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Nitric oxide and its possible implication in ME/CFS (Part 2 of 2)
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THE STAGES OF METHYLATION AND HEALING

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Freddd, Feb 7, 2013.

  1. Freddd

    Freddd Senior Member

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    THE COMPLETE METHYLATION REVIEW



    This is new overview towards which I was working with Rich before his sudden death. There were holes in each of our hypotheses, which we both pointed out to each other and which often came down to “insufficient data” and insufficient understanding. I reviewed some of the raw data from Rich’s study, and reanalyzed it, and we discussed the holes therein, how it fit the symptoms questionnaire patterns and the questions thereby raised. I think we both succeeded in keeping each other more on target. I miss our correspondence and discussion. He knew far more biochemistry and such than I do and was much better at finding explanations for things that repeatedly occurred. I’m a data analyst, not a biochemist. On saying that, I must also point out that Rich was not a systems analyst. He did not adapt well to the changing ideas and like many researchers was defending prior works and ideas.


    UNRAVALING THE MYSTERY

    Sometimes major scientific misunderstanding or non-understanding acquires great standing and unwarranted belief creating a mystery.

    The System is Corrupt

    “Gentlemen, get this straight. The police are not here to cause disorder. The police are here to preserve disorder.” Mayor Daley, 1968 Democratic convention police riot.

    Deficiency vs. Insufficiency - B12 and folate deficiencies manifest in very dose proportionate ways. There are no sharp cutoffs until one gets to 100% needed dose or zero. In the list of the folate deficiency symptoms under many names, some people might have mood effects before they have IBS, some might never have angular cheilitis, but what does happen is that there are several different groupings of symptoms that tend to appear together. There are approximately 4 or 5 layers of symptoms that appear to come on relatively independent of each other in a progressive manner and dependent upon relative deficiencies of the Deadlock Quartet and 7 or so other critical cofactors and even basic essentials.


    So in an extreme folate deficiency body wide inflammation would be present with lots of joint and muscle pain, MCS. Allergies and asthma come in somewhere but it can vary. The greater the insufficiency the more symptoms and the worse the symptoms are. While any of the insufficiencies can cause the same symptoms they cause them in different groupings at different rates and extents. It is necessary to remove all the b12 insufficiency symptoms to expose all the remaining methylfolate insufficiency symptoms. That is how it happens in the titrations. Endless words and time has been wasted disagreeing as to “absolute deficiency” vs “functional deficiency” and what it means, if anything, for therapy. The idea of an absolute deficiency in either of these is ridiculous. MeCbl and AdoCbl have dose proportionality in the 1mcg to 10,000 mcg range or more and L-methylfolate has dose proportionate characteristics from 1 to 32,000mcg at least. As the level of folate/b12 function approaches zero the last symptom in the progression is paralysis of the diaphragm or heart failure followed shortly by death. Everything short of that is a summation of successive insufficiencies starting with 1 symptom and increasing up to several hundred symptoms and signs generally before diaphragm paralysis or heart failure and death.

    The old idea of “absolute” deficiency was based on low enough levels of b12 to cause Pernicious Anemia. Then other lesser symptoms then were not really deficiency but rather “functional deficiency” caused by some other lack. This was based on CyCbl or HyCbl only partially helping some dozens out of the hundreds of symptoms the active b12s and folate affect. So the 0.01-1% effectiveness of HyCbl and CyCbl, and the poor or even negative effectiveness of folic acid, has skewed the understanding of cobalamins and folate. That whole idea fought against the natural effectiveness of the active AdoCbl, MeCbl and L-methylfolate as some kind of aberration of “forced” healing as opposed to “normal” healing of HyCbl which turns out to be the starvation survival mode.


    Instead it now looks like the “fallback starvation” mode of limited healing of HyCbl and CyCbl versus normal fully effective healing of the active natural b12s somehow has become sacrosanct through 60 years of skewed research. The excellent first rate healing of real b12 became the aberration as the abnormal limited starvation mode became “normal”. This is exactly what has happened with blood test results. The normal of red cell MCV < 93 has been displaced as MCV < 100 or even MCV < 102 has become “normal” as acceptance of starvation mode as normal spreads and becomes “normal”. Many other blood measures are also affected and in those the abnormal has become the new “normal”. At the point that deficiency symptoms have taken over test results to the point of making the abnormal test results become normal, the system has been corrupted. The test results ranges as now defined are set to maintain deficiency and illness as the norm. The tests now serve to maintain disorders.


    Many other tests, in fact all the ones that might be affected by methylation and ATP availability, are biased now to support a set of chronic deficiency states that have become the norm by invading our food supply. Our biochemistry evolved over hundreds of millions of years. Somewhere very early on in our evolution bacteria started producing MeCbl and/or AdoCbl. Somewhere along the way they became the normal cobalamins for all animal life on this planet, just as hemoglobin (iron based) became the oxygen carrier system in animals. Nature is a tough master. Anything that can’t make it dies. Given 300,000,000 years we could have evolved to use HyCbl or CyCbl if that is what the whole lineage of micro and macro animals had evolved with it. It would have had full effectiveness if we had so evolved. However we didn’t evolve that way. We didn’t have billions and billions die from inability to use it effectively. We didn’t pay that price. However, we are now paying that price, completely unnecessarily at that. We have a significant portion of our population with untreatable chronic diseases.


    WHY DON’T HyCbl AND CyCbl WORK WELL?

    So when asked why don’t HyCbl and CyCbl work well it’s because they are not what our biochemistry evolved to use over hundreds of millions of years starting before mammals even existed. We did evolve a starvation mode of survival in which some of the previously used cobalamins that had become unusable throwaway forms after MeCbl breaks down or detoxifies cyanide and reclaim them. As with other work around methods it isn’t very effective and it doesn’t provide enough active cobalamins to do any major healing but it is enough to stay alive during a famine or a bad winter. It does require the presence of some reduced amount of each MeCbl, AdoCbl, l-methylfolate and l-carnitine fumarate to provide the needed biochemistry to fuel the conversion, allowing the body to tread water for a while.


    WHY ARE THERE ALL THESE COBALAMIN A, B, C, D, ETC DISEASES?

