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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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    Hi Jeffrez,

    I've even seen reports that some poeple have gotten worse on methylation treatments.

    Yup, "detox" to a terrible extent forcing discontinuance. Most of the time it is hypokalemia and/or induced folate insufficiency. Then there is the "anxiety" variation which will be covered. That has to do with ATP startup. Most of the problems are actually ATP startup and have nothing at all to do with methylation. If they are methylation related, hypokalemia and induced folarte insufficiency. Hypokalemia can be fatal for any of several reasons. It needs to be dealt with, not called "detox" and ignored.

    What is the track record turning out to be?

    Those that get better go back to work and live a life. The ONLY reason I am still here is that I have set out to nail this problem before they prevent the possibility and condemn me to a miserable death, by making any supplement formulation not available in 1992 (AdoCbl, MeCbl, and L-methyfolate but that one has had the full pharmaceutical testing). I have made figuring out what went wrong what I am doing now. I used to do that for hire before I becasme too disabled to work. Then I took myself on. I'm playing for the survival of my family with the same problems I have. I know that the people that healed are those that were able to titrate the various components getting rid of those problems leaving them with the neurological brightening of everything with the MeCbl to deal with and the energized feeling (without calling it all sorts of scary names and believeing them) from the AdoCbl and/or L-Carnitne fumarate, which needs to be titrated to keep it managable. The ones that can follow it precisely with all the cutomizations, everything is done by paying attention to the body and correctly interpreting what is happening and titrating the various items as needed. I am going to be able to lay out a significantly better version. There are a lot fewer unknowns now. The substantial recovery, returning to work or physical rehab from years of disuse takes about a year from when the last body layer that needs to start healing does so. CNS healing is more difficult and takes longer. How well it works depends upon which pattern the persons symptoms follows. In various groupings the rate appears to be something like this.

    RESTART METHYLATION - ESSENTIALLY 100% even if it takes several more things than the deadlock - quartet. Here is the first make or break point. Figure out the balance points at the AdoCbl-MeCbl and L=methylfolate with potassium and l-methylfolate. This a titrate to criteria. It may take a number of other supplements required to achieve this level of startup so a willingness to do trials is important. The basics nutrients are basic. So compliance in a customized way is complicated and not always achieved.

    The other levels of healing startup depends upon the intial sucessful startup.

    Have you run through this list yet? This list is the result of changing something from less than 5% effectiveness to something that works on 400 symptoms in a sizable percentage of people. There are damages and other problems that remain unaffected. Sometimes other things cause similar symptoms. It can be tricky. Following the clues is a difficult thing sometimes. I learned all the lessons in the following list by hitting the wall with them. I learned from each of my setbacks. I bet we can figure out what kept you from having a response.


    THE 95% REASONS B12 AND FOLATE THERAPIES FAIL

    Version 2.0 - 03/10/11, Version 2.1 - 05/08/11. Version 3.0 – 10/25/2012, Version 3.1 10/26/2012, Version 11/05/2012 3.2



    1) 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 10-30mcg/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 enzymes or ATP

    2) They take active b12 as an oral tablet reducing absorption 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.3. They take a sublingual tablet of active b12 and chew it or slurp it down quickly reducing absorption back to that same 1% and limited to binding capacity. With sublingual tablets absorption is proportionate to time in contact with tissues. I performed a series of absorption tests comparing sublingual absorption to injection via hypersensitive response and urine colorimetry.

    3) Of the many brands of sublingual methylb12 only some are very effective. Some are completely ineffective and some have a little effect.

    4) 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. Adenosylb12 from sublinguals can ride along with injected methylb12.

    5) They don’t take BOTH active b12s.

    6) They don’t take enough active b12s for the purpose.

    7) Lack of methylfolate

    8) Lack of sufficient Methylfolate, a dose can start more healing than the same dose can complete.

    9) Paradoxical Folate Deficiency - Folic acid is taken which can block at least 10 times as much methylfolate from being active inducing folate deficiency even if methylfolate is also taken. These induced deficiency symptoms are often called "detox" symptoms. Folinic acid is taken which can block at least 10-20 times as much methylfolate from being active inducing folate deficiency even if methylfolate is also taken. These induced deficiency symptoms are often called "detox" symptoms.

    10) Lack of l-carnitine fumarate (rarely ALCAR), the 4th of the Deadlock Quartet

    11) Lack of other critical cofactors.

    12) Lack of basic cofactors

    13) Glutathione, glutathione direct precursors, NAC and /or whey is taken causing what is often called "detox" while actually being induced folate and b12 deficiencies.

    14) Having many additional supplements, drugs and herbs of unknown interactions and effects that block or antagonize primarily folate. Many drugs interfer with folate and/or B12.

