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Study: Folinic acid beneficial to 81% of CFS patients...plus biomarker?

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by dannybex, Feb 8, 2013.

  1. dbkita

    dbkita Senior Member

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    Ok that makes sense. I understand more now. You are saying with only the methyb12 and other basics you ended up with some definite improvements in some ways but drove yourself into folate insufficiency that was made worse by folic acid and plant folates and only improved when you brought in sufficient levels of the deadlock quartet. Got it.



    I think you are mixing two things up here to reach your conclusion. You are assuming that fatty acids are used directly in brain energy metabolism because you and others feel better and think better on LCF. The two are not necessarily linked.

    Your brain / CNS and body are interconnected. If your body has more energy and vitality, your autonomic nervous system will be happier. And vice versa. There is often a false division when looking at clinical symptoms sometimes. The BBB prevents most fatty acids from getting across. The lipid regulation in the brain is very tight. Has to be. There are transport channels for choline and acetyl COA but not to be used for energy metabolism. More for myelin, membranes and acetylcholine formation, etc.. So yes fatty acids can help the CNS but is it NOT for energy. That is glucose and to a lesser extent ketones.

    I agree adb12 is important. But adb12 has importance to the health of the mitochondria and peroxynitite removal. I don't dispute the elevated MMAs in Parkinson's, et al. But that does not say anything about the primary metabolic aspects of neurons. Not even close. Also why do you never bring up the high levels of microglial activation and inflammation now know to be signatures of most of the CNS diseases you listed. You focus exclusively it seems on the MMA levels. Why not the inflammation? Can't that tie back into adb12 / BH4 and peroxynitite removal and the low MMAs are a correlative finding?

    As far as carnitine goes with the brain you cannot even ABSORB carnitine in the CNS unless either (a) it is acetyl-carnitne or (b) you have a very leaky BBB. However, if someone has a very leaky BBB, I have no idea how they will react to l-carnitine (note the fumarate will be long gone by the time anything gets past the leaky BBB). Will it be used as a primary pathway for energy metabolism? Dunno.


    Again inflammation and microglial activation is elevated also. And I am sorry again to have to re-iterate this but ... without a leaky BBB (which admittedly may be a big component of all of this) you cannot absorb LCF in the brain. It does not cross a healthy BBB. It just doesn't. Now why the LCF has such a dramatic effect on the limbic system as you have observed, I do not know. If it is not an indirect effect through the periphery (which is not impossible given how there is a big chunk of the ANS living in your abdomen) or it is not due to a leaky BBB ... then I don't know why.

    Btw I am not sure why you think I am dismissing anything. I am simply trying to understand things. Clinical trial and error is not enough for me being a physicist and bioinformatics professional. Sorry that is just the way I am built.

    Nor did I intend my simple response about the Krebs cycle and brain metabolism to in any way be considered adversarial. In fact my intent was to SUPPORT your idea that mitochondria in the brain are relevant. Let me repeat that: I was supporting you.

    I have no idea why Rich Vank would ever think mitochondria in the brain are not important for neuronal health. Of course they are. Is adb12 important? Sure. But your conjecture that adb12 is important BECAUSE of the MMA pathways alone is by no means a given. It simply is not going to be the primary adjunct to the Krebs cycle. It could be a block if too low but it will never be the main fuel ... that is all I was trying to say by those comments. Just like burning fatty acids is not the main fuel in the brain. If your only conclusion based on your clinical experiences and people's reaction to carnitine is that burning fatty acids in the brain will bolster the Krebs cycle or the MMA pathway being stimulated will power the TCA on its own ... well then let's just choose to disagree.


    What is so wrong with theory? Theory and experiment go hand in hand. Again I don't doubt your observations. I also NEVER in this or any other posts challenged your deadlock quartet idea. I find it quite attractive. I am just trying to understand why things happen. Is that so bad? Engineering is great but civilization would not have gotten very far if there wasn't theory as well to work with it.

