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How to Titrate to Get Out of Donut Hole Insufficiency

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Freddd, Apr 2, 2013.

  1. Victronix

    Victronix Senior Member

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    I take Synthyroid also for Hashimoto's and have had an extreme reaction to methylfolate, wondered if thyroid could play a role, making it more difficult. It would be interesting to create a profile of those who have a huge response to tiny dosages. I had a Spectrocell test in 2010 that showed no folate deficiency despite catching other deficiencies that were supported by the genetics testing, such as Vitamin A (I have a hard time converting it).

    When I took 400 mcg methylfolate I was wiped out for days, in bed for most of one whole day. For me, the side effects take days to subside after a single dose, even just 25 mcg. That does not support the idea of methylfolate being cleared in a matter of hours, or, it suggests that a process has been started that is independent of the methylfolate, or that folic is still in my system and interacting somehow.
  2. pela

    pela

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    It's been on Amazon for several months. I thought about buying it last summer but tried some other brands instead. I bought it through Amazon since I don't shop at Costco. When I put in my zipcode at this website I get a list of Costco stores:

    http://webbernaturals.com/caen/where
  3. pela

    pela

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    I should have mentioned that I divide my 14 tablets of folate into 4 daily doses. 4 at dawn, 3 at noon, 3 at 5pm and 4 at bedtime
  4. Freddd

    Freddd Senior Member

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    Hi Pela,

    Interesting, they only show it at one SLC Costco, the one farthest from my home. Perhaps they are testing the Webber in some stores and the Kirkland in others.
  5. Freddd

    Freddd Senior Member

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    Hi Vitronix,

    That does not support the idea of methylfolate being cleared in a matter of hours, or, it suggests that a process has been started that is independent of the methylfolate, or that folic is still in my system and interacting somehow


    A halflife is not clearance time. 2 halflifes take it down to 1/4. 4 halflifes take it down to 1/16 the level. When methylfolate is the most limiting factor, it can be the cause of methylation turning on. If methylation is happening at one tenth of 1% and increases to 1% that is a HUGE perceivable increase, 10x. Increasing from 1% to 10% then is the same effect and 10% to 100% is another such increase. This kind of increase indicates real severe folate deficiency. Then within a few days the donut hole insufficiency symptoms can take over. People who are not deficient don't have any response. It merely has no effect at all. I suspect you will have better success if you keep the titration going to give it a chance to come up to normal levels rather than stopping it every time it starts. There is no way to know without trying it despite the anticipated unpleasantness. Some people have panic attacks when they feel the start of methylation or even on taking a placebo and are anticipating methylation. It's also possible that the little bit of methylation that gets going then triggers ATP startup which would be even larger and hit directly at the limbic system in the brain if the person has anxiety.

    What are the symptoms that put you in bed for a day and wiped out for days?

    What I do know is that nobody I know of who has largely healed does so without starting up methylation and ATP. I know of no way to start these up without sensing that they are starting. They are just as powerful being reversed as going into partial ATP block and methyltrap is powerful nasty. Some have had to do micro-titrations, maybe 10mcg 4x a day increasing by 10% each day. The actual startup brightness does fade whereas low potassium and paradoxical folate insufficiency can go on for monrths.
    Victronix and Xara like this.
  6. Red04

    Red04 Senior Member

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    My wife needs 8000mcgs metafolin to recover from a relapse and during her initial recovery she would take those same high dosages. Somewhere between 1600 and 2400 seems to be enough to maintain her health now. 800mcgs was just enough to keep her on the border of healing if she never missed a dose. More always seems to be better. She had startup symptoms early on. But now it's real slow to react. Like starting and stopping a train.
    Xara likes this.
  7. cph13

    cph13 Senior Member

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    My recent serum b12 was 2,000. I told both drs. my pcp and endo to CHILL. I'm shocked...they did!

    I was wondering what the latest "Rabbit pellets" feces was all about for a day or so; followed by what seemed GERD last evening "for the first time since I was???? 30". I upted my mag. oxide and all was well in the bathroom this morning AMEN. I also have not had any esop. "gerd" issues. IT IS AMAZING how one MUST READ every post not to miss anything. Thanks for SHARING! Hugs, C
  8. Lou

    Lou Senior Member

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    I take it Fredd for whatever reason is not going to respond to question about increasing b12 with much higher doses of Metafolin.