    These are the cataloging of all the ways our bodies didn’t evolve to use HyCbl and CyCbl. These gene variations never got culled out of us by disease and death in a natural environment. Those that had these enzymes might survive starvation better as they can use some trace cobalamins, but not enough difference to cull out those that don’t. General starvation isn’t selective enough. So many people don’t have the enzymes needed to transform trace cobalamins that the body creates from MeCbl for special purposes or post use or breakdown products, to recycle them for a workaround for starvation for a while. Some have even suggested that the lethargy of metabolic shutdown (seasonal CFS) achieved by AdoCbl/MeCbl starvation allowed early humans to survive long winters of semi starvation with very low food requirements substituting for true hibernation or winter sleep.


    WHY DOESN’T FOLIC ACID WORK WELL FOR EVERYBODY?

    When the same questions are asked about folic acid the same answers arise. If it were food it would be “stale” and spoiled. It’s too oxidized. It is to l-methylfolate as flaxseed oil is to linoleum. We never evolved to use that. It’s no wonder that nobody can convert enough folic acid to fulfill all folate requirements. It’s no wonder 20% can’t convert it at all, 30% can convert limited amounts and about 50% can convert up to about 800mcg daily of folic acid which is not as much as the body needs to heal. We never evolved to use it. 60 years of usage since it’s invention hasn’t killed the billions yet that would allow evolution to adapt to folic acid.


    WHY DO SOME PEOPLE FIND FOLINIC ACID UNUSABLE?

    Folinic acid is another matter. It is the natural folate of most vegetables. It is a handicap not to be able to use vegetable folate but lots of people can survive on the animal form of folate. It is a handicap to not be able to digest milk as an adult. Adults can do fine without milk and cheese. It is a handicap not to be able to utilize gluten, a protein in some grains. There are lots of alternatives to gluten. Milk as an adult food is a recent arrival on the scene. Grain containing gluten as a dietary mainstay is a more recent arrival on the scene. 10,000 years more or less hasn’t been long enough to for humans to fully genetically adjust. However, some populations have evolved to be able to drink milk as adult. Most people in the world can’t digest milk as adults. I “should” be able to digest milk as “should” my ex-wife. We both come from northern long term dairy drinking white folks. Neither of us can do so. Chances are our children won’t be able to either. I miss it but I sure don’t miss the digestive problems. Fortunately gluten gives me no problem at all. On these variables like adult milk and gluten, 10,000 or 20,000 years or whatever isn’t enough for a population to fully adapt. For vegetable folate, even 400,000,000 years hasn’t been long enough for 100%. However, I can use the natural animal form of folate, L-methylfolate or I wouldn’t be alive to write this as can 100% of people. Vegetable folate is an “also” or a biological workaround. However it is amply effective for the majority of persons. Some tribes evolved on high meat diets for a long time and some did not.



    In a normal software system after too many generations of changes it becomes unmaintainable and needs to be reconceptualized and redesigned. A college I went to in the 1960s had brand new physics and chemistry buildings both with standard air pressure, humidity and temperature. The only thing not standardized was local gravity. That standardization has NEVER been done in nutrition with all the active natural forms of the vitamins. What we have standardized on are CyCbl , HyCbl and folic acid. We are reaping the results, with all these rapidly increasing neurological, metabolic, neuro-psyc diseases and generally poor health with lots of symptoms and no treatments that actually work. Even worse is that these symptoms and diseases have become the “norm” as these fake vitamins are in many foods. I eat almost no white flour products, no fortified products, no corn syrup, minimal trans-fats and almost no processed foods. I avoid folic acid and CyCbl like the poisons they are to me. Instead I take the natural forms in sufficient quantity to allow my damaged body to function.



    Rich’s number one objection to what I first presented was that IT, whatever IT is, was widely happening and could not because of genetic inability to use HyCbl. He placed a lot of emphasis on the vanishingly small percentage of people that have the lettered cobalamin “diseases”; Cobalamin A, Cobalamin B, Cobalamin C and other such diseases. He was partially correct. The lettered diseases are terribly rare and were only invented (recognized) because of CyCbl and HyCbl. In the absence of these two oxidized inactive cobalamins none of these genetic conditions (“diseases”) would have been found. They were found because infants being given formula with CyCbl had failure to thrive. In fact they were starving to death rapidly because of a lack of the MeCbl, AdoCbl and l-methylfolate found in milk (at first) and basically all foods of animal origin that instead had soy milk with corn syrup and inactive oxidized artificial folic acid and CyCbl or HyCbl vitamins instead of the animal based forms.



    Carmen Wheatley’s “Giant Gorilla … Adenosylcobalamin …” (free download, don’t miss it http://www.researchgate.net/profile/Carmen_Wheatley/publications/ ) article couldn’t have said it more plainly. It looks like the NATURAL effectiveness of the natural active forms of cobalamin is radically greater than HyCbl and CyCbl (I’ve said 100 to 10,000 times more effective for 9 years) and that the body being able to use HyCbl at all is a starvation workaround. It is the ALTERNATE pathway when starving to death that will barely maintain life but not health. Cobalamin A, B, C, D, E, etc are highly technical deficiency diseases lacking enzymes to convert one form to another, that only become visible when inactive cobalamins are substituted for active ones during man-made starvation of active cobalamins. There is a deadlock here too, as ATP is absolutely needed to power those enzymes. To make the ATP one MUST have some working AdoCbl and l-carnitine fumarate in the mitochondria already and some methylation capacity (MeCbl and l-methylfolate). In other words, those lettered diseases are also the result of the laboratory mistake that said that CyCbl was the real thing. In a “natural” environment they almost don’t exist. The only ones that do exist naturally relate to interconversion between AdoCbl and MeCbl and eating a mix makes that unimportant. Further they, the inactive forms, can only be converted to active forms if one has sufficient of the active forms to make the enzymes and energy for the conversion in the first place.



