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

dbkita

Senior Member
Messages
655
Once upon time back in the dark ages, for me in 2003, I started MeCbl all by itself. Not exactly all by itself, but, without AdoCbl, L-methylfolate or LCF. I was taking all the basics, vitamins, minerals and fats. In a backwards look I can see the layers. I had partial methylation block, methyltrap and partial ATP block at the start. I was skin and bones balloon all filled up wirh water and watery fat. I had to rest halfway up a flight of stairs. I needed help in the shower. I couldln't comb my hair or shave, arm and shoulder pain). I could barely brush and floss. When I started taking MeCbl I had incredibly intense neurological startup. I went from depressed to a realization "I could be happy now" in an hour.. The buring mouth and burning red tongue and and burning bladder stopped burning in 10 days, months longer to heal all the way. I regained a normalized sense of smell and taste. The lights literally came on that day have have stayed on since, going on 10 years now. Previously they stayed on several times for a few months during the desiccated liver trial. My burning muscles had the fire go out that first day and the burning subsided 100% in 10 days.



Mentioned at the time by me and orthers, was skin lesions. The acne type lesions started spreading and got much worse and infected. The IBS was terrible then because of food intolerances and IBS as such. The angular cheilitis got ever so much worse. So the methyltrap was broken but the partial methylation block was not. As I apparently do convert MeCbl to AdoCbl reasonably well (this is based on CURRENT understanding, at the time I thought anything not 100% effective was not good) and the partial ATP block reduced to about 75% of what it had been, enough to allow overdoing and crash and recrash. The partial methylation block remained in place. A person can have hypokalemia at the same time as partial methylation block in these reactions. They are not mutually exclusive.One layer can be healing and others breaking down at the same time.



Basically I went from constant mild folate specific symptoms to severe donut hole paradoxical folate deficiency. I took more folic acid but that didn't help at all and I had no idea at all. I focused on what I could affect. The inflammatory muscle pain continued or worsened. Joint pain worsened. MCS, asthma, allergies varied all over the place but didn't go away for several years more, after adding AdoCbl and 400mcg of methylfolate. That was when I started needing noticably more potassium. I think I was doing 200mg twice a day originally.

With just Mecbl added to basics, SACD continued to worsen, muscles contiuned to atrophy, edema and congestive heart failure continued to worsen. blood pressure WITH CoQ10 got dangerously high right away and I had to discontinue CoQ10 until AFTER the AdoCbl, LCF and Metafolin were in place (repairing the inferred cardiomyopathy of congestive heart failure). To start, or complete, tissue healing on all levels took the entire Deadlock Quartet.

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.


If it DIDN"T use fatty acid chains, then the LCF would make no CNS difference much lass a massive energy difference. Further AdoCbl processes the fatty acids into the form needed for myelin repair in the brain and elevated CSF MMA wouldn't be apparent in Parkinson's, a suspected cause of Parkinson's. For people so afflicted AdoCbl and LCF make an unbelievably huge CNS difference in CNS healing and even many functional items.


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.


Elevated CSF MMA in ALS and Parkinson’s and several others (I need to update that survey) is prominent. And the effects of AdoCbl and LCF is truly massive for Parkinson’s and” pseudo” or perhaps “pre”, Parkinson’s and affects dramatically dopamine and response in the limbic system. It’s practically a guided tour of the emotions of the limbic system. Even those not going down the Parkinson’s pathway, no MMA in the CSF, can have major response to CNS doses of AdoCbl and LCF. If a person has a specifc CNS response to MeCbl, most of those folks will have a major CNS response to AdoCbl ANDOR LCF. There are those with no significant MeCbl CNS response who will have massive CNS response to AdoCbl and LCF (down to below 1 mg total dose, HYPER response to minute oral doses of LCF). Your dismissal of this idea is a 100% missing the boat response. While it doesn’t prove anything, it is approximately 90+% predictable from symptoms. I don’t care what the diagnoses are. Those are very poor at predicting these responses generally. For those on the MeCbl & L-methylfolate pathway (SACD, MS) the response to AdoCbl & LCF is reduction of depression and relative euphoria. I call it relative euphoria because each level seems like “Ah, it feels so good that at last I feel good”. “Good” is relative. And that can happen at each step. Compared to feeling indescribably bad, feeling 0.25 better can be euphoric. A middle aged lady I know with MS tried these things, and did the worst possible thing. She danced exuberantly all evening and overdid it outrageously and crashed hard the next day. That is also predictable. I did the same thing over and over. It took me a year to get that tendency under control. Don’t increase distance walked by a mile. Just keep stepping it up at 50 feet a day. It is the most common cause of repeat crashes, feeling so good so suddenly that our common sense goes to the winds.