    Would perhaps some of you who take large daily amounts of Metafolin (for example, larger than 5000mcgs) share how much b12 feels sufficient? This just for some rough gauge, realizing it will vary for different people.
  9. Red04

    Red04 Senior Member

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    I think everyone just has to try it out. I took the approach that more metafolin or more b12 were always better. My wife now reacts so slowly, its hard to really pinpoint the dose she "needs".

    Deplin is 15000mcgs and has low side effects and the b12 is well tolerated by pregnant women, heart patients, etc...So taking more was just expensive and annoying to dissolve all the b12. I never looked at it as having any downside. I think sometimes during the initial recovery my wife would dissolve 3-4 X 5mg Jarrow mb12's along with 8000 mcgs of methylfolate.

    Now she takes 3-5 x 800mcgs solgar methylfolate, 2 X 1 mg ET MB12, and 1 x 10 mg source naturals adb12. If she misses a few days or starts feeling bad I will give her that same dose twice a day. She has regressed some in the immune system department. She has had a cold lingering for a few months and actually missed work for the first time in a few years over the winter. I don't know if it's allergies or the change from Jarrow to ET MB12 or what. I have played with the dosages and she has not really bounced back. We also have an 8 month old who likes to bring home germs from daycare. It's been puzzling.

    I am interested as to where immune response fits in to the methylation titration decision tree.....
    Lou and Xara like this.
  10. Freddd

    Freddd Senior Member

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    Hi Lou,

    Actually I will answer that, but I have been contemplating the answer as it isn't actually an easy one. This ties into the ZONES of healing in it's most recent form.



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

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

    II. DIFFUSION – BODY TRANSPORT ZONE - Sublingual proven effective (5 star) methylb12 and adenosylb12 500mcg (approx 100mcg absorbed) or 100mcg injection. Threshold dose for “turning on healing”. Strongly dose proportionate 1-100mcg absorbed. Moderately dose proportionate 100-3000mcg absorbed, weakly dose proportionate 3000-20,000?mcg absorbed.

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

    IV. INTRATHECAL INJECTION 2.5MG METHYLB12– Japanese research has tried this and found effectiveness lasted 3 months to 4 years (latest report)

    The active transport zone, ZONE I, is the one in use by all forms of cobalamin that are eaten and absorbed via IF, HTC1 and HTC2. It takes about 25mcg absorbed to fully saturate the TC2 changing it to HTC2. The b12 is distributed according to whatever triage methods the body has built in for allocating this almost always near most limiting vitamin. Healing happens slowly at best and frequently not at all perhaps because nothing is left after most critical allocation is made.

    ZONE II, body distribution by diffusion. This occurs when a large enough dose is taken that a significant amoint is absorbed by diffusion in the intestine and is absorbed as whatever the form of cobalamin used happens to be. For MeCbl and AdoCbl this puts the two active forms available for essentially 100% of the body tissues it can reach before excretion. The higher the dose, the deeper the diffusion.

    Let's consider what the curve looks like. Research has shown that it takes an oral dose of 125mcg available for absorption with a fully functional active absorption system to saturate the TC2 to HTC2. For that part of the dose, 1 to 125mcg oral, general healing doesn't turn on.

    Over the next 100mcg absorbed directly into the blood as active MeCbl and/or AdoCbl healing goes up potentially from several percent effective to perhaps 80% effective (all approximate estimates). The studies showing oral dose proportionate healing used typically 2 doses; 120mcg and 1500mcg in one study of MeCbl. The smaller dose is sufficient to saturate the HTC2. The other dose was large enough to allow direct absorption of MeCbl and distribution by diffusion. The larger dose started healing faster (peripheral neuropathy in this one study) and healed noticeably more during the study period. The average serum level at the start of the study was over 700pg/ml and the highest treated were over 1500. Nobody was excluded based on test results. Admission was via symptoms. 62% of those having effective healing would have been excluded from treatment by test results in most studies and medical practice based on inactive cobalamin studies.