    We never went through the culling that would evolve us to use folic acid, CyCbl and HyCbl because they don’t exist in natural foods. All we ever achieved is a workaround pathway that salvages a minimum amount of usable cobalamins from the otherwise unusable cobalamins when the supply of fresh cobalamins runs out. We are being culled right now. MS, ME, FMS, CFS, Parkinson’s, Alzheimer’s, Autism, Supra nuclear Palsy, IBS, Neuropathies, Subacute combined degeneration, reproduction failure, congestive heart failure, endothelial inflammation and failure, early death from a multitude of causes, all part of these manmade mystery diseases. They are the result of systematic starvation of the body of three absolutely needed vitamins with <1% effective oxidized (spoiled) pseudo vitamins substituted. This is the 21st century equivalent of Scurvy, Pellagra and Beriberi all rolled into one. Food when it is oxidized becomes spoiled, stale and rancid, not supporting health. Folic acid, CyCbl and HyCbl are all forms of concentrated food (vitamins ) that are oxidized, spoiled, rancid, stale and not supporting of health. Would you eat linoleum instead of fresh salad oil? It’s just oxidized edible oil. Sure, it keeps better but is it nutritionally the same? How about a nice meal of tanned leather instead whole roast pig? The leather keeps lots longer. But it isn’t the same when it comes to eating.



    Our children are suffering tremendously with these manmade diseases. I grew up in the 50s and 60s. I NEVER even heard of or saw a single child with ADD or AHDH or any of these many neurological disorders of children. Yes, we had Osgood Schlatter’s disease and Mono, mumps, scarlet fever, measles and chicken pox, anorexia was very rare and nobody at all had CFS or FMS. I see it all the time in pre-teens and teens now. There were NO children “stimming”. Now it can’t be avoided. You just didn’t see it then. I was in a lot of homes and saw all the children. Autism was extremely rare, not rarely recognized. Parkinson’s was rare. MS was rare. All these neurological diseases were rare. And don’t tell me it was because people died so much younger. Life expectancy at 65 in 1937 before antibiotics was just 3-4 years less than it is today, with lots of smokers at that time. It was life expectancy before age 5 or 10 that changed mostly. Now it is possible that all of us sick folks were the ones that would have died without childhood antibiotics and so we are being culled later. However, it appears more likely that the damage to the immune system that made us sick and needing antibiotics originally was caused by paradoxical folate deficiency to folinic acid which now expanded to include folic acid and CyCbl and/or HyCbl in ALL formulas and fortified cereals etc.



    So, chasing down all these cobalamin “diseases” is fruitless, a waste of money and effort since they don’t exist or don’t matter if everybody gets the real vitamins. Rich convinced me that I was barking up the wrong tree theoretically (not pragmatically, 2 different things as I was getting excellent results, I GOT WELL). If these genetic variations are too rare to be making so many people so sick then what is doing so? That answer is complicated.



    Rich was correct in calling what he was looking at “partial methylation block”. It is a partial block. Rich was looking at only the lowest level of the blockage, the folate-Cbl level. This is the most visible level of DNA-RNA transactions using MeCbl and l-methylfolate. The body, using the active transport system of transcobalamin has its own triage methods for supplying MeCbl and AdoCbl to various tissues. It can transport a few 10s of mcg per day to various tissues which is far more than the typical 5mcg or so eaten and absorbed. Rich said that using huge doses of MeCbl was “forcing” activity. Along the way he did say that he didn’t think that 1mg of oral or sublingual MeCbl was huge or forcing. However since MeCbl has a rather dose proportionate response range but was unmapped, it was some vague amount like 10mg injections. There were all sorts of wild ideas of how the active b12 protocol “ought” to be applied. So now, Wheatley has identified the “radically” more effective AdoCbl as the natural normal path and the HyCbl path as a barely working workaround for starvation in the control of inflammation.

    end part 1
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  2. Freddd

    Freddd Senior Member

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    part 2


    I have mapped the dose responsiveness of the active cobalamins. Generalized healing comes in 5 layers. Four of them can be “turned on” with 100mcg of mixed AdoCbl-MeCbl absorbed daily. This is basically ¼ of a 1mg sublingual MeCbl and the equivalent of AdoCbl. All it takes to turn on widespread healing in the body is somewhat more than active cobalamins then can be delivered in the active holotranscobalamin system. As soon as there is enough MeCbl/AdoCbl distributed by diffusion healing turns on throughout the body. Some healing takes place starting with the first mcg. The entire layer 1 of healing turns on with 100mcg mixed active cobalamins daily with l-methylfolate. The difference in effectiveness between 10mcg and 100mcg appears to be approximately 100 times. The difference in the body between 100mcg and 10,000mcg is approximately 20%-40% (0.2-0.4 times). The difference in the body between 10,000mcg and 100,000mcg daily is approximately zero. There is no apparent forcing of anything in the body by large amounts of active cobalamins. In 1mg quantity their serum halflife is 30 minutes. The use of that word “forcing” gives the entirely wrong idea creating fear of healing. 100mcg of mixed active cobalamins is certainly possible by eating a large serving of liver, or a seacoast area sized serving of steamed clams or oysters.



    My grandfather was kept reasonably healthy for decades by an old German cook whose “nerve tonic” stew slowed down his ALS. He was diagnosed in 1942 and died in 1973 after my grandmother got lung cancer and he was moved to a nursing home. He survived 6 months after the end of the nerve tonic stew. He was served every day a “stew” that was made by extracting all the good stuff from 5 pounds of liver daily and adding meat and veggies. He was being given every day the miracle working “protein mystery factor” which was liver extract and misidentified as CyCbl when actually it was MeCbl, AdoCbl, l-methylfolate and carnitine (the natural form of the deadlock quartet) plus all sorts of other vitamins.



    So, the first level of methylation and cell formation is confined to mostly the fastest reproducing cells in the body, epithelial tissues including skin, lungs, GI mouth to anus, vaginal and so forth. 100mcg of MeCbl plus 200mcg of L-methylfolate will turn on methylation approximately 100% of the time if it is not working and if the other cofactors are present in the body, but may not until all other deadlocking items are present. The other 2 items of the 95% deadlock are AdoCbl and L-carnitine fumarate. HyCbl competes for methyl groups. HyCbl requires ATP produced by AdoCbl and l-carnitine fumarate as well as an enzyme and a methyl group supplied by MeCbl, l-methylfolate or SAM-e (produced by MeCbl and l-methylfolate).



    It is this dependency of HyCbl on the presence of the products of MeCbl, L-methylfolate, AdoCbl and L-carnitine fumarate that makes it a poor choice. If the deadlock exists HyCbl can’t break the deadlock, ever, and if it does at first, it can exhaust that capacity over time and cause the deadlock to re-establish.



