Methylation completely stopped working...Can’t find the missing cofactor.

[Hip]

My "theory" is based on what we know about metabolic pathways, on the study of literature, and on the empirical data on my patients.

Are you a medical doctor, @DrHouse_Italy? It's always good to have doctors on the forum. Do to treat ME/CFS patients, or are you an ME/CFS patient yourself?

Such chronic high doses of B12 (it looks like there's a balloon to fill with b12 and the more the better..) are, in my humble opinion, totally insane and potentially dangerous.

I've never come across anyone getting serious side effects from high-dose B12 on this forum. It's a treatment employed by several doctors who treat ME/CFS, including Dr Paul Cheney in the US (now retired), Dr Sarah Myhill in the UK, and Prof Gottfries in Sweden. Gottfries published a study on high-dose B12 for ME/CFS and fibromyalgia.

High-dose methylcobalamin has been shown to promote nerve regeneration, shown to protect against glutamate-induced neurotoxicity, and is known to boost natural killer cell and CD8 cell immunity.

Professor Martin Pall theorizes that B12 might work in ME/CFS because B12 in the hydroxocobalamin form is a nitric oxide scavenger.

 

[BodyMindSpirit77]

Are you a medical doctor, @DrHouse_Italy? It's always good to have doctors on the forum. Do to treat ME/CFS patients, or are you an ME/CFS patient yourself?





I've never come across anyone getting serious side effects from high-dose B12 on this forum. It's a treatment employed by several doctors who treat ME/CFS, including Dr Paul Cheney in the US (now retired), Dr Sarah Myhill in the UK, and Prof Gottfries in Sweden. Gottfries published a study on high-dose B12 for ME/CFS and fibromyalgia.

High-dose methylcobalamin has been shown to promote nerve regeneration, shown to protect against glutamate-induced neurotoxicity, and is known to boost natural killer cell and CD8 cell immunity.

Professor Martin Pall theorizes that B12 might work in ME/CFS because B12 in the hydroxocobalamin form is a nitric oxide scavenger.

Here in Italy I del with Physical Medicine and Rehabilitation, and Functional Medicine. No, I don't have such conditions.. I'm searching and studying to optimize energy production even in healthy people. I'm also a Calisthenics and Ashtanga Yoga practitioner, I workout every day 2-3 hours, so I experiment on myself how to increase our energy potential, besides meditation and spiritual-energy practices.

Regarding b12, I think it needs folate to work properly..it's like a kind of magic.. each of the them alone is useless, together they do the magic.. so balance is really important.

 

[Busson]

Now, it takes 1-3 months to replenish b2 and restore FAD dependent enzymatic activity.

If B2 is water soluble then wouldn't it wash out in hours not months?

 

[Busson]

If you look into these pathways you can see that even 5-methylfolate if in excess will go back through MTHFR to 5,10-methylenetetrahydrofolate, for pyrimidine biosynthesis, and this will consume again riboflavin (FAD).

Are you sure about this? The diagrams I have seen do NOT show a path from methyl-THF to methylene-THF. They only show a path in the other direction.

 

[BodyMindSpirit77]

If B2 is water soluble then wouldn't it wash out in hours not months?

Who said that riboflavin remains stocked for months? Yes it's water soluble and it has a very short half life. It takes a few weeks to restore FAD activity in full. I'm talking about restoring riboflavin/FAD and you about its elimination..

 

[BodyMindSpirit77]

Are you sure about this? The diagrams I have seen do NOT show a path from methyl-THF to methylene-THF. They only show a path in the other direction.

This is a very good question!
In biochemistry texts and in literature there is some commentary on a 'reverse reaction', even though this however is not universally agreed upon. But I'm pretty sure this is so.. or rather, the enzyme is it is predominantly unidirectional, but it has a possible bidirectional activity depending on the concentration of the substrates.
This is a very common fact in biochemistry ...

 

[Busson]

Are you sure about this? The diagrams I have seen do NOT show a path from methyl-THF to methylene-THF. They only show a path in the other direction.

