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methylation: VERY low, very slow.....results

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by determined, Apr 22, 2011.

  1. richvank

    richvank Senior Member

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    Hi, redo.

    FolaPro can just be taken orally. It is absorbed well by the gut. B12 should be taken sublingually in order to get enough into the blood. The normal absorption process in the gut, involving haptocorrin and intrinsic factor, is limited in the amount it will absorb. It works fine in a normal, healthy person, but in ME/CFS, more B12 is needed to overcome the functional deficiency that is caused by glutathione depletion.

    If, in addition, a person has an inborn error of metabolism in their B12 processing enzymes, such as Freddd appears to have, then even more B12 is needed, and it must be the coenzyme forms methyl B12 and adenosyl B12, as Freddd recommends. We don't yet know what fraction of those who have ME/CFS also have such an inborn error of metabolism. The clinical study that Dr. Nathan and I performed suggests that most do not have this issue, but Freddd's experience suggests that it may still be present in quite a few people.

    I still suggest trying hydroxocobalamin as the B12 form first. If this hasn't produced benefit in 3 months, then I would suggest doing some testing to find out why, or doing a trial of Freddd's protocol. I would suggest starting at lower dosages than he recommends at first, if you do this, in order to lower the likelihood of a severe drop in potassium in the blood, which can be hazardous, and also to allow glutathione to come up, as we showed in our clinical study will occur if the methylation cycle is not overdriven.

    I realize that Freddd may have different views on this, but I think it is wise to proceed cautiously, because large dosages of methyl B12 together with 5L-methylfolate will take control away from the cells. I have seen a few cases now in which testing has shown that this can overdrive the methylation cycle to the detriment of building glutathione, which is necessary to correct many of the symptoms of ME/CFS.

    I suspect that the rapid rise in folates in the cells with this high-dose protocol also gives rise to rapid proliferation of cells, leading to a high demand for potassium. Since it has been shown that whole-body potassium is low in ME/CFS, a large potassium demand can lower the blood level of potassium, and this can have serious detrimental consequences.

    I realize that if a person has an inborn error of metabolism in the B12 processing enzymes, as Freddd appears to have, there is no other choice but to use methyl B12 and adenosyl B12, together with L5-methylfolate. In that case, I still think it is a good idea to start at lower dosages at first, to see how it goes. As Freddd has repeatedly pointed out, it is hazardous to drive potassium too low.

    Best regards,

    Rich
    Lotus97 likes this.
  2. Freddd

    Freddd Senior Member

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    Hi Rich,

    I have received 2 disturbing private communications in the past few weeks and then done some reading investigating the possibilities. The old hazard of folic acid and why the MDR was set to 400mcg, with maximum at 800mcg, was that people might take more without b12 (in this case it meant specifically mb12 and possibly adb12 by function though simply specified as b12 at the time) causing a sudden onset or worsening of SubAcute Combined Degeneration. The only research done on Metafolin which was applied to specific doses, so size of dose effect isn't known, suggested that comparable doses of Metafolin compared to folic acid produced 7x more methylfolate in the serum. For those folks unable to convert hycbl adequately to mb12 and/or adb12 AND to get adequate amounts of those active b12s into the CSF/CNS, and who take Metafolin, there is a distinct possibility of Subacute combined degeneration being triggered or worsened. I experienced that with the induced deficiencies from glutathione, a distinct and rapid worsening of Sub Acute Combined Degeneration. Further in the literature it is noted that Metafolin can sometimes have an unexpected very large neurological benenfit (reading between the lines it seems to apply to those with paradoxical folate deficiency unrecognized and unknown) so this is obviously in presence of b12. It would indicate that Metafolin gets into the CNS quite well despite whatever cobalamin transport ptroblems there might be.

    Based on my personal experience, these reports from people, reunderstanding some things in the past which were difficult to get past before understanding paradoxical folate deficiency and/or induced low potassium, the research findings showing the difficulty of having adequate cobalamin in the cerebral spinal fluid of people with CFS and FMS I am more concerned than ever about people taking hycbl with Metafolin. I now see a mechanism that could explain a lot of the WORSENING neurological symptoms some people have seen in specific circumstance. Even if they can process enough hycbl in the body to have some degree of benefit, at that low level it can't get into the brain for those with low csf cobalamin. SACD is not somethong safely ignored. It bears a whole lof of resemblence to various aspects of MS and is a result of holes forming in the myelin. It is diagnosed as MS if it isn't bilateral and a body b12 deficiency confimed by elevated uMMA, elvated serum Hcy and low serum cobalamin below 170 or so. MS even comes in a form that mimics the coming and going of paradoxical folate deficiency.