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.


In order to form a set of hypotheses that allows one to heal, build a conditional system and model that assumes AdoCbl and LCF with omega3 fatty acids are absolutely critical to the brain affecting personality and moods rapidly. With this in place the understanding of what is happening in the brain with these various nutrients becomes predictable. Build the pragmatic model that works, then look to see why/how it works. I did check out each and every item in the literature before I added it. The difference is I interpreted severe side effects of certain kinds in a different way. The only “mistake” I made was glutathione. Everything else was dead on target. Without the extreme responses of myself and 9 others to glutathione I doubt that I would have recognized paradoxical folate deficiency. I built these items on one at a time, each one having to fit the model and prove it by working consistently on certain groups of symptoms. I build models and systems, not theories. My opinions and theories are just those. The point is I have adopted all sorts of theories and rejected others based on what fits. The model I have built is highly engineered, NOT THEORATIZED.

Instead of having a theory and throwing mud up on the wall and analyzing in microscopic detail and statistically saying “0.5% of people have an unexplainable hyper extreme response to LCF of an intolerable level of anxiety and had to be removed from the study. At only a 0.5% rate of such response it is just another side effect and matching placebo rates of anxiety and is only found in those with pre-existing anxiety and so can be safely ignored by prescreening for anxiety, if it isn’t a placebo effect”

I would say “Those people with a specific profile of symptoms including anxiety have a range of extreme responses to LCF at an approximately 95% predictable rate with a small percentage having this response unpredictably and a small percentage not having the predicted response of a mood sequence of anxiety, fear, panic, anger, rage, homicidal rage and severe depression over a 18 to 72 hour period. It is reproducible at will. Further refinement of the screening process may improve the selectivity.

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.


Then when we get to Biotin which appears to be a “critical” cofactor because it can basically shut off ATP response by it’s relative deficiency or insufficiency. In these terms than being able to tolerate 4000mcg of biotin when some other critical cofactor is missing and that is no longer broken and biotin tolerance goes down to 1000mcg because it is NOW what then makes the difference, the most limiting factor. This is fits perfectly into the bottom up system I have been building. Then the next step is figuring out what is causing the shortage of biotin and test that. If that works, it kind of confirms the hypothesis and extends the system. Built piece by piece, from the bottom up leads to a working engineered system. It is also something I can walk into an HMO with and tie my compensation by obtaining specified results in XX% of people, based on indirect measures such as lowered pharmacy costs and less utilization all the way around on the selected persons.

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.

You are working towards a different goal with different measures. I don’t have to prove a thing. All I am doing is to produce a system that is predictive of desirable results at a given or above a certain rate. Further the screening system must be cheap and a mass screening system. The AMA etc says in essence “testing everybody for b12 is not cost effective as it only finds 1% of population and they are expensive to treat forever with all the comorbidities”. 100% of that is based on folic acid, CyCbl and HyCbl. There is zero expectation that anybody will actually heal or reduce expenses. So detecting and treating b12 deficiency is very difficult, expensive and not worthwhile as they won’t really get well anyway unless you define that as getting MCV< 102 these days and maintain serum cobalamin level at or above 300pg/ml just before the next injection or with oral CyCbl tablets. By these definitions it is a complete surprise that mecbl and AdoCbl are completely unpredictable based on CyCbl and HyCbl experience.


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.
 

Freddd

Senior Member
Messages
5,184
Location
Salt Lake City
what I dont understand is why they dont make ME/CFS like they do with another illnesses by taking a handful of the common test abnormality findings and saying something like one has to have 2-3 of those for a diagnoses eg i 94% of ME/CFS patients have this one.. this one be a great one to use for something like that.

it seems to me thou that those high up just do not want to make ME/CFS a valid illnesses hence use test abnormalities.

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.
 

taniaaust1

Senior Member
Messages
13,054
Location
Sth Australia
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.