    So, the question arises, after that 100mcg directly absorbed active cobalamins, how much difference does more make and is that influenced by quantity of l-methylfolate present? This is something I was unable to test because Metafolin wasn't available in 2003 when I started this. What I did observe in myself and many others since then is that for the next several thousand mcg absorbed the breadth of healing and the speed of healing increases so more healing occurs per unit time. However, the difference between 100mcg and 3,000 mcg absorbed (injection or 15,000mcg sublingual or so is relatively small. The difference can be felt by letting the brightening fade at a given dose and then increase the dose. At some point no further increase makes any noticeable difference and that is typically around 15,000mcg sublingual. For healing the body, 15,000 taken 1-3 tablets at a time keeps the serum level high enough to penetrate the CNS (ZONE III) for 15+ hours a day. Taken all at once that is true for only a few hours.

    The CNS penetration is the most difficult to achieve by diffusion and appears needed for the "enhanced neurological healing" that MeCbl is known to stimulate. I would include AdoCbl in that too but it has not been researched in that way.

    Following the newer version of the titration pattern then the steps look like this.

    1 - Titrate AdoCbl/MeCbl combo to approximately 100mcg absorbed where healing can "turn on" with 200-800mcg of l-methylfolate. 200mcg will not be enough and will immediately (3 days) give "detox" symptoms composed of low potassium and donut hole folate insufficiency. If startup does not occur by the time one gets to 1000mcg combined absorbed cobalamins, titrate LCF

    2- Identify low potassium symptoms and titrate potassium.

    3 - Identify donut hole folate insufficiency and titrate with 4x-8x dose size of l-methylfolate several times a day until those symptoms are strongly diminishing.

    4 - titrate AdoCbl and MeCbl to perhaps a nominal sublingual dose of 1000mcg each, watching for low potassium, donut hole folate insufficiency and identify any other new symptoms, and what isn't being taken care of

    5 - Finish titrating LCF to 500-1000mg for now, then identify what isn't healing or not enough. Try SAM-e, TMG, D- ribose, Vit D, Zinc, B-vits and various things as needed to improve performance. It isn't a try 1 thing and then another. It is add SAM-e and then TMG and various other things. It is usually combinations that yield results. SAM-e need titration over several months. LCF could take six months to titrate up to the 500mg dose and try 1000mg to see if it makes a difference. Don't rush things. Think things through. Look at the symptoms and effective supplements for them to get ideas. Most people will fall into one of several groups. Almost everybody here has appears to have complicating factors and more severe things going on, with me it is SACD which is basically long term damage from prolonged deficiency. Hormones get all messed up and will often change during these titrations.. There isn't a system of the body that is immune to damage from these deficiencies. As there are at least 600 reactions affected by the methylation and ATP the variations are huge in number.

    6 - Titrate MeCbl separately until it makes no difference.

    7 - Adjust potassium and l-methylfolate as needed by response to symptoms

    8 - Titrate AdoCbl separately until maximum amount that makes a difference.

    9 - Adjust LCF

    10 - Adjust various factors.


    This description is an approximate description of the process. There is no fixed specific ratio I can even begin to suggest between MeCbl, AdoCbl and l-methylfolate. It is all by titration AND VERY CUSTOM FOR EACH PERSON.

    Watch out for unusual things like needing huge amounts of potassium beyond perhaps 3000mg or so. The range of Metafolin is very large and based on what appears to be genetic factors and influence of other folate antagonist medications etc.
    ahmo, Lou and Xara like this.
  11. Freddd

    Freddd Senior Member

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    Hi Red,

    I found Vit C, A, Zinc and the Deadlock Quartet to all be important for the immune function. For me it was Vit C above 2 grams a day made a massive difference for generally infectious diseases. Insufficient folate, and specifically Methyltrap, drastically disorders the immune system.