    Anyways I already stated my points about adb12 and LCF with respect to the brain. L-carnitine is not absorbable through BBB unless the BBB is damaged ... which may very well be the case for many with CFS and is KNOWN to be the case with MS, ALS and is now being suspected with Parkinson's. The Omega 3s are important for sure. Ironically the DHA is a major component in BBB integrity. So ... maybe a leaky BBB is highly relevant to this discussion. Maybe people with a leaky BBB hyper-react to LCF at the limbic system level. Which if so means I am probably in for a rough ride since my Stiff Person Syndrome only occurs because of a leaky BBB, but that is a separate issue.


    No argument. I already posted how biotin affects the Krebs cycle since there seemed to be some confusion on the forums about it. Biotin plays a critical role in the brain. How else do you think the pyruvate from glycolysis gets into the Krebs cycle in the brain? I also agree that biotin can really speed things up and so there is an important balance with other factors. No doubt. Definitely is a good avenue for further research. As would any of the critical cofactors for entry into the Krebs cycle. Biotin though may be of more importance due to its pivotal role in the brain. Btw biotin is also now believed to be a critical cofactor for glutamine synthetase. That could be huge for the brain function as well.


    I am not sure why this even came up here. I have no clue why MCV is showing up here. I have no disagreement about your views of cycbl or hb12. Nor does what I am saying about the Krebs cycle and brain metabolism have anything whatsoever to do with cycbl or hb12 or their malignant use by the medical community. I am simply talking biochemistry. Ironically a new outsider reading your post would presume that I must disagree with everything that you propose. Huh? Far from that. So why all of this?

    No one said you have to prove anything. Thought this was an open forum with dialog. Understanding is important to many of us. Again my comments were to SUPPORT your side of the argument you had with Rich Vank in that brain mitochondria are directly relevant to neuronal health.

    Peace.
    Lotus97 likes this.
  2. Freddd

    Freddd Senior Member

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    Hi Taniaaust,

    The problem is that "treating to test results" doesn't work. Reducing Hcy doesn't stop the damage from continuing. It doesn't change mortality. It doesn't do much of anything except sometimes raise MCV. Lowering LDL doesn't help as the drug makers are finding out. When a person has partial methykation block and methyltrap and partial ATP block fixing one doesn't work. All of the tests that stem from the 600 or so biological bellyflops that happen with the Deadlock Quartet, based on a population in which NORMAL has 50% of the people having chronic b12/folate/carnitine deficiencies merely serves to keep people in the abnormal. Over and over treating to test results in a positive feedback of deficiencies just doesn't work. Also, to correct any few of them will cause others to go out of whack even further. That is why it takes years to heal as it happens in stages and wanting for other dependencies to resolve. Fixing one specifc measure out of 600 or 10 out of 600 is some kind of bad joke.

    Defining "partial methylation block" helps/ However, that is a tiny fraction of the whole and can't resolve if methyltrap and partial ATP block are not also repaired.
  3. taniaaust1

    taniaaust1 Senior Member

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    Hi Fredd. My reply was on the diagnostic criteria for ME/CFS rather then treating it and if abnormalities can help to distinguish who has ME/CFS and who hasnt or helping to subgroupt more, they should be being used but that being said I'd like to say I do treat on my test results.

    In my case after trying to treat myself for 12 years in a hit or miss way and basically finding NOTHING at all helped much (except calicum, vit C, undenatured whey which came with a lot of other stuff added and hydroxy B12 injections.. the most those things helped was just one symptom).. I must of trialed at least 30-40+ things in that time!!! So the odds of me finding something that worked throu just random trialing in that way was only about 1:15+ (so I dont think that is the right way to go with treatment as its just a massive waste of money and is hugely discouraging).

    I then went to trialing only things based on my test abnormalities and since Ive done that..nearly every thing Ive tried has helped some (except lithium thou my test showed a lithium deficiency.. maybe Im not supplementing enough? so need retesting to see if Ive brought my levels into normal range). Due to my test results.. I trialed molybdenum (which made a major difference to my brain), I tried selenium (which helped), folinic acid and methyl B12 (combo which helped a lot). Without my abnormal results.. I would of never tried those.. my abnormalities are helping to tailor what i need (eg my MTHFR polymorphism indicated that folate acid was no good to me which was true as I didnt get any response to it in the past thou on high doses).