    Folic acid and folinic acid suffer from the same deadlocked conditions. Assuming that the person is genetically capable of the conversion (approx 20% of population are not for folic acid) the conversion still requires ATP (AdoCbl + LCF and secondarily MeCbl + L-methylfolate), enzyme and methyl group (MeCbl + L-methylfolate or SAM-e). Even if the amount converted is adequate when healing isn’t in high gear it likely won’t be adequate when all levels kick in.



    DEPENDENCIES

    So in order for HyCbl and folinic acid to actually work, one has to have enough MeCbl, AdoCbl, L-methylfolate and LCF to produce the enzymes and ATP and donate the methyl groups in the first place. Further folinic acid (and folic acid) can even block 10-20 times as much l-methylfolate for various suspected and unknown reasons.

    In other words:

    1. METHYLCOBALAMIN IS DEPENDENT UPON AdoCbl, L-Methylfolate and L-Carnitine Fumarate

    2. ADENOSYLCOBALAMIN IS DEPENDENT UPON Mecbl, L-methylfolate and L-Carnitine Fumarate

    3. L-METHYLFOLATE IS DEPENDENT UPON MeCbl, AdoCbl and L-Carnitine Fumarate

    4. L-CARNTINE FUMARATE IS DEPENDENT UPON MeCbl, AdoCbl and L-methylfolate

    5. FOLIC ACID IS DEPENDENT UPON MeCbl, AdoCbl, L-Carnitine Fumarate and L-methylfolate

    6. FOLINIC ACID IS DEPENDENT UPON MeCbl, AdoCbl, L-Carnitine Fumarate and L-methylfolate

    7. HyCbl IS DEPENDENT UPON MeCbl, AdoCbl, L-Carnitine Fumarate and L-methylfolate

    8. CyCbl IS DEPENDENT UPON MeCbl, AdoCbl, L-Carnitine Fumarate and L-methylfolate



    Rich hypothesized that the reason that HyCbl and CyCbl were completely ineffective in 20-40% of trials and studies for whatever the study symptoms or signs were was that the necessary cofactors were missing. I pointed out that single item MeCbl was also ineffective in studies in the 20-30% range as a single item, also likely because lack of cofactors. The mystery for Rich and me for the past 4 years or so has been which cofactors? They certainly were not usually things like C, or D, or E or magnesium, though all of those can be a most limiting factor, they are collectively less than 5% causality. It turns out from pragmatic evidence from thousands of us at this and other boards, and a few people here and elsewhere including myself and friends, who worked through it step by excruciating step, that the Deadlock Quartet is the key to it all.



    NECESSARY AND SUFFICIENT

    The idea of necessary and sufficient is necessary for solving problems logically and effectively. What is the minimum required to allow a system to work? It’s a good test to apply. The current state of health in the USA demonstrates that what we are eating does not fulfill that “necessary and sufficient” for good health criteria. Obesity and chronic ill health run rampant.



    · The Deadlock Quartet is necessary and sufficient for good health. All four items are required to be present for any one of them to perform all it’s functions. The lack of any one can prevent methylation startup, ATP startup and general healing.

    · CyCbl is not necessary or sufficient for good health.

    · HyCbl is not necessary or sufficient for good health.

    · Folic acid is not necessary or sufficient for good health

    · Folinic acid is not necessary or sufficient for good health.

    · No combination of folic acid, folinic acid, CyCbl and HyCbl is necessary or sufficient for good health, even if LCF is included.



    To be sufficient they all need the Deadlock Quartet. None of these other items are necessary for the Deadlock quartet and only hinder or cripple it’s sufficiency or at best do nothing at all. The six levels of healing below can be turned on 1 or more at a time. Each level is dependent upon having the correct combination and quantity from the Deadlock Quartet.



    1. First level methylation blockage - We have epithelial cell formation at this first to shut down and first to startup level of the blocked methylation. It can come and go in days. MeCbl & L-methylfolate can cause methylation startup in hours generally. These are the first things to appear when paradoxical folate deficiency occurs or for some when HyCbl is consumed and epithelial methylation is shut down (2-3 days), acne type lesions first on scalp and face and spreading to body, angular cheilitis (sores at corner of mouth), IBS (4-5 days) and other symptoms. MeCbl 100mcg absorbed & L-methylfolate 200+mcg will start correcting, and titrate to sufficiency, 100mcg diffusion level, lesser insufficiency of other factors

    2. Second level of methylation blockage – Endothelial inflammation and failure, lack of deep tissue healing, deep tissue inflammation. MeCbl & AdoCbl 100mcg absorbed & L-methylfolate 800+mcg will start correcting and titrate to sufficiency, 100mcg diffusion level, greater insufficiency of other factors

    3. Third level methylation blockage, METHYL TRAP. This often has sudden hard onset. It occurs for lack of MeCbl in cells so L-methylfolate is expelled from cells. Rich pointed this out when the symptoms and circumstances were described. It starts suddenly, widespread inflammation and pain, severe muscle aches and pain, MCS, asthma, allergies, sudden severe flu like illness with little or no fever. May or may not be accompanied by severe abnormal fatigue. MeCbl & (AdoCbl & LCF - fatigue) 100mcg absorbed & L-methylfolate 800+mcg will start correcting and titrate to sufficiency, 100mcg diffusion level, greater insufficiency of all factors.

    4. Severe abnormal fatigue. Muscles don’t repair well. Severe muscle pains of many types. No exercise tolerance. Exercise doesn’t increase muscle or mitochondria increase. Edema, congestive heart failure. MeCbl & AdoCbl 1000mcg absorbed & L-Carnitine Fumarate & L-methylfolate 3200+mcg will start correcting and titrate to sufficiency, 1000mcg diffusion level, greater insufficiency of all factors before treatment.

    5. Severe abnormal fatigue. Muscles don’t repair well. Severe muscle pains of many types. No exercise tolerance. Exercise doesn’t increase muscle or mitochondria increase. Muscles atrophy. Everything is breaking down. Edema and congestive heart failure. Only watery fat, if anything, increases. Large weight gains on minimal food. MeCbl & AdoCbl 1000mcg absorbed & L-Carnitine Fumarate & L-methylfolate 3200+mcg (titrated to sufficiency) will start correcting, 1,000mcg daily diffusion level, greater insufficiency of all factors before treatment.

