I played with mercury as a child on a few occasions, with demonstrations of how it would combine with various materials such as the surface of a silver coin and how it would not wet non metals. I think that you make overly much of the possible toxicity from amalgams. While Im used to having data from 30,000 to 100,000 participants groups to work with, here I have to make do with much smaller populations. While I have heard much fear expressed out of all proportion of the actual scale of the possible problem, with hundreds of people taking sublingual doses of methylb12 and adenosylb12 in this protocol, I have never actually been told of any unusual reactions of concern. Nearly 100% have neurological startup effects which for the most part quickly fade. Nobody that I am aware of has had any discernable effect from the mercury that isnt identical with that of everybody else and passes quickly.

I am concerned about this. I have heard of two cases in which high dosages of methylcobalamin were applied intravenously

The only high dose IV methylb12 therapy I know of is to remove cyanide from the body. The usual dose is repeated 35 gram IV infusions. Rest assured that at no time do I advocate any IV infusions of methylb12 of any dosage other than for cyanide or botulism.

in the presence of significant apparent body burdens of mercury, and in both cases, the people reported what seemed to me to be symptoms of neurotoxicity shortly afterward

I suspect that might be hard to distinguish mercury specific neurotoxicity from ordinary b12 neurological damages that are essentially identical to that of apparent mercury neurotoxicity. As many deficient people have wide ranging neuropathic and neuropsychiatric damages and symptoms, and as a dose of methylb12 intensifies most all of these symptoms and causes immediate changes and widespread shifting of these symptoms and activation of these symptoms in unaccustomed manners it sounds like a feat of magic to pick out mercury specific ones, or a lack of familiarity of what constitutes the usual methylb12 deficiency damage. If you look at the list of active b12 and methylfolate symptoms, signs and co-correlates, you will find that there are about 90 neurological and neuropsychiatric items. There is some redundancy but also a lot of combining of items. If that list were stretched out to maximum unique detail Im sure it would go to close to 200 neurological and neuropsychiatric items. Some are functional and some represent neurological damage. Perhaps you could let me know of which specific mercury related neurotoxic items which are not on that list showed up in those two cases. The sudden high contrast illumination of neurological and other symptoms as brainfog starts clearing is not enjoyed by everybody. It can be rather unpleasant. It may be triggered by methylb12 and/or adenosylb12 and/or several other supplements but the two active b12s are the predominant ones. It is not gradual but rather a sudden stripping away of years of fog. The mb12 and adb12 are not causing the symptoms, just allowing them to be seen. Dont shoot the messenger.

When sufficiently large dosages of methylcobalamin are given, as you have noted, the carrying capacity of the transcobalamin carrier protein in the blood plasma is saturated, and the excess methylcobalamin exists for a time in the blood as free molecules. It is this methylcobalamin that concerns me, in terms of its capability to react with mercury. I realize that you need to do this to get enough methylcobalamin into your cells, given your IEM, but this is not true for the majority of people with CFS, and I think there is a risk in doing it this way if there is much inorganic mercury present. I can't prove that this is a problem, but I'm concerned that it might be.

Freddd · Aug 21, 2009

Part 3 of reply to Rich's statement

First, the question arises as to what amount of cobalamin saturates TCII for it to become HTCII. As HTCII circulates, dropping off the cobalamin at the various cells as needed and then can go back for another load as TCII, there is always a percentage without a cobalamin wrapped up. Perhaps it’s more accurate to ask “What is the channel capacity per day”? As 1mcg provides a temporary boost of 200pg/ml to the serum in bound cobalamin, it’s not very much. This whole enterohepatic circulating mechanism is rife with conflicting use of terminologies, data of doubtful origin and wishful thinking. The most commonly mentioned number is 10mcg per day can be transported. That just happens to match the most frequent number given for the maximum efficient absorbtion rate via IF and TCI/HTCI.

Whether or not these are accurate or approximately accurate I can’t vouch for. Let’s assume that they are close enough for talking about. Now, in looking at measured tissue content in humans of b12 in the liver, other organs, muscles and other tissues and blood it is hard to get past 2-2.5mg total b12 content of the human body. Long pig is similar to beef in organ and muscle content of b12 and considerably higher than rats. There just is no place that the frequently quoted 5mg total content can get it from according to actual measurements. As the higher the total the worse the situation when a person becomes depleted it doesn’t matter for my purpose here. Let us assume a 50% depletion, that being 1mg more or less. In a normal functional situation total losses exactly equals total gains on the average as it is an equilibrium situation. A meat eater is estimated to consume 3-6 mcg per day and to lose 3-6mcg per day via urine and bile. Again, the numbers one comes across vary all over the place. As this is an equilibrium situation outgo always equals income or serum level would climb to very high levels over time and they don’t. Outgo increases as serum level increases so equilibrium is always reached. So if supplementing succeeds in saturating the TCII/HTCII channel there is a limit to how fast the body’s level can go up. Very high serum levels in the absence of supplementation indicates certain diseases and liver damage. If supplementing succeeds in adding 1mcg/day that would then take 1000 days at a 1mg body load deficiency to refill. In a pharmacokinetic model with a serum half life of 100 days it takes 1000 days to reach equilibrium at a changed dose. It would be getting close at 500 days but as excretion goes up as serum level goes up, it takes a long time to fill that gap as it isn’t a simple linear addition problem, it’s a serum half life equilibrium problem and is exponential in nature. If the body load deficiency is 2mg or 3 mg that means it takes even longer to reach equilibrium since the channel capacity doesn’t change and is independent of dose largely. I read a recent Dutch study indicating that 6mcg a day, according to their measurements of “bound b12” is sufficient to saturate the channel. This bound b12 test is the newest latest hottest test out there for proving that 6 mcg a day is sufficient for anybody because it fills the channel. It may be used to limit vitamins sales to “reasonable amounts” like 25mcg.

Now let’s consider what this may all mean. If a person takes inactive cobalamin they are strictly limited to the channel capacity. That means it can take 3 years to a lifetime to reach equilibrium once a deficiency has occurred, and that equilibrium may not be adequate for healing.