    I'm going to have to give this a serious consideration of how real and widespread hycbl-folate triggered/worsened SACD might be. And that is a very real risk of a very serious problem. I've been comparing the possiblity of induced SACD to playing Russian Roulette since they both knock holes in the brain and cord. If anything SACD is far worse than temportary low potassium and rapidly becomes permanent, the old figure being 3 weeks after symptoms appear is tthe window of reversibility. This is rare or maybe rarely recognized. I've only recently started recognizing it since having a couple of cases presented on a platter. Please help me with this.

    Just last week I was wondering what the next layer of problem might be after recognition and removal of induced folate deficiency and paradoxical folate deficiency and induced low potassium. Looks like induced SACD might be on that next level. The logic chains are there and all fit. The symptoms etc are there. I know it when I see/feel it in myself. So now the question is, how best to protect against that.



    A whole lot of pieces are falling into place on some sets of side effects.
    greenshots likes this.
  3. redo

    redo Senior Member

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    Than you for a thorough reply richvank! About the B12, if it's held under the tounge, should it be done for a couple of minutes, or longer? I might opt for the (cumbersome) IM shots of 'sterop' if it's helt long, but if it's quick, than I'd prefer to do it sublingual.
  4. gu3vara

    gu3vara Senior Member

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    Jarrow's MethylB12 takes about an hour to fully dissolve, it's impossible for me not to swallow excess saliva for an hour, but I guess it accounts for the partial absorption of the b12, which is 30 to 40 % after about an hour if I remember correctly.

    Source naturals dibencozoide dissolves in less than 15 minutes but I try to keep it longer before swallowing.

    It's a bit tedious indeed...!
  5. Freddd

    Freddd Senior Member

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    Hi Gu3vara,

    My long series of tests indicate typically 15% at 45 minutes in the range of 10-20%, and 120 minutes typically 25%, range 20-33%, and that was under tongue or upper lip. I make the Source Naturals last 60-90 minutes under upper lip/cheek against the gum.
  6. Freddd

    Freddd Senior Member

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    Hi Redo,

    IM injections absorb very quickly, have a 30 minute peak and it's downhill all the way. A subcutaneous injection, of 10 times as much keeps the peak going for 10 hours or so with a slower falloff allowing time for absorbtion into the CNS. Also the 2 5 star brands of mb12 are superior to most injectable mb12 and much more reliably so.
  7. richvank

    richvank Senior Member

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    Hi, Freddd.

    I think that what needs to be done is to figure out how people can be separated into groups on the basis of their genetic polymorphisms, so it can be known what treatment is most suited to them. I'm hopeful that the 23andme genotyping will be useful for this. As I've posted before, the folic acid intolerance likely depends on polymorphisms in the DHFR gene. The folinic acid intolerance likely depends on polymorphisms in the MTHFS gene. The inability to use B12 forms other than methyl B12 and adenosyl B12 and the glutathione intolerance are likely due to polymorphisms in the MMACHC gene.

    Concerning the difficulty in getting enough B12 into the brain, here's a thought: As you know, in your case, I have suggested that there is a genetic issue with the MMACHC gene, so that your cells are not able to convert other forms of B12 to the two active coenzyme forms, and you have gotten around this problem by raising the concentration of these coenzyme forms in the blood high enough that sufficient amounts of them will get into the cells by diffusion across the cell membranes, without use of the transcobalamin transport mechanism. O.K., now consider the brain. The cells in the brain will likewise have this genetic problem with the MMACHC gene, so they will need to receive methyl B12 and adenosyl B12 directly, also. However, there is an additional hurdle to be overcome for them, because they are behind the blood-brain barrier. So it will be necessary to push the coenzyme B12 forms through the blood-brain barrier first, before they can diffuse into cells in the brain. Perhaps this is the reason that you have found that much larger dosages are needed to help the brain in your case. The B12 forms have to surmount two diffusion barriers to get into the brain cells, and that will require higher concentrations in the blood. What do you think about this?