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)
 

dannybex

Senior Member
Messages
3,561
Location
Seattle
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. :)
 

dbkita

Senior Member
Messages
655
Any misunderstandings of mine you can aid me in clearing up I appreciate.
Sure. Likewise :) My first rule in life is to always be learning.


Let’s go first at a general way to why I have the opinions on AdoCbl and LCF I do as regards the CNS.



First, when I get the symptoms/nutrients all up you will be able to see the order of repair. The peripheral nervous systems, all of them, appeared to largely heal during the time of MeCbl with basics, folic acid and veggie folate. I hadn’t started eating meat again at that point. Then in a series of trials I and many others have done. There is a clear distinction between CNS effect of MeCbl at 7.5mg or more absorbed via sublingual or subcutaneous injection (spread across hours of absorption). There is a similar but different response with the CNS with 7.5mg or more absorbed in the same way as MeCbl and most people who have one response have both. Noticeable body response to doses has to be gone in both cases as they are overwhelmingly strong compared to the CNS only response. They both exhibit marked CNS only effects that lesser doses do not. I do not know why LCF has about a 10:1 response rate as compared to ALCAR in all this. Then people with all the usual symptoms PLUS anxiety demonstrate hyper sensitive response in the limbic system specifically. There is no way that 500mcg of oral l-carnitine fumarate could have such a dramatic effect in only the limbic system if it were not getting there. I also know the feel of directly energized neurons though it doesn’t throw me into extreme limbic response. It is unmistakable. Anything that says l-carnitine fumarate can’t have a prompt and direct effect that ALCAR does not have is WRONG. How many times does it have to be demonstrated? Of course there is the opposite too, those with dramatic CNS effect of ALCAR but not of LCF.

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).




Check out physiological neural psychology to see why I say limbic system, also that is where the damage is, or maybe inflammation and damage. I have raised that possibility of inflammation on the main description thread. 500mcg of LCF or freebase carnitine of any kind has no body response I am aware of or anybody is that I know of but it sure sets off the limbic system in people with the so-called “Parkinson’s personality” with dramatic and rapid results. I have no idea how it gets there or why so little has such a disproportionate effect. My body had a huge body response to LCF and having ALCAR and/or any other forms mixed in or instead of stopped the effectiveness 100%. I had a very mild CNS response to AdoCbl and who knows about CNS noticeable effect from LCF since it did not have the double threshold that the cobalamins have. However, SACD started recovering only AFTER I got the AdoCbl into my body at the CNS penetrating levels. This major CNS healing effect is noticeable in 1 hour or less when all factors are present. I had mood and personality changes at normal sublingual doses of MeCbl/AdoCbl but no healing of cord demyelinizations. Those required all four of the Deadlock Quartet in sufficient doses. And those are more of an equilibrium situation, breaking down and healing all the time in a slightly different pattern. If something occurs to shift towards a different equilibrium point in a month I lose some numbness (a painful path however) or it shifts towards more numbness (more comfortable) but makes me feel like I am wearing ski boots all the time.

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.


I think there is misunderstanding here. It is a very big difference in approach. You talked about to “prove” this or that. I can’t prove a thing. I can predict and demonstrate. That is a different thing. I was trying to make a distinction of my objectives. Rich was out to “prove” his theory. It requires a different approach. An engineering approach often doesn’t prove anything. I debugged this like I debug a computer program. I learn how to make it fail reliably and repeatedly at the same time I learn how to make it succeed reliably and repeatedly. In this I am a Roman engineer learning how to make domes and arches that don’t fall down, not figuring out how to build the twin towers via a different theory which introduced a whole new possible failure mode for skyscrapers. The Empire State Building didn’t collapse straight down when a bomber ran into it and burned. It didn’t collapse in any way. Granite is tough stuff.

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.


I used this as a spectacularly bad example of how different approaches have different results. The standard model research resulted in this travesty and the beliefs based upon the body of knowledge that is distorted by assumptions and preconceptions. My life was severely damaged, damn near destroyed and costing me almost everything, by the AMA’s approach. Everything about the above paragraph leads to the worst possible treatment being used for as few people as possible. It puts in place roadblocks to care that are insurmountable for most people. I come from a lifetime of experience in a mostly a managed care environment. We were all about removing the roadblocks to care.

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.




I misunderstood. I’m sure we both misunderstand much. That’s why we are having a fruitful dialog. Thankyou.

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.