Now let’s consider personally observed data combined with research data. Being hypersensitive to methylb12 levels in my body and brain has its uses. My system works normally for absorbtion (IF and TCI/HTCI) and transport (TCII/HTCII). If I have a problem other than interconversions of types it is in the retention area. My kidney tubules that collect cobalamins work normally as I demonstrate every day. My liver appears to be normal. As much pharmacokinetic data shows the initial serum half life after injection of any unbound cobalamin is 20-50 minutes once it hits the blood stream. Whether that is due to dispersal into the tissues, which also get saturated and reaches an equilibrium, or is purely excreted is perhaps not fully settled. In 12 hours it drops to around 4 hours and then averages 12.9 hours over the next 36 hours, showing an exponential drop-off pattern. My injections are 6-8 hours apart and are subcutaneous so I never get out of the under 4 hours serum half life range. A four hour serum half-life would double my serum level compared to a 2 hour serum half life. The bound b12 serum level becomes totally inconsequential compared to the free b12 serum level. It takes longer than 6-8 hours for the subcutaneous injections to absorb into the blood so I average 1.25mg/hr into serum with some degree of smoothness. This keeps my serum level above the threshold for stimulated neurological healing level continuously. There are 50mg/day IV trials attempting to do just this running in Japan. I didn’t jump right in there. I experienced the path to equilibrium at 1- 5mg/day sublingual, 10mg/day sublingual, 15mg/day sublingual, 25mg/day sublingual, 2.5mg/day injected SC, 4.4mg/day injected SC, 5.0mg/day injected SC in one or two doses, 7.5mg/day SC injected, 7.5mg/dose SC injected BID, 7.5mg/dose injected SC QID and 10mg/dose injected SC TID. I further ran a series of injections from 5mg to 25mg SC establishing that there was a discontinuous threshold effect between 6mg and 7.5mg and no apparent dose proportionality beyond 7.5mg per dose, which agrees approximately with the Japanese high dose trials. I ran a series of trials with 5 hypersensitives of 10 brands of methylcobalamin, each brand reaching equilibrium with an easily made comparison when switching brands as to whether and how the equilibrium was changed. I ran a series of tests comparing by equilibrium effect and urine colorimetry absorbtion rates of the 5 star sublingual brands as compared to SC injections. This established an absorbtion rate of 15% at 45 minutes increasing to 25% at 120 minutes.

Studies working with methylb12 using a high dose and low dose format indicate a dose proportionality with methylb12 not present with hydroxycobalamin or cyanocobalamin, as stated in those studies. The effects of dose are summarized in the ZONES table I compiled and posted elsewhere on this site. Based on personal experience and the reports of some hundreds of people there is a non-linear continuous dose proportionality over the range 100mcg to 25mg of sublingual dose held for 45 minutes or more. If the effect is “1” at 1000mcg, then it appears to diminish as a converging series approximating 1 + + + 1/8 + … with each dose doubling adding half the effect. Then at 50mg sublingual in a single dose an effect equal to 7.5mg SC is reached. At this level there is a sudden quite noticeable increase in neurological changes and healing. For me that translated to the continuing deterioration I was experiencing as increasing numbness in my feet stopped and reversed. At 30mg/day injected SC in 3 or 4 doses the reversal improvement was continuous all day and night reversing footdrop, lack of location sense, regaining motor control over leg, ankle, foot and toes and the ability to balance on one foot with eyes closed.

Reaching tissue equilibrium, with all receptors occupied to the maximum at that serum level takes less time at higher doses. At 1mg sublingual (150-250mcg) it appears to take about 3 or more months. At 5mg sublingual (750-1250mcg) about 2-3 months, at 10mg sublingual (1500-2500mcg) about 6-10 weeks, at 5mg sc injected about 4-6 weeks and at 7.5mg sc injected about 3-6 weeks body, 3 months or more for CNS/CSF, at 15mg in 2 doses about 3-4 weeks body and 2-3 months CSF/CNS and at 30mg sc injected in 3 or 4 doses about 3 weeks body and about 1-2 months CSF/CNS . The very first dose of methylfolate changed the dose level at which the b12 became visible in the urine, from 2.5mg to 4.4mg, and with subsequent doses to 5.0mg. Rich, if you can explain why, I would be glad to know.

The result of this tissue saturation with free b12 is very rapid healing that is clearly not achieved with purely bound b12. This happens generally with most people who have any response at all.

My experience of the past 6 years with others indicated that people taking inactive cobalamins had slow and limited healing at best. They tended to have far worse startup reactions when starting active b12s than those taking nothing at all with paranoia and fear being prominent. Now I arrive here at this website and find all sorts of people mired in “detox” reactions from a methylation protocol that appear to consist of certain intensified b12 deficiency symptoms sometimes appearing a year or 18 months after starting when I would reasonably have expected them to be approaching a 90% healed of those symptoms if they were taking all needed cofactors with active b12s. The startup symptoms rarely last more than a few months by which time they are well into the shifting symptoms of healing and chasing down the symptoms that are not responding. To find so many people having this intensity of reaction after so long was a genuine surprise as it is in such extreme contrast to my experience personally and with many others.

I would also like to comment on glutathione. You have emphasized that adding glutathione torpedoes your ability to make use of methylcobalamin. I can understand this, since it will react to form glutathionylcobalamin, and given your IEM, your body is not able to convert this back to methylcobalamin. However, for the great majority of people who have CFS, this is not a problem, and in fact, if my hypothesis is correct, the lack of enough glutathione to form glutathionylcobalamin, which normally protects cobalamin from reacting with toxins at an intermediate stage of its processing in the cell, is at the root of the pathogenesis of CFS

“Torpedoes” is a good description. It blows the effects of unbound active b12, primarily methylb12, out of the water. It throws me into hard deficiency immediately, no gentle onset like merely skipping mb12 for a week or having some photolytic breakdown mb12 (hdroxyb12). Instead it starts within an hour or two. Some of it’s effects lasted for 3 months beyond the end of the trial. I guess that does show how well NAC and glutamine do combine in the body making glutathione. It really does work as advertised. It also increases the excretion rate of b12. My urine was the color for the entire 6 week trial that it attained for a few hours when I took a single injection of 25mg of mb12. It was the red river. For comparison, a 7.5mg sc injection puts about a magenta 05-10 coloration (color filter, 05 is just noticeable difference) into my urine for a few hours during peak absorbtion. The glutathione added a 30-60 magenta, a substantial difference. However, the problem is not limited to me and my “rare” IEM. 100% of the other people trying it, had the same basic effects. One guy was a vegetarian and probably had no other problems. Several persons were changing from a hydroxyb12 protocol and long standing symptoms suddenly went away when they stopped the glutathione infusions. All in all some were receiving glutathione infusions and the rest were taking various precursors including “hidden” ones divided between two multi component supplements only to be discovered by looking them up. The folks taking the methylb12 and trying the glutathione producing supplements had basically the same awful experience I had, sudden deficiency and return of symptoms. The ones who had been taking it and stopped when they started active b12s made progress with long established symptoms going away. There wasn’t a single person who found it benign in our admittedly small sample. It would be very difficult to make the case for all 9 to have the same IEM (1 in a million persons was the approx rate you indicated) as I have. I thought I read somewhere that 1 in 3 with CFS have that reaction to glutathione.

which normally protects cobalamin from reacting with toxins at an intermediate stage of its processing in the cell

Freddd · Aug 21, 2009

Part 4 of reply to Rich's statement

Interesting! As that is considered a benefit of abundant methylb12, protection from toxins, because it does interact with them and removes them, why is it desirable to block that?

