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Metafolin and the Donut Hole - Latest Chapter of Pradoxical Folate Deficiency

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Freddd, Feb 10, 2012.

  1. Freddd

    Freddd Senior Member

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    It now appears that there is a new twist on both paradoxical folate deficiency and Metafolin. There are other people, like myself who go into folate deficiency symptoms on small doses of Metafolin, after a little while. This may be more pronounced with mb12 but may not be. The first place I recall seeing it was with people taking Hycbl and small amounts of folinic acid and small amounts of Metafolin. My experience and of some others and not of others, is that when we increase the amount of Metafolin to around the dose sizes of Deplin, 7.5mg to 15mg, that this donut hole of paradeoxical folate deficiency goes away.

    So perhpas the explanation goes something like this. The Metafolin gets the methylation going. It is, at each level an on or off binary situation. When it turns on a small amount of Metafolin is not enough to sustain it and a person starts getting their characteristic low folate symptoms. As this has been well demonstrated with hycbl and and the SMP, and those doing the ABP also have the same effect. A low dose of Metafolin, gradually increased causes all sorts of problems in susceptable people, paradoxical folate deficiency symptoms. It takes around 7.5mg or more of Metafolin to overcome that and have an unblocked methylation without folagte deficiency symptoms. The company doing Deplin got it right.
  2. alex3619

    alex3619 Senior Member

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    Hi Freddd, I think you might be right about this. Deplin would have been clinically tested, and the dose would have been based on clinical response thresholds. Lower doses probably were less reliable, higher doses not much more reliable. Does anyone know the research history of Deplin? I tried to find Deplin in listings on Australian pharmacies, but they kept coming up "no result".

    The only counter-argument I can think of is that Deplin would have been tested as a single pharmacological intervention, and not in combination with other things.

    Bye, Alex
  3. adreno

    adreno 3% neanderthal

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  4. richvank

    richvank Senior Member

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    Hi, Alex.

    I think this is a very important point. Methionine synthase needs both methylfolate and methyl B12. If B12 is insufficient, methylfolate will be less effective in boosting the methylation cycle function and thus the level of SAMe and the folate metabolism in general. The folate metabolism is linked to the biopterin cycle, and both tetrahydrobiopterin and SAMe are important in the synthesis and metabolism of the neurotransmitters, which impact depression.

    Personally, I think that if a balanced treatment is used, for most PWMEs the dosages of Deplin are too high. If Deplin is combined with a significant dosage of methyl B12, this combination appears to overdrive the methylation cycle in most PWMEs, and the result is that the methylation cycle speeds up higher than normal, and the flow of homocysteine into the transsulfuration pathway is too low, so that glutathione cannot come up. I think I've seen this in the test results of two people, and a third person has reported it to me as well.

    I hasten to add that I think that the reason Freddd and perhaps some others benefit from this high dosage of methylfolate, is that they are overdriving their methylation cycle to produce large amounts of sarcosine, which transfers methyl groups back to the folate metabolism. This makes up for the inhibition of the SHMT reaction due to elevation of 5-formyl tetrahydrofolate (folinic acid). I think the latter occurs because of a polymorphism in the MTHFS enzyme, which normally converts folinic acid to methyenyl tetrahydrofolate, which in turn can be converted to other folate forms.

    In Freddd's case, he also has a problem if glutathione rises too much, apparently because of a polymorphism that affects the CblC complementation group, which normally processes B12 within the cells. So overdriving the methylation cycle and keeping glutathione somewhat low is actually a benefit to him. I don't think this applies very widely in the ME/CFS community, though, based on the results of our clinical study. I realize that Freddd differs with me on this. I hope that we will be able to figure out a way to determine this using 23andme polymorphism data.

    Best regards,

    Rich
    susieq777 likes this.
  5. gu3vara

    gu3vara Senior Member

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    Make senses to me that those high doses of methylfolate and methylb12 should be try after trying the more normal doses have been given time to work, which can happen in a fair amount of people. If I don't make progress after a couple more months, I might be tempted to try 7.5 mg or more of methylfolate and more b12. Right now, I feel uncomfortable messing with natural physiology with those mega doses.

