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

[nerd]

I've read different viewpoints of what the problem is with methylation and its potential causes. I have my own theory about this, but I don't think I'm aware of all the existing theories so that I can check if it is consistent with all the evidence that is linked to the methylation cycle. This is why I'd like to reopen the discussion about the methylation cycle. I'd ask for your opinions about what is going wrong and the different states that the trapped methylation cycle has. I'd appreciate references to any research that support these theories and to potential causally related findings. Maybe we can have an updated compendium here of all the possibilities and their consistencies and inconsistencies with research. Let's narrow this down step by step as far as we can.

Thanks in advance!

@Pyrrhus @drmullin30 @mitoMAN

 

[Pyrrhus]

Well, here is one way that a localized methylfolate trap might be a possible symptom (not cause) of ME:

Assuming a localized methylfolate trap is indeed a symptom of ME, it would be a symptom that can be treated with a few simple vitamins, with no need for complex "methylation protocols". Treating this symptom may improve the quality of life of an ME patient, but it wouldn't be a cure.

When I use the term "methylfolate trap", I am NOT referring to any of the "methyl trap" hypotheses put forward by Ben Lynch, Amy Yasko, Rich Van Konynenburg, or by @Freddd that have floated around Phoenix Rising for years. Although these hypotheses are clearly related to and clearly inspired by the original "methylfolate trap", they are distinct hypotheses.

I only talk about the original "methylfolate trap" that accompanies B12 deficiency, which predicts that B12 deficiency can lead to elevated homocysteine. The clearest description of the original "methylfolate trap" is the 1981 paper by Weir:
https://www.thelancet.com/journals/lancet/article/PIIS0140673681906504/fulltext

Basically, the original "methylfolate trap" describes how the body misinterprets B12 deficiency as a methionine deficiency, triggering metabolic changes that had evolved to protect the supply of methionine, but which inadvertently trap folate in the methylfolate state. If there is B6 deficiency at the same time, the "methylfolate trap" predicts elevated homocysteine as well.

I don't know of any simple way to test for the "methylfolate trap", but there was a thorough test of the "methylfolate trap" in a 2006 case study:
https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2141.2005.05913.x

 

[Pyrrhus]

Many people mean different things when they use the term “methylation”. It’s a confused situation.

The simplest definition refers to the blood concentration of S-Adenosyl-Methionine, also known as AdoMet or SAMe. This AdoMet is the main “methyl donor” that the body uses to carry out many different important chemical reactions in the body, which are known in chemistry as "methylation reactions". Without sufficient AdoMet, the body can not carry out these important metabolic functions.

When the blood concentration of AdoMet is too low, one might be tempted to say the body is "undermethylated”. However, there is no scientific definition for “undermethylated”.

Conversely, when the blood concentration of AdoMet is very high, one might be tempted to say the body is “overmethylated”. However, there is no scientific research on the effects of a high AdoMet blood concentration.

Folate and B12 are both needed for the proper generation and utilization of AdoMet. This is why folate and B12 supplements are commonly used to correct low AdoMet levels. This is also why low folate or low B12 can lead to low AdoMet.

To correct low AdoMet due to a methylfolate trap, you would typically take both folate and B12. You may also want to take other B vitamins, especially the “pyridoxal-5’-phosphate” form of vitamin B6, which is the form that is naturally used by the body. Methylfolate is the naturally circulating form of folate in the body. Hydroxo-B12 or methyl-B12 are good forms of B12.

Note that many people experience horrible start-up effects when they first try to correct low AdoMet. These horrible start-up effects appear to be perfectly normal and tend to go away over time. This may just be a reality of proper supplementation. People use all sorts of terms to describe these start-up effects, such as "start-up effects", “detox”, "Herxheimer", or “herx”, or many other words.

 

[Pyrrhus]

So, according to the original "methylfolate trap" described by Weir in his 1981 paper, the trigger of the methylfolate trap is B12 deficiency. (Although some genetic mutations may make this B12 deficiency or methylfolate trap more likely.)

But there are many different types of B12 deficiency, and not all of them are obvious. In fact, you can actually have both a B12 deficiency in one part of the body, but normal or elevated levels of B12 in the blood!