    Its great to be getting things right now with what Im trialing helping 2/3 of the time seeing Im making my judgements now based on my test results (up from 1/15+).

    Ive been lucky so far **fingers crossed** as so far treating things like this hasnt as far as Im aware made me any worst and just has helped my symptoms (without having taken those supplements, my brain would stil be completely unfunctional..eg I was forgetting every day objects eg how to use a door and what it was.. once I tried to get out of a room throu the roof as I forgot there was doors in walls. I lost ability to know one is supposed to walk on foot paths and not roads etc.. hydroxy B12 got my brain functional some again).

    There are thou some things which are being extremely hard to treat and as yet I havent managed to get within normal range eg one of my Ds and my cholestrol doesnt respond to anything at all and just continues to climb.. same with my insulin (3 times higher then normal range)... but they were heading up before I did the supplements etc. My ESR thou has come down and my iron issue seems to be improving spontanously (I cant take iron), my D decided to spontanously improve last year and almost hit normal range before dropping again. My abnormal EEGs are now normal..and my positive Rombergs test.. now is negative. My MCS is far less then it used to be. So I think Im on the right tract with some definate major improvements showing on my test results. (still got a way long way to go thou esp since Ive crashed more recently due to moving house)
    Skyline likes this.
  4. dannybex

    dannybex Senior Member

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    If at all possible, it would be really helpful if these replies could be shorter. Some of us just don't have the brain (or currently eye) power to read through long paragraphs. THANKS. :)
  5. Freddd

    Freddd Senior Member

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  6. dbkita

    dbkita Senior Member

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    Sure. Likewise :) My first rule in life is to always be learning.


    Ok understood I don't dispute the observed effects. So now there is a big mystery for me.

    ALCAR is much more blood brain penetratable. Carnitine is very controlled in transport across the BBB. Note to be clear I never said that carnitine is not in the brain nor does it not have any function there but that it could not be the primary source of fuel for the Krebs cycle. Beta oxidation in neurons is normally very low. Hence the emphasis on glucose or ketones.

    Here for example is a paper (one of several) that discusses absorption, transport and beta oxidation in the brain involving carnitine.

    http://cellial.com/joomla1.5/images/documents/carnitine transport and physiological 2004.pdf

    Now maybe there is something special about LCF transport and the brain. Have not been able to track that down. Even then beta oxidation is meant to be only a small percentage of the energy process normally. Maybe even very small amounts of LCF have significant impact on the limbic system. That part of the brain is very complex. Again all I am saying is normal carnitine abundance and transport is carefully controlled in a normal healthy person. Another option is maybe LCF supplies an alternate pathway sometimes with tough startup consequences. Dunno.

    Perhaps people who are hypersensitive have a blood brain barrier integrity problem. Blood brain barrier integrity is an often overlooked defect that has major implication to multiple neurological diseases. The irony is I have a very leaky BBB as either or precursor or a result of my rare autoimmune disease. I have had LCF before several years ago when I was at my worst. It did raise anxiety and insomnia but did not flip me out. I will know soon enough for the present when I have an available testing window (too many things going on at work at the moment to throw myself into the fire atm).




    Where there is smoke there is fire. If there is damage in the CNS there is inflammation almost guaranteed.

    I don't dispute that the MMA-succinyl COA pathway is important for mitochondrial health. But from everything I have researched it is not a primary source of fuel for the Krebs cycle. On the other hand Adb12 clearly has some profound impact on the entire body if one is deficient. I still think the Gorilla in the Room hypothesis could have enormous impact on the CNS just considering that effect alone.