These researchers did find, however, that the initial form of the cobalamin did have an effect on the relative amounts of methyl- and adenosylcobalamin that were formed. Based on this, I do not think it is valid to state that hydroxocobalamin cannot be used in the treatment of CFS.
In actuality there is a night and day difference. The quantitative and qualitative differences of having substantial amounts of unbound active b12s present day after day are so dramatic in many cases as to be completely different things. The explanation does not do it justice. Of people who have switched to active b12s (and I do mean only the 5 star brands held for 45+ minutes) with all needed cofactors, Im not aware of any who choose to revert when they realize the cause of the differences. In any case hydroxycobalamin has 20-40% non responders and leaves out entirely all healing caused by a large amount of unbound methylb12 and adenosylb12. Certainly some people have some benefit but it leaves out so many and is incomplete for the rest.

Well, I just wanted to make those points. It is not my desire to be argumentative, and I certainly do not want to discourage you from helping a lot of people. I'm willing to listen, and hopefully learn, from any response you might want to offer on these issues. I just wanted to try to clear up differences, to the degree possible.
Im hoping that you can help me with the understanding and theory to fit the observed facts of the dramatic differences in effectiveness. As there are differences I think that an awareness of them is essential. I am troubled by a solution that leaves out the 20-40% of non-responders and only works partially when more effective solutions appear available especially as I have always, up until 6 years ago, been a non responder. I wouldnt voluntarily put anyone else in the position I was in at the cost of nearly everything in my life and almost the cost of my life itself. Perhaps you might even be tempted to observe the differences yourself. There are no secrets concerning this. Im trying to reveal it to all who are interested

1. Methylb12 has dose proportionate healing noted in suitable literature, hydroxyb12 does not.
2. Healing with methylb12 shifts into high gear when there is significant amounts of unbound methylb12 and increases as the amount of unbound methylb12 increases, not so with hydroxyb12 which is limited to bound b12.
3. Methylb12 has neurological healing effects that inactive forms dont have noted in literature.
4. Methylb12 shifts into neurological healing overdrive above certain amounts (suprathreshold, about 7.5mg). It is hypothesized that this occurs when diffusion gradient is steep enough to force methylb12 into CSF/CNS in at least persons with the lower CSF cobalamin levels relative to serum level for unknown reasons.
5. Methylcobalamin can maintain body equilibrium on daily dose
6. Methylb12 can maintain CNS equilibrium on 1-4 suprathreshold doses per day depending upon person and healing status.
7. Adenosylb12 can also penetrate CSF with steep enough diffusion gradient enhancing CNS functioning. Can reach equilibrium in two weeks.
8. Adenosylb12 can reach equilibrium in muscles with one or two doses.
9. Adenosylb12 can maintain CNS equilibrium with weekly large dose for many.
10. Adenosylb12 can maintain body/muscle equilibrium with weekly dose for many.
11. The combination of methylb12 and adensoylb12 affects perhaps 300 symptoms and signs whereas hydroxycobalamin affects perhaps one fourth or fifth as many. Perhaps this is a cause for such significant differences in various national lists inclusions and exclusions.

richvank · Aug 21, 2009

To freddd re: Active cobalamin treatment

Hi, Fred.

Thank you for the comprehensive reply. You've given me a lot to consider, and I'm going to have to do some studying and thinking before I will be able to put together a decent response to all the various issues you touched upon. I just want you to know that I did receive your message. Reading it was something like the proverbial "trying to drink from a fire hose," but I plan to read it again in small pieces!

I appreciate interacting with you about this, because it forces me to take a closer look at the biochemical issues involved with B12 and folate. You've correctly noted that the recovery of people on the protocol I have suggested is slow, and that is something I would like to see improved, if it can be done without causing other intolerable problems for them. There's no question in my mind that glutathione depletion and a partial block in the methylation cycle are core biochemical issues in most cases of CFS, and folate and B12 are key to fixing these problems. How best to go about it is what I want to understand better, and I think that interacting with you is going to help me in that pursuit. (I'm not "wedded" to the current Simplified Treatment Approach." I suggested it partly as a way to test the GD-MCB hypothesis for CFS, and partly to help people with CFS now, even though we don't yet understand all the details.) And along the way, maybe I will be able to help you to find answers to some of your questions, too.

I would like to bounce a couple of hypotheses off you even though though they are still half-baked. Let's assume for the moment that you are right in claiming that the high dosages of methyl B12 that you advocate do not end up causing mercury neurotoxicity problems in the brain. (Note that I'm not totally on board with you on this, but let's make that assumption for purposes of this discussion.) If methyl B12 has the ability to methylate mercury (which it does), and methylmercury can readily cross the blood-brain barrier (which it can) how could this be explained?

My understanding of the biochemistry of mercury in the brain is that it is transported in as organic mercury, such as ethylmercury in the case of the kids who received the vaccines with thimerosol preservative in them, or methylmercury in the case of the people eating a lot of fish, because the organic forms are able to cross the blood-brain barrier readily. Once inside the brain, my understanding is that the organic forms revert to inorganic mercuric mercury, which binds primarily to sulfur atoms in enzymes and other proteins, and that this is the form that actually causes the neurotoxicity.

Some years ago I suggested that perhaps a way to get the mercury back out of the brain might be to use high dosages of methyl B12 to methylate the mercury, so that it would be able to pass back across the blood-brain barrier and be removed from the brain. I didn't encourage people to try that, though, because I was concerned that if there was inorganic mercury elsewhere in the body, these high dosages of methylmercury might move it into the brain, and I couldn't be sure that the mechanism I suggested for removing mercury from the brain would really work.

I'd like to suggest that perhaps you have unwittingly (sorry about that word

)already performed that experiment. Perhaps if one uses enough methyl B12 for a long enough time, one can achieve a net effect of moving mercury out of the brain, even though perhaps some mercury would be moved in initially.

I don't know if this is true. I'm just throwing it out there. I think it could explain why you don't see a problem with mercury neurotoxicity when you use these high dosages for extended times. If this does in fact work this way, it would be a very important development, because we have not had a way to remove mercury from the brain, and the usual residence times of mercury in the brain have been estimated to be measured in years.

One other thing, as long as I'm bending over backward

, let's also suppose that you are right in claiming that your high-dosage active B12 treatment does not produce extended detox symptoms. (Again, I'm not totally agreeing with you on this, but let's make that assumption.) Given that people who have had a dysfunctional sulfur metabolism, and hence a dysfunctional detox system for many years can be expected to have accumulated large body burdens of toxins, why wouldn't these cause problems on your treatment?

