What is your understanding of the methylation cycle trap or blockage?

pamojja

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What I don't get is how people can have a B12 deficiency without having ME!
It is indeed mindboggling how different bio-chemical individualities can handle the situation differently well, even without symptoms. Like me after 30 years of being a low fat vegetarian and according to B12 blood test severely deficient. Having since supplemented to sufficiency (also folates and all Bs) never felt an immetiate difference.
 
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It is indeed mindboggling how different bio-chemical individualities can handle the situation differently well, even without symptoms. Like me after 30 years of being a low fat vegetarian and according to B12 blood test severely deficient. Having since supplemented to sufficiency (also folates and all Bs) never felt an immetiate difference.
What form of b12 supplement have you used? Greg (of b12oils fame) says you can't replenish the b12 supplies of the brain and nervous system with oral doses, even lozenges. I was taking B12 for months and when I tried a tiny little drop of his oil I had a profound effect. That tiny drop was clearly getting a lot more b12 into my system than a large oral or liquid sublingual dose.
 

pamojja

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What form of b12 supplement have you used?
All of them for 12 years. Also by enhaced sublingual absorbtion with the help of DSMO. Since after that long time even methylmalonic acid came back normal, I experienced long-term remission from COPD in 2013, from a walking-disabilty from PAD in 2017 and from remaining PEMs in 2019, I see no reason further to import the expensive oils.

What was the profound effect for you? And would it apply to me, since I never had neurological or psychological symptoms?
 
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What was the profound effect for you?
I'm still quite early on in treating this, but I'd been taking B12 for a few months in liquid sublingual form (so not as good as lozenges). When I took the oil I had some negative effects like pain in my spine when bending over. Very weird, alarming pain. When I lowered the dose and took for a few more days I began to get a tingling in my spine, not unpleasant but felt like electricity, that radiated up through my arms and head. It felt like my nerves were coming back to life after being asleep.

It's also been affecting my fatigue. When I level-out on a dose I feel great. When I up the dose, I get increased fatigue and pain. Still haven't made it to the full dose, but I'm hoping when I get there that I'll be fixed. Even the negative effects say to me that I need it.

I also need folate with it, or it causes me air hunger.
 

Learner1

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I also need folate with it, or it causes me air hunger.
Other nutrients are needed, too. Like B2, B6, B1, zinc, potassium, glutamine, glycine and cysteine.
Would you (or anyone else) like to share their understanding of methylation, potential problems with methylation, or how it might relate to ME? :thumbsup:
Let's look at what methylation impacts:

Screenshot_20210414-071512.png

And then what happens if it's not working properly:
Screenshot_20210414-071534.png

, why the methylation supplements are not a cure for most people?
Because people have other problems, too, like infections, autoimmunity, toxicity, hormone imbalances, etc.
 
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Other nutrients are needed, too. Like B2, B6, B1, zinc, potassium, glutamine, glycine and cysteine.
I periodically dose those vitamins and minerals, but I'm curious about the amino acids. The ones you mention aren't essential amino acids. I can maybe see how glycine might get used up, being converted to serine by cbl and 5mthf... What about the others?

Would I benefit from supplementing the essential aminos, plus the ones you mention? If so, any good brands which give what I need?
 

Learner1

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I periodically dose those vitamins and minerals, but I'm curious about the amino acids. The ones you mention aren't essential amino acids. I can maybe see how glycine might get used up, being converted to serine by cbl and 5mthf... What about the others?

Would I benefit from supplementing the essential aminos, plus the ones you mention? If so, any good brands which give what I need?
Aminos are somewhat of a commodity. The best way to know what you need us to do a plasma amino acids test.

Glycine, glutamine and cysteine are needed to make glutathione. A lot of sites recommend NAC, N-acetylcysteine, but I find I'm usually short of glycine and need to supplement it.

I also have found that I tend to run out of methionine: homocysteine and methionine recycle each other, do running out of methionine could give you a lower homocysteine level.thsn you might expect, masking a deficiency of folate, B6 or B12.