Here is a paper that describes many possible reasons why one can have high B12 in the blood, but still have a functional B12 deficiency elsewhere in the body:

Supraphysiological vitamin B12 serum concentrations without supplementation: the pitfalls of interpretation (Vollbracht et al., 2020)​

https://academic.oup.com/qjmed/article/113/9/619/5524896​

Of particular relevance to ME, where oxidative stress and low glutathione has been documented in the brain, the paper has this to say:

Elevated serum B12 levels may also be associated with a functional deficiency of the vitamin. Functional deficiency has been described despite high B12 concentrations and is due to a failure of cellular uptake or intracellular processing, trafficking or utilization.
[...]
Recent findings in diseases associated with oxidative stress have revealed that intracellular oxidative stress results in local functional B12 deficiency.8 Insufficient intracellular processing of B12 due to oxidative stress has been reported in diabetes mellitus or in Alzheimer’s disease,9,10 where it has been postulated to be a significant pathophysiological factor.9 Intracellular reduction of the central cobalt atom is essential for the formation of the metabolically active forms of B12. This process requires reduced glutathione and the hydroquinone form of flavin adenine dinucleotide (FADH2), it is therefore compromised by oxidative stress.9 In such conditions treatment with glutathione and/or vitamin C, a key physiological regenerator of intracellular glutathione, may provide therapeutic benefit. This warrants further investigation.

 

[Pyrrhus]

Evidence for oxidative stress in ME:
If you're wondering about the evidence for oxidative stress in ME, here are two papers that documented oxidative stress and low glutathione in the brain of ME patients:

Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology (Shungu et al., 2012)​

https://forums.phoenixrising.me/threads/increased-ventricular-lactate-in-cfs.14392/​

​

Neurochemical abnormalities in CFS: a pilot magnetic resonance spectroscopy study at 7 Tesla (Godlewska et al., 2021)​

https://forums.phoenixrising.me/thr...-study-at-7-tesla-godlewska-et-al-2021.85779/​

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How oxidative stress leads to low glutathione:
If you're wondering about the evidence for how oxidative stress leads to low glutathione, here are some papers that describe the relationship well:

Assessment at the Single-Cell Level Identifies Neuronal Glutathione Depletion As Both a Cause and Effect of Ischemia-Reperfusion Oxidative Stress (Won et al., 2015)​

https://www.jneurosci.org/content/35/18/7143.long​

​

Glutathione, oxidative stress and neurodegeneration (Schulz et al., 2000)​

https://febs.onlinelibrary.wiley.com/doi/full/10.1046/j.1432-1327.2000.01595.x​

------------------------------------------------------

How low glutathione and oxidative stress can lead to low intracellular B12
And if you're wondering about the evidence for how low glutathione and oxidative stress can lead to low intracellular B12, note that the cobalt ion in B12 is extremely sensitive to oxidative stress. Here is one paper that mentions this:

A new role for glutathione: protection of vitamin B12 from depletion by xenobiotics (Watson et al., 2004)​

https://pubmed.ncbi.nlm.nih.gov/15606130/​

------------------------------------------------------

How there can be a B12 deficiency in parts of the brain, but with normal B12 levels in the blood:
And if you're wondering about the evidence for how there can be a B12 deficiency in parts of the brain, but with normal B12 levels in the blood, here are two papers:
(remember that homocysteine is a marker for B12 deficiency)

Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia (Zhang et al., 2016)​

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146797​

​

Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome (Regland et al., 1997)​

https://pubmed.ncbi.nlm.nih.gov/9310111/​

EDIT: added a study

 

[Pyrrhus]

...And let's not forget that, in addition to preserving B12 inside the cell, glutathione is also required for converting B12 from one form to another as needed by the cell:

I found a really good paper that explains some of the details of how glutathione is essential for a cell's utilization of B12.[1] It may be a bit hard to read, but there is a more readable paper in reference [2].

In addition to glutathione protecting B12 from degradation inside the cell, it also strips the "methyl-" and the "adenosyl-" from methyl-cobalamin or adenosyl-cobalamin when methyl-cobalamin or adenosyl-cobalamin first enters the cell. (The cell later adds back the "methyl-" or "adenosyl-" if or when it is needed.)