    Question for Rich, if someone takes mb12 and not hydroxyb12, how much do you consider as the upper limit of daily intake to avoid overdriving methylation? I currently take 2 mg of mb12 a day. I'm sure it varies for each person but I'd like have a ball park number.

    Thx!
  6. madietodd

    madietodd Senior Member

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    Are there a lot of people who can tell which symptom sets belong to:

    paradoxical folate deficiency (need more metafolin, less folates)
    low potassium
    missing/low co-factor (need something other than metafolin)
    insufficient or incorrect form of B12
    too much B12
    etc.

    I added CoQ10 (100mg) and L-Carnatine Fumarate (500mg) last week, and got brain fog. It took me a week to remember to check on what I'd changed, because brain fog is my normal not-methylating symptom. I was busy adjusting metafolin.

    I think once somebody is stable, they could lower their metafolin and see if they get these paradoxical... symptoms. But while I'm still figuring out my personal equation, I have no way of knowing for sure what's causing what.
  7. Rosebud Dairy

    Rosebud Dairy Senior Member

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    After a folic episode last week (perhaps combined with PFD), I was crashing, but somehow with folic, there is no quick recovery for me at this time. I'd love to see more genetics on myself.

    Low potassium - Feeling queazy and having some muscle spasm pain in the places near old injuries of the neck is an early symptom. Being nauseated nearly to the point of vomiting is a later symptom, as is extreme dizziness. Feeling like I am about to pass out is also.

    Brain fog - I think is for me, PFD, and not taking enough metafolin.

    That is what I have figured out so far.
  8. Freddd

    Freddd Senior Member

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    Hi Madie,

    Are there a lot of people who can tell which symptom sets belong to:

    All of the possibilities you mention are not created equal. One of them, and only one, is potentially quickly dangerous, low potassium.

    low potassium - muscle spasms when muscles relaxed, atypical. Itching, headaches, heart arrythmias, nausea, mallaise, paralyzed illium, muscle paralysis, paralyzed breathing, heart failure. It can end up in the ER and NOT BE RECOGNIZED.


    Let's look at the other possibilities you mention and what could happen


    paradoxical folate deficiency (need more metafolin, less folates) - Partial methylation block remains in place or returns. Healing is restricted to level of active folate available and not blocked. Unpleasant. IBS, cheilitis, peeling fingertips, inflammation, body pain, nausea, depression, joint pain, allergies, asthma, brain fog. May be no different than what has been going on for decades. Temporary neurological damge may increase and become permanent neurological damage.


    insufficient b12 - Nothing at all for the most part. Symptoms continue unchanged or very little changed. A sick person continues sick. The only hazard could be where the level of CNS b12 is very low and the person takes a sizable dose of methylfolate, CNS neurological damage might possibly occur especially if maintained over weeks without adding suitable amounts of suitable mb12. Temporary neurological damge may increase and become permanent neurological damage.

    incorrect form of B12 - Nothing at all for the most part. Symptoms continue unchanged. A sick person remains sick. The only hazard could be where the level of CNS b12 is very low and the person takes a dose of methylfolate or other folate if effective, CNS neurological damage might possibly occur and become permanent, especially if maintained over weeks without adding suitable amounts of suitable b12. Temporary neurological damge may increase and become permanent neurological damage.


    missing/low co-factor (need something other than metafolin) - assuming healing had started, some healing will continue, some will stop in mid stride, possibly frustrating and/or unpleasant but nothing significant is likely to happen


    too much MB12 - Hypothetical possibilty of "overdriven methylation". May shift some lab test results. Symptoms unknown if any. I'm not aware of any demonstrations of any actual problems or symptoms. Remains hypothetical. No known danger of any kind. No known toxic effects of any kind with multiple doses up to 35,000,000 mcg each. Can be used at these doses for cyanide clearance.

    too much ADB12 - If a lot too much ADb12 is taken over a period of time at CNS penetration levels without corresponding amounts of Mb12 there may be mood changes. Subtle. Quickly correctable with a dose of mb12. This is quite unknown except for 1 instance in trial by two people. I was one of them and had no effect at all. No know danger of any kind. No known toxic effects of any kind at with multiple doses up to 35,000,000 mcg each. Can be used at these doses for cyanide clearance.