No apologies necessary for the way you are built or anything else. I end up doing the same quite often. I am 100% for understanding and find it stimulating to hash it out. Dialog is extremely valuable. I would not be here with what I have without Rich, and you by the way, and many before both of you, now as my understandings are progressing by the day. It is good to know. I looked up bioinformatics. I started HMO consulting the year the term was invented. I helped develop the basic ideas behind object oriented design and programming and medical record “data mining”. I was invited my Yourdon to do some writing for him. I crashed a month later and was quite unable to do anything for a year. I had to drop out of college 5 times for health reasons, the same ones I have been describing but at an earlier stage of deterioration. I started college at WPI (Yep, Whoopi Tech) as an engineering freshman. I had already selected physics as my major when I got mono. That was that for WPI.

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 a major misunderstanding. There was nothing trial and error in what I did. Everything I did was based on journals and data mining the internet and the results of the trial and error practitioners, professional and otherwise. I did an N=1000 questionnaire development study. When I could no longer work I set out to solve my own problems and get well, and followed the clues, and I already had the first clue. I had a theory about liver extract concentrate and set out to duplicate it. I systematically tested brands until I found the effective forms and/or brands. There was nothing at all trial and error. It was targeted, hypothesized, experiment performed, understood and modified. It was very systematic titrations of through entire ranges.

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

The normal model research has taken the beliefs about “b12” and “folate” so far from being predictive in any way as to what to expect from the Deadlock Quartet that I literally don’t know how to describe such a cognitive defect when applied to so many intelligent people. I see how it happened. I have lost faith in a sense in the whole model of research. In the 60s the term “group think” was invented. That doesn’t quite get at it. How in 80 years of research looking for and then working with substances, could they come to rely upon the worst possible form that has any effect at all, known as a mistake since 1959, known from the early 50s not to replicate concentrated liver extract except in the most minimal way. Folic acid I can see. Folic acid was the best they could do in 1942. Now we have Metafolin. That is progress. People are learning to use it. CyCbl? HyCbl? How can people be so blind for so long and go so far astray from what works. The incorrect assumptions from these three items corrupts understanding downstream. How could they not? They have made hundreds or probably thousands of deficiency symptoms and signs into incurable mystery diseases. I would think that would be of concern. I was dying. I couldn’t wait any longer. I had been waiting since 1979 thinking a mistaken Nobel Prize being the scandal of a century for causing millions of chronically ill people would surely get noticed and remedied. No such luck. Instead in the most bizarre twist chronic deficiency diseases have become enshrined as the standard. The FDA prohibits vitamin claims that they prevent deficiency diseases, obviously for good reasons.

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 :)


I think that it leads to a complete reconceptualization. And with lots of help, fill in some of the other less common branches, like the biotin.

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).


Nothing at all wrong with theory. I engage in such at a different level. I work from theory but design from the bottom up or occasionally from the middle out. I determine what I the whole thing is about and then work from the database design up in general. My understanding is at a pragmatic level and pattern recognition. Please do dig in as deeply as you can. All this desperately needs to be understood. Right now the questions that I desperately need answered are:

1. What makes a 5 star MeCbl such?

2. What are the tests?

If either of the two theories I’ve heard are correct an NMR and mass spec should be able to do the job. I have no access or expertise in instrumental chemistry and don’t know anybody currently who does. I have frozen samples.

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

I agree theory is needed, and refinement and corrections over and over. Civilization wouldn’t have gotten very far without it. Fully agreed. The theory has gone very badly astray, like Galopping Gertie.

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.


I just got “it”. I don’t speak biochemistry and I am using various analogies indicating a screwed up structure, or logic or assumptions and so on. I look at it as part of the gestalt that makes up our whole you might say holographic interpretative mechanism. I was saying wrong results can occur due to how something is thought as much what is thought. I’m sort of looking at it as a virtual Monte Carlo simulation in my head and then picking the path(s) that work(s). Maybe I’m practicing too much philosophy without a license in the wrong place. Yours and mine are quite different. As we continue we will both learn to translate better and better understanding

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?


I knew nothing about that. I haven’t filled in that piece of the puzzle yet. The CSF MMA, CSF Hcy and low CSF cobalamin are common factors across a range of diseases that all will likely react in differentiating, but predictable when recognized, ways dependent upon the specific damage each has for all sorts of secondary and tertiary deficiencies and other reasons. It sure could tie back to AdoCbl. High MMA in Parkinson’s and ALS, high Hcy in MS and ALS. So where does CSF MMA come from if not neuronal mitochondria utilizing AdoCbl and LCF, however it got there?