This is a very good question!
In biochemistry texts and in literature there is some commentary on a 'reverse reaction', even though this however is not universally agreed upon. But I'm pretty sure this is so.. or rather, the enzyme is it is predominantly unidirectional, but it has a possible bidirectional activity depending on the concentration of the substrates.
This is a very common fact in biochemistry ...

If there is a path, as you suggest, from methyl-THF to methylene-THF then methylfolate trapping wouldn't be possible.

 

[BodyMindSpirit77]

Can you please explain what you're referring about "methylfolate trapping" ?

This is a controversial argument, and I would prefer calling it "folate trapping", not "methylfolate trapping", in spite of some dated studies .

Maybe we have two different conceptions about the subject. For me "folate trapping" is related to low b12 and/or low riboflavin. If anything it concerns Methionine Synthase, not MTHFR, and if it's related to MTHFR depends upon low riboflavin.

I can tell after years of experimentations.. no patient meets "folate trapping" if they have optimal b12 and riboflavin status.. I can assure you that they need more folate than normal, that will never be trapped !

What's your idea of folate trapping?

 

[percyval577]

Regarding b12, I think it needs folate to work properly..it's like a kind of magic.. each of the them alone is useless, together they ...

Not in my experience. Not at all.

I have very helpful effects from cyanocobalamin
(75-150µg in 1l water, drinking it over some time, a day or some hours)

but when I recently tried folate (very small amount) I got a bad effect
(I knew this very effect already from more than ten years ago when it appeared from normal eating).


Inhibition of Nitric Oxide Synthase By Cobalamins And Cobinamides Weinberg et al 2009
I get also bad effects from arginine (precursor of NO).

And I get good effects from a low manganese diet, and it works progredient.
Manganese potentiates in vitro proinflammatory cytokines and nitric oxide by microglia through a [NF-kB] dependent mechanism
Filipov et al 2005 e.g. Or Chen et al 2006.

I should say here that my illness started from ticks (I can remember that), and borrelia accumulate huge Mn.
A manganesese-rich environment supports [SOD] activity in a the Lyme disease pathogen

 

[Judee]

If B2 is water soluble then wouldn't it wash out in hours not months?

I think @DrHouse_Italy meant that it takes 1-3 months of replenishing b2 to restore FAD dependent enzymatic activity.

I think it was the B12 that she was saying to only take once monthly (see her quote below) but that a person should take "low doses of folate (methyl-folate and folinic, detached from each other) how many times a day is needed, riboflavin daily, and the other cofactors." [underlines added by me]

I think it's better reduce those 5 mg of methylcobalamin. Think about the fact that b12 storage needs, in a healthy person, more than 4 years to deplete.. I think that taking it once monthly is more than enough, after you have filled up the stocks.

Thank you, @DrHouse_Italy for contributing to our forum. It's nice to have a doctor who can advise us.

 

[BodyMindSpirit77]

I think @DrHouse_Italy meant that it takes 1-3 months of replenishing b2 to restore FAD dependent enzymatic activity.

I think it was the B12 that she was saying to only take once monthly (see her quote below) but that a person should take "low doses of folate (methyl-folate and folinic, detached from each other) how many times a day is needed, riboflavin daily, and the other cofactors." [underlines added by me]



Thank you, @DrHouse_Italy for contributing to our forum. It's nice to have a doctor who can advise us.

Thanks to you, Judee.. since everything is one, helping you is helping me.

My opinion regarding 1-3 months to restore FAD activity is because 80-85% of plasma riboflavin is in erythrocytes, and since the average life of erythrocytes is 120 days, it takes 2-3 months for most of them to regain proper glutathione reductase activity.

In my experience, the main causes for which methylation stops working are:
- underestimate the importance of riboflavin
- too much b12
- too much/too little folate.

The riboflavin deficiency is really dangerous, in the long periodo can really impair you energy production and your ability to neutralize oxidants, leading to serious illness.

Since I have been reading you for a while and many here are at risk because of unbalanced protocols, I felt the need to register and have my say.

Regarding the reason why it would be better not to overdose b12, here a pubmed link about the period covered by b12 stocked in the liver..

ttps://www.ncbi.nlm.nih.gov/books/NBK114329/

it is obvious that it is not good to overdose a vitamin that is stored. It may take months then to engage and consume excess b12, with the risk of getting low potassium and folate symptoms. Better to avoid it.