Therefore, if there is insufficient glutathione available inside the cell, methyl-cobalamin or adenosyl-cobalamin might get stuck in the CblC complex (AKA MMACHC), unable to bind the CblD (AKA MMADHC) needed to transport it to the enzymes that use B12.

Here is a diagram from the paper:
("methyl-" or "adenosyl-" is represented by "R-" and B12 is referred to as "cobalamin" or "Cbl")

References:
[1] https://pubmed.ncbi.nlm.nih.gov/23539619/
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312744/

 

[nerd]

@Pyrrhus Thanks for contributing.

What is your understanding of the Ben Lynch, Amy Yasko, Rich Van Konynenburg methylation trap? @Pyrrhus @Freddd
All I've read from them in this context are SNPs and nothing specific about why the trap is supposed to happen in CFS/ME patients and how the trap is manifested.

 

[Pyrrhus]

What is your understanding of the Ben Lynch, Amy Yasko, Rich Van Konynenburg methylation trap?

I think these are three separate hypotheses, but all inspired by the original "methylfolate trap" described by Weir in his 1981 paper. It's hard to tell what exactly these hypotheses say, but the following is my basic understanding of their hypotheses:

Ben Lynch:

• People develop health problems related to the methylfolate trap because of genetic mutations.
• See: https://www.amazon.com/Dirty-Genes-Breakthrough-Program-Optimize/dp/006269815X/

Amy Yasko:

• Autism is due to genetic mutations that lead to a methylfolate trap.
• See: https://www.knowyourgenetics.com/media/pdf/Autism Pathways to Recovery Book by Dr Amy.pdf

Rich van Konynenburg:

• ME is due to a glutathione deficiency that leads to a methylfolate trap.
• See: https://phoenixrising.me/research/m...ichard-van-konynenburg-independent-researcher
• See: https://phoenixrising.me/research/m...ue-syndrome-by-richard-a-van-konynenbury-ph-d

Hope this helps.

 

[Busson]

I think these are three separate hypotheses, but all inspired by the original "methylfolate trap" described by Weir in his 1981 paper.

@Pyrrhus I have a note copied from somewhere saying the original folate trap papers were in 1962.

"Interrelations of vitamin B12 and folic acid metabolism: folic acid clearance studies" by Herbert & Zalusky
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC291041/

"On folic acid, vitamin B12, methionine and formiminoglutamic acid" by Noronha & Silverman
In: Heinrich HC (ed) Vitamin B12 und intrinsic factor 2. Enke, Stuttgart, pp728-736 (1962)
https://www.google.co.uk/books/edition/Vitamin_B12_und_Intrinsic_Factor/JQVrAAAAMAAJ

I'm afraid I haven't followed these up as methyl folate traps don't much interest me now and a reading of Scott & Wier's 1981 paper told me most of what I was interested in, especially the methionine connection. I find a lot of what is written about methyl trapping in this forum is confusing and sometimes contradictory.

If you're interested in the old papers, I see I once downloaded a 1977 paper on methyl folate trapping which never got read! Sigh.
"Cobalamin dependent methionine synthesis and methyl-folate-trap in human vitamin B12 deficiency" by Sauer
https://pubmed.ncbi.nlm.nih.gov/871432/

 

[Pyrrhus]

I have a note copied from somewhere saying the original folate trap papers were in 1962.

"Interrelations of vitamin B12 and folic acid metabolism: folic acid clearance studies" by Herbert & Zalusky
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC291041/

"On folic acid, vitamin B12, methionine and formiminoglutamic acid" by Noronha & Silverman
In: Heinrich HC (ed) Vitamin B12 und intrinsic factor 2. Enke, Stuttgart, pp728-736 (1962)
https://www.google.co.uk/books/edition/Vitamin_B12_und_Intrinsic_Factor/JQVrAAAAMAAJ

If you're interested in the old papers, I see I once downloaded a 1977 paper on methyl folate trapping which never got read! Sigh.
"Cobalamin dependent methionine synthesis and methyl-folate-trap in human vitamin B12 deficiency" by Sauer
https://pubmed.ncbi.nlm.nih.gov/871432/

Thanks for sharing these earlier papers!