It is known that B12 is one of the most chemically reactive substances in the body when its cobalt ion is in the +1 oxidation state, which it is at a certain stage of its cycle in methionine synthase. It has been called a "supernucleophile," which means that it is very reactive with substances that would tend to remove electrons from it, i.e., to oxidize it. Many toxins are electrophiles, which fill the bill. Perhaps by using such high dosages of methyl B12, you are using a lot of the excess B12 as a toxin binder, and in that way are removing toxins via the kidneys, into the urine, thus clearing them out rapidly and avoiding a drawn-out detox reaction. Again, I don't know if this is true. I'm just throwing it out as a possible hypothesis. I think this would explain things, including the fact that Amy Yasko has found that some patients need fairly large dosages of B12 to experience improvement, and I think your dosages are higher than hers are.

I'll get back to you again after I've had a chance to do some homework on the other issues. These two are the ones that I think are most crucial in trying to mesh what you have reported doing and finding to what seems to make sense to me in terms of known biochemistry. I of course haven't seen the detailed observational data to back up the claims you have made, but I'm willing to entertain the possibility that you have such data, and that you have correctly interpreted what you have seen. If so, all of this has to fit together somehow, since the truth is the truth. As you can see, I'm a hardheaded scientist, not a postmodernist.

Best regards and thanks again,

Rich

Michael Dessin · Aug 21, 2009

Rich/Fred

WOW!!

Thanks for taking the time to share this information, it's a lot to digest but well worth the reading!!

I really can't comment more than that, as I just don't feel qualified to speak on that level. However, I can extend my thanks again..THANK YOU!

Mike

dmholmes · Aug 21, 2009

Ditto, awesome. I wish I could comprehend 10% of it. Hoping something very good comes out of this kind of collaboration.

jenbooks · Aug 21, 2009

Fabulous discussion. History is being made here.

Lisa · Aug 22, 2009

Rich Van K

Hello Rich!

I saw that in your last post you asked freddd two questions that I have some experience with.

1. If methyl B12 has the ability to methylate mercury (which it does), and methylmercury can readily cross the blood-brain barrier (which it can) how could this be explained? (in reference to it possibly not crossing the blood-brain barrier)

2. Given that people who have had a dysfunctional sulfur metabolism, and hence a dysfunctional detox system for many years can be expected to have accumulated large body burdens of toxins, why wouldn't these cause problems on your treatment?

In June of this year, I came across Freddd's methods on a different forum. As I was already on all the main co-factors he listed and only missing the two forms of b-12, I decided to try both myself and my fiance on them at his suggested dosages. Both myself and fiance (Jeremy) have extremely similiar conditions of CFS/MCS due to sharing the life factors that made us both crash. We have been very ill since 2002 with little done in the way of treatment other than high anti-oxidant supplements and basic vitamins, but somehow missing supplemented b12.

After five weeks on the methyl-b12's and adeno-b12, we finally had no choice but to stop using them due to the severity of the problems they were causing us. We initially tried backing down to 1/4 of a methyl-b12 lozenge per day, but even this remained too strong. At this point we use hydroxy b-12, one perque lozenge/day. It has been about four weeks since we stopped the bulk of methyl-b12, adeno we were taking occasionally but have since stopped this as well.

The symptoms we have had and continue to have, seem to be directly related to both your questions above.

Both Jeremy and I have significant body toxicity loads. I would be very surprised if we didn't both have high mercury loads as well due to the number of fillings for each of us, plus the fish we had been consuming off and on over the last several years. In my experience, our MCS is related to the toxic load and has become so severe as to prevent us from living in conventional housing any longer.

During 18 months prior to adding in the methyl-b12 to our supplement program, we had gone from a health rating of 20% functional up to around 30%. After five weeks on the methyl-b12 I had to make us stop as I realized our health rating had plummeted to about 15%. Had we continued to become worse, I have to question our ability to continue chores required for basic survival such as cooking a simple meal.

Over the past four weeks, I have read a lot and talked with a few people about what has occurred. The only conclusions I have been able to draw are that we were detoxing far faster than our bodies could handle due to the methyl-b12, and very possibly that mercury was being transported around in quantity. I hate saying it, but in my case it feels like there has been some very noticeable damage caused to my cognitive abilities and memory skills. Its one of the reasons I have to wonder about the mercury. Large swaths of memory have been almost completely erased and writing completely new memory is often difficult if it involves much detail.

Both of us are much more chemically reactive again from our MCS, in a very significant amount more body pain then there has ever been before, and we seem to have had our health settle at 15-20% depending on the day. I attribute these symptoms largely to the detoxing running rampant and causing havoc when the toxins could not be removed in time.

I hope this helps with finding some answers.
Lisa

Freddd · Aug 22, 2009

Lisa said:

Hello Rich!

I saw that in your last post you asked freddd two questions that I have some experience with.

1. If methyl B12 has the ability to methylate mercury (which it does), and methylmercury can readily cross the blood-brain barrier (which it can) how could this be explained? (in reference to it possibly not crossing the blood-brain barrier)

2. Given that people who have had a dysfunctional sulfur metabolism, and hence a dysfunctional detox system for many years can be expected to have accumulated large body burdens of toxins, why wouldn't these cause problems on your treatment?

In June of this year, I came across Freddd's methods on a different forum. As I was already on all the main co-factors he listed and only missing the two forms of b-12, I decided to try both myself and my fiance on them at his suggested dosages. Both myself and fiance (Jeremy) have extremely similiar conditions of CFS/MCS due to sharing the life factors that made us both crash. We have been very ill since 2002 with little done in the way of treatment other than high anti-oxidant supplements and basic vitamins, but somehow missing supplemented b12.

After five weeks on the methyl-b12's and adeno-b12, we finally had no choice but to stop using them due to the severity of the problems they were causing us. We initially tried backing down to 1/4 of a methyl-b12 lozenge per day, but even this remained too strong. At this point we use hydroxy b-12, one perque lozenge/day. It has been about four weeks since we stopped the bulk of methyl-b12, adeno we were taking occasionally but have since stopped this as well.

The symptoms we have had and continue to have, seem to be directly related to both your questions above.

Both Jeremy and I have significant body toxicity loads. I would be very surprised if we didn't both have high mercury loads as well due to the number of fillings for each of us, plus the fish we had been consuming off and on over the last several years. In my experience, our MCS is related to the toxic load and has become so severe as to prevent us from living in conventional housing any longer.