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]


Thankyou. I apologize for any misunderstanding.

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.
 

Xara

Senior Member
Messages
135
Location
The Netherlands
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?
 

triffid113

Day of the Square Peg
Messages
831
Location
Michigan
Vitamin C helps Bh4 by aiding recycling from BH4 to BH4. Mfolate aids BH4 but I have not yet heard a real reason how it does it. The fact that vitamin C destabilizes mfolate is independent of the fact that both help BH4 levels.

Note I think buffered mineral ascorbates have a much less deleterious effect on Metafolin absorption. I think ascorbic acid is MUCH worse. I can attest to this by personal experience. Makes sense theoretically as well.

Your COMT +/+ while a challenge in its own rights is actually very protective against a low BH4 (less needed to make catecholamines since more are lying around longer). However, the COMT +/+ will do nothing for serotonin production which is just as important as dopamine.

As you probably know, BH4 mitigation is also based on removing factors that lower it such as aluminum, ammonia. etc. BH4 is used with adb12 in reducing peroxynitrite. BH4 is key for making NO and for functioning of the urea cycle. That is a lot of demands on one poor little molecule.

But one of the biggest drains is of course inflammation. The production pathyway for biopterin is shunted to neopterin when there is high inflammation. Some of Yasko's latest presentations suggest this is maybe the MAJOR pathway disruption of BH4 at an epigenetic level.

Your homocysteine look great. But it is not the only relevant diagnostic. More important is how you feel. Do you have enough neurotransmitters? What are your energy and pain levels like? How do you sleep, etc.? Lab tests are sometimes of limited utility.

Btw which test are you referring to for BH4? Which company? Do you mean a neopterin / biopterin test or something else? Just curious.
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
 
Messages
10,157
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.
 

Lotus97

Senior Member
Messages
2,041
Location
United States
[Rich] started suggesting folinic years before l-methylfolate was available, as the only superior to folic acid form available. That's why I tried it and plunged into folate insufficiency worse than ever. It took 3 days to build up and it got so bad in a week I went back to folic acid.
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.
 

dannybex

Senior Member
Messages
3,561
Location
Seattle
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...?
 

Lotus97

Senior Member
Messages
2,041
Location
United States
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...?
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.
 

Xara

Senior Member
Messages
135
Location
The Netherlands
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?
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.
 

Sushi

Moderation Resource Albuquerque
Messages
19,935
Location
Albuquerque
Hi Lotus,

He started suggesting folinic years before l-methylfolate was available, as the only superior to folic acid form available. That's why I tried it and plunged into folate insufficiency worse than ever. It took 3 days to build up and it got so bad in a week I went back to folic acid.

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
 

Freddd

Senior Member
Messages
5,184
Location
Salt Lake City
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.

Are you referring to something Rich suggested before 2007?

Sushi

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?
 

Freddd

Senior Member
Messages
5,184
Location
Salt Lake City
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.

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.
 

Lotus97

Senior Member
Messages
2,041
Location
United States
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).
Folinic acid is a 5-formyl derivative of THF. The folates in vegetables are not folinic or folic acid (a fully oxidized synthetic folate, i.e. pteroylmonoglutamic acid). This is a notorious misconception in the research community. The folates in food are metabolites of THF packed within polyglutamates. In the intestinal lumen these polyglutmate dietary forms are broken down into monoglutamate variants which can then be converted to DHF and then THF by their respective enzymes. The DHFR enzyme is not present in humans for the synthetic folic acid it is present for processing dietary folates. Folinic acid is readily converted to 5,10 methylene THF without use of DHFR. That being said dietary folates parallel more with folic acid than with folinic acid with one crucial difference ... they can be processed in the intestinal lumen and the liver. Folic acid (I am pretty sure) being fully oxidized must be converted in the liver.

I don't think this changes the fact that high dietary folates could be an issue for some people who can not make use of them, have intestinal wall damage, or critical needs for 5mthf but let's be honest while maybe garden feasts are not a good idea, it is not wise probably to eschew vegetables entirely as a general rule.
 

Freddd

Senior Member
Messages
5,184
Location
Salt Lake City
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.

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.