    Rich
    Lotus97 likes this.
  8. Adster

    Adster Senior Member

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    Rich, I have 9 snp's in the MMACHC gene, according to my 23andme results, if you are interested. I really don't quite understand all this snp stuff yet though. PM me if you'd like me to send a grab of it.
  9. Freddd

    Freddd Senior Member

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    Hi Rich,

    Yes, I do need that higher dose to get the mb12 into my brain. To put it in perspective today I did another 50mg dose of Jarrow. I am taking 30mg of a not as good mb12 injections each day. I take the challange doses to make sure I'm getting enough of the quality mb12 into my brain. Today I was waching very carefully. I start with 4 tablets and add 4 more in about an hour when the others have turned to mush and another hour 2 more. I could feel the effect quite suddenly abour 2.5 hours in, right around the time an estimated 7-8 mgs is absorbed. That threshold is very definite. If I am holding equilibrium, there is no threshold effect. So I test it from time to time to be sure.

    We need to establish what people do find this CNS threshold exists for them. These are the people for whom low doses of b12 with methylfolate could be damaging, especially if they have a significant CSF/CNS b12 deficiency. I hycbl would be more dangerous because it doesn't supply sufficient mb12/adb12 to the brain as fast as the methylfolate gets in there. There are many more possible permutations for causing this problem. So, we know from research that at least the studied sets of persons with CFS and FMS in looking for low CSF cobalamin had that low CSF cobalamin with normal or high serum level. The question comes up, is that a defining characteristic of CFS/FMS? Does this population need a CSF/CNS loading dose of mb12 (50mg sublingual, 10mg injected) BEFORE methylfolate is taken and periodic CNS penetrating doses to prevent onset or worsening of subacute combined degeneration.

    Consider the neurological pain component of FMS. I know this all too well. Some of the muscle pains are also caused by early stages of SACD, before it is likely to be identified as such I would hypothesize. The hyper-responsiveness, non-painful stimuli becoming painful, just plain "buzzing" pain, the reverse curvature of neck (ME). I have hypothesized that a significant part of the ME and FMS effects were from the CNS-mb12 especially, and/or CNS-adb12 deficiencies. This is beginning to look more likely. This is where that spreadsheet I sent you with certain symptoms pointing at body or cns and mb12, adb12 etc comes in.

    So basically we are looking for the genetic characteristics that distinguish CFS from FMS from ME and from general population. These would presumably have to do with cobalamin processing, folate processing and cobalamin transort into and out of the CSF/CNS.


    I think that the glutathione combining with and causing rapid dumping of the b12 in a body is universal. This would be easily testable in a 10 days series of injections first with no folate, then with Metafolin and then with glutathione. The differences would be an easy colorimetry with 8 hour urine collection post injection in 2 hour increments each day. That could also be a way to test for paradoxical folate deficiency as that would increase cobalamin excretion as well. A day or two of glutathione I doubt would be dangerous, espcailly with corrective measures following completeion.
  10. redo

    redo Senior Member

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    Hi Freddd,

    What makes you say that?

    According to this study, even water based B12 solutions does peak until it's gone a day:
    www.ajcn.org/content/8/2/214.full.pdf html
    Oil based solutions makes the patient retain elevated levels for over a week.
  11. Freddd

    Freddd Senior Member

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    Hi Redo,

    What makes you say that?

    50 years of pharmacokinetic studies of vaious cobalamins and 8000 personal injections. I'm not blind. I can see it in urine and how quickly and for how long at visible levels. In addition I can feel a lot of it.

    You are misinterpreting what you are reading.

    Please note from the article:

    administered in an aqueous medium.
    In the latter instance essentially all of the administered
    vitamin appeared to be recovered
    in the urine within twenty-four hours.


    Previous articles have quantified that as 98-99% of injected aqueous coblamin is excreted in the urine in 24 hours.
    h
    When one is injecting into the muscle serum peak is under 30 minutes, whether it is morphine or cobalamin. It is essentially cleared from the muscle in 30 minutes as many studies have shown If large enough doses to be visible in the urine is used one sees one large surge of b12 in the urine and non visible a few hours later. In the first 2 hours it goes through approximately 4 serum half lifes leaving 1/16 of the intial amount. For those who can feel the effects, most of it is gone in an hour.

    With SC injections, dependent upon dose and concentration, the peak lasts about 6-10 hours. Again visibility in the urine allows one to chart that if desired. Again, the effects one feels are consitant with the relatively steady and then falling serum level. The same thing occurs with CNS penetrating injections, their effects fall off at about the same rate.

