Glutathione depletion blocks conversion of OH-B12 to methyl-B12: new evidence

hixxy

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Hi hixxy,
I think mB12 (or maybe the combined effect of mB12 and methylfolate) has increased my MCS too. I have basically stayed at my starting dose because of this. As things stand, the trade-off has been worth it. I am still able to work part time.

I think you mentiioned somewhere else, hixxy, that you feel your gut is the big problem regarding MCS? I agree with this.

I know you are feeling low lately; you are on my mind and I am hoping that you can rest up a bit, then go back at it. When I was diagnosed with cancer years ago, many people mentioned "resilience" as being most important in the battle. Multiply that by 10 or so, and that's what is required with this illness. Be gentle with yourself - it is perfectly rational to feel the full burden every now and again and wonder if you can bear it.


Thanks determined. For me any worsening of MCS of any level is just an unacceptable side effect. I'm just too bad! I can tolerate almost any other kind of worsening -- just not that!
 

aquariusgirl

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Hi, not sure if this is the best place for this, but given this paper..I am wondering if a person could still overdrive their methylation cycle by taking too much methyl B12?
I guess I am wondering if as little as 15mg of methyl a day could be detrimental?
Thanks.


QUOTE=richvank;256843]Hi, hixxy.

Yes, a recent paper from Korean researchers has reported that glutathione increases the affinity of the CblC complementation group for cobalamin by a factor of over 100. The CblC complementation group is part of the intracellular B12 processing pathway. When glutathione becomes depleted, its affinity for cobalamin drops, and that inhibits the flow of B12 through the processing pathway to make both methyl B12 and adenosyl B12.

No, I don't have a quantitative value for the cutoff, but if you find that you need methyl B12 to get a good effect, I think that you need it. You wrote that it is a bit horrible because of your COMT SNPs. Do you mean that you experience neurotransmitter-related symptoms when you use methyl B12? Please explain.

Best regards,

Rich[/QUOTE]
 

nanonug

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As little as 15mg MethylB12?? Do many people on here actually take that much MethylB12 on a daily basis?
I currently take 6mg/day but I haven taken as much as 15mg. The intent was indeed (and still is) to overdrive the methylation cycle. I don't think this needs to be done by everybody, though.
 

aquariusgirl

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Argh. Did not mean to say as little as 15 mg methyl.

I just kind of wonder what rich thinks the optimal dosage of B12 is? I know it varies case to case .. but I am really confused about this overdriving the methylation cycle thing...Is it only a risk where a person is taking high dosages of METHYL B12 & METHYLTETRAHYDROFOLATE?
 

richvank

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Argh. Did not mean to say as little as 15 mg methyl.

I just kind of wonder what rich thinks the optimal dosage of B12 is? I know it varies case to case .. but I am really confused about this overdriving the methylation cycle thing...Is it only a risk where a person is taking high dosages of METHYL B12 & METHYLTETRAHYDROFOLATE?
Hi, AQ.

I don't have lab data from people taking high-dose methylfolate together with high-dose hydroxocobalamin, so I can't say for sure, but I don't think this would overdrive the methylation cycle, because the cells would still have to do the conversion from hydroxo to methylcobalamin, and that rate would be limited because of the low affinity of the CblC complementation group for cobalamin, given the glutathione depletion.

I do have data from a few people who took high-dose methylfolate with high-dose methylcobalamin (methylation pathways panel together with amino acids panel), as in Freddd's protocol, and I think the data are very clear that the methylation cycle is being overdriven in that case, and glutathione is then hindered from coming up, because the homocysteine is rapidly converted back to methionine, and there is not enough available to go into the transsulfuration pathway in order to make cysteine for glutathione synthesis. I suspect that the potassium deficit will be more of an issue in that case, too, because cell division will likely be ramped up faster because of the concomitant rise in 5,10 methylene tetrahydrofolate when the methylation cycle is driven hard. 5,10 methylene tetrahydrofolate can be used to make thymidine, and it can also be converted to 10-formyl tetrahydrofolate, which is needed to make purines. Purines and thymidine are used to make new DNA and RNA, and they allow more rapid cell division, to make new cells. The new cells need potassium, because it is the main positive ion inside all cells.