During 18 months prior to adding in the methyl-b12 to our supplement program, we had gone from a health rating of 20% functional up to around 30%. After five weeks on the methyl-b12 I had to make us stop as I realized our health rating had plummeted to about 15%. Had we continued to become worse, I have to question our ability to continue chores required for basic survival such as cooking a simple meal.

Over the past four weeks, I have read a lot and talked with a few people about what has occurred. The only conclusions I have been able to draw are that we were detoxing far faster than our bodies could handle due to the methyl-b12, and very possibly that mercury was being transported around in quantity. I hate saying it, but in my case it feels like there has been some very noticeable damage caused to my cognitive abilities and memory skills. Its one of the reasons I have to wonder about the mercury. Large swaths of memory have been almost completely erased and writing completely new memory is often difficult if it involves much detail.

Both of us are much more chemically reactive again from our MCS, in a very significant amount more body pain then there has ever been before, and we seem to have had our health settle at 15-20% depending on the day. I attribute these symptoms largely to the detoxing running rampant and causing havoc when the toxins could not be removed in time.

I hope this helps with finding some answers.
Lisa

Hi Lisa,

I don't remember if you were taking hydroxyb12 before. I am just becoming aware of the changover problem for people in a particular stage of things. I don't know a cause or solution or even specifically being able to identify where it is most likley to occur as many folks have made the change from hydroxyb12 but not necessarily from the methylation program. I have noted and mentioned before that those coming from cyanob12 or hydroxyb12 do have a rougher ride in general, myself included having been on oral 1mg cyanob12 for 30 years approximately, than those starting fresh. Up till now the roughest I'd seen was some folks with PA having had cyanob12 injections for 20+ years. I'm sorry to hear of your difficulties.

I had severe cognitive and memory problems for more than 10 years. Many of the neurological problems didn't stop progressing until I went up to the high dose injections, 7.5mg. Sublingual and smaller injections didn't stop it. Then there may be additionally the problem of state associated memory as our neural nets change whether by deterioration or by healing.

Good luck.

jenbooks · Aug 22, 2009

Freddd why would prior hydroxy be a problem

Freddd said:

Hi Freddd, aren't B vitamins water soluble? Wouldn't they quickly exit the body? Why would prior consumption of hydroxy cause a problem later? I can't think of a mechanism for this. Thanks...

And all these stories do indicate that we all have to listen as closely as we can to our own bodies. Another possibility I don't see being considered here is that certain pathogens are stimulated by high doses of certain supplements. Before I got lyme/babesia I liked CoQ10. After I could not take it, it made me so jittery and made my cells feel so toxic. I assumed it was stimulating one of the bugs.

Freddd · Aug 22, 2009

jenbooks said:

Hi Jenbooks,

With the cyanob12 I had hypothecized a methylation depletion because even if cyanob12 has had a beneficial effect initially, it quickly goes away in most people and they have a huge reaction from SAM-e and/or methylb12. I just haven't had the personal or observational experience in great detail of hydroxyb12 to have any hypothesis. I've had an on and off relationship with CoQ10. Before mb12 nothing perceptable and I hadn't taken it for years. Based on some reading I restarted it about 1 month into mb12 and had a huge reaction, bp shot up to 195/110 with one dose. Discontinued immeditately, retried twice to confirm. Tried CoQ10 again after a year and all was well. As hydroxyb12 needs an outside methylator I just sort of assumed it was similar to cyanob12 in that regard but haven't examined it in detail. Assumptions can be a problem.

Lisa · Aug 22, 2009

Hey Jen!

Two very good points!

I have to wonder about what you said regarding the load of pathogens. I have been thinking of talking with my Doctor about getting some virus testing done before my next visit this fall. I've not a clue what my load of bad hitchhikers might be in my system.

--------------

Hi Freddd. Been a while since we last posted to each other.

Prior to starting the methyl-b12/adeno-b12, I had used hydroxy-b12 rarely. It amounted to one or two lozenges in a three month period.

While I was active at your other forums, I saw several references you had made regarding the neural net changes. With this in mind, I was able to be more aware of how things were changing in the brain for the first couple weeks. After those first couple weeks, I became too cloudy to keep track again until off being the methyl/adeno b12s allowed me to lose some of the thickened fog. Not much fog loss, but enough to actually form complete sentences unless I am doing really badly.

What seems to have happened is that in the first few days of starting the b12s things seemed to be going bang, zip, pop in my head in a good way. Felt like healing. This effect disappeared after maybe four days, but I assumed it was still going on just not as noticeable as a change anymore.

Then as the brain fog deepened immensely, that feeling of healing left completely. At this point, it feels more like brain damage instead of brain healing was the final result. Having suffered through the decline of brain functions as my health originally was crashing, this feels a lot like that only worse. Swiss cheese memory is what we termed it back then. Now it is like swiss cheese that is sitting in pea soup fog.

Prior to the b12s, there had been some definite mental improvements over the previous 18 months. This doesn't feel at all like those. Some of those did leave me with the effect you describe as the neural net change, new pathways that need to develop connections with the old ones. This doesn't feel like that. Feels like someone ran a magnet past sections of my hard drive and popped a few gigs of RAM out of my system too. Most things of substance end up processing slower than at any point in my life. Very noticeably slower and with less depth, detail, and color. I can't even read a book anymore, can't process the plot as I go nor retain enough of it in my memory between one day to the next.

Hope this helps clarify things.
Lisa

ps. You posted while I was typing this so wanted to edit something in real fast. For about four months prior to starting the methyl-b12/adeno-b12, both Jeremy and I were taking SAM-e 200mg twice a day six days a week. Had no trouble with it other than some intestinal cramps if I took it the seventh day in a row. One day off seemed to do the trick. It helped speed healing in our muscles from the new exercise we were able to do. Prevented most injuries and helped them heal hugely faster if we did pull something or overexert.

Freddd · Aug 22, 2009

A few interacting ideas

Hi Rich2,

You have raised some interesting issues. I don’t have any answers, just considerations and ideas. Let’s call it brainstorming. Much understanding can result. In a way it’s an application of picking information out of the noise, of playing Sherlock Holmes and solving a mystery. It’s the cyborg supercomputer of the internet functioning. Let's consider the nature of the toxins that mb12 is suspected or demonstrated to deal with.

Cyanide - converts to cyanob12 which is essentially nontoxic and rapidly excreted
Nitrous oxide - attaches to cobalamin and rapidly excreted
Botulism toxin - disposition unknown, but neutralizes it, examples, Botox is neutralized for about 24 hours per mb12 dose, needs repeat until gone, avian botulism requires a single 5mg injection
Tetanus toxin, thereby causing occult tetanus, disposition not known
Glutamate toxicity to neurons, disposition unknown to me
Whatever it is that causes cascading neuron death - tentative, I have just seen one research mention
Arsenic - converts to volatile multi methyl gas that is exhaled smelling of garlic

http://www.lifeextensionvitamins.com/metcob1.html A discussion of toxin induced neurological damage repair by methylb12 with references to research.