    However, we both went to babysit for my grandchildren, letting him get out alone all evening with his wife for the first time in a year. We both have been sick with gastro problems since then, and fading. We didn't wash our hands well enough often enough and picked up, let's call it diaper residue. Allergies seem to relate to folate levels but B12s are part of that too. In addition to formerly mentioned vitamins, vit D can be significant too. For me the immune things faded aver about 2 years. I also had 2 mysterious lingering sore throat-colds-allergies? during the first two-three years. I'm not sure what stopped them but something changed. The timing suggests methylfolate. But it also took some time for some things to heal. Since them I have had this one gastro upset and a mild flu a year ago and that is total in 7-8 years. Prior to 10 years ago I would have been sick 4 months of the year.
  12. Victronix

    Victronix Senior Member

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    What are the symptoms that put you in bed for a day and wiped out for days?

    It's hard to remember the details of what happened but the symptoms I remember best were total exhaustion to the point of needing to lie in bed and just watch video all day, having a very hard time getting up in the mornings, feeling like I had a fever (but didn't) for most of the day, weak muscles, painful muscles, my feet / lower legs feeling freezing cold, numb and like the muscles were twisting, for lack of a better term, and my forearms aching and feeling like I had carpal tunnel syndrome. I know that potassium can address many of these, but at just ~50 mcg, the need for potassium (which I prefer to address with food) quickly became overwhelming.

    The symptoms in my forearms and lower legs have been going on at a low level since last Fall and I suspect that's when B-Right started using the 50 mcg methylfolate (which I was taking with C, thank god, or I'd have been totally baffled and freaked out about what was going on with me). The website says that the formula was changed in Spring of 2012, so it may have percolated down to me in the Fall, ordering it online at iherb.

    With my most recent miniature dose of 25 mcg folinic (which I thought would be benign relative to methylfolate), the symptoms have been annoying but manageable with food potassium, and are changing every day since I took it. The symptoms cycle around, lasting for a variable period of time, then disappearing, and then a different one popping up. They are continuing now on the third day since taking that dose at about the same rate.

    The very first symptom I got was a raspy throat. I'd thought folinic would be benign and then I noticed that my voice was hoarse, and thought, "Oh no, it's starting again!", since I remembered that odd symptom from before. It's also a hallmark hypothyroid symptom, which is why I noticed it. My husband was sure it was just in my mind but then a few moments later all the other ones started up, starting with my mouth feeling sore and actual angular chelitis, which I haven't had in years. Folinic apparently doesn't cross the blood brain barrier but it did give me a positive mood (possibly due to the excess energy). Other symptoms are burning muscles (like when I was starting B-12), headache, the typical muscle cramping in my feet/lower legs ,etc.

    Stomach cramping and feeling like I can't breathe and some of the more difficult symptoms because when they are bad I have no desire to eat anything, much less drink potassium containing drinks, but have to force myself to. The feeling of not being able to breathe I had attributed to the stomach cramping, but now I think it really is it's own thing.

    Odd symptoms include very focused and specific muscle pains. One day I woke up with a single tooth really aching to the point of feeling like I must have a bad cavity and better deal with it right away, such that I called the dentist and made an appt for 7 am the next day. This went on for hours, until I had some orange juice and then realized that it was gone and likely the potassium had relieved it. Another day I woke up with the area right over my right kidney really hurting, highly focused pain, but nowhere else. I thought, I better drink a lot of water, so did, and when that made no difference, again I realized it was the methylfolate, and so had a lot of juice and banana and it went away. Another odd symptom was sore breasts. That's since gone away. B-12 never did any of this, although it had a lot of odd symptoms.

    I suppose I could write a novel about my symptoms . . .

    So what happened to me last weekend was that my period started and then it was like dropping a bomb in my little experiment and everything went ballistic. Someone I know described my sensory experiences as being similar to taking Harmaline, if you've ever tried it (and my MAO A is +/+). That I can self-generate that type of experience is why I've never experimented with psychedelics and take no mind altering substances aside from wine and beer and espresso. It's too long to describe here but the most difficult component was huge waves of anxiety coming on suddenly and that went on intermittently for about 3 days. It was directly hormonally related and disappeared as soon as the bleeding lessened. I know that serotonin and estrogen both drop significantly with menstruation, so I presume that was what was going on. But it's not something I want to allow to repeat.