    Not sure if this relevant to LCF but I had stumbled onto this a little while ago since my maternal grandmother died from MS and one of my paternal aunts has MS. As an aside I also have two family members who died of ALS and myself with the Stiff Person Syndrome. So studying of neurological diseases, the functions of microglia, astrocytes, neurotransmitters, etc. has been a common topic of research for me for some time now sadly.

    http://www.google.com/url?sa=t&rct=...vPYip9XQdsExDw_d8kTRizw&bvm=bv.42965579,d.cGE

    It is a pdf from Biogen Idec about the history of fumarate as a therapeutic and about dimethylfumarate, monomethylfumarate and their protective effect on neurons and then more recent investigational drugs.


    Ok fair enough.

    I said "Just because there are indications of low B12 in certain neurodegenerative diseases does not in any way prove that neuronal mitochondria make heavy use of the methymalonic pathway as a primary energy source."

    I should not have used the word "prove". I apologize. Honestly we can't really prove anything at the moment. There are too many variables and too much complexity. But proof is not required. I should have said
    " ... neurodegenerative diseases does NOT have to mean that neuronal mitochondria make heavy use of the methymalonic pathway as a primary energy source". There are other alternate explanations is all I am suggesting.

    Understand I am not out to prove any theory. I have no theory. I am by no means Rich Vank. He was a great guy who helped a lot of people. My goal is perhaps self-centered. Like many on here I want to understand what is going on so I can make the best choices in terms of improving my health. If along the way my questions and knowledge help someone else also then that is great.

    Unlike many on here I have an extremely rare automimmune disease so I have to be very careful about what changes I make. I am already a living testimonial which is outside the realm of my disease. By all accounts I should be stuck in a wheelchair by now with an intrathecal baclofen pump. On the other hand, eventually my disease will cripple and kill me that is inevitable. But in the mean time I want to have as much quality of life as I can for my wife and children and myself. If that is self centered, then so be it.


    Fair enough. Just please realize it was not my intention to attack anything you said. I was simply stating what I know about brain energy metabolic processes. You don't need to convince me about the idiocy rampant in the medical community. I could tell you horror stories (as I suppose many on here could) about a decade worth of misdiagnosis and fighting with doctors to get to someone who could save my life. Not fun.




    Misunderstanding is the beginning towards understanding as far as I am concerned. Humanity still knows very little about the natural world including how are bodies work. Even less about the human brain I might add.



    Thank you for all the information, hypotheses and experiences you have shared. You have access to some wonderful information that quite frankly does not exist elsewhere.


    My emphasis is more on the biophysical modeling of proteins. But I was also at the ground floor for a numbes of years developing algorithms for identifying novel genes during the genome gold rush of the mid 90s.

    It is a small world. I almost went to WPI for undergraduate but ended up going to the Univ of Wisconsin-Madison. In hindsight my decline probably started at the end of college, was still not so bad I could not get my PhD in astrophysics but after a decade in biotech startups that was it. Everything was spent and everything collapsed in blinding pain.



    That is great to know. I honestly commend your diligence.

    Such idiocy is rampant in all scientific fields to one extent or another. The crime in medicine is how it directly harms people's lives. None of us respect health until we lose it. Those of us who have almost completely lost health, value it far beyond any need for pretentions or horse blinders or enormous egos as are otherwise encountered in all walks of life much to my eternal sadness. It is the sad state of our race quite frankly. Never attribute to malice what is otherwise explained by incompetence :)


    Personally what I find attractive is you are talking about a merger between two of the most important biochemical processes in the body namely ATP production (aerobic respiration) and methylation (which affects gene expression among many other things). But I would add that there may be important effects involving the immune system / inflammation and others like blood brain barrier integrity for the CNS. While not as compact as the Deadlock quartet, they may explain some people's differing responses to increasing the flux through these two cycles (three if you add in the folate cycle).


    To clarify, when you say "what are the tests", what for? For assessing a methyl b12 supplement?

    See my distinction is this. For example, when I read up on numerous research articles about the limits on beta oxidation in neurons in a normal brain, that is no longer theory to me (of course maybe I misinterpreted something, Lord knows that has happened numerous times). Instead that is research information that any theory I might suggest I feel should embrace and encompass. Just like in physics when I was studying black holes and neutron stars. Any hypotheseses had to obey constraints placed on me by other research data.