Some years ago I suggested that perhaps a way to get the mercury back out of the brain might be to use high dosages of methyl B12 to methylate the mercury, so that it would be able to pass back across the blood-brain barrier and be removed from the brain. I didn't encourage people to try that, though, because I was concerned that if there was inorganic mercury elsewhere in the body, these high dosages of methylmercury might move it into the brain, and I couldn't be sure that the mechanism I suggested for removing mercury from the brain would really work.
I'd like to suggest that perhaps you have unwittingly (sorry about that word) already performed that experiment. Perhaps if one uses enough methyl B12 for a long enough time, one can achieve a net effect of moving mercury out of the brain, even though perhaps some mercury would be moved in initially.

Very disarming, I hope you are not an amputee. Lay on the puns and cursed be he who first cries Hold, enough!

Let’s consider how the body gets rid of methylmercury as that is a mobilized form. Perhaps that can even be increased in the urine via selenium. I haven’t found anything definite there but lots that is suggestive. Then there is the question, and I have no answer, of whether the enhanced neurologic healing of toxic neurological damage can happen even as the toxin is present perhaps netting out at being protective.

Excretion:

Methyl mercury is excreted primarily in the feces as inorganic mercury (Norseth and Clarkson, 1971). This is the result of biliary excretion of the compound and subsequent conversion to he inorganic form by intestinal flora. Some of the methyl mercury excreted in the bile may also be reabsorbed thereby creating enterohepatic circulation of the organic form. Less than 1% of the body burden of methyl mercury is excreted daily, resulting in a biological half-life of approximately 70 days (Berlin, 1983). Over a 4-day period, a human volunteer excreted only about 6% of the ingested dose of radiolabeled, protein-bound methyl mercury, the biological half-life ultimately being 76 days (Miettinen, 1973). Methyl mercury is also secreted in breast milk with concentrations being about 5% of that in the blood. Removal of inorganic mercury via exhalation, saliva, and sweat results from the metabolism of the organic form (ATSDR, 1989).
http://rais.ornl.gov/tox/profiles/methyl_mercury_f_V1.shtml

Acute Toxicity:

Berlin (1983) noted that there are no differences between acute and chronic effects of methyl mercury; the toxic effects occurring when a toxic level has accumulated. According to the World Health Organization (WHO, 1976), the earliest effects of methyl mercury in humans occur when blood concentrations are between 200 and 500 ng/mL. These blood concentrations correspond to body burdens of 30 to 50 mg Hg/70 kg and are equivalent to daily intakes of 3 to 7 g/kg. It is important to note that the onset of methyl mercury poisoning may be delayed for weeks or even months depending on the total body accumulation of the compound.

Dr Myhill who uses methylb12 despite being a UK doc has a say on detox at http://www.drmyhill.co.uk/article.cfm?id=407 and refers folks to you, Rich as the authority on it.

Dr Carmen Wheatley, in the three “scarlet pimpernel” papers considers that b12 actually controls inflammation and when started, increases inflammation before bring it under control in a cycle with NO. She is working from a hydroxyb12 basis being a UK oncologist.

Just to mention some other factors sometimes mentioned with mercury. I've been taking 200mcg of selenium for decades as well as Alpha lipoic acid and vit E.

A 1% per day decrease is actually quite substantial. It amounts to about 25% per month of the declining balance. It is the rate at which antidepressants, antiseizure, antipsychotics, benzos, methadone and other difficult meds can be tapered at without rebound or protracted withdrawal syndrome being triggered and without any daily noticeable difference. At one percent per day the decrease is 97.4482% in a year and 99.9349% reduction in 2 years. That is also 93.5671% reduction in 9 months.

Perhaps by using such high dosages of methyl B12, you are using a lot of the excess B12 as a toxin binder, and in that way are removing toxins via the kidneys, into the urine, thus clearing them out rapidly and avoiding a drawn-out detox

Perhaps. If bound to cobalamin, HTCIII transports it back to liver for excretion in bile. Kidney's grab unbound cobalamins quickly; quite short serum half-life for these misc cobalamins. There are two mechanisms for removing inactive cobalamins, waste cobalamins; one that subjects them to intestinal recycling and selection for the select few b12s for recycling and kidney excretion without possibility of reabsorbtion. Only one kind of tubules filters cobalamins and there is no reabsorbtion possible from those.

I think this would explain things, including the fact that Amy Yasko has found that some patients need fairly large dosages of B12 to experience improvement, and I think your dosages are higher than hers are.

The current sized dose is quite recent. I didn’t try 7.5mg until footdrop developed last fall (quite literally) despite 5mg daily single dose injections. It corrected quickly, then I started the glutathione precursors and I lost 6 months of progress in lessening numbness of my feet and footdrop was approaching and inflammatory processes started up all over were running wild. Those had all diminished and gone away in the first year of mb12. After that setback was when I escalated the dose first to 2x 7.5mg daily and then to 4x after noting the on and off effects twice a day that diminished some as equilibrium was reached but never became continuous. My internist has worked with me willingly through all this as it has produced such outstanding results. My blood pressure is down to 108/70 or so now and he’s tickled pink. Reducing my weight some has taken over our discussions. It went up as a side effect of feeling good and lacking nausea and vomiting which discouraged eating which had become kind of a dicey proposition. I was skin and bones with 80 pounds of extra water swelling my body. Who wants to fix food when feeling so terrible and tired and all that? I also had discontinued use of my French chef’s knife when I started having clumsy accidents with it and confined myself to small knives. I have restarted using it the past 3 years. My handwriting still stinks and I have too many typos but I have recovered substantial control of my hands. About the time I ceased being able to focus my eyes and read the number of typos increased 20x suddenly after two decades of making my living at a keyboard. Programming has to be flawless to work. My now ex-wife read me the entire Lord of the Rings. I regained focusing within days of starting mb12 but the motor control has been much slower in coming back.

Something to note for which I have never had a good explanation: when I started dumping that excess water, right after starting l-carnitine fumarate, my urine stank like slimy rotting vegetation.