    I know you've benefited, Fred, but I think you'll agree you're a unique case, with unique genetic profile, etc
    Actually, I'm not as unique genetically than many might think. When I first showed up here I was quite unaware of paradoxical folate deficiency and my working hypotheisis turned out to be incorrect, but Rich ended up pointing me right at it. I have folic acid conversion to l-methylfolate problems, just as 20% of population and many of not most of the people here. I also have folinic acid to l-methylfoalte problems and that is of unknown frequency. Those that need 15mg or so of Metafolin, the most common effective dose in the Deplin FDA studies, most likely have paradoxical folate deficiency. How many folks here have folate problems of some sort? Very common

    My response to CyCbl and HyCbl is common, they reduce MCV in me and that is really what they were researched to do and they do it for 2/3 of people. It does a little more but very little. It makes a just noticable difference but not enough to heal me or even heal my skin. I was extremely deficient and hence extremely responsive. I was deficienct in all 4 of the Deadlock Quartet. The only uniqueness is that I can remeber most all illnesses back to 2 years old, very systematically explored and debugged the pathway and figured out many of the main pathways, and arrange all my exeperiences and those of some thousands of others into a system
     
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  2. Marcus2013

    Marcus2013

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    Hi Freddd,

    First of all, thank you very much for all this information. It all really makes sense.

    I would like to ask you a question. I know you are not a physician or certified practitioner but I would be really glad if you could give me some advice.

    Do you think that all you have explained can apply to patients suffering mild chronic unipolar depression (dysthimia) and/or brainfog ? I've read studies stating most depressive patients show lacks of b12/folate. Well, in fact, after reading your post, I understand almost everybody is b12/folate dificient!! But I suffer from this kind of depression, that it also has a moderate fatigue included. I don't think I have CFS/ME because I can go to work, run, I exercise 3 times a week, etc..

    Thanks.

    All the Best,
    Marcus
     
  3. Red04

    Red04 Senior Member

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    I would say my wife had your symptoms before developing the rest of CFS/ME. She was on antidepressants and other psycho-drugs for several years while exercising and working and got a college degree with no major fatigue obstacles. She slept a lot and was prone to getting colds and staying sick longer than an average person. But maintained a relatively normal life with the assistance of a therapist and prozac/xanax/wellbutrin/klonopin whatever the flavor of the month was.

    She immediately got off of all of that when we started Freddd's protocol. She gets a little depressed now and then, but the depression/anxiety is 90% cured to where we don't consider therapy or drugs. And probably due to her childhood of always being on them, my wife likes drugs. I suspect if she was better about following the protocol, she would never get depressed.

    And they are treating depression with deplin....definitely worth looking into methylation supplements. Methylation was the first thing I thought about with the last school shooting.
     
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  4. jeffrez

    jeffrez Senior Member

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    Lots of good information and reports here - thanks everybody, very much appreciate it!
     
  5. Marcus2013

    Marcus2013

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    Wow! Thank you very much for all this information Red04! I also had prozac / therapist in the past and it worked but I always felt that wasn't the right path to follow (not mentioning side effects). This gives me hope!

    Please could you tell me exactly what is/was your wife taking ? I mean, the protocol has 6 steps. It starts with small doses of MeB12+l-methylfolate and keeps on increasing doses and adding AdB12, Carnitine fumarate, etc...

    For me it's not clear when or how you should pass from step 1 to step 2 and forth... If you could tell me how your wife did it, I would be really grateful.

    Best wishes,
    Marcus
     
  6. Red04

    Red04 Senior Member

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    Back then it was the shotgun approach. Dump it all in and wait for something to trigger "startup". I think startup is now better defined as potassium def. and pradoxical folate def. We didn't know folic acid was a "blocker" back then, so a lot has changed. I think Freddd is developing a titration plan. I think essentially you put all the basics in place and titrate up mb12/methylfolate/adb12. All while keeping potassium in check.

    Start small and add 50% until you trigger potassium or paradoxical folate definciency. Go back down, add potassium or mothylfolate, and move back up. Repeat until you get up to the high dosages. Get healed and then titrate things back down. Now that my wife is stable, the answer always seems to be more methylfolate.

    Here was Freddd's last titration protocol:

    http://forums.phoenixrising.me/inde...tocol-with-micro-titration.17818/#post-273588

    If you read the stickied protocol at the top, with this link and freddd's latest, you can probably put most of it together. You mentioned you don't have all the CFS/ME issues, you will probably slam through the titration. Especially, if you are relatively healthy. This is simply a hunch from what I've seen my wife have when she stops the supplements. Depression and anxiey come creeping in around a week or so without supplements. There are no startup effects when she resumes the protocol. I am not a doctor, so don't sue me if you die from severe startup effects or go crazy and harm someone else. It would likely be better to go slow.

    The more likely problem I see is that you might have to try it for several months before noticing or being confident that it is working. Where people with more symptoms may see more obvious relief. You have less symptoms, so it will be more ambigous to track. I would set out a long term plan (say 6 months) and try to track the depression symptoms as best as you can. Maybe enlist someone to help you and observe you from the outside. My wife doesn't see it coming or going. I have to tell her that she is depressed and she needs to get back on the supplements, it's kinda weird.
     