As the ancients said, "in medio stat virtus".

 

[BodyMindSpirit77]

..ops.. I'm forgetting something..
since we know that oral b12 is is as effective as intramuscular or subcutaneous or percutaneous administration,


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993789/

https://www.ncbi.nlm.nih.gov/pubmed/29931179

I would say that once stocks have been restored, a monthly oral intake, in a balanced protocol, is more than sufficient. The "point" is the "balanced protocol" beyond the b12 ! Of course it's just my opinion. Each patient must be evaluated according to his individual characteristics.

 

[Learner1]

Each patient must be evaluated according to his individual characteristics.

I think this is key. I find these rule of thumb pronouncments to be rather dangerous.

My body needs the equivalent of 10mg MB12 daily, or I don't function. I also take all of the cofactors in fairly high doses. And I've been on this protocol, with occasional adjustments for over 2 years. My doctors base this protocol on my labs, and think I'm blowing through B vitamins due to my immune dysfunction, infections depleting them, and the drugs I'm taking.

Riboflavin is also important in supporting mitochondrial complex II. Without adequate riboflavin, one can't make enough ATP.

And, its not just methylation. Nitrosative stress, through the production of peroxynitrites, is a known problem in ME/CFS. This damages the mitochondrial membranes and make ATP production. B12 and folate can help to reverse this problem.

 

[Learner1]

Generally speaking, the methylation protocol has not turned out to be a great treatment for ME/CFS.

This forum poll showed that methylation compares badly to other ME/CFS treatments: only 3% of patients made a major improvement using the methylation protocol, whereas for example 50% made a major improvement using Valcyte, and 13% made a major improvement on oxymatrine or LDN.

Given the state of the practice of medicine around ME/CFS, the best we can say is there is no standard of care. One can count the number of doctors in the world who competently treat ME/CFS on less than 2 hands. So, the idea of having a democratic poll of what "works" in treating ME/CFS is ludicrous.

Valcyte has helped me, as has LDN. But the comprehensive methylation protocol I am on has helped me get rid of arsenic compromising ATP production, reverse peroxynitrite production to reduce/reverse damage to mitochondrial membranes, improve thyroid function, and increase glutathione production which has helped rid me of mycotoxins, reverse oxidative stress after exercise to reduce PEM, and reduce overall toxicity.

This has all been measurable with various labs. As discussed above, bottlenecks in the process through lack of cofactors can greatly impact the success of a methylation protocol, and various genetic differences can affect the process, too.

And though methylation is an extremely important biochemical process, it is only one aspect of successfully trrating a disease as complex as ME/CFS.

 

[Busson]

Can you please explain what you're referring about "methylfolate trapping" ? This is a controversial argument, and I would prefer calling it "folate trapping", not "methylfolate trapping", in spite of some dated studies .

Maybe we have two different conceptions about the subject. For me "folate trapping" is related to low b12 and/or low riboflavin. If anything it concerns Methionine Synthase, not MTHFR, and if it's related to MTHFR depends upon low riboflavin.

I can tell after years of experimentations.. no patient meets "folate trapping" if they have optimal b12 and riboflavin status.. I can assure you that they need more folate than normal, that will never be trapped !

What's your idea of folate trapping?

One author explains it like this: "a lack of methionine synthase activity resulting from vitamin B12 deficiency
leads to reduced synthesis of methionine and THF and accumulation of homocysteine and 5-methyl-THF."

It is underpinned by (1) poor function in methioinine synthase for whatever reason but usually B12 deficiency and (2) the irreversible direction of the pathway from methylene-THF to methyl-THF in the folate cycle. Methylfolate accumulates and causes a blockage on its pathway which, in turn, backs up and limits various preceding reactions in the folate cycle.

Another author explains it as "Because the formation of 5-methyl THF is irreversible, a vitamin B12 deficiency traps body folate in the 5-methyl form, in what is known as the methyl-folate trap hypothesis."