    Hehe understood. Trust me I have never stopped being a physicist regardless of my occupation. We are what we are, nothing more, nothing less.

    Not even close. Also why do you never bring up the high levels of microglial activation and inflammation now know to be signatures of most of the CNS diseases you listed. You focus exclusively it seems on the MMA levels. Why not the inflammation? Can't that tie back into adb12 / BH4 and peroxynitite removal and the low MMAs are a correlative finding?


    First I am not certain that neurons and glial cells process mitochondrial fuels the same way. I have to check on that. People often focus on the neurons for obvious reasons, but glial cells and microglia are extremely important and being strongly implicated in several neurological disorders.

    Second, I am positive that mitochondria in the brain does use the MMA pathway. I never said that they didn't. Just like someone with high glutamate excitotoxicity probably amplifies the AKG input path. But again like I stated before, in a normal brain the primary fuel is glucose via pyruvate with (I am pretty sure) entry into the Krebs cycle via biotin and not via the beta oxidation path involving carnitine and acetyl COA. If someone can correct me on that aspect, I would be much obliged.

    If I remember right, the brain consumes roughly 120 grams of glucose or more a day on average for a healthy person. My neuroendocrinologist used to say the brain needs three primary elements: (a) oxygen, (b) glucose, and (c) blood brain barrier integrity; in that order. A simplistic viewpoint but there is merit to it. When any one of those three get disrupted there is *bleep* to pay. I think long term deficiencies in the deadlock quartet and / or other factors like severe inflammation can and do disrupt those three factors causing ultimately terrible havoc for the person who is suffering.
    [/quote]


    No problem. I apologize for any misunderstanding as well. I probably should have been clearer in what I was writing, something that is hard to do when I am in a rush.

    Take care.
  7. Xara

    Xara Senior Member

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    I had no reaction, to my knowledge, to LCF. I had reactions to mB12, methylfolate and aB12. So does that, this non-reaction of mine to LCF, mean my BBB is intact?

    (I am taking 1 capsule, 855 mg, of LCF a day.)

    BTW. I am having tight, painful muscles, 24/7. The bottle of LCF says I can take up to 4 capsules a day. Do you think increasing my dose of LCF could make a difference or should I look elsewhere?
  8. triffid113

    triffid113 Day of the Square Peg

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    Thanks. I did not know about some of the metals/contaminants affecting BH4, but I do take high antioxidants and keep my blood sugar low to conserve BH4. I am out of energy on my laptop. Thanks
  9. Kina

    Kina Moderation Team Lead

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    Hello all.

    We have received a complaint that this thread has gone dramatically off-topic. Could you please stick to discussing to the topic at hand -- the study that showed folinic acid helped 81% of ME/CFS patients in the study.

    If members wish to discuss their own particular theory of related topics, the best thing to do is to start a new thread and leave the original thread for discussion of the specific topic that was introduced in the first post.

    Thank you.
  10. Lotus97

    Lotus97 Senior Member

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    I'm unaware of a time when Rich ever used only folinic acid and I'm surprised you would suggest this since Rich told you specifically back in 2009 that he used both folinic acid and methylfolate. Rich's post suggests that he was using that combo since 2007 when he started his simplified protocol
    http://forums.phoenixrising.me/index.php?threads/methylation.228/page-2#post-6455

    Hi, freddd.