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  7. Linda828

    Linda828

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    Hi, I’m a new kid on the block and this is my first post. I guess it is as good a place as any to jump in. I’ve been reading in the background and haphazardly following a methylation protocol for the last 8 months.
    Freddd’s initial post interested me because he talked about how all the inherited metabolic disorders of B12 only became life threatening issues with the advent of CNCbl and OHCbl. Recently I have been trying to understand the inherited metabolic disorders of B12 to prepare for an appointment with a geneticist. I don’t have a biochemistry background, so this has been an overwhelming project.
    In regards to the genetic disorders, I can understand how CblC protein might be affected by the type of Cbl ingested or injected, especially since mutant CblC protein is known to bind only weakly to CNCbl and the mutant protein gets increased stabilization by AdoCbl and MeCbl. On the other hand the CblA, CblB, CblD – CblG proteins only combine with the Cbl after it has been stripped by the CblC of its R group (methyl, hydoxy, adenyl, Cyano). How could all these disorders be exacerbated by the type of initial Cbl entering the cell? Is it because the presence of the methyl or adenysl group released in the cystol is necessary for reassembling the molecule? Where would I read more about this?
    Also, I’ve heard it said many times on this talk group that some people have poor inter conversion between AdoCbl and MeCbl. In my very minimal studies, I haven’t come across any research about this in other places, or mechanisms about how this happens. Can someone point me to a good place to get a clearer understanding of this?
    I have lots of other questions about how the disorders of transport and absorption might be exacerbated by the inactive Cbl’s , but that is enough of the technical stuff.
    On a more personal note, I do keep bumbling along with high dose MeCbl and AdoCbl, and methylfolate (with lots of other supplements). Bumbling is the word because I don’t have a clear sense of cause and effect, like some people do who carefully titrate according to symptoms. I can take large and variable doses of these main three and not notice much difference. On the other hand, when something affects me badly, I can go into massive brain fog with only minute amounts. That happened initially with the folic acid in the country life dibencozide and most recently with vitamin D.
    My most bothersome symptom at this point is severe multiple chemical sensitivity. Many other issues have resolved after starting the high dose B12 and methylfolate last Spring.
    I’ve appreciated all the shared experience and insight of this group and most especially Freddd, your generosity in communicating your hard earned discoveries. I haven’t had much to share, because I’m still so absorbed in just trying to put the pieces together.
    Blessings
    Linda
     
  8. dannybex

    dannybex Senior Member

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    It was "sufficient" for the autistic kids in this study, and it's working very well for me -- after 2 years of avoiding it.

    http://ajcn.nutrition.org/content/80/6/1611.full

    Also, folinic acid was found to be beneficial in 81% of CFS patients in this trial:

    http://www.natural-holistic-health.com/cd19-blood-test-and-chronic-fatigue-syndrome/

    Here's the PDF of that study:

    http://www.ncf-net.org/pdf/UckunCFSCD19.pdf

    It may not be helpful for everyone (possibly depending on their genetics), but it does help others. Making blanket statements to the contrary (as above) is IMHO unwise, and could cause others to remain sick because they're not getting what their own particular, individual body needs.

    Dan
     
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  9. Freddd

    Freddd Senior Member

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    Hi Linda,

    he talked about how all the inherited metabolic disorders of B12 only became life threatening issues with the advent of CNCbl and OHCbl

    They became life threatening to infants on formula after it ceased being an animal product and especially with the folic acid and CyCbl when that became the alternative. They then would treat with HyCbl (after about 1970, before that more fatal) to which 2/3 or so of infants would respond leaving 1/3 to die. When they investigated the cause of failure to thrive B12 version, they found a lack of enzyme to be the genetic cause. As they explored they found that there were a any number of enzymes or their lack that could cause a failure in conversion of cobalamin forms. One of those is lettered diseases is the one that does not convert MeCbl to AdoCbl which isn't normally dangerous if one eats a mix. If one supplements ONLY with MeCbl and can't convert then all the AdoCbl deficiency symptoms won't heal and insufficient ATP, muscle atrophy. These are PRAGMATIC determinations by me.


    I can understand how CblC protein might be affected by the type of Cbl ingested or injected, especially since mutant CblC protein is known to bind only weakly to CNCbl and the mutant protein gets increased stabilization by AdoCbl and MeCbl. On the other hand the CblA, CblB, CblD – CblG proteins only combine with the Cbl after it has been stripped by the CblC of its R group (methyl, hydoxy, adenyl, Cyano). How could all these disorders be exacerbated by the type of initial Cbl entering the cell?