It was proposed in 1962 and has proven elusive because not all researchers can account for it from their results. There are a couple of slight variations on what occurs - such as the role of dietary methioinine. Nevertheless, the general conclusion is that there is a series of highly dysfunctional biochemical outcomes from (1) and (2) above and which may need dealing with when overcoming a B12 deficiency.

It has been very widely discussed in this forum, although sometimes under names like "donut hole deficiency" or "paradoxical folate deficiency". It is often said that the high levels of accumulating folate gets dumped out of the cell into a non-functional compartment leading to a functional deficiency of folate.

We started this by you posting that methyl-THF can convert to methylene-THF but I have never come across that.

 

[Hip]

So, the idea of having a democratic poll of what "works" in treating ME/CFS is ludicrous.

I am not sure what you mean by a "democratic poll". We are not voting for political parties here (ie, this is not a vote for your favorite treatment, but rather a poll which precisely questions how effectively a treatment worked for you).

The poll is a questionnaire asking patients how much they improved from various treatments, using the standard ME/CFS scale of: very severe, moderate, mild, remission. Any one-level improvement on that scale (eg, when a patient moves up from severe to moderate, or from mild to remission) is defined as a "major improvement" in my poll.

Only 3% of ME/CFS patients reported a major improvement using methylation. Thus the tract record of methylation is not great.

 

[Learner1]

Which is not a very scientific method, and at best, queries people with vastly differing quality of care, access to experts, tests, and treatments, which across the board is rather poor at this point. No rational conclusion can be drawn.

Additionally, I'm not sure I could answer such a questionnaire accurately. In July, 2016, I was operating at about 40% of normal, and today, after a comprehensive treatment program, I am at 85% of normal. I still crash, etc. but my life involves careful normal activity interrupted by regular treatment which can last all day on a regular basis.

So, I don't think I was ever "very severe" though I was extremely ill and much worse than "moderate," and I am not in remission, but probably "mild." And, I can't really say that any treatment lifted me up one level on this scale.

But, optimizing methylation and reducing oxidative and nitrosative stress has been a foundation of my successful treatment plan, with IVIG, Valcyte, pyridostigmine, mast cell meds, beta blockers, HBOT, and hormones each having important roles. Any one of these treatments would not be sufficient to change my level on your scale.

The other aspect of this is that it is well understood that there are different subsets of patients with different triggers and characteristics producing the same symptoms. So, if you were to do Chiari surgery on everyone, it would dramatically help those who actually needed it, and could make many others much worse. So, any across the board treatment is pretty meaningless, unless proper testing is done to identify who needs it and how much they need, with what cofactors.

 

[Hip]

Which is not a very scientific method

Many medical studies use patient questionnaires to examine how much a treatment has improved (or worsened) their symptoms, especially in diseases where it is impossible to objectively measure symptoms (for example, with high blood pressure you can objectively measure this, but something like depression you cannot really objectively detect, so you have to use questionnaires).

Obviously good medical studies are conducted with a placebo group, which can't be done on a forum poll. So that's one shortcoming of the poll, because we know that even patients given a placebo pill will improve.

But even without a placebo group, you can still use the poll results to compare relatively one treatment to another.

So, I don't think I was ever "very severe" though I was extremely ill and much worse than "moderate," and I am not in remission, but probably "mild." And, I can't really say that any treatment lifted me up one level on this scale.

If you started taking numerous different treatments simultaneously, it's almost impossible to work out which ones are responsible for the improvements attained. It's only if you try treatments one-by-one that you can pin down any improvements to a particular therapy.

Lots of ME/CFS patients do try treatments individually, so in these cases they have a clear sense of where their improvements come from.

 

[Learner1]

Not sure I find questionnaites superior to lab results in tracking progress. As we saw with the PACE study they can be manipulated by the ignorant or unscrupulous.

As for RCTs with placebos, there is a fallacy. Human brings are not identical widgets. We are unique individuals with varied genetics and envirinmental factors that can greatly change our outcomes. I have been damaged by amlodipine, by ciprofloxacin, by carboplatin and by paclitaxel, taken as prescribed by my doctor and which worked fine for others in clinical trials. So, having a majority of folks doing well on each of these drugs means little to me aa something is obvipusly different that made them harm me. So "voting" for the "best" treatment may not be too useful....