    too much Hycbl - Might displace active forms from where needed. Mostly nothing at all happens, much healing may cease. No known danger of any kind. No known toxic effects of any kind with multiple doses up to 35,000,000 mcg each. Can be used at these doses for cyanide clearance. May casue acne like lesions. Temporary neurological damge may increase and become permanent neurological damage.


    too much Cycbl - Might displace active forms from where needed. Mostly nothing at all happens, much healing may cease. In case of Leber's hereditary optic neuropathy cyanide is deposited around optic nerve killing the optic nerve and causing permanent blindness. Temporary neurological damge may increase and become permanent neurological damage.


    The other things are all non-events. Mostly nothing at all happens. A sick person continues sick with a few symptoms changed around. Nothing else at all compares to the effects of low potassium. What the situation actually is can be clarified by what the symptoms are, or are not and the circumstances.
    susieq777 likes this.
  9. Freddd

    Freddd Senior Member

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    Hi Gu3vara,

    You need to understand that I have been at this for going on 9 years. I titrated everything, mb12 from 1mg, metafolin from 400mcg. I had years of paradoxical folate defieincy. I had years of marginal low potassium with symptoms. I had temporary neurological damage turn to permanent neurological damage over the years of inadequate or wrong treatment.
  10. Freddd

    Freddd Senior Member

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    Hi Rich,

    We need to have 10 sucessfully treated people of each category to test with 23andme. I'll see what I can come up with for a possiblitlies matrix. I do disagree with you on some interpretations but what you posted here and that CblC post on another thread night help clarify what pragmatic tests we can come up with.
  11. adreno

    adreno 3% neanderthal

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    I'm still wondering whether we're talking about a ratio or a threshold dose here. If we take, say 15mg mf, can we then take any amount of mb12, or do we still have to consider ratio? That is an interesting question, I believe.
  12. adreno

    adreno 3% neanderthal

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    I'm also wondering whether we could somehow safeguard ourselves from the hypothetical methylation overdrive, by supporting the shorter methylation pathway, using SAM-e or TMG, this way ensuring that some glutathione is created?
  13. madietodd

    madietodd Senior Member

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    Adreno, I'm addressing this hypothetical problem by sticking with my hydroxyB12 from Rich's protocol. According to Freddd's detailed analysis above, the worst that can happen is nothing.

    I discovered that for me, Hb12 + co-factors + Solgar + potassium + low folate diet = sea change. My biggest problems have come from the first few days of start-up, and from low potassium as I figured out my dose. The start-up might have been low potassium as well, as I was using tiny amounts of potassium at the beginning. Minor problems are on-going as I adjust my supplements and dosages.
  14. Dreambirdie

    Dreambirdie work in progress

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    Hi Madie--

    How much are you taking of each of these? And which cofactors are you taking?
  15. madietodd

    madietodd Senior Member

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    DB -

    I'll stick that information on my Folates Issues thread in my update on Monday. I don't want to divert this thread.
  16. Dreambirdie

    Dreambirdie work in progress

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    Okay, Madie. Please PM me that thread if I don't find it.
  17. topaz

    topaz Senior Member

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    Rich

    Do you still suggest 2000 mcg Hydroxycobalamin to 400 mcg methylfolate as the optimal ratio?

    thanks
  18. Vance

    Vance

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    I believe what Rich recommended was:
    * 2000mcg hydroxylcobalamin (although this last summer he was considering a switch to methyl)
    * 200mcg 5-MTHF ("methylfolate")
    * 200mcg folinic acid (aka 5-formyl-THF)
    * (in addition to the lecithin/PS and baseline multivitamin)

    However, I think the right ratio of B12 to 5-MTHF is heavily affected by polymorphisms in the folate cycle, particularly MTHFR. As an example, I'm homozygous for MTHFR C677T, which means my conversion from what I call the 'upper-level folates' (i.e., folinic acid) back to 5-MTHF runs at less than half what it should, causing lower 5-MTHF. So arguably, I should be taking twice the 5-MTHF, or more, just on that account.