    At least according to some research the conversion takes place in the cell. If there isn't sufficient ATP (made in the cell then the enzyme can't work. I have just started noticing how "local" b12 and folate deficiencies can be. Other than that I really have no idea how that all works. There is new research in progress to determine ways to identify all the temporary cobalanins that form up and how. I don't know the details either. That wasn't what I was searching as it was irrelevant to dealing with the CNS and was nothing I could inveastigate myself.

    Also, I’ve heard it said many times on this talk group that some people have poor inter conversion between AdoCbl and MeCbl. In my very minimal studies, I haven’t come across any research about this in other places, or mechanisms about how this

    happens. Can someone point me to a good place to get a clearer understanding of this?

    That is one of the lettered diseases to my understanding. Regardless of HOW it happens I can describe what makes it visible. First, let me state that I have not seen ANYBODY not have an AdoCbl startup separately from the initial MeCbl startup at the time. As an illustration I started at 1mg SL per day of MeCbl. In 9 months even at 25mg SL it had run out of gas. Then I tried AdoCbl. It was like MeCbl for the first time all over again. In 9 months the deficit of AdoCbl could not be filled with essentially unlimited MeCbl. Based on the effects of the that first few months of MeCbl startup I would suggest that MeCbl was able to satisfy about half of the AdoCbl needed and it reached equilibrium in several months. One can perform this trial in either direction and will have both startup effect separately. However some people don’t have ATP startup with MeCbl. They appear to be the people who have to take AdoCbl daily as if it had the same persistence in serum as MeCbl or they can notice a startup difference after only missing a few days. For me, I can maintain without AdoCbl startup for a month or more. My only 3 experiences of AdoCbl body startup was first dose, first larger dose months after finishing a 6 week glutathione trial and when I changed brands to Anabol Dibencoplex. I had one CNS startup the first 50mg dose and again with first 50mg dose after glutathione. There are various experience reports people have posted but I can’t tell you where. Search might find them

    I have lots of other questions about how the disorders of transport and absorption might be exacerbated by the inactive Cbl’s , but that is enough of the technical stuff.

    Simple enough. The inactive cobalamins have to go through the keyhole of IF absorption and be distributed by the active HTC2 system. That is the most complicated distribution of any vitamin. Anything goes wrong, no b12. Even if you inject CyCbl/HyCbl, diffusion doesn’t help much. With the active AdoCbl and MeCbl in the times of high serum levels the need can be filled directly out of the serum without any energy cost. Everything that needs some gets some immediately. That starts generalized healing.

    My most bothersome symptom at this point is severe multiple chemical sensitivity

    That sounds more like an l-methylfolate deficiency. It took mine about a year to normalize. It happened slowly. One day I noticed I could go down the detergent aisle without problems. Good luck.
     
  10. Freddd

    Freddd Senior Member

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    Dan,

    As I have said, an unknown percentage have trouble with folinic acid. So here we have a number 81%, have effect. That could be close. So let me make the statement more explicitly. As long as a person has sufficient L-methylfolate folinic acid is not necessary for anyone or sufficient for everyone.

    I wasn't putting it in the context of CyCbl, HyCbl and folic acid. In the context of the whole post I had made clear that folinic acid isn't the same. Also that does not change what the meaning of what I meant in this reworded form. NOBODY HAS TO HAVE FOLINIC ACID (NOT NECESSARY) and EVERYONE MUST HAVE L-METHYLFOLATE (NOT SUFFICIENT) (in their body, unspoken).

    I trust that my restatement makes clear what I meant. I'm sure it is more satifying in these forms.

    Also, I am trying to find the items that work for EVERYBODY, not just those of "normal" genes. Maybe finding myself always in that 19% category (the same as folic acid it might appear) I remove all assumptoins about what "should" work because to be here, most people have multiple casues based on lots of assumptions. As we all know this forum is a hotbed of those with folate related polymorphisms. My suggestion of folates has ALWAYS been get the healing started and then trila the other folates to see if they work for you. Until somebody gets healing started they are not getting any clues to healing. A lack of sucess in getting healing started is the same old illness that got them here. It does tell them that they are not doing something required for healing. Once one gets healing started one can find things that turn healing off or increase healing. Those are the clues needed to solve the problem. So if one trials folinic acid and it doesn't work, they still have to trial l-methylfolate. So if somebody says, "I'm not happy with my healing rate" I'll send them to the same old reasons b12/folate doesn't work. If it still doesn't work after checking all items, then it is likely either a critical cofactor or basic missing or glutathione/NAC. which are all on the list but often ignored.

    And because of your own hypersensitivities shared by some others, I do caution on L-carnitine fumarate and have worked out a titration starting at 100mcg of carnitine for hypersensitives.and not make the assumption that everybody can take it. in "normal" doses. I reviewed why it was banned for sale in Canada, a complaint from somebody taking klonopin and they had the expected carnitine response and nobody understood it so they banned it. So, trying to come up with a protocol safe and effective for as many as possible I have to take in account all of us folks that have one thing or another at < 20% proability just the same. What is the safest most effective way to heal? With that as a goal I can suggest l-methylfolafte as most likely to succeed in starting healing for the largest percentage of everyone.. I'll never succeed but then how close can I get? Somebody not being able to utilize folinic acid is a lot more likely than someone having a massive overkill response to (usually) l-carnitine or occasionally AdoCbl. What I hope to be able to do is map to symptoms the ten or so most frequent pathways making the responses predictable.