I think that when methylcobalamin is taken in high dosage, either sublingually or by injection, the concentration in the blood goes high enough that there is significant diffusion through the cell membranes into the cells, bypassing the usual B12 transport system and the usual B12 intracellular processing pathway. Thus, giving high-dose methylcobalamin together with high-dose methylfolate takes control of the rate of the methionine synthase reaction away from the cells themselves, and overdrives it.

So there are a couple of reasons why I don't favor taking high-dose methylcobalamin together with high-dose methylfolate. I think that Freddd has to do that himself because of what I suspect are his inherited polymorphisms (not characterized). I think he has polymorphisms in the CblC complementation group (MMACHC gene) and the MTHFS gene (not to be confused with MTHFR). But I still think that these polymorphisms must be rare.

As to what the optimum dosage of hydroxoB12 should be, I don't know. I suspect that the lower glutathione is, the higher it would need to be, because the affinity of the CblC complementation group for cobalamin would go lower as glutathione went lower. That's probably one reason why some people need more, in addition to the things that Amy Yasko has pointed out about SNPs in MTR and MTRR causing a greater need for B12. Sorry I can't do better than that at this point.

Best regards,

Rich
 

nanonug

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I am really confused about this overdriving the methylation cycle thing...
Rich has already essentially provided the answer. I just want to explain why I am overdriving methylation: basically, to get rid of as much histamine as possible via the histamine N-methyltransferase pathway. Obviously, one only needs to do this in cases of histamine overload. However, I am also supplementing with acetyl-glutathione and methionine to address the potential problems Rich mentioned in his answer.
 

Freddd

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Hi, aquariusgirl.

Yeah, thanks for the slow pitches!! :)-)

I continue to struggle with the issue of what should be the form or forms of B12 that a person should try first as part of a methylation-type treatment, and I still don't have a very satifying answer. Different people do seem to respond differently. Please bring me up to date on your experience. I know that the initial simplified protocol with hydroxo B12 did some good things for you at the beginning, and then I recall that you hit a plateau and that switching to methyl B12 was beneficial. Is that correct? What is your situation now with respect to these two forms? Are there things that aren't being resolved by taking either of them as a component of methylation treatment?

It's true that hydroxo B12 does have these downsides, but it did seem to help over two thirds of the women in our clinical study. I realize that for many people it is not feasible to run much in the way of lab tests, either for reasons of finances or inability to get to a physician or phlebotomist, or to find one who will order the tests that require doctor's orders. For those who are able to run lab tests, the picture can be made somewhat clearer, but as you know, there are usually still some unknowns.

With regard to overdriving the methylation cycle, I continue to have concern about that when high dosages of sublingual or injected methyl B12 and high dosages of methylfolate are used together. It makes sense biochemically that this would occur, and the data I've seen from I think three people now does confirm that this does happen. In the cases I've had data from so far, the result of it seemed to be low flow of homocysteine into the transsulfuration pathway and thus low rate of synthesis of glutathione and other sulfur-containing substances. Overdriving the methylation cycle causes the methylation cycle and the folate metabolism to go into a "futile cycle," in which excess methyl groups are passed back and forth between the two by sarcosine and 5-methyl THF. So long as the person has functioning glycine N-methyltransferase, sarcosine dehydrogenase, and MTHFR enzymes, which nearly everyone does, though some have SNPs in MTHFR, this is all that happens. I still have concerns that some may have genomic abnormalities that could cause other effects, though.

I don't know how low the dosages of methylfolate and methyl B12 would need to be to prevent this futile cycle and allow flow into the transsulfuration pathway, but my guess is that a few hundred micrograms per day of the folates and somewhere in the low milligrams per day of methyl B12 would probably be the ranges.

I do think that it is important to get some flow going into the transsulfuration pathway, while also restoring the methylation cycle to more normal flow.

My current suggestion is that if it is not feasible for a person to do lab testing, but if they clearly do have ME/CFS, then they should try the current version of the simplified treatment approach, which uses hydroxo B12 as its B12 form. If they do not experience improvements within 3 months, and they are still not able to do testing, then I suggest that they switch to methyl B12 and see if that helps.