Other aminos are important, too. Tyrosine us needed to make dopamine, asparagine is needed to kill off old mitochondria, branched chain aminos (leucine, isoleucine and valine) can help mitos work and reduce PEM, and so on.

Fluge and Mella found ME/CFS Patients tend to be short of amino acids. I found I was short of the ones in the pattern that they found, and have found being on a higher protein diet has been beneficial, about 1.4 to 1.8 grams per kilogram of body weight of protein per day.
Is there a SIMPLE quick guide for the methylation protocol and which supplements are recommended exactly?
you can look up richvank's Simplified Methylation Protocol discussed in detail on this site

However, my experience is that my needs have changed dramatically over time, and that customizing a protocol for one's genetics and environmental factors is much smarter. Doing comprehensive nutrient testing and then building a protocol based on what you find increases your odds of success and diminishes your chances of reacting badly to a new protocol. It definitely takes more than just folate and B12, Which is where many people get into trouble.
 

Learner1

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I guess one could supplement with whole spectrum aminos in case testing is not available or not affordable, not talking of my case, it might even be provided for free here in Italy.
Sure, or just increase protein intake to 2.0g/kg body weight daily. That would be somewhat expensive, though ...
 
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Is there a SIMPLE quick guide for the methylation protocol and which supplements are recommended exactly?
I'm sure if you look around Phoenix Rising, you will find a couple of different methylation protocols, some of which come with simplified versions.

From a theoretical perspective, though, in order to break a methylfolate trap you would really only need a few basic things:
  1. Vitamin B12: This breaks the methylfolate trap.
  2. Folate (Vitamin B9): Once the methylfolate trap is broken, there will be an increased demand for folate.
  3. Vitamin B6: This will reduce any homocysteine that accumulated during the methylfolate trap.
  4. Potassium: Once the methylfolate trap is broken, there may be a sudden, but temporary, drop in potassium. Unexplained muscle cramps are a good sign of this phenomenon.
Hope this helps.
 
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I'm sure if you look around Phoenix Rising, you will find a couple of different methylation protocols, some of which come with simplified versions.

From a theoretical perspective, though, in order to break a methylfolate trap you would really only need a few basic things:
  1. Vitamin B12: This breaks the methylfolate trap.
  2. Folate (Vitamin B9): Once the methylfolate trap is broken, there will be an increased demand for folate.
  3. Vitamin B6: This will reduce any homocysteine that accumulated during the methylfolate trap.
  4. Potassium: Once the methylfolate trap is broken, there may be a sudden, but temporary, drop in potassium. Unexplained muscle cramps are a good sign of this phenomenon.
Hope this helps.
I've been taking bog-standard B6 every-so-often. Is this ok, or do you think the active form is better in this case?

How much methylfolate do you take and how often? I've been noticing I've had to increase my folate intake but I'm hoping I don't have to reach Fred levels (for financial reasons above anything). I'm at around 300mcg now. I'm also increasing my B12 oil dose so maybe this is the reason. I wonder if I should be cutting back on the B12 or not. Trial and error and hope the errors aren't catastrophes.
 
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I've been taking bog-standard B6 every-so-often. Is this ok, or do you think the active form is better in this case?
The form of vitamin B6 does indeed matter, for the following reason.

The most common vitamin B6 supplements use the synthetic pyridoxine instead of the natural pyridoxal-5'-phosphate, because the synthetic version is more shelf-stable than the natural form.

A small portion of the synthetic pyridoxine may be converted into the natural pyridoxal-5'-phosphate in the body, but a significant portion remains as the synthetic pyridoxine. As it turns out, the unconverted pyridoxine can block the action of the converted pyridoxal-5'-phosphate. If you take excessive doses, then the small converted portion will be overwhelmed by the large unconverted portion, and you may end up with a paradoxical B6 deficiency.

Unfortunately, there have been people here on Phoenix Rising who developed peripheral neuropathy from excessive doses of pyridoxine. Fortunately, the peripheral neuropathy appears to be mostly reversible by supplementation with the natural pyridoxal-5'-phosphate.