    So I would like to ask a question. As my questionaire was built largely on MeCbl and AdoCbl single dose screening, what I found is that those with no deficiency symptoms have no responses of any kind to either or both, 75% for one, 80% for both. How l-methylfolate fits into that will be posted later. That is a combination effect, not L-methylfolate alone or compared to folinic acid. Does no deficiency no response hold true with L-methylfolate? Do you have any differential effectivness from l-methylfolate? Have you done A-B swtichs for alternating months to see? Was that done with all the folks who found folinic effective? Or would those folks have a differntial effect of L-methylfolate being say 50% more effective? And if so, what would that mean? I don't know. I've never looked for it or had it come out an announce itself. I ran that test and found folinic acid made me very sick in a week or less. Running these A-B trials is part of the whole process for a person who is seeking to optimize their program for their own personal healing.
     
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  11. dannybex

    dannybex Senior Member

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    I understand, but consider the possibility that since folinic can break down more slowly to into other forms of folate (including methylfolate) it may be easier to tolerate than taking methylfolate directly. It may even be essential.

    And as you've heard repeatedly on these forums, many people do indeed have difficulty tolerating even small doses of methylfolate.
     
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  12. Freddd

    Freddd Senior Member

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    Hii Dan,

    I did edit the post while you were making the reply, an addition. So what does "difficulty tolerating even small doses of methylfolate." mean? In those where I have investigated personally it turns out to be donut hole folate deficiency and/or hypokalemia or rarely the whole darn startup of methylation on all levels along with the other two. I haven't seen any problem other than those attendent to turning on healing when the get methylfolate. Methylfolate is the most limiting factor for 10-15% of the people with suitable symptoms and can cause multiple levels of startup at once including ATP startup which some folks find intolerable.
     
  13. dannybex

    dannybex Senior Member

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    I think for some people folinic is like a 'buffered' form of methylfolate -- as it can break down to m-folate, so perhaps that's why I personally didn't have any problem starting with 800mcgs. It (along with TMG as in the study) calmed me down considerably, especially compared to the hell of 2011 and half of 2012.
     
  14. Lotus97

    Lotus97 Senior Member

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    Rich Van Konynenburg, Ph.D., was a biochemist and independent researcher who has studied ME/CFS since 1996.
    The first post is where Rich very clearly and succinctly outlines the methodology for designing his methylation protocol.
    I actually prefer including both folinic acid and 5-MTHF. 5-MTHF is the form needed by methionine synthase, which is the enzyme with the partial block. Many people's cells are able to convert folinic acid to 5-MTHF well, but many others have inherited genetic polymorphisms that slow this conversion down considerably. The polymorphisms in the MTHFR enzyme are a good example, and these are very prevalent in the population.
    Folinic acid is helpful for a couple of reasons. One is that it is very versatile, in that it can be converted to other forms of folate, which are needed to make DNA, RNA, and purines in general. Another factor is that folinic acid is polyglutamated when it is inside the cells, and this can help to lower the amount of free glutamate, which is an excitotoxin. Excitotoxicity is a problem in CFS, and it is often exacerbated when methylation cycle treatment is entered upon.

    I prefer hydroxocobalamin for several reasons. One is that it allows the cells to control the amounts of the coenzyme forms of B12 (methylcobalamin and adenosylcobalamin) that they make, so that they can be matched to the need. Taking methylcobalamin in large dosages by injection or sublingually can overdrive the methylation cycle, as evidenced by a major rise in sarcosine, which I've seen in amino acids testing on some people who have been on this treatment for a while. I am not comfortable with overdriving the methylation cycle, both because I think it slows flow down the transsulfuration pathway and thus limits the normalization of the balance of the sulfur metabolism, including cysteine, glutathione, taurine and sulfate, and also because I am concerned about the possibility of overmethylation of DNA, which could have other deleterious effects.

    My other concern is that methylcobalamin is known to be chemically able to methylate inorganic mercury. Many PWCs have significant body burdens of inorganic mercury as a result of having amalgam fillings in their teeth during an extended period while glutathione has been low, so that they have not been able to detox mercury at normal rates. Methylmercury can cross the blood-brain barrier readily. Mercury is a potent neurotoxin if it gets into the brain. This problem has been observed in guinea pigs. I don't have solid evidence for it in humans, but have heard from perhaps three people who may have had this problem, based on what they have reported. So I prefer to be cautious.