Freddd · Aug 22, 2009

A few interacting ideas part 2

Medications discontinued or reduced

I had been using Compozine suppositories for frequent nausea and vomiting. I never refilled the prescription again after starting mb12 and didn’t even finish the one I had. I had been taking Dilantin for 13 years for neurological pain, quite effectively I may add, and it also controlled otherwise uncontrollable muscle spasms. I tapered that between 9 months and 1 year as it was no longer needed. I was able to taper Provigil at the same period as I no longer had sleep problems. I was able to discontinue 2400mg/day of ibuprofen as it no longer was needed or made any effect. Somewhere along the way in the same time period I ceased needing Albuterol and never refilled. I haven’t needed antihistamines or pseudoephedrine for 5 years for hay fever. My use of diazepam and lorazapam for acute spasms and such decreased 95% in a taper over the next year or two. I am no longer accommodated to them and just use a half or quarter pill occasionally. When I was on the glutathione precursors my use of these, one or the other, went back to daily and I had to do a short taper again and just recently returned to very occasional usage of fractions of a pill. I am still having increased hay fever, inflammation and spasms subsequent to the glutathione precursors, but they are slowly diminishing and may be gone in the same 9-12 months as originally. My use of Reglan has decreased from 2 or 3 times per week to less than one per month. And finally, I was able to decrease the morphine from 300mg/day to 180mg/day as the many pains diminished and some disappeared. I have much better pain control now on 180mg than I ever had on 300mg. There was no change what so ever in my very depressed hormone levels and continue on 20mg/day (injected each 7 to 10 days, 7 is more effective, 10 is more practical) of testosterone. It was unaffected. I do suggest everybody have theirs checked as this makes a big difference. My Levothyroxine continues unchanged as well. It has always fluctuated back and forth on the edge between two doses and continues to do so.

One other thing, as long as I'm bending over backward let's also suppose that you are right in claiming that your high-dosage active B12 treatment does not produce extended detox symptoms. (Again, I'm not totally agreeing with you on this, but let's make that assumption.) Given that people who have had a dysfunctional sulfur metabolism, and hence a dysfunctional detox system for many years can be expected to have accumulated large body burdens of toxins, why wouldn't these cause problems on your treatment?

The central neurological healing did not get substantially under way for 9 months. Maybe the delay was while toxins were being cleared out. During that time there was much peripheral healing and many central functional issues resolved. The flurry of startup reactions were entirely gone by that time, many just disappearing in their entirety. A question then; if the toxins act to exacerbate existing symptoms, as that is what happens generally when starting mb12, and the underlying causes of those symptoms heal, how would the toxins then manifest? The medication changes all occurred between 9 and 12 months. My energy had returned very significantly on day 1 during the first hour. It was to an overwhelming degree. If all the other supplements influencing that were added at the same time it would have been way way too much. There were several other increments, in order listed, as adenosylb12 (large), SAM-e (moderate), L-carnitine fumarate (gigantic) and increased Zinc (moderate) were added. To describe it another way the first day I went from operating on 3 volts to 110. The adb12 stepped up to 220, the SAM-e to 330, the carnitine to 1760 and the zinc to 2420. The methylb12 converted sufficiently to adb12 and turned off the lactic acid production and burning muscle pain diminished starting immediately and was 100% gone in 10 days. It was never enough to completely occupy all mitochondria so the adb12 had a large effect 9 months later.

I'll get back to you again after I've had a chance to do some homework on the other issues. These two are the ones that I think are most crucial in trying to mesh what you have reported doing and finding to what seems to make sense to me in terms of known biochemistry. I of course haven't seen the detailed observational data to back up the claims you have made, but I'm willing to entertain the possibility that you have such data, and that you have correctly interpreted what you have seen.

If so, all of this has to fit together somehow, since the truth is the truth. As you can see, I'm a hardheaded scientist, not a postmodernist.

Hmmmmmm. I’m not trying to distract from the question here because I also agree that “all of this must fit together somehow”. So where does that leave you on the Copenhagen Convention; classical, neo or many worlds? Or is relativity because it’s “intuitively obvious to the most casual observer” (oops, there is that danged observer again) the Schrdinger's Cat’s meow? Are we dealing with algebraic or differential equation material here? Maybe we are just looking for a real root amongst the fuzzy logic and data.

“Since the truth is the truth”

A change in symptoms can be one persons “healing” and another’s “still sick but in remission without symptoms” and that affects how they act and how they think of themselves and all manner of things. Don’t get me wrong. I’m a hardheaded systems analyst and have to deal with human based data that is inherently fuzzy and interpretations that are even fuzzier. One persons “terrible reaction” is another’s “signpost to healing”. Or as the time traveling Ferdinand Feghoot told his son at a cannibals feast “One man’s meat is another man’s poi, son”.

I truly hope that I have correctly interpreted the data. I’m enjoying being well and in good health and planning on escaping the fate of Alzheimer’s that is befalling my father because I think we have a smoking gun here. He so believed in his doctors opinions about cyanob12 and everything he wouldn’t even try these things long before it became a problem despite seeing my miraculous appearing healing. He didn’t believe me that there was good hard core scientific reasons for it that produce reliable and predictable results in selected persons.

My caution to you Rick is in researching this, understand that the entire structure of nutritional research is built on quicksand if what I am saying is correct, even a little (there is that fuzzy logic element, degree of truth). Unlike chemistry and physics that have their standard temperature and pressure and G, there is no standard nutritional basis established only on fully active vitamins against which to compare the performance of the non active. I am NOT willing to trust that b6 and p-5-p are fully equivalent in everybody, that calcium pantothenate is fully equivalent in everybody to pantethine, that folic acid is fully equivalent in everybody to methylfolate or that hydroxycobalamin is fully equivalent in everybody to a combination of mb12 and adb12, that everybody can self generate sufficient biotin, inositol and choline and so many more. Each of these inactive substitutions requires a change in the presumed chemistry required to work. It only takes one example to the contrary to prove the presumption false. How many examples to the contrary would you like? So in the research, when the chemistry in question is based on these assumptions at first, second or third hand or deeper, doubt them. They lead directly to therapies that don't work well and not at all for that with which we are faced. Figure out what the undistorted chemistry would have to look like. Not being a chemist or biochemist, it still looks to me like a methylation block could not exist in the first place if everybody had been taking mb12 and methylfolate all along, that this thing and all its consequences are the artifacts of incorrect nutrition at the root and is an aspect of this stealth deficiency disease set I’ve been speaking about. This last section is just my opinion, not fact. Maybe it will help in the search for the beauty of truth and more important, how to correct it without damaging people. Unpleasantness isn’t the same as damage. Have fun.

Freddd · Aug 23, 2009

A few interacting ideas, additional factors

Hi Rich,

Something I'm not sure I mentioned allong the way in this series. I consider a source of potassium quite important for anybody starting the active b12s. Sudden startup of healing when essential factors are added can produce the beginning of hypokalimia in 3 days based on experience. I have had that unpleasant experience 3 times; startup of mb12, startup of adb12 and startup of methylfolate on top of both b12s. It was the methylfolate that finally corrected my MCV and MCH etc. Hypokalemia was not limited to startup of blood correction only. I've also had people with MCV at or under 94 have the same problem. Also, starting glutathion precursors triggered the same problems for unknown reasons. How and why does glutathione affect the mineral balance? I had to increase calcium and potassium. I'm just trying to give you data here as glutathione knocked me and others for a loop and I don't know why.