The first one by Herbert & Zalusky I have already read, and that one is the first published description of the methylfolate trap. Although they don't use the term "methylfolate trap", they do use the term "metabolic trap".

There is also a 1953 paper by Osmond & Smythies that identified an abnormality of methylation in neurological disease. (Using the terminology of the time, they referred to it as "an abnormality in the one-carbon cycle in psychiatric disease".) This paper is discussed by Smythies in this 2012 retrospective:

The Role of Abnormalities Related to the One Carbon Cycle in Depression and Schizophrenia (Smythies, 2012)​

https://www.scirp.org/pdf/NM20120100013_29580433.pdf​

I'm afraid I haven't followed these up as methyl folate traps don't much interest me now and a reading of Scott & Wier's 1981 paper told me most of what I was interested in, especially the methionine connection.

If you liked Scott & Weir's 1981 paper, then you may be interested in their 1995 paper which explains how impaired methylation may directly cause neuropathy and other neurological dysfunction:

​

The biochemical basis of the neuropathy in cobalamin deficiency (Weir and Scott, 1995)​

https://pubmed.ncbi.nlm.nih.gov/8534958/​

 

[nerd]

Also, this is tied to the CDR state, where cells down-regulate methylation on purpose in order to prevent virus from steeling our cellular machinery to form viral RNA or DNA...

I think it would be helpful if you could add here how you think this downregulation works and what evidence for this exists. @serg1942

 

[serg1942]

I think it would be helpful if you could add here how you think this downregulation works and what evidence for this exists. @serg1942

Hey, congrats for opening uo the thread!!! I'll read all of it carefully!

To your question,

This Naviaux's paper explains it really well:

"(...) Under oxidizing conditions of the CDR, SAM is directed preferentially to polyamine synthesis to assist with ROS and antiviral and antimicrobial polyamine aldehyde synthesis and release (Bachrach, 2007). This lowers the SAM/SAH ratio, while simultaneously decreasing net availability of SAM for DNA methylation reactions.(...)"

https://www.sciencedirect.com/science/article/pii/S1567724913002390

Also the GSH, folate and B12 metabolism is switched from the normal routes, as also reviewed in the above paper.

Every aspect of the pathophysiology of ME/CFS is explained by the changes induced by the mitochondria under CDR state.

So, why the methylation supplements are not a cure for most people? Well, probably because the partial methylation cycle blockage is a ancestral defensive mechanism orchestrated by mitochondria sensing danger (toxins, pathogens...)... So, I guess we should focus on allowing the cells to get out of the CDR state. (easier said than done!!!).

This is explained in easy wording by Dr. Neil Nathan in his last book.

Sergio

 

[nerd]

"(...) Under oxidizing conditions of the CDR, SAM is directed preferentially to polyamine synthesis to assist with ROS and antiviral and antimicrobial polyamine aldehyde synthesis and release (Bachrach, 2007). This lowers the SAM/SAH ratio, while simultaneously decreasing net availability of SAM for DNA methylation reactions.(...)"

Thanks!

What an amazing piece of work from Naviaux. It surveys all the relevant pathways that I intended to review. Naviaux's model is not only consistent with my own theory of the methylation trap, but it also shows many more possible interactions than I anticipated. Methylation plays an integral part in many subpathologies of cell danger response, and I think we can find consistencies with other existing theories such as the IDO trap, the B12 "deficiency" theory, different pathogen pathophysiologies, and the existing findings for CFS/ME in particular.

 

[seamyb]

I made a quick diagram that may help with this discussion:

View attachment 42370

Hope this helps!

So, a lot of this diagram chimes with what I'm thinking about in terms of my own illness. However, why would supplementing methylfolate help me if I have a build up of it? It does help me, I think... but why? Even if it's lost (slowly) from the cell, then why doesn't folinic acid help as much as methylfolate?

 

[ljimbo423]

My experience with a partial methylation block I found really intriguing. I had been taking sublingual methylcobalamin for months or even a couple of years.