    Anyway, so I appreciated this part of your message:

    Some have had to do micro-titrations, maybe 10mcg 4x a day increasing by 10% each day.

    I'm not yet ready for even that amount because each dose is additive at this point. What's worked is doing every other day, which gives me a chance to get a sense of what's going to happen. As I get more comfortable, maybe I can improve that.

    This kind of increase indicates real severe folate deficiency.

    Perhaps, but given that I can self-generate a sensory experience that others have to take drugs for, suggests that my perceptions may be a little distorted by my biochemistry, so experiences of my symptoms may not be a 1:1 relationship with the actual intensity of a deficiency in my case.
  13. Xara

    Xara Senior Member

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    Hi Freddd!

    Thank you very much for your information, very helpful indeed.

    I'm happy to say that I have been noticing more and more symptoms that fall in group 3 lately.
    Skin peeling around some fingernails, and (never had this one before) feeling of having a tiny painful splinter in some of the fingertips (only lasting for several hours), a white lie bump at the tip of the tongue (only lasted for a day), reduced coordination, sleepiness, sluggishness, runny nose every now and then, sneezing every now and then, increased fatigue (group 2b).

    I'll start upping my methylfolate on Friday. I am taking 1200 mcg ATM.

    Do I understand correctly that, according to you, Freddd, I could up this dose 3 or 4 x every three hours and see what will happen? Continue the increase when nothing happens, continue when things start to improve, and stop as soon as I feel worse or when symptoms of group 3 are gone? Right?

    The thing I am most scared about when trippling the mfolate dose is getting hypokalemia very fast.
    Last time I upped the methylfolate (from 1200 to 1600 mcg IIRC) I got abnormal heart rythms and a fast pulse when doing anything besides sitting still (and got a bunch of other symtoms). My starting position is much better now, I have upped several vitamins and minerals, I am spreading the doses, my electrolytes are better balanced, my heart's at ease, and I have clearly symptoms of group 3. But still...
    How fast can symptoms of hypokalemia occur when trippling mfolate, any idea? As soon as I notice heart problems, will taking extra potassium gluconate, niacin and curcumin deal with it swiftly? Will they be a secure safety net?

    adreno
    I remember you are very sensitive to lack of potassium (heart), but you once doubled(?) methylfolate every three hours or so, didn't you? When you did that experiment did you run into any potassium problems that day?

    Thanks to you in advance, Freddd and adreno, if you can help me to decide what to do on Friday. And thanks to anyone else who's willing to make a suggestion.
  14. Red04

    Red04 Senior Member

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    Thanks for the advice. I had gotten rid of most of the basics because my wife was doing so well. She hasn't lost a step as far as energy, depression, anxiety, etc.... Just a sore throat and a weakened immune response. I'm going to add back in those basics and see if it helps.
  15. pela

    pela

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    I can tell you my experience but can't tell you how you will react to more folate. When I developed paradoxical folate deficiency I experienced agitation and restlessness, along with canker sores, runny nose and bouts of insomnia. More folate calmed me right down and did not produce low potassium symptoms. I do keep potassium handy for when I need it, and normally eat a high potassium diet--5000-5500 mg per day. Why are you waiting until Friday?
  16. Freddd

    Freddd Senior Member

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    Hi Xara,

    The low potassium symptoms typically the third day after the methylfolate. it may not be a pathological low potassium because it appears all based on serum level which can change rapidly. It may be what happens when serum potassium is falling, as with falling blood sugar often has more intense symptoms for some people than an actual low blood sugar My experience was that initially, with one layer of healing with MeCbl only was about 1/3 of the total potassium I needed when all the layers were healing. The two biggest were the first and the healing and growing muscles. The CNS makes little difference in this need for potassium in my experience. Food based potassium doesn't help for today. It helps for tomorrow as the serum potassium peak is 14 hours after the meal. It takes a supplement taken with water (picture a sport drink with 3 times as much potassium) can provide relief in 15-30 minutes, increasing for a couple of hours.

    I was taking 400mcg of Metafolin to start with (availability and cost). I got the worst low potassium I'd ever had and that allowed me to notice the difference when I took a couple based on reading. The next worse was when I started LCF and my muscles started healing and growing. That happened twice, once when I started LCF and a second time when I increased Metafolin to 8000mcg or so. Both times my need for potassium went up for the duration of muscle growth.