    This having been said, some people have had good experience with methylcobalamin. It can be especially helpful if a person has a shortage of methyl groups, though that can also be helped by taking some additional trimethylglycine (some of which is in the multi that is part of the simplified treatment). or some SAMe. It's used a lot subcutaneously by the DAN! doctors in autism treatment, and as you probably know, freddd on this forum advocates its use as well. In his case, because of a mutation in the intracellular B12 processing enzymes, his body is not able to utilized hydroxocobalamin readily. But I believe that this is a rare situation, based on the published literature. freddd does not agree that it is rare, based on his experience.

    Best regards,

    Rich

    Dr. Neil Nathan M.D. has used Rich's methylation protocol to great success with his CFS/Fibromyalgia patients.
    Dr. Neil Nathan is a noted specialist in integrative treatment of complex medical illnesses such as fibromyalgia, chronic fatigue syndrome, and Lyme. In addition to his clinical work with Gordon Medical Associates near Mendocino, CA, he is a respected educator, and author of the new book, On Hope and Healing: For Those Who Have Fallen Through the Medical Cracks.

    Dr. Nathan
    To my delight, 70% of my patients had improved within 3 months, and 20% reported that they were much better, occasionally to the point of feeling cured.

    This is a conversation between Rich and another member who was having low potassium symptoms from too much methylcobalamin and methylfolate. Low potassium can result in death. Rich explains the low potassium symptom that happens from overmethylation and also expresses concern about the growing frequency of overmethylation in these forums.
    Adreno:
    When I take 5mg methylcobalamin it causes me tachycardia. I then need massive amounts of potassium to calm down my heart rate (about 10 grams). Why?

    I also take 3 x 800mg methylfolate. When I take it with hydroxycobalamin, I can control my POTS/tachycardia with a steady dose of about 5 grams potassium daily. When I switch to methylcobalamin, my heart rate gets out of control and I need much more.

    I have heard the theory that there is a drop in potassium levels, caused by new cells being created. But come on, 10 grams!? Also, I do have doubts about this theory. What about other people who create lots of new cells, like people who just gave blood, people who had surgery, people who had chemotherapy, or athletes/bodybuilders? I have never heard of anyone needing to take 10 grams of potassium daily.

    Rich:
    Hi, Adreno.

    As you know, I have suggested a somewhat different approach to treating the methylation cycle partial block than Freddd has suggested.

    When high dosages of methylfolate and methyl B12 are taken together, the cells are no longer able to control the rate of the methylation cycle, and it becomes overdriven.

    One result of this is a rapid buildup of folates in the cells, because of the rapid production of tetrahydrofolate by the methionine synthase reaction.

    Tetrahydrofolate is readily converted to the forms of folate needed to support DNA and RNA synthesis, and this releases cells from a block at the S phase of the cell cycle.

    They rapidly start dividing, and this produces a strong demand for potassium.

    As Alex has noted, it has been shown that the intracellular potassium levels are low in CFS (likely because of an ATP deficit at the membrane ion pumps, due to mito dysfunction, in turn due to primarily to glutathione depletion), so there is no reserve there.

    The result is that the plasma level of potassium drops, and that accounts for the tachycardia.

    It is notable that hydroxo B12 does not have as severe an effect in your case as does methyl B12. That's because the cells have control of the rate of conversion of hydroxo to methyl B12, and thus have more control of the rate of the methylation cycle.

    Note that another effect of overdriving the methylation cycle is a further drop in glutathione, as less homocysteine is available to go toward cysteine synthesis.

    There seem to be more and more people who are exhibiting effects of overdriving the methylation cycle from taking high dosages of methylfolate and methyl B12 together. I do not recommend this approach.

    My suggestion would be to lower the dosage of methylfolate to something nearer the folate RDA (400 to 800 micrograms) and try hydroxo B12 instead of methyl B12, perhaps starting at 2 milligrams sublingually and working up from there if needed.

    Note: Rich's newest protocol recommends starting with 200 mcg folinic acid and 200 mcg methylfolate to prevent overmethylation and overdriving the methylation cycle. His recommendation in this thread was specifically directed at Adreno.

    As always, I recommend working with a physician while on this type of protocol.

    Best regards,

    Rich

    Adreno:
    Thanks Rich. I now only take a B complex (Thorne) twice daily, which gives me a little methylcobalamin/adenosylcobalamin, and 400mcg folinic acid/methylfolate each. I take this with 2mg hydroxycobalamin. This seems to work much better for me, and I can get by with a more reasonable dose of 1600-2400mg potassium. I also take a long list of other supplements. Mostly my POTS has been under control lately, which is fantastic.
     
