I moved Freddd's spectacular post on B-12 from the story section to here in order to focus on it more fully. Many, many people try B12 for ME/CFS but few are cured. Freddd was actually cured when he stumbled upon the right type of B12 for him. This sparked an extensive examination of why one brand of B12 could have such strikingly different results than another. He started in on why B12 doesn't always produce good results in ME/CFS. Reasons B12 doesn't work for a person They take active b12 as an oral tablet reducing absorbtion to below 1%. A 1000mcg active b12 oral tablet might bind as much as 10mcg of b12. Again the b12 has to be squeezed through a keyhole that limits the amount and is subject to binding problems in the person whether genetic or acquired. They take an inactive b12, either cyanob12 or hydroxyb12. The research “validating” their use was primarily for reducing blood cell size in Pernicious Anemia, keeping the serum b12 level over 300pg/ml at the end of the period between injections. They make a statistically significant effect that can be seen in lab tests in a significant percentage of people compared to placebo. They do not heal most damage done by active b12 deficiencies and have little or no effect on the vast majority of symptoms. They may even block active b12 from receptor sites hindering the effects of real b12. They both cause a keyhole effect of having only a very limited amount (estimated at 10mcg/day) that can actually be bound and converted to active forms. They in no way increase the level of unbound active cobalamins which appear required for most healing. They do nothing beneficial in a substantial percentage of people (20-40%) while giving the illusion that the problem is being treated and if it doesn’t work, oh well, that’s the accepted therapy. There is no “dose proportionate” healing with these inactive b12s because it all has to go through this keyhole. Some people are totally incapable of converting these to active forms because they lack the enzyme. They take a sublingual tablet of active b12 and chew it or slurp it down quickly reducing absorbtionback to that same 1% and limited to binding capacity. With sublingual tablets absorbtion is proportionate to time in contact with tissues. I performed a series of absorbtion tests comparing sublingual absorbtion to injection via hypersensitive response and urine colorimetry. (EDITOR - let your sublingual B-12 dissolve in your mouth!) Wrong Brand - Of the many brands of sublingual methylb12 only some are very effective. Some are completely ineffective and some have a little effect. For injectable methylb12, if it is exposed to too much light (very little light actually is too much) it breaks down. Broken down methylb12 is hydroxyb12. It doesn’t work at healing brain/cord problems of those who have a presumed low CSF cobalamin level. That requires a flood of unbound methylb12 and adenosylb12 (2 separate deficiencies) that can enter by diffusion. Adenosyl12from sublinguals can ride along with injected methylb12. They don’t take BOTH active b12s. They don’t take enough active b12s for the purpose, espcially amounts needed to penetrate CSF by diffusion. Lack of methylfolate. Lack of other critical cofactors. Lack of basic cofactors. Taking glutathione or glutathione generating cofactors that induce an active b12 deficiency. So why is this the case? First, most people consider b12 deficiency to be a unitary thing. it isn't. There are 4 distinct and different b12 deficiencies each with it's own set of characteristics, and a person can have any combination of the 4. In addition is the definition of "deficiency" itself. In CFS/ME/FMS it has been shown that people in some studies had a specific kind of b12 deficiency, they had a cobalamin deficiency in the cerebral spinal fluid, the same as found in Alzheimer's. As it was "cobalamin" specified, there is no definition as to whether it is methylb12 deficiency, adenosylb12 deficiency or some combination of both. Each type of active b12 has it's own deficiency symptoms. The results of shutting down the neuronal mitochondria are different from loosing myelin or slowing down impulses or lacking a wide variety of neural transmitters or who knows what other effects. Unless a CSF draw is done, there is no way to detect these deficiencies. There are no standards of what is "deficient" even if a draw is done. Pragmatically these deficiencies can both be detected and differentiated. For a variety of reasons I won't go into now, I could make a case for ME being a CSF deficiency of largely methylb12 specifically for instance. It is not known what mechanism reduces coblamins in CSF to significantly lower levels compared to blood serum levels, in some people, from 50% to 75% lower compared to various control groups in different studies. As all 3 of my children have all the same problems I do chances appear good that it is genetic. Producing healing in this sector is sometimes the most challanging depending upon the other, mostly genetic, challenges a person has. Basic Challanges, some causes unknown Can't absorb b12 for a wide variety of reasons including IF insufficiency (Pernicious Anemia) of either genetic or autoimmune causality. Can't bind b12s for transport Genetic Challanges Decreased CSF cobalamin levels - hypothetical cause, confirmed problem Lacking Enzyme to convert methylb12 to adenosylb12 - confimed, named cobalamin letter disease Lacking Enzyme to convert adenosylb12 to methylb12 - confimed, named cobalamin letter disease Lacking Enzyme to convert cyanocobalamin to methylb12 or adenosylb12 - confimed, named cobalamin letter disease Lacking Enzyme to convert hydroxycobalamin to methylb12 or adenosylb12 - confimed, named cobalamin letter disease Lacking Enzyme to convert glutathionylcobalamin to methylb12 or adenosylb12 - hypothetical cause, some evidence for problem Lacking enough enzyme(s) to convert folic acid to sufficient methylfolate, - confirmed cause Each of those can be overcome. On top of the genetic reasons, the methylb12 generated by bacteria is not all the same and some bacteria breeds may generate superior methylb12. This is totally unexplored but may account for some brand differences. Of 10 brands of methylb12 systematically tested, 2 rated 5 stars with 5 hypersensitive testers. They were Enzymatic Therapy 1mg, and Jarrow Formulas 1 mg and 5mg. In addition Country Life Dibencozide (adenosylb12) also rated 5 stars. One brand of 5mg methylb12 rated ZERO stars, completely ineffective in all testers. The other 7 brands rated 1-3 stars. The sublingual b12s must be retained under the upper lip or tongue for 45 minutes to two hours for effectiveness with verified absorbtion ranging from 15% to 25% with urine colorimetry and by effect. Solgar Metafolin (methylfolate) is one of two brands available and is superior to folic acid in every way. Jody, I spent more of the years learning what didn't work than what did. I had some serendipidous events and some outright incredible luck and some terrible setbacks. I don't do things by halves. I personally appear to lack all of those enzymes for interconversion of forms of b12 and folic acid for instance and had all four b12 deficiencies. When I find something that works 5% of the time I find out why it doesn't work 100% of the time. That's engineering. Because my body is hypersensitive to these changes it's very much like debugging software and I can know sometimes in hours or less what takes others weeks or months to find out. Sometimes I'm just too bullheaded to get the message and keep on past all reason until it is clear. The information I am presenting here is a distillation of decades of experience and 6 years of active experimentation on myself and children. And I always do much reading to find why I should try some things or why they worked/didn't work afterwards. End of first part of explanation. More to come.