    Since they are measuring the serum levels at 1 day intervals they are trying to establish how well their oil-aluminum stearate preparation is utilized versus aqueous solution. They are NOT measuring temporary post injection levels, but rather how much sticks around a little while. Since the oil based injection has a slower absorbtion of course the serum levels are higher as it is still absorbing and can't all be excreted so quickly.

    To keep in mind what we are taliking about, 1 mg IM injection in a human with 5L of blood, the instataneous serum level is about 100,000-200,000pg/ml. The person may have started at 300pg/ml. A day later it's down to some hundreds to thousands of pg/ml. A month later 300pg/ml.

    If the pharmaceutical companies are going to make MONEY off of b12 they have to have something to offer, always something patentable and different or hopefully beter, like Metafolin. They want to make billions and billions off of us. They want to get us into that $500-$1000/month payment for $10 manufacturing cost product. Suppose that some company developed a product that would hold my CNS mb12 level at a level such that all my SACD symptoms went away with x number of injections, what would it be worth? A slow release injection with an oil carrier might be very helpful for a lot of people. Right now people on a monthly or 3 monthly schedual feel ok for only a few days after injection. However, they are not basing treatment on that. They are basing it on maintianing a level of 300pg/ml at the end of the period before the next injection.
  12. redo

    redo Senior Member

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    If it stays at 600pg/ml the week after a IM injection (which the study indicates), wouldn't that be good enough? One dose is 10 milligrams, so it's rather higher concentration than in the study.
  13. Freddd

    Freddd Senior Member

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    Hi Redo,

    Well, 600pg/ml indicate that there is 2-3 mcg more b12 in the entire 5 L of blood than at 200pg/ml. Good enough for what? Studies based on symptoms indicate very different things than ones based on test results. In one study on mb12 and neuropthy wherein the participants were chosen based on symptoms as I work with found that 63% of positive responders would have been excluded based on test results, that the average responsder started with a serum level of over 700pg/ml and some of over 1500pg/ml. 600pg/ml is just a nudge above the Japanese LOW ALERT level of 550pg/ml. I would have over 200 symptoms and be dying with that level of 600pg/ml. So what is it "good enough" for? Certainly not me or probably anybody here who wants to heal. It's good enough to be sure you probably won't die of b12 induced macrocytic anemia. People on these monthly injections are the walking dead. They don't die but they don't really heal. And most b12 deficiency symptoms continue to worsen.
  14. redo

    redo Senior Member

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    It's you whom pinned the baseline at "The person may have started at 300pg/ml.", so the study where they injected it, they showed that it doubled. If the baseline is 600, and the dose is 10 mg, I really don't see why that wouldn't do just as much as sublingual dosing.

    Don't get me wrong, I appreciate your input, How long are one supposed to hold the drops sublingually? Would taking them nasally be a viable option.

    It sounds like you have vast experience with this. Have you published any studies?


    EDIT: I see that other forms of B12 are given nasally http://www.nascobal.com/, so when that's done, I am sure it would be fine to give hydroxy B12 nasally as well.
  15. Freddd

    Freddd Senior Member

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    Hi Redo,

    I used the 300pg/ml because that is the level at which 50 years of research, mostly aimed at pernicious anemia for the forst 20 years, used as the lowest acceptable level for the b12 therapies to deliver, hence 1mg injection each month with cyanocbl, 1mg each 3 months with hycbl and 1000mcg orally of cyanocbl or hycbl. It's a mighty low standard. It was achieved by observing that nobody who got macrocytic anemia AND responded to b12 (cyanocbl=b12 officially) had a level above 200pg/ml. So, in this study, they were trying to show that an oil base injectable gives a higher level for longer. True, it doesn't shoot up to 200,000 initially, but that generally isn't recognized as necessary or desirable, just characteristic of b12. So yes, 600 will be the serum level at some time bertween the post injection peek and thge time it comes down to near 300 at the end of the month. As 600 is only margianally above the 550pg/ml low alert in Japan, it's nothing to write home about.

    I have no idea how to hold the drops for 2 hours. I've thought about that and speculated. Soak it into small pieces of bread and put in in under your lips or something for 2 hours. The tablets turn to mush anyway and conform very well. The other problem I have with adb12 and mb12 as drops is the stability. Adb12 in sterile saline starts to break down in 5 days in the dark in the regrigerator. Mb12 is stable for 6 months or more in that situation. 5 or 10 minutes in even dim light and adb12 and mb12 both start breaking down to hycbl/aquacbl (in an equilibrium). However, in doing so they loose 99+% of their potency and some people get acne from it as tissue no longer forms correctly.


    the dose is 10 mg

    Dose of what taken how?