    6. CNS functioning and healing may require much larger doses of AdoCbl and MeCbl to penetrate the CSF/CNS by diffusion. MeCbl & AdoCbl 10000mcg absorbed 3 times daily & L-Carnitine Fumarate & L-methylfolate 3200+mcg (titrated to sufficiency) will start correcting, 30,000mcg daily diffusion level needed.



    Rich largely ignored AdoCbl. I had been lumping it in with MeCbl for a small specialized role in the mitochondria. We were both wrong. Over time processing the fats for making myelin was added to the understood functions of AdoCbl. However, that did not explain why some people had such a dramatic difference by taking it daily, such as my own daughter. For 8 years I had suggested taking AdoCbl from once a week to once a day. With the publication of Carmen Wheatley’s “Large Gorilla … Adenosylcobalamin …” (free download, don’t miss it http://www.researchgate.net/profile/Carmen_Wheatley/publications/ ) I found a reason to take it daily myself and a proposed hypothesis for why there is so much variation in its effect between people. Utilization of B12/folate in the body operates on two major levels. When the necessary nutrients are in the body in sufficient quantity and distribution, generalized healing turns on. When any of these are insufficient, generalized healing turns off and goes into a starvation mode of conserving resources and barely getting by. This starvation mode is what has been researched for the past 60 years. Rich did see the key to getting out of that starvation mode, turn on methylation.



    I think that the differences we see in different people is related to how well people convert MeCbl to AdoCbl and that some people don’t appear to convert it at all. The results over the years also show that virtually nobody converts as much MeCbl to AdoCbl as the body actually can use and that there is a great deal of variability across a population. Eating meat, people get a mix of AdoCbl and MeCbl. Most of our bodies appear to be able to handle small scale interconversion making the exact ratio unimportant. However, those who can’t interconvert require both forms every day. In those people the diffusion level of healing of AdoCbl disappears if they don’t have some every day. For people who CAN’T interconvert MeCbl to AdoCbl adequately the HTC2 transport doesn’t deliver AdoCbl for use in controlling inflammation. It HAS to come via diffusion as AdoCbl in the first place. Right here is a reason that 100mcg of AdoCbl/MeCbl in diffusion has such a dramatically greater effectiveness in healing than 10mcg of cobalamin (MeCbl? or stripped of ligand requiring assembly at point of usage?) bound in HTC2. To convert MeCbl or a stripped cobalamin to AdoCbl requires an enzyme and ATP (requiring presence of AdoCbl in mitochondria and l-carnitine fumarate as well, Deadlock Quartet raises its head again). That would explain why these people who require AdoCbl daily require another 2 pharmacodynamic compartments to model this different behavior of AdoCbl in body and CNS, why it models like serum MeCbl.
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  3. pela

    pela

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    Thank you, Freddd, for all of the hard work you put in to writing this very informative post.
    Will this be pinned?
  4. Freddd

    Freddd Senior Member

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    I don't know. That is up to the management. I have a lot more new and revised things I'm getting into form to post. Things have been coming together. What I have come to realise is that while these things are critical to our health, the far bigger story affecting far more than what we consider right here, is the way the medical-industrial-research system has become corrupt, not in the sense of political corruption, but rather that what should be a negative feedback system (via test results) has become a positive feedback system that self perpetuates.
  5. jeffrez

    jeffrez Senior Member

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    Is anyone actually improving from any of these "methylation protocols?" I don't think I've ever seen more written for such little return as there has been on methylation, with the possible exception of XMRV. I know you've benefited, Fred, but I think you'll agree you're a unique case, with unique genetic profile, etc. I've even seen reports that some poeple have gotten worse on methylation treatments. What is the track record turning out to be? Are there success stories posted somewhere? I'd like to hear from people who improved and hear about what they did, how long it took, what setbacks they faced, etc.
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  6. cph13

    cph13 Senior Member

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    Fred, I knew U were working arduosly on something. LITERLLY "thumbs up". The end of the day for me but I will take a nap, if I can, so I can read and try to digest this.
    Fred, Thank You ever so much for all your hard work. I'm sure U have read the e-mail I sent you privately. If not, I'm getting better, I'm ecstatic, thrilled, unfogged...but doin' it slow. Later my friend. Be well and Happy Healing
    LaurieL likes this.
  7. Crux

    Crux Senior Member

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    jeffrez;
    Dude, are your 'eyes wide shut'?
    I've noticed more improvements discussed from people trying methylation protocols than any other treatments here.
    I don't know the numbers, not everyone polls here, most get better and move right along.
    I've improved greatly, had tremendous set backs, and risen again. I can't follow the protocols verbatum, but that's the rub of it. We have to find our own dosages, types, etc.
    It's taken me 5 yrs. to get this far; I'm a slow moving barge, but I'm moving now. Good!
    The MB12 is the essential substance for my success, everything else is an adjunct, but must be supportive.
    helen1 likes this.
  8. Red04

    Red04 Senior Member

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    My wife has 95% healed. And it was fast and miraculous. All from methylation supplements. Not only that but if she stops, the symptoms come right back. This has been repeated over and over. So it's not some fluke.
    abporter, helen1 and Wayne like this.
  9. jeffrez

    jeffrez Senior Member

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    Well, I don't "live" here, like some apparently do. No need to be insulting about it. Can you provide any links to the discussions you're referring to?

    How do you know they're better if they've "moved along?"

    [/quote]

    So you would rate yourself as definitely improved from some variation of the methylation protocol. In what ways are you better? For example, where did you start, and where are you now? Five years is a long time. How do you know the improvements you've noticed are definitely related to the methylation protocol and not just a general improvement that might have happened anyway, was the result of something else, etc. ?
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  10. jeffrez

    jeffrez Senior Member

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    That sounds like a success. Could you provide more details, like was she diagnosed ME/CFS, how long she was ill, the severity of illness, how long "fast" is, etc.? I'm not doubting she improved, only trying to get a better idea of the specific case.
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  11. Dreambirdie

    Dreambirdie work in progress

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    jeffrez AnneLikes Red and greenshots (Angela) have also had considerable improvements. They are both working and traveling, etc. I know each of them studied their genetic SNPS (via 23&Me) and did a lot of research, and trial and error with methylation supps and diet to get where they got. They don't show up as often, because they are busy with LIFE.