I then slowly added Methylfolate. When I reached 6.4 mg of methylfolate a day, it felt like somebody flipped a switch and turned my body on.

My energy was much, much higher and I could think clearer. I really thought I had found the cause of my ME/CFS. Unfortunately this slowly faded over several weeks.

I think I was still getting benefits but they weren't anywhere near what they were when what I assume was a partial methylation block, opened up. I still take Methylcobalamin and Methylfolate now, because it does help some with energy, detoxification and other things.

 

[Pyrrhus]

However, why would supplementing methylfolate help me if I have a build up of it?

Over time, the built-up "trapped" methylfolate is slowly lost from the cell because methylfolate is harder to poly-glutamise than the tetra-hydro-folate (THF) form of folate. (Poly-glutamisation is a way that the cell retains folate inside the cell.) This is briefly explained in:

Cellular folate vitamer distribution during and after correction of vitamin B12 deficiency: a case for the methylfolate trap​

https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2141.2005.05913.x​

I assume you have been taking vitamin B12 as well? Taking vitamin B12 breaks the methylfolate trap, allowing methylfolate to once again be converted to tetra-hydro-folate (THF). At that point, taking methylfolate would help to replenish the lost folate inside the cell.

why doesn't folinic acid help as much as methylfolate?

That's a slightly harder question to answer without knowing more about your situation.

Methylfolate is the natural form of folate that circulates in the blood, so it is ready to be absorbed by cells and spring into action. Folinic acid must first be converted to methylfolate before it can be used by the cell.

Although most people have no problem converting folinic acid to methylfolate, people with certain mutations in the MTHFR gene have a hard time converting folinic acid or folic acid to methylfolate:

Treatment with Mefolinate (5-Methyltetrahydrofolate), but Not Folic Acid or Folinic Acid, Leads to Measurable 5-Methyltetrahydrofolate in Cerebrospinal Fluid in Methylenetetrahydrofolate Reductase Deficiency​

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059208/​

Similarly, some people have mutations in the DHFR gene, which means they have a hard time converting folic acid (but not folinic acid) into methylfolate:

The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake​

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2730961/​

 

[Busson]

I found a really good paper that explains some of the details of how glutathione is essential for a cell's utilization of B12.[1] It may be a bit hard to read, but there is a more readable paper in reference [2].

In addition to glutathione protecting B12 from degradation inside the cell, it also strips the "methyl-" and the "adenosyl-" from methyl-cobalamin or adenosyl-cobalamin when methyl-cobalamin or adenosyl-cobalamin first enters the cell. (The cell later adds back the "methyl-" or "adenosyl-" if or when it is needed.)

@Pyrrhus That article has the caveat at the end that this is an in vitro study and may not translate fully to in vivo but let's assume it does.

How does this match up with one poster's (Freddd) comments on this forum that NAC, which replenishes glutathione, gave him so much trouble that he advises against taking it at all?

 

[Pyrrhus]

@Pyrrhus That article has the caveat at the end that this is an in vitro study and may not translate fully to in vivo but let's assume it does.

Thank you for pointing that out.

How does this match up with one poster's (Freddd) comments on this forum that NAC, which replenishes glutathione, gave him so much trouble that he advises against taking it at all?

I believe that is discussed in this thread:

The plausibility of NAC inducing b12 deficiency or 'methyl-trap'
https://forums.phoenixrising.me/thr...inducing-b12-deficiency-or-methyl-trap.79380/

 

[Pyrrhus]

I've read different viewpoints of what the problem is with methylation and its potential causes. I have my own theory about this, but I don't think I'm aware of all the existing theories so that I can check if it is consistent with all the evidence that is linked to the methylation cycle

Would you (or anyone else) like to share their understanding of methylation, potential problems with methylation, or how it might relate to ME?

 

[seamyb]

Would you (or anyone else) like to share their understanding of methylation, potential problems with methylation, or how it might relate to ME?

I'm just amazed at how much of a catch 22 the whole cycle is. A reduction in the cycle means decreased capacity to deal with oxidative stress. Oxidative metabolites can degrade B12. This results in a reduction in the cycle. Go to step 1.

What I don't get is how people can have a B12 deficiency without having ME!