    1mg or 10mg of hydroxcbl produces 10 to 30mcg of mb12/adb12 if at all.
    10mg of sublingual mb12/adb12 will give an absorbed dose of 1.5 to 2.5mg when held 45-120 minutes
    10mg mb12 or adb12 injection gives 10mg absorbed mb12 or adb12

    A 10mg subcutaneously injected mb12/adb12 raises the serum peak to 150,000pg/ml for about 6 hours amd falls off after that for 24 hours. Taken as a series of overlapping injections 8 hours apart it maintains the serum level at about 200,000pg/ml around the clock.
  16. rydra_wong

    rydra_wong Guest

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    Fredd said: I'm not blind. I can see it in urine and how quickly and for how long at visible levels. In addition I can feel a lot of it.

    Freddd, tell me again about how you see B12 in your pee? I have never done so. Does that mean you're taking too much or I'm not taking enough?

    Ryrda
  17. rydra_wong

    rydra_wong Guest

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    Determined, have you ever had your genes mapped? I seem to be sensitive to all perscription drugs and many other chemicals (but I am generally ok because I avoid them and don't sound anywhere near as bad as you), but I wondered if the CBS gene might have something to do with multiple chemical sensitivities. I have two CBS mutations. Do you?

    Also, sounds like you started this slow, steady approach a year ago. Any updates?

    Thanks
    Rydra
  18. rydra_wong

    rydra_wong Guest

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    Freddd, unfortunately this is not a sufficient test. I can tell you what ELSE is in dark green leafies that affects the methyl cycle -- cadmium. cadmium displaces copper and copper is a cofactor of methionine synthase. Estrogen increases the half life of copper. I believe testosterone does too. So as you get older you have trouble getting enough copper. (Also happens if you take too much zinc). I know you take DHEA and pregnenolone, but it's not replacing what you had when your prostate pumped it out. I am not suggesting a solution, but only a potential snag in your theory for consideration.
  19. redo

    redo Senior Member

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    Thank you for taking the time to give thorough answers.

    I don't know what the baseline is, but what I could see from the study was that they doubled the baseline (at the end of the week) with a dose which wasn't large. My question is really, given a 10mg Hydroxy B12 shot once weekly, wouldn't that surpass the levels one get from taking sublingual doses (at the end of the week)? How much high (compared to baseline) would the serum levels go, if one took a couple of drops daily?

    If quadruple of the baseline is a good serum level to stay at, I assume a really high IM dose once weekly of hydroxy B12 would be sufficient to achieve that (correct me if I am wrong).

    Do you take sub-linguals, sub-cutaneous or intra muscular B12 yourself?

    The point of sublingual administration seems to me to get the B12 in contact with mucous membranes, and raise the serum levels that way. Wouldn't the mucous membranes in the nose do just as well? I see that there are other forms of B12 which is given through the nose.

    What you think the optimal serum level of B12 would be? 6000 pg/ml? 60000 pg/ml? Higher? If the optimal level for a PWME is 6000+, than I agree that IM shots once weekly most likely wouldn't be the best way to go.

    "1mg or 10mg of hydroxcbl produces 10 to 30mcg of mb12/adb12 if at all." What do you mean with this?
  20. determined

    determined Senior Member

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    USA: Deep South
    Hi Rydra,
    I have had a 23andme analysis....I don't know about the CBS SNPs (do you have the "rs" numbers? I'd be happy to check) but I do have "poor metabolizer" status (CYP2C19) and I am "CC" (risk allele?) for the A1298C MTHFR SNP (rs 1801131).

    Update: Even though I have never changed my dose from the diluted specks of mB12 and methylfolate, I continue to enjoy the higher energy levels. Energy-wise, I have gone from being overwhelmed by my part-time job to feeling like I could do more (the chemical sensitivity and electromagnetic sensitivity seem to be the sticking points now).

    I believe that the chemical sensitivity is very much related to the microbiome, due to many observations I have made over the years....for example, the day or two before I have had strep, my chemical sensitivities seemed to disappear. It was a very dramatic effect, going from being totally unable to walk into, say, Target, to being able to go in there and actually shop for 15 or twenty minutes...and then there is the effect of doxycycline. Whenever I increase the dose (or the dose isn't consistent) my chemical sensitivities flare.

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