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  15. Freddd

    Freddd Senior Member

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    Hi Lotus,

    Rich revised quite a bit in the end before he died. However, this is NOT a propaganda piece I'm trying to write up here. I am trying to describe the system I have been working on since 1979 and what I have found in the last 20,000+ hours of work I've done on this in the last 11 years now. You are protesting it massively before I can even get it out. Look, I can point out every flaw in Rich's program, and have. And the older you go the worse it looks. It works poorly at best for all sorts of reasons. Rich is trying to defend all the decades of flawed research on inactive cobalamins and folate as are most. Hey I used to work in the industry too. I am offerring a complete reconception of the whole thing more like if research hadn't gone off trying to make pigs fly for 60 years with inactive cobalamins. We didn't evolve for HyCbl. It works less than1% as well. It is a mistaken replacement of a hugely flawed mistake. Yes , it can work a little for some people on a few symptoms. It doesn't in any way predict the effectivenss of AdoCbl and MeCbl. It leaves 99% of b12 deficiency symptoms untouched in 99% of people. The folinic acid situation can be easily resolved in an A-B test for any specific person. There is a lot of unknown there. We know it can support a lot of people in so-so health. No combination of HyCbl and folinic acid can duplicate liver extract results. That we are even having this discussion demonstrates that HyCbl and folinic acid don't work adequately or none of us would be here. In looking through the many various things I have found 1 person claimed to be healed enough to return to work from the HyCbl/folinic acid combo in all these years. If there are any more where are they? While plenty of people have healed and returned to work with the active b12 protocol despite all the rough edges and difficulties. The SMP appears to produce these results at 1:10,000 or so. The active protocol more like 1:10 to 1:3 or so, and almost all of them had already failed with HyCbl and other such things. When the main problem is too strong an onset with multiple induced deficiencies versus no onset should tell you something. When you have to look for microscopic test results to "prove" benefit versus naked eye healing over days and weeks that should tell you something. In any case you make your choices and do as you wish. I'm going to continue the anaylsis of a working system. The main problem remaining is identifying the specific secondary and tertiary healing pathways. In 1998 I had hundreds of symptoms and was dying slowly. SInce then I have learned how to heal, for me and many of those for whom HyCbl hasn't worked and never will work. At best HyCbl can work pretty well for a vanishingly small percentage of people. It doesn't can't and never will match AdoCbl and MeCbl, it CAN'T. It needs both of those and l-methyofolate (where produced in ones own body or not) and carnitine for it to "reboot" the system. Without the active cobalamins, sufficient l-methylfolate and carnitine in place HyCbl is totally inactive. That's why most people get worse and worse the longer they take HyCbl. Be in good health.
     
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  16. Sushi

    Sushi Moderator and Senior Member Albuquerque

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    Lotus97

    Thanks so much for reposting Rich's posts and discussions with another forum member. Many of us have worked with Rich on methylation for years and have found his knowledge and his willingness to continue to research and learn to have been enormously beneficial to us. He has also always urged us to seek competent medical supervision when considering a methylation protocol.

    Methylation is a basic and vital biochemical process and when it is disrupted by a disease process, restoring methylation is tricky--as many members have reported here. All the more reason for as much supervision as we can find and also careful reading the published research which is available. Dr. Nathan's report quoted above

    (http://www.prohealth.com/fibromyalgia/library/showarticle.cfm?libid=16138)

    and Rich's own papers and videos

    (http://phoenixrising.me/treating-cf...e-mecfs-glutathione-and-the-methylation-cycle)

    are very important resources for those undertaking methylation protocols. There are important cautions to be aware of and it is vital to be well informed.

    All of the information Rich gave us was carefully documented and referenced which is essential when we are using information from a forum to inform our personal health decisions.

    As he can no longer respond to methylation issues it is very important to keep his voice alive be referring to his posts. Thanks for putting this together so well.

    Sushi
     
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  17. Freddd

    Freddd Senior Member

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    B12 ZONES – Version 3.1 02/08/2013

    This is the recent re-conceptualization taking recent knowledge into account.

    I. ACTIVE TRANSPORT ONLY ZONE - Oral or injected cyanocbl or hydroxcbl, about 10-20mcg possible absorption via active means per meal and ends up transported by HTCII and subject to the body’s triage methods. Weakly dose proportionate up to doses of 125mcg orally, saturating the active transport system. Limited symptom effectiveness.

    II. DIFFUSION – BODY TRANSPORT ZONE - Sublingual proven effective (5 star) methylb12 and adenosylb12 500mcg total (approx 100mcg absorbed) or 100mcg injection, estimated serum peak 10,000pg/ml to 20,000pg/ml. Threshold dose for “turning on healing”. Strongly dose proportionate 1-100mcg absorbed. Moderately dose proportionate 100-3000mcg absorbed; weakly dose proportionate 3000-10,000? mcg absorbed. Healing in body “turns on” at about 100mcg absorbed mixed active b12s and needed cofactors.

    III. DIFFUSION CSF/CNS TRANSPORT ZONE – An estimated serum cobalamin level of 100,000pg/ml to 200,000pg/ml maintained 24/7. 7.5mg QID, 10mg TID or 15mg BID of 5 star mb12 has worked for many trying it. CNS threshold effect at between 6 and 7.5mg SC injection.