    I think methylation is a BIG issue for many with ME/CFS. If you read some of the threads on the GENETIC TESTING AND SNPs forum, you will get the gist of what people are working with: http://forums.phoenixrising.me/index.php?forums/genetic-testing-and-snps.12/
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  12. jeffrez

    jeffrez Senior Member

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    I thought it was, too, based on what people were saying, Nathan's study, etc. but I've been on methylation supplements for going on two years now with no improvement whatsoever. I'll look at the Genetic testing forum, thanks.
  13. dbkita

    dbkita Senior Member

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    jeffrez:

    Methylation treatment has definitely been beneficial to me, but it is tricky since I have also experienced long periods of time with over methylation. Maybe this is complicated by my COMT + mutation as well. On the other hand I have the A1298C defect (hetero) and none of the other MTHFR defective SNPs so my conversion and production of methylfolate is probably quite reasonable. When overmethylated I definitely encountered the dreaded potassium problem (which I suspect is still not well understood in the community) having to intake 250 meQ per day (food and supplements) and still suffering from hypokalemia (that told me way too much). But if I undermethylate, I hurt more, have less drive, and take less joy in things. I suspect BH4 depletion is also a concern for me.

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

    Freddd:

    Thank you for the well thought write-up. I especially like your approach of splitting the healing into stages. It seems to make a lot of sense. Being a physicist (who later turned into a bioinformaticist), I would say it is almost like you are crafting a "grand unified field" theory for methylation treatment that bridges some of the gaps between your active b12 protocol and Rich Vank's variant. I think we come to these forums with many diverse case histories and with many different reactions to the supplements dependent not only on our individual biochemistry but also what level of healing we really need.

    I did have a couple questions. I notice you seem to recommend a 1:1 ratio for mb12 and adb12. Is there a specific reason for that? Also do you have a recent post or other information that discusses the amount absorbed from sublinguals dependent on dosing? I suspect the 40% factor you quote for 250 mcg dose (1/4 of 1000 mcg sublingual) may not scale linearly as doses go up (though I suppose say two Enzymatic Therapy B12's on the upper gum on opposite sides of the mouth probably would scale linearly, i.e. 2x).
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  14. Red04

    Red04 Senior Member

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    She was a sick child and on anti depressants as a teen. Anxiety as a child as well. She had TMJ problems and slept 12+ hours. But she still played sports in high school. I guess she always had a weak immune system. After college she was really ill for a few years before finding methylation. IBS. Fibromyalgia. Chronic Fatigue. Plus about 20 other symptoms. You can read my early posts to see her whole story. We went to every specialist in Houston and had no luck. About 2 months on freddds protocol she made major improvements. 4 months in she was 95%. She didn't have a cold for a year. This was the same woman who had a standing Rx of zpac and was in the ER 3 times a year for pneumonia. Her chronic sore throat and losing her voice constantly were all just gone.
  15. Ema

    Ema Senior Member

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    "4. Severe abnormal fatigue. Muscles don’t repair well. Severe muscle pains of many types. No exercise tolerance. Exercise doesn’t increase muscle or mitochondria increase. Edema, congestive heart failure. MeCbl & AdoCbl 1000mcg absorbed & L-Carnitine Fumarate & L-methylfolate 3200+mcg will start correcting and titrate to sufficiency, 1000mcg diffusion level, greater insufficiency of all factors before treatment.

    5. Severe abnormal fatigue. Muscles don’t repair well. Severe muscle pains of many types. No exercise tolerance. Exercise doesn’t increase muscle or mitochondria increase. Muscles atrophy. Everything is breaking down. Edema and congestive heart failure. Only watery fat, if anything, increases. Large weight gains on minimal food. MeCbl & AdoCbl 1000mcg absorbed & L-Carnitine Fumarate & L-methylfolate 3200+mcg (titrated to sufficiency) will start correcting, 1,000mcg daily diffusion level, greater insufficiency of all factors before treatment."

    Freddd, are these two stages (4 & 5) increasing in severity or the same thing twice?

    When you write 1000 mcg absorbed, is it possible to absorb 100% of a sublingual tablet or would this likely require more?

    Do you have any thoughts on L-carnitine's inhibitory effect on the thyroid? As someone with hypothyroidism, I am cautious about supplementing until I understand how it works better.

    Thanks for all your work. It is very interesting.

    Ema
  16. dbkita

    dbkita Senior Member

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    Freddd:

    One more question when you say "titrate to sufficiency" do you mean break the doses up according to a schedule or to titrate up to the quoted amount (e.g. 800 mcg 5mthf for stage 2).
  17. LaurieL

    LaurieL Senior Member

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    Jeffrez,

    I have had significant improvements, on a scale of 0-10, when I started methylation, I was a 3 or less. I am a solid nine presently. I have worked diligently for almost three years on methylation and symptom targeting with SNP's. I was one sick puppy when I started, and I now work two jobs. Thank you Freddd, and RIP Rich.

    Jeffrez, I think this goes way beyond CFS/ME, methylation that is. I believe this program is the key to general good health and can be applied to so many health problems. I believe because of my own experiences. If you have been working on this for two years without improvement then there has to be a contributing factor or a limiting factor in your case. Just because you haven't seen resolution, doesn't mean a solution does not exist.

    Freddd,

    It is my understanding, that adcbl is the base b vitamin in the body (mother) in which all others rest on, including methylb.

    Methyl b can be made from adcbl?? by adding the methyl group and methyl b can be recycled through the MTR,MTRR reactions in the methylation cycle?

    If this were true, then this may help to explain why some need more adcbl than methylb? I can't take a 1:1 ratio. I need 2:1, adcbl to methylb, 10,000 to 5,000.

    So what causes the dysfunction or deficiency in adcbl? Is it the methylation cycle or is it something else? I am just not understanding the adcbl side of things.

    Lauriel
    Sparrowhawk and jeffrez like this.
  18. Freddd

    Freddd Senior Member

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    Hi dbkita,

    Being a physicist (who later turned into a bioinformaticist), I would say it is almost like you are crafting a "grand unified field" theory for methylation treatment that bridges some of the gaps between your active b12 protocol and Rich Vank's variant.