    I found that it takes more to reverse the insufficiency (momentum?) than it takes the next day. So when I got clobbered by the glutathione (precursors) it took me more to reverse the symptoms than I needed to remain on until the next episode. I've experimented all which ways on this and it's not easy to find any hard linkages other than those already identified. So after that first day of higher folate there is a residual amount left in the morning. It takes about 10 halflifes for any given dose to fade to zero. If a person takes a dose each halflife (say 3 hours) then in 30 hours serum equilibrium is reached at 2x the single dose produces. One dose each 6 hours equilibrium is reached at approx. 1 3/8 x the single dose but the troughs are deeper and longer. AUC (area under curve) is much less then the drop in peak. It really looks like the amount needed to reverse it isn't necessarily the amount needed to maintain that reversal. The incidents happen every couple of weeks, and there is always something, usually a missed dose these days, but I also sometimes overdo the veggies. I have the most trouble when there are so many absolutely delightful things very fresh for the eating in the garden.

    So when the low potassium hits which can be at the same time as donut hole insufficiency, 300 or 400 mg (of potassium) of potassium gluconate will generally reverse many symptoms starting in 15-30 minutes. However, that too only lasts a few hours when healing is happening rapidly. So on potassium summing up all the doses and spreading them out 5-6 doses keeps the total dose lower, The response with potassium is almost immediate. With the muscles, and sometimes heart palpitations, I'll feel something is wrong before it is as definite as nasty spasms. I can catch it sooner and take only 300mg instead of the 500mg I used to have to use. For those things that happen and are relieved every time with potassium, I have found it 100% reliable, even if I miss a dose unlike the Metafolin.

    I hope this is clear. Some of these things are just fuzzy.
  17. EastWest

    EastWest

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    I gradually worked my way up on the dose of Metafolin over 5 months to about 14-15 a day. Then went to a trial on 15 mg Deplin. I had a very quick positive leap forward and have so far done well on the 15 mg/day for the past 4 months. I had been able to gradually increase my B12 dosage, but once I reached the 15 mg/day folate level, I had enough to support a fairly rapid move to high dose injected MB12 (35-40 mg injected daily divided into 3 doses). I am making progress on this so far.

    My doctor told me he has tested quite a number of patients and found a high number who have antibodies to the folate receptors. He said that the person has to take enough folate to overcome this resistance. He also told me he suspects that I *might* have a defect in the transporter function for carrying B12 around in the body.

    So I wonder if a person takes a small amount of folate, whether it activates the antibody response? Could this sometimes be an explanation for symptoms?
    ahmo likes this.
  18. Victronix

    Victronix Senior Member

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    That's very interesting. I had no idea there were folate receptors.
  19. Freddd

    Freddd Senior Member

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    Hi EastWest,

    So I wonder if a person takes a small amount of folate, whether it activates the antibody response? Could this sometimes be an explanation for symptoms

    Antibody response seems to be hindered by all three; partial methylation block, methyltrap and partial ATP block. In methylblock everything goes hyper-reactive. However, for my immune system to get well working required healing startup for a number of years. I don't really see how that would happen on a tiny amount. If it does happen what would be the specific symptoms? The symptoms would be non-responsive to more l-methylfolate and more potassium.

    Also, l-methylfolate reduces urine losses of b12 by about 50% in the first several hours at least and is involved with both forms of b12.
  20. adreno

    adreno 3% neanderthal

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    Like Freddd says, hypokalemia takes some time to develop (3-4 days in my case). You can probably go as high as you want with folate on a single day, without getting into trouble. But if you continue the high folate doses for several days in a row, K will start to drop. It least this is what happens to me.

    Btw, I have done pretty high doses lately, without any hypokalemia. As I have said before, I do not believe the hypokalemia is induced by healing (or the creation of new cells). It's simply that more K is being excreted (for whatever reason). In my case it seems to have something to do with ALCAR. I am not supplementing any K at the moment, and even avoid high K foods. Still my pulse has been low and I need extra salt.

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