    The results of the Vitamin Diagnostics methylation panel also feed into this. In my case, all my folate cycle intermediates were low, so even though I'm supplementing >400mcg 5-MTHF, I'm keeping the 200mcg folinic. After methylation kicks in for awhile (I'm working my way up in dosage), I may remove the folinic, since the methionine synthase reaction should be feeding the upper side of the cycle OK. After 2-3 months on the full-strength protocol, I intend to do another Vitamin Diagnostics panel and see where things ended up, and tweak as necessary.
  19. Freddd

    Freddd Senior Member

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    Hi Adreno,

    So far I can find no evidence of any symptoms to pin on "overmethylation". Everything pointed to are deficiency symptoms of the Deadlock Quartet. For some people, taking SAM-e and/or TMG actually kicks things off, breaking a logjam. This appears to happen in <5% of people. It's more common than vit D, zinc or magnesium being the kickoff item but far less than adb12 and/or l-carnitine. The symptoms that sometimes are pointed to as "overmethylation" might more often be adb12/carnitine deficiency symptoms and might be more a matter of getting some of that to get the ATP generation going. I haven't revisited this question since realizing that there is a 4 way deadlock and how each blockade might look different. I find that 200-400mg of SAM-e make a noticable difference for me. It didn't break any logjams. I have been on and off TMG several times in trials trying to pin down just what effects it has now. It made a difference when the l-carnitine had me very energized as it was healing and growing my muscles. It removed the "stimulated" effect without stopping the healing. With that intial muscle healing phase long over, I can't tell if it makes any difference at all for me right now. I am always running various trials.

    There appears to be no problem in getting glutathione going. When methylation starts, it appears that glutathione production starts shortly thereafter. The problem with glutathione is when it is in large oversupply. The effects on cobalamins, most all cobalamins, appears to be an immediate flushing from the body of all of them not nailed down in a way that prevents recycling. It could serve the purpose of clearing out the dozens of junk cobalamins that are hypothecized to accumulate in the body that are normally scavanged by the liver and excreted in the bile from which a small amount of (hypothecized active) cobalamins are reabsorbed in the small intestine. On the other hand as b12 is very active in detoxifying the body, especially the neurology, the b12 might represent a negative feedback mechanism to keep the glutathione in the ideal range by immediately removing excesses from the body to the extent of available cobalamins. Perhaps it is the only actual useage of junk and plant cobalmins that are otherwise in the way, for a good purpose.

    The problem of the "over methylation" hypothesis is that it does not appear to be demonstrable or predictable or to predict a more effective nutritional path.

    The whole problem is complicated by hydroxcbl only being partially active and does not make for predictable restart of methylation or ATP production. Every biochemical reaction requiring an enzyme and energy input, such as glutathione synthesis runs on ATP. The deadlock can remain in place with hydroxycbl and folate because of lack of adb12/carnitine. The conversion of hycbl to mbcbl and then to adcbl requires a methyl group not supplied by folinic acid, an enzyme which a person may not produce adequately and ATP requiring carnitine and adb12. In other words the inactive forms need the existing active forms in working amounts to be converted. So the process rarely gets going with the inactive forms. In some people at least, probably concentrated in this population, the inactive forms can block the active ones if coexistant.

    So, as with the famous lost in the wilderness recipe for roast wild duck, first bring me the wild duck. If methylation doesn't get started nothing else can work. If ATP is depressed (abnormal fatigue is common symptom) the methylation can't get started. Without the methylation, ATP can't get started. The Deadlock Quartet looks like the real key to it.
    helen1, dbkita and peem like this.
  20. GenDylan

    GenDylan

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    Does low dose Metafolin induced folate deficiency symptoms mean that you have a folate deficiency? Or is it simply giving you those symptoms because the dose can't keep up with the rate of heeling needed? Low dose Metafolin gave me the symptoms and I just need to know if I have a folate deficiency.. Im thinking this is a stupid,overly paranoid question - it indeed means you have a folate deficiency

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