As this potassium is not something I see stressed with hydroxycobalamin is it overlooked or because there is not the same kind of sudden healing startup or what?

Also, regarding stopped medications, others who were taking them, I was not, were able to stop or taper antidepressants, antipsychotics and a wide variety of other meds being used to control symptoms.

You might check out the very early studies, if you can find them, done with liver extract without cyanide enhancement done on post partum depression and schizophrenia. Their results were never able to be duplicated with cyanocobalamin and as Thorazine and such were on the market the whole problem became ignored in favor of the drugs. I have just seen descriptions or references of those studies and they had many of the knock your socks off aspects that I have found with the active b12s.

Now to highlight a major difference in approach between us. If I were setting up a study at an HMO, part of the selection process would be for those with high pharmacy bills of drugs that could be discontinued for the symptoms listed and screening questioinaire and positive challange dose results, then use as a measure both changes in symptoms and medication changes, and ultimately, reduced cost, which is the measure on which an HMO could be sold on the idea. Reducing costs $1000/member-month can get an HMO's attention. People don't go off medications unless they are no longer needed so it is likely a reliable measure.

Something you said just rang a bell; about autistic children being treated with mb12 not having amalgams. That might not be true. There are a lot of children with bottlemouth who have a mouthful of amalgams. I no longer have data access to lots of records so I can't look for the records of autistic kids with amalgams receiving mb12 treatment. Dr Neubrander may or may not note quantity of amalgams but he would be the person to check with. I suspect that they are not as rare as you may think.

Another special interest group I came across was teenaged male drug users. Of a dozen or so, they all reacted with things like "Oh wow" and "That's the best legal high I've ever had". Seems to me they were 100% deficient. That may be significant.

Another consideration is of methylb12 comparatively as a methylator. My understanding of it is that methylb12 generates SAM-e in the course of the HCY-Methionine cycle. The methyl group of methylb12 is slightly more than 1% of the mass of the molecule. Strictly as a methyl donor then how does 1mg of methylb12 (a very good yield from a 5mg sublingual) stack up compared to 400mg of SAM-e?

Is fair to say that methylb12 is only a small source of methyl groups as compared to SAM-e, methylfolate, choline, TMG and probably other things? Then, in the same way it would be expected that most of the effect of methylb12 doesn't come from it's methyl donor status, as that disables it from it's other functions in any case, as cyanide does. So is it fair to say that 95% maybe of mb12's total effect is not as a methylator, especially when other methylators are already being taken? If that is the case, then most of it's effect comes from it fulfilling it's unique functions as active b12 that NOTHING else can fullfill? If after a year on hydroxyb12 and methylators and somebody still has any reaction what so ever to mb12, isn't it likely that is coming from it's unique functions as active b12 that are not fulfilled by conversion of hydroxyb12 to mb12 and not the small contribution it makes to methylation? If this isn't so, please explain to me why. Somebody who has no defciency symptoms has no reaction to methylb12. That's easy to demonstrate. Just pass it out to a bunch of healthy vigorous people who have no symptoms. Give it to somebody who has supplemented it to saturated equilibrium. More does absolutely nothing unlike methamphetamine. For me, 7.5mg or 25mg injection makes no detectable difference at all except in urine color. It seems to me that the only way 20mcg of methylb12 can make a huge difference is as active b12, not a methylator. If the hydroxycobalamin were really being converted adequately to methylb12 there would be some kind of equilibrium level established and 20 mcg would make no difference. It is demonstrated by a number of persons here that the conversion isn't happpening. If it were they would have no reaction to any modest amount of methylb12 and/or adb12 much less a strong reaction. That they do indicates to me that their body's are literally starved for mb12 and/or adb12 after more than a year on hydroxyb12. That is why I am sticking with the "hydroxyb12 doesn't work adequately" thesis for now. It just doesn't make sense to me otherwise. If you can explain that please do. If you would like to keep bouncing it back and forth, please do because I want to get to the bottom of this, to make it fit together. Thankyou Rich for providing an interesting and stimulating interaction.

Sushi · Aug 23, 2009

Freddd said:

Hi Freddd,

Just to add my personal experience with the detox symptoms being discussed. I did not experience them as "exacerbations of existing symptoms" at all. What I experience are the classic symptoms that happen when one undergoes most any detoxification protocol--they are not anything like my usual daily symptoms related to ME/CFS. I am talking about symptoms specifically associated with overworked, congested detoxification channels.

Just a clarification that might help us look at this phenomenon.

Thanks for this discussion--it is great and I hope it leads to great new insights and healing.

Sushi

Freddd · Aug 23, 2009

Sushi said:

Hi Sushi,

I see the misunderstanding. I didn't mean your usual daily symptoms from the ME/CFS set of symptoms. I wasn't being specific enough. I mean symptoms chosen from the larger b12 deficiency universe that often may have popped up along the way and faded out long ago or are totally obscurred by other symptoms sets and not even visible or activated and then are revealed and/or activated or are different steps along the way when active b12 intensifies and shifts symptoms and changes the balances between them. I don't know what causes the symptoms at their root so you may have the cause nailed. I'm looking at these from a different perspective is all. I've seen in myself and others layer upon layer of symptoms revealed in this process at different stages in the process. This is not an either/or situation. Both descriptions can be accurate in their own ways at the same time. This might actually be more of a philosphic and semantic difference than a real difference. It is quite normal in the experience of the process with active b12s to have symptoms shift "wildly" is how I've described it. If there are 10,000 steps to healing for a speciific item, until the very last step things are still not right and that item may go through 10,000 changes along the way. Also, what the symptoms are and how they appear seems to be very influenced by order and combinations of supplements. Since I've seen such extreme shifting as a common feature I have been hesitant to latch onto a specific explanation for each stage because I've seen how that affects what we think and do and narrows down the possiblities. I try to find the explanations that get us through the maze.

I think hashing this out is quite important because we get to see that what we say isn't understood the way we intend often. Communications may be the most difficult part of this problem.

Freddd · Aug 24, 2009

Hi Rich,

I'll be posting a possible mercury solution later today after I get it written out.

Methylation

Senior Member

Senior Member

Senior Member

Senior Member

Senior Member

Senior Member

Senior Member

Senior Member

Guest

Senior Member

Senior Member

Guest

Senior Member

Senior Member

Senior Member

Senior Member

Senior Member

Moderation Resource Albuquerque

Senior Member

Senior Member