This phenomenon has been studied and is discussed in this scientific publication:

Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function (Vrolijk et al., 2017)
https://forums.phoenixrising.me/thr...leads-to-decreased-vitamin-b6-function.53293/

How much methylfolate do you take and how often?
I wonder if I should be cutting back on the B12 or not.
I can't tell you what's best for you, but I can share what works for me:
  • I take 400mcg methylfolate per day, which is roughly the U.S. Recommended Daily Allowance (RDA).
  • I also take 250mcg hydroxo-B12 per week, which is roughly 15x the U.S. RDA. (This is still the lowest dose I could find.)
 
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@Pyrrhus May I ask if you find Greg's protocol to be a thorough one, in particular titrating transdermal minerals (I-Se-Mo) and being on just them for a few weeks. I see similarities with Fredd's, i.e. no 5MTHF early on. You've probably already expressed your take on it but can't find it.
One big difference I see is Fredd's suggestion to have AdeB12 and MetB12 introduced at different times although that is possible ordering separate Ade and Met oils.

I was going for a hassle-free one such as taking a big multi like this one with minerals in the suggested form, b12 transdermal oils, multi-aminos and lithium (considering mercury history). Cons would be Mg,Ca,vitC limiting minerals absorption, and 5MTHF from the beginning.
I'd appreciate some feedback.
 

Busson

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The form of vitamin B6 does indeed matter, for the following reason. ... This phenomenon has been studied and is discussed in this scientific publication:

Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function (Vrolijk et al., 2017)
@Pyrrhus That's a remarkable finding in the research paper about unconverted B6 from a high dose blocking the active form. I looked to see if this finding had been replicated in other studies but couldn't find much. In fact the original study here seems to have gone unnoticed as it is not cited much, according to PubMed. I wonder if this finding has become accepted by the mainstream scientific community?
 

pamojja

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I wonder if this finding has become accepted by the mainstream scientific community?
If with mainstream scientific cummunity you mean most MDs? They didn't take the time to read and havent even heard about.

In fact, here in the EU any B6 is limited to a daily dose of 20mgs since last year, because of possible neuropathy shown with high pyridoxine only.
 

nerd

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Would you (or anyone else) like to share their understanding of methylation, potential problems with methylation, or how it might relate to ME? :thumbsup:
I will eventually come back to this. I think the discussion has become a little bit too broad and there are still papers to read. In summary, my hypothesis is that it isn't B12 deficiency that causes the methylation issues but it is an overmethylation demand, which means that there isn't sufficient S-Adenosylmethionine (SAMe) available to donate methyl groups to dependant metabolic processes such as COMT hyperexcitability (10.1111/j.1365-2796.2011.02405.x), histamine methylation due to allergies, and intracellular histone dysregulation due to cell danger response and pathogenic effects on the mitochondria (10.1016/j.clinthera.2019.02.012). Moreover, the IDO trap theory also supports the idea that there is a partial Niacin dysregulation and this can block the S-Adenosylhomocysteine (SAH) hydrolase due to NAD+ dysbalance. Irritatingly, SAH is a methylation inhibitor and can turn the methylation cycle completely under extreme NAD+ dysbalance or homocysteine buildup because the homocysteine can be adenolysed to SAH again.