    I'm the guy who (about two and a half years ago) extracted (with the help of a person who has CFS) part of step 2 of Amy Yasko's treatment program (primarily used in autism), called it the "Simplified Treatment Approach," and suggested that it be tried as a treatment for CFS. This protocol includes five supplements. The main B12 supplement is sublingual hydroxocobalamin. It also includes both 5-methyl tetrahydrofolate and folinic acid.
  11. dannybex

    dannybex Senior Member

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    Re-reading this study, I'm surprised to find they used 25 MILLIGRAMS of folinic acid. Yet it still had a beneficial effect on over 80% of the patients studied. I wonder if they reduced the amount later on...?
  12. dbkita

    dbkita Senior Member

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    25 mg seems excessive. Yikes!
  13. Lotus97

    Lotus97 Senior Member

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    If I converted even a fraction of that to methylfolate I'd be in serious trouble, but that is interesting that so many people were able to tolerate it. Another thing I was wondering is that I thought you were supposed to take B12 with folate or folate could cause problems. Is this not true or is it true only in certain instances?

    I know most people are able to take just a little bit of B12 orally and that's sufficient, but I thought it was different in this community. This is something I've been wondering about for awhile since I noticed that Thorne's B complexes and multis both have a lot of folate and only a little B12. Other brands with active Bs have a better ratio. Again, I realize that this doesn't affect healthy people, but I thought all of us needed B12 sublinguals.
  14. Xara

    Xara Senior Member

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    It is true when being B12 deficient. But e.g. taking extra folate without supplementing B12 when having no B12 deficiency but a folate deficiency, seems a sensible idea to me.
  15. Sushi

    Sushi Moderator and Senior Member Albuquerque

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    Rich formulated the Simplified Protocol in 2007--his recommendation then and it all years following was for FoloPro--5-methyl tetrahydrofolate or another brand of 5mthf PLUS some folinic acid.

    Are you referring to something Rich suggested before 2007?

    Sushi
  16. Freddd

    Freddd Senior Member

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    Hi Sushi,

    At one point I recall, and I could be wrong becasue I did not go back and look it up, there was a change form folinic only to a combination. Now as I have read everything he wrote, in no particular order, and I ran into his writings first on Dr MyHill's web site and chsed them down by name, read other things dating to before 2004 and wached all the videos, I have no idea what year any given thing happened. I recently found a convention presentation from 2004. I have NO IDEA when he first started calling it a "Simplified" protocol. That was already in place when I showed up here. So I have my "before" idea from a random access order of reading all over the place.. Also, wasn't Folapro a mix of folates at one time, or am I thinking of another suggested brand?
  17. Sushi

    Sushi Moderator and Senior Member Albuquerque

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    FoloPro--at least from 2007--was only 5 methyl tetrahydrofolate.

    Sushi
  18. Freddd

    Freddd Senior Member

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    Hi Xara,

    A person who takesnan increased folate amount that is effective can casue a very rapid depletion of MeCbl in the body and go into b12 deficiency represented by the methyltrap which looks like a folate deficiency and frequently called "detox". Calling it "detox" makes the b12 deficiency methylrtrap portion invisible. That is why there are folate warnings. Methyltrap whether recognizied or not can cause SACD and all sorts of horrid allergic and other affects, MCS, asthma, severe flulike body pain, joint pain and so on.
  19. Lotus97

    Lotus97 Senior Member

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    dbkita believes that the folinic acid in plant folate was different than supplemental folinic acid (I assume he menas more than just vegetables such as beans, grains, fruit, nuts, and seeds).
  20. Freddd

    Freddd Senior Member

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    Hi Lotus,

    Well, I don't know what he called it and it may well of been years earlier. What year did Rich go to Salt Lake for an FMS/CFS conferrence? Was it the 2005 OFFER patient conference?

    I looked at this clip, and there may be more if one checks around. It's not on this topic, but rather sex and relationships. I beleive they took video of all speakers and discussion. It looks like the one I went to here, but any of a dozen others too. Anyway, at some time he was suggesting folic acid or even the hot new item on the block, folinic acid. It was some number of years before Metafolin became avaialble, at least as a vitamin. I don't know or care if he CALLED it the Simplified Methylation Protocol or not. His ideas on methylation have been brewing since, what, 2003? Earlier? There arfe recordongs going back to 2004 or earlier. He couldn't possibly have been suggesting L-methylfolate, the only ones even available by prescription being Metanx and then Deplin. But he sure did talk about vitamins.

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