    I have a GUT feeling you are correct. I'm going to tell you a little of my background. At age 12 (1960) I did my first actuarial work after deveolping practice profiles of demographically different dental practices for an early dental plan. Before becoming insurance, the company did their own actuarial analysis after we had it all put together and went with our numbers basically. They didn't have the total provider profiles and demographic data we had. For a couple of years after that I assisted with the sliderule calculations (team of 3 with 100% agreement) on numbers from an NMR at Sohio Labs with my neighbor, a prof at the local medical school, figuring out what all those graphs and numbers meant. I started consulting in group health in 1979 and by 1983 was doing software design and production for HMO and insurance companies and consulting and reviewing plans. In 1979 I identified, through strictly paper journal, that my problems were very largely b12 related.

    The active b12 protocol was a pragmatic set of results with no understanding of the entire paradoxical folate deficiency situation, the only function of AdoCbl was in the mitochondria, and no understanding of the 4 way deadlock. There were a lot of holes and "I don't know" places. There were lots of pieces of data and relationships with other data, incomplete patterns and so on that have, with these additional understandings, and additional series of MeCbl, AdoCbl, l-methylfolate, l-carnitine fumarate and potassium titrations in hyper reactors, allowed a much more complete understanding.

    Rich helped a lot by asking those terribly important difficult questions and pointing out what he saw as problems. In that he provided a lot of guidance to filling in the holes.

    I notice you seem to recommend a 1:1 ratio for mb12 and adb12. Is there a specific reason for that?

    Yes. It is below the 3:1 Ado:Me ratio at which neuropsyc effects appear as artifacts of the ratio in people who otherwise had no indication of such.. I had noticed the tremendously wide variation in apparant serum halflife of AdoCbl in different people. Carmen Wheatley's Large Gorilla ... Adenosylcobalamin ... paper gave me the clues I needed to have the data "gel" that acuumulated over 9 years. There was this function of AdoCbl that wasn't restricted to a parking place in the mitochondria, that in fact had to be in serum in diffusion distribution and did not function if limited only to HTC2 distribution and handled inflammation completely without the mutitude of loose ends HyCbl left in place (see her earlier 3 Scarlet Pimpernel papers). THAT was the BINGO I needed.

    Also do you have a recent post or other information that discusses the amount absorbed from sublinguals dependent on dosing?

    There were several size series and conditions (folates, glutathione). Those are discussed elsewhere in some detail spread through perhaps a dozen poasts over some years here and will be consolidated and put into perspective along the way here. The final test with the sublinguals is the effect it has and the differential effectiveness by brand and dose. The dose mapping to effectiveness that I have done is pragmatic and ties in quite nicely with the kidney excretion measures.

    I suspect the 40% factor you quote for 250 mcg dose (1/4 of 1000 mcg sublingual) may not scale linearly as doses go up

    Wrong question and assumption. The amount of absorbtion I am assuming is 20% (50mcg) and the same from the AdoCbl for a combined total of 100mcg. The correct question is "does it scale DOWN to a nominal sublingual dose of only 250mcg?" as the tests were performed with nominal SL doses of 10mg to 100mg because of the lower limits of visibility. Nothing below 10mg SL could produce any reliable visibility, depending upon folate and gljutathione conditions. The SC injection series was 1mg to 100mg in single doses (several series) and comparison via urine colorimetry. Also, types of folate and quantities had to be given consideration in runninbg the series. The first sets were run with folic acid, the next with l-Methylfolate and the third with glutathione in body. Then a duplication with Metafolin after the glutathione documentimng the return to "normal" in b12 and folate handling.


    When overmethylated I definitely encountered the dreaded potassium problem (which I suspect is still not well understood in the community) having to intake 250 meQ per day (food and supplements) and still suffering from hypokalemia (that told me way too much).

    That is why titration to effectiveness is the only way to come up with the effective answer. The prescription time release potassium chloride is way too dangerous for these quantities. Are you sure that it is not an induced paradoxical folate deficiency? There are overlapping symptoms that can be mis-interpreted. I think this potassium thing is very much not understood. For me the first big kick was level 1 methyaltion startup, the second was the upwards spiral of l-methylfolate > potassium > l-methylfolate > potassium cycle and the third was l-carnitine fumarate. When those muscles start forming when they had been releasing potassium as they atrophy it really appears that it starts to suck up the potassium. There will be more coming on potassium but that is right now lacking in citable references. In the b12 studies for decades the few who developed hypokalemia were removed from the studies rather than figuring out the portassium situation. With CyCbl and HyCbl hypokalemia was "rare". With the deadlock quartet it is extremely common and predictable. Watch out for too much calcium as that could also be mistaken for low potassium. There is a ratio here that is not at all clear but is important.


    I have a problem with the term “overmethylation”. There is no evidence I have ever seen that fits into this system that supports the idea. It’s based on the assumption that HyCbl and CyCbl are the standard of effectiveness rather than a starvation mode workaround that barely supports survival but not health. Those symptoms cited as overmethylation are typically simply b12 deficiency symptoms. Another thing typically called “overmethylation” is ATP startup with AdoCbl and especially Alpha Lipoic Acid with L-carnitine fumarate. For unknown reasons, again, but pragmatically supported, TMG often reduces the ATP startup intensity to some degree. There is a balance situation here that is not well defined. This starts replacing atrophied muscles at high speed as well as stopping the release to serum of potassium as the muscle cells die in the first place. There is a whole lot of semantically induced misunderstanding in all these things. The problem is similar to the cartoon physics belief and people’s failure to solve the simple practical Newtonian physics problems of driving a car.
  19. Freddd

    Freddd Senior Member

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    Hi Lauriel,

    The answers I can give you are all based on reading of papers as I have no direct way to know the biochemistry and I haven't done it myself.


    It is my understanding, that adcbl is the base b vitamin in the body (mother) in which all others rest on, including methylb.

    Just the opposite. MeCbl is the base and "main circulating form" and is what all the special purpose cobalamins are made from. Chemicals, like cyanide, can take any lesser oxidized cobalamin, like HyCbl, AdoCbl and MeCblo and convert them and others to CyCbl. Glutathione is just as bad as cyanide on all acrive cobalamins flushing them from the body in hours. Nitrous oxide destroys active cobalamins. It is a whole different matter going to the less oxidized more useful forms of cobalamin. That is an uphill energy transaction and requires ATP and an enzyme, a relatively expensive transaction. MeCbl destroys many toxins by being destroyed by them Keep in mind that the body contains mostly AdoCbl but tied up in the mitochondria until the cell dies. There is a method being worked out right now to identify temporary cobalamins in extremely small quantities that makes picograms look big so that they can know all the so many functions of these perhaps hundreds of special purpose cobalamins. It may be possible in 20 years to tailor a cobalamin mix that is dead on tarrget for a specific person's problems.