You see, my model could be split up into phases which result in kind of an overexcitability and overexhaustibility of the methylation cycle.
  1. Hypermethylation due to CFS/ME pathology <=> Hypomethylation due to SAMe overdemand
    • can be alleviated by increasing methylation buffer
    • a ketogenic diet can help to reduce the histone-mediated overmethylation
    • a causal fix for pathogen residual activity could eliminate cell danger response-mediated overmethylation, including the histone-mediated one
  2. NAD+ dysbalance <=> underactivation of SAH hydrolase <=> SAH buildup (<=> hypomethylation, see 3.) <=> homocysteine deficiency <=> folate trap + BH4 trap + choline deficiency + SAMe deficiency + cysteine deficiency
    • can be alleviated by increasing NAD+ buffer and supporting phosphorylation
    • hopefully, there will be a repurposed drug that blocks the IDO trap and its effects on Niacin availability
    • another causality might be reduced phosphorylation which is mediated by mitochondrial dysregulation/dysfunction (pmid: 22837795)
  3. B12 deficiency and/or B6 deficiency and/or TMG deficiency <=> homocysteine buildup <=> SAH buildup <=> methylation blockage <=> hypomethylation <=> SAMe buildup
    • can be alleviated by supplementing B12, B6, and TMG
Once the cycle is in the hypomethylation state, there is DNA damage to cells, impairment of protein synthesis, impairment of the glucose and lipid metabolism, histamine buildup (potentially triggering mast cell release), COMT overactivation, just to name a few.

I think the reason why B12 deficiency is often recognized in CFS/ME patients is that the overmethylation potential also needs more B12 as fuel. I would try TMG and not only B12 for methionine recycling because the BHMT has greater potential and sensitivity for a fast resupply of SAMe. In addition, I would take B6. This avoids homocysteine buildup without the induction of an undersupply of cysteine.

I would also fuel up on antioxidants of all kinds because they all link to the NAD+ balance. I would also take Thiamine and Niacin in low doses. Many supplements overdose Thiamine, or Niacin to over 1000% of the RDA and B12 to over 100 mcg. Overdosing is contraproductive.

EDIT: Antioxidants might not help with NAD+ dysbalance. This was completely speculative. It's only Coenzyme Q10 that plays a role in oxidative phosphorylation (pmid: 22837795).
 
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The form of vitamin B6 does indeed matter, for the following reason.

The most common vitamin B6 supplements use the synthetic pyridoxine instead of the natural pyridoxal-5'-phosphate, because the synthetic version is more shelf-stable than the natural form.

A small portion of the synthetic pyridoxine may be converted into the natural pyridoxal-5'-phosphate in the body, but a significant portion remains as the synthetic pyridoxine. As it turns out, the unconverted pyridoxine can block the action of the converted pyridoxal-5'-phosphate. If you take excessive doses, then the small converted portion will be overwhelmed by the large unconverted portion, and you may end up with a paradoxical B6 deficiency.

Unfortunately, there have been people here on Phoenix Rising who developed peripheral neuropathy from excessive doses of pyridoxine. Fortunately, the peripheral neuropathy appears to be mostly reversible by supplementation with the natural pyridoxal-5'-phosphate.

This phenomenon has been studied and is discussed in this scientific publication:

Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function (Vrolijk et al., 2017)
https://forums.phoenixrising.me/thr...leads-to-decreased-vitamin-b6-function.53293/




I can't tell you what's best for you, but I can share what works for me:
  • I take 400mcg methylfolate per day, which is roughly the U.S. Recommended Daily Allowance (RDA).
  • I also take 250mcg hydroxo-B12 per week, which is roughly 15x the U.S. RDA. (This is still the lowest dose I could find.)
@Pyrrhus Hi Pyrrhus... This is similar to the the amounts that I was taking. 400 mcg methyl folate (680 DFE) and 500 mcg of methylcobalamin-b12. I started not to feel well after several months. Having explored this forum more, I worried that I induced a “donut hole deficiency” by taking small amounts. Do you believe in this theory? The idea that you start up healing by taking folate and b12 and need to take increasing amounts to keep up with the healing otherwise you cause a deficiency in them because they’re spread too thin? I am trying to learn more about it but not sure if I believe it or not.

There is also the theory of a paradoxical folate deficiency where you don’t take enough b12 so the folate can’t be used... I wondered if I took too little b12 in comparison to methyl folate? But you do not seem to have this issue at these same amounts.

I was also taking it with creatine, vitamin A, vitamin D, fish oil, and iron. I took the other b vitamins as well but only for a few weeks. I wondered if I induced some other deficiency but I’m not sure what... I have stopped all supplements and am trying to wait it out but still feel bad.
 
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