    IV. INTRATHECAL INJECTION 2.5MG METHYLB12– Japanese research has tried this and found effectiveness lasted 3 months to 4 years (latest report) on subjects with diabetic neuropathies, not selected for population with known CSF cobalamin deficiency. To my knowledge it has not been tried in those populations with known low CSF/CNS cobalamin while body is normal or high. The results of those receiving the intrathecal injections were not different from similar results in the daily high dose studies with ALS and MS populations.



     
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  18. Freddd

    Freddd Senior Member

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    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. 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. So in an extreme deficiency body wide inflammation would be up with lots of joint and muscle pain, MCS. Allergies and asthma come in somewhere but it can vary. So 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. So 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 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 as the last symptom in the progression is paralysis of the diaphragm followed shortly by death. Everything short of that is a summation of successive insufficiencies.

    The old idea of “absolute” deficiency was based on low enough levels of b12 to cause PA. Then other lesser symptoms were not really deficiency but rather “functional deficiency” caused by some other lack. That whole idea fought against the effectiveness of the active AdoCbl and MeCbl as some kind of aberration of “forced” healing as opposed to “normal” healing of HyCbl versus the “fallback starvation” mode of limited healing versus normal fully effective healing. 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 < 93 MCV has been displaced as < 100 or even < 102 has become “normal” as starvation mode spreads and becomes “normal”

     
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  19. Freddd

    Freddd Senior Member

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    This is a different way of looking at the levels of startup by single nutrients.
    In phased introduction of nutrients the idea of “most limiting factor” comes strongly into play. When started in order #1, it looks like his. These appear to define 4 layers of startup that are further subdivided by having methyltrap shutdown in selective layers and not others. As Rich VK stated it “partial methylation block” because only some levels of methylation stop whole others continue.

    1. Startup 1 – MeCbl - body neurological, limited CNS to extensive CNS dependent upon dose, epithelial tissue, some anti-inflammatory, MCS, Asthma, Allergies, Hyper-response, some ATP startup

    2. Startup 2 – AdoCbl - muscle healing, widespread anti-inflammatory, ATP startup partial, myelin formation, CNS healing

    3. Startup 3 – L-Carnitine Fumarate - Muscle growth, exercise enabled, increased energy generation – ATP startup finishes, myelin formation, CNS healing

    4. Startup 4 – L-Methylfolate - epithelial tissue deeper healing, major anti-inflammatory, Muscle growth, CNS healing, MCS, Asthma, Allergies, Hyper-response, Appears to improve AdoCbl/MeCbl distribution by diffusion and increases serum halflife of MeCbl.

    Endothelial tissues figure in here too though that is more difficult to observe naked eye.

    APPROXIMATIONS OF RELATIVE EFFECTIVENESS AREAS, order of most limiting factor startup and effects, see attached spreadsheet, determined by commercial availability

    1. MeCbl – 75% have major initial startup effect for this alone as first factor

    a. SU1, 50%

    b. SU2 15%

    c. SU3 5%

    d. SU4 5%

    2. AdoCbl – 75% have major initial startup effect for this alone as first factor

    a. SU1, 15%

    b. SU2, 50%

    c. SU3, 5%

    d. SU4, 5%

    3. L-carnitine fumarate (occasionally ALCAR works) <5% have initial startup effect for this alone as first factor

    a. SU1, 10%

    b. SU2, 10%

    c. SU3, 60%

    d. SU4, 5%

    4. L-methylfolate-Metafolin <10% have startup effect for this alone as first factor

    a. SU1, 10%

    b. SU2, 10%

    c. SU3, 15%

    d. SU4, 90%

    5. Zinc, Vit D, Magnesium, p5p, Pantethine D-ribose, TMG, Vit C , SAM-e, B2, B1 <2% have major startup effect for each of these alone as first factor and delaying startup until added (increased). Generally some or all of these step up healing activity indicating that each of these has the potential to be the most limiting factor in some people. Kicking off overall startup is rare. Sam-e first isn’t a good test of need because it’s formation is dependent upon the Deadlock Quartet. As a later add-on it can break the logjam or rebalance the combinations..

     
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  20. Kina

    Kina Moderation Team Lead

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    Freddd -- I think it's fair to comment that some members have some very serious concerns regarding your protocol -- eg suggesting doses of things that may be harmful. It may be true that what applies to you and some people you have treated is not true for everybody with ME/CFS. If anything, this website shows that we are a difficult group and what works for one person may have no effect on the next or be harmful. Perhaps, it's not wise to try to apply your own personal experience to a whole population.

    As far as pointing out the flaws in Rich's protocol, he also pointed out the flaws in yours. It is tragic that Rich is not here to address your posts. It would indeed be helpful to members just wandering into this territory.

    I hope our members can research the issue completely and most of all not take anything without the input of a doctor. I would honestly hate to know that any of our members have been harmed by any suggestions regarding protocols made on this site.
     
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