If you started taking numerous different treatments simultaneously, it's almost impossible to work out which ones are responsible for the improvements attained. It's only if you try treatments one-by-one that you can pin down any improvements to a particular therapy.

Lots of ME/CFS patients do try treatments individually, so in these cases they have a clear sense of where their improvements come from.

ME/CFS is a multiorgan system disease. It has many different etiologies and many different measurable and treatable abnormalities. And the body is a system of interrelated systems.

Making one change can easily throw other pieces out of kilter. So, a coordinated approach can be the most fruitful.

I realize your NHS doesn't look at health and disease this way, and truth be told, our US healthcare system with its fee for service model isn't so good at it either, but systems biology offers great promise in tackling disease in a comprehensive way. I am fortunate to live in a city where there is a growing school of thought (and growing practice of medicine) using systems biology. One of the leaders is a visionary scientist named Leroy Hood - this is an explanation from his Wikipedia page on "P4 Medicine:"

From: https://en.m.wikipedia.org/wiki/Leroy_Hood

Since 2002 Hood has progressively expanded his vision of the future of medicine: first focusing on predictive and preventive (2P) Medicine; then predictive, preventive and personalized (3P) Medicine; and finally predictive, preventive, personalized and participatory, also known as P4 Medicine.[117] Hood states that P4 Medicine is the convergence of systems medicine, big data and patient (consumer) driven healthcare and social networks.[116]

Hood envisions that by the mid-2020s each individual will be surrounded by a virtual cloud of billions of data points and will have the computational tools to analyze this data and produce simple approaches to optimize wellness and minimize disease for each individual.[41][52][53] According to this view, the patient's demand for better healthcare will be the real driving force for the acceptance of P4 Medicine by the medical community. This driving force is exemplified by the movement known as the quantified self, which uses digital devices to monitor self-parameters such as weight, activity, sleep, diet, etc. His view is that P4 Medicine will transform the practice of medicine over the next decade, moving it from a largely reactive, disease-care approach to a proactive P4 approach that is predictive, preventive, personalized and participatory.[116]

In 2010, Hood co-founded the P4 Medicine institute (P4Mi), for the development of Predictive, Preventive, Personalized and Participatory (P4) Medicine.[42] He argues that P4 Medicine will improve healthcare, decrease its cost and promote innovation.

He founded the Institute for Systems Biology here and people from his circle founded the Institute for Functional Medicine, the clinical part that trains doctors to think of the body as a system of systems and treat patients more holistically.

Attached is a now dated white paper explaining functional medicine and this holistic approach, contrasting it with conventional medicine. It is personalized and data driven and uses multiple tools from a large toolbox to treat patients.

As a patient with multiple issues, I am thankful to have benefited from multiple treatments prescribed concurrently. It has been far more effective than a single treatment at a time.

 

[Hip]

As for RCTs with placebos, there is a fallacy. Human brings are not identical widgets. We are unique individuals with varied genetics and envirinmental factors that can greatly change our outcomes.

Without RCT, how do you suggest that we gather evidence for the efficacy of a treatment?

If a drug company develops a new drug to treat disease X, and wants to test how effective that drug is, how are you going to do that without performing a RCT?

What replacement for RCTs would you suggest that works better?


And other question: without drug treatment efficacy data from RCTs, how would functional doctors know which treatments to try?

As a patient with multiple issues, I am thankful to have benefited from multiple treatments prescribed concurrently. It has been far more effective than a single treatment at a time.

Conventional medicine treats multiple illnesses with multiple treatments. Nothing unusual about doing that. If you are a diabetic with high blood pressure and depression, you will be treated for all three illnesses at the same time.

. I have been damaged by amlodipine, by ciprofloxacin, by carboplatin and by paclitaxel, taken as prescribed by my doctor and which worked fine for others in clinical trials. So, having a majority of folks doing well on each of these drugs means little to me aa something is obvipusly different that made them harm me.

Many treatments have serious side effects, and going to a functional doctor (or ecological doctor as they are called in the UK) will not give you some indemnity against them. IVIG for example can sometimes cause serious side effects like meningitis; a functional doctor cannot protect you from these risks.