If it is feasible to do lab testing, then I suggest as a minimum that they run the Health Diagnostics and Research Institute (or European Laboratory of Nutrients) methylation pathways panel and the Metametrix plasma 50-amino acids panel, and from these decide whether hydroxo- or methyl-B12 would be the best form to use, based on the levels of SAMe, SAH and glutathione, and decide on whether additional supplements (such as methionine, serine, magnesium, B6 and others) are needed based on the amino acids panel.

In all cases, I continue to recommend that people be monitored by a physician while on this type of treatment, to make sure that if any serious adverse effects arise, they will be recognized early and dealt with promptly and properly.

Best regards,

Rich
HI Rich,

As I have been gathering a variety of information from people to see where the balance of mb12 and methylfolate is and let's throw in potassium while we are at it.

First, there is virtually NO proportionality evidenced between methylb12 and methylfolate as would have to be evident if they linked together to drive the methylation into the hypothetical "overmethylation".


First, here are 4 specific people illustrating a range of quantities.
person 1 - 40,000mgs/day absorbed mb12/adb12, 15000mcg Metafolin, 2000-3000mg potassium
person 2 - 2000mcgs/day absorbed mb12/ADB12, 800mcg Metafolin, 99mg potassium
person 3 - 50-250mcg/day absorbed mb12/adb12, 1600-2400mcg Metafolin, 2100-2800mg potassium (updated when copied)
person 4 - 200mcg/day absorbed mb12, 3200mcg Metafolin, 2400+mg potassium

Range of b12 doses that have turned on healing evidenced by sudden increase in potassium and Metafolin needed

methylb12 dose 15mcg absorbed estimated to 180mg injected daily
adenosylb12 dose - 15mcg absorbed to 10mg absorbed

Methylfolate - person without b12 deficiency, no B12 startup, no methylation startup, no ATP startup - 800mcg
Methylfolate - person with b12 deficiency, b12 startup, methylation startup, ATP startup - 1600-4000mcg
Methylfolate - person with b12 deficiency, methylation startup, ATP startup, paradoxical folate deficiency with folic acid, 6000-8000mcg
Methylfolate - person with b12 deficiency, b12 startup, ATP startup, paradoxical folate deficiency with folic acid and folinic acid-veggie-folate, 12mg - 30mg

Potassium - with b12 deficiency, B12 startup, methylation startup, ATP startup - 1600mg- 3000mg
Potassium - no deficiency, no cfs, no fms, no methylation startup, no ATP startup, no B12 startup, - 99mg

You have suggested that there is some proportionality in healing start-up and I maintained it turned on suddenly. You said that was because of the large doses of mb12. With healing able to "turn on" as low as 15-50mcg absorbed (1/10-1/4 of a 1mg sublingual) mb12 and 200mcg of Metafolin, and then to have the healing so triggered not stop with folate insufficiency symptoms until the doses reached the range above determined NOT by mb12 and/or adb12 dose, but rather by how the person reacts to folic/folinic acid it would appear, and for the potassium to go to that same range in a single sudden jump and sometimes needing relatively minor adjustment in certain predictable circumstances.

Higher doses of mb12 increases greatly the extent, especially CNS and peripheral nerves, and slightly the speed of healing. As many researchers say "B12 allows the body to seek to normal". To relieve the neurological deficiency of adb12 in these people I have recently identified, and hydroxycbl doesn't work and mb12 often doesn't work, and l-carnitine fumarate plus adenosylb12 are both usually needed, mb12 often becoming effective only AFTER the adb12 and l-carnitine, and effective doses of l-carnitine fumarate around 0.5mg before they have absolutely intolerable anxiety, panic etcfrom ATP startup if they have had the adenosylb12 first, otherwise if the have the LCF first then the adb12 has to be micro-titrated from 10mcg or less.. So the person has to titrate slowly along with 200mcg of Metafolin (which causes no particular effects) from < 10mcg of mb12 and < 10mcg of adb12, increasing by like amounts daily until healing turns on. Then the person titrates rapidly on potassium by effect, every couple of hours will do between doses, usually to between 1600 and 2400mg of potassium. Then the person titrates Metafolin by effect every 90 minutes until the folate insufficiency symptoms start decreasing or 3200mcg is reached. Continue the next day if the symptoms continue. Level of folate is determined by type and degree of paradoxical folate deficiency.