    Methyl b can be made from adcbl?? by adding the methyl group and methyl b can be recycled through the MTR,MTRR reactions in the methylation cycle?

    According to the reading I have done on the active cobalamins MeCbl is the root form from which all the others in the body are derived. The papers and pragmatic results are that people have differring capacities to convert MeCbl to AdoCbl. Other papers also say that there is no direct routE from HyCbl or CyCbl to AdoCbl. The pathway is CyCbl + enzyme + CH4 (from a donor, typically illustrated as l-methylfolate or SAM-e, a product of MeCbl) + lots of ATP >> MeCbl then + enzyme + lesser amount of ATP >> AdoCbl.

    The problem is that HyCbl and CyCbl are that both are 100% dependent upon the Deadlock Quartet producing the ATP and for the methyl group source (MeCbl, l-methylfolate, SAM-e (MeCbl)). Any one of those deficient enough can deadlock the body's ability to reprocess HyCbl (a natural breakdown product of MeCbl). That is why HyCbl is 100% ineffective for 400 MeCbl/AdoCbl deficiency symptoms and 1% effective for 2/3 of people for a few symptoms and the rest, non of the measured sysmptoms or signs.

    AdoCbl without MeCbl produces sometimes dramatic neuropsyc effects. Maybe those are the folks who can't convert enough to MeCbl, and if so, it's seems to be a high percentage. Mostly this is insufficient information. The one thing I can tell you pragmatically is that NOBODY has a sufficiency of conversion even if just limited to AdoCbl and Mecbl. The each can produce independent results in both the body and, in low CSF cobalamin groups, in the CNS.

    Pragmatically, prolonged consumption of HyCbl or CyCbl increases most deficiency symptoms and causes far worse startup effects when the active forms are actually taken.

    If this were true, then this may help to explain why some need more adcbl than methylb? I can't take a 1:1 ratio. I need 2:1, adcbl to methylb, 10,000 to 5,000.

    Are you using the Enzymatic Therapy b12 infusion and Anabol Dibencoplex AdoCbl? Are you holding them for as long as possilbe, 2 hours if possible, against oral tissues under lips? There may be any of several reaosn that I am aware of. One of them is that some people have a CSF/CNS deficiency of AdoCbl but NOT MeCbl. It takes a higher diffusion gradiant to penetrate the CNS than people need in the body. If you take these at the same time they combine in CNS penetrating gradiant by my own and others pragmatic experience.. This is research results and I have no idea why transfer to or loss from the CSF can be that specific, but it may have something to do with insufficient l-methylfolate somehow or something else. Also it could indicate that you don't convert MeCbl well to AdoCbl. I'm glad to hear of these results. They are a lot like my daughter's and some other people. If another 10 or 15 folks with similar requriements step out and tell us about this we might be able to figure out what the factor involved is. That is why titration to maximum effectiveness is a must as a method


    So what causes the dysfunction or deficiency in adcbl? Is it the methylation cycle or is it something else? I am just not understanding the adcbl side of things.

    1. Dietary lack in approx b12 potentcy high to low; no liver, organ meat, clams, oysters, red muscle meat, poultry, fish, insects and worms, eggs, cheese, milk, fermented manure, fresh manure. No veggies, yeast or anything else has b12 unless it is added. deficiency or insufficiency
    2. L-carnitine, dietary lack, causes dysfunction in mitochondria
    3. MeCbl, L-methylfolate, dysfunction, ATP production is deadlocked by insufficient methylation
    4. Alpha Lipoic Acid - dysfunctions, increases l-carnitine efficiency perhaps 50% in transporting fats to mitochondria.
    5. D-ribose deficiency, dysfunction in recycling used ATP back to ATP
  20. Freddd

    Freddd Senior Member

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    Hi Ema,

    Thankyou for pointing that out. It is partly an editing error of a cut and paste and partly not being sure how to say it. The distinction is that in ME the #5 case represents titrating to zero folate insufficiency symtpoms which is 16 mgs in 4-5 doses daily. In people with no paradoxical folate deficiency, it's when they reach the zero folate insufficiency symnptoms which is often about 3200mcg. They do represent a difference. In 5 there is muscle atrophy, not just a lack of recovery and exercise induced growrth. I would have to check the symptoms detials but I think there are a couple of more specific types of pain present. There are 10 distinctive muscle pain types described in the symptoms and I think they might make this distinction.


    When you write 1000 mcg absorbed, is it possible to absorb 100% of a sublingual tablet or would this likely require more?

    On the average 45 to 120 minutes produces 15-25% (10-30% full range). I would say that of the tested tablets, right now only the Enzymatic Therapy B12 infusion and Anabol Dibencoplex capsule contents used under the lower lip, absorb this high and actually can be counted on working. At this time most other tested brands just won't work like these or some even at all. Typically then 5 of the Enzy tablets or half a Dibencoplex cap used under lip would give 1000mcg absorbtion each, or 2.5 of Enzy and 1/4 of a cap of the other give 1000mcg in all absorbed, more or less. The difference is indistinguishable in the range 750mcg to 1250mcg.


    Do you have any thoughts on L-carnitine's inhibitory effect on the thyroid? As someone with hypothyroidism, I am cautious about supplementing until I understand how it works better.

    I've been hypothyroid since 8 years old and on thyroid of one variety or another for the last 57 years. Nothing I have done, or not done, has made any difference in my levels and supplementation level. Some people in the active stage of Hashimoto's have had function restored before it was fully destoyed too much. with MeCbl. Plenty of people have tried to micromanage their thyroid becasue they believed that ATP startup somehow affected their thyroid and did screw thinbgs up for themselves becasue they tried to force things to change faster than the body's adaptation time and started some nasty oscillations. I'm not aware of any other connection of to the thyroid and not any of L-carnitine except the ATP mistaken identity. There has been nothing that shows up in anybody tests that has told me about it or posted it that I have read and plenty to the contrary.

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