• Welcome to Phoenix Rising!

    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of and finding treatments for complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

    To become a member, simply click the Register button at the top right.

Functional Vitamin B12 deficiency in Chronic Fatigue Syndrome... (Russel-Jones, 2022)

Messages
600
Abstract

Chronic Fatigue Syndrome/Myalgic encephalomyelitis (CFS/ME) is a complex chronic condition, characterized by periods of extreme fatigue, for which an underlying medical condition has previously not been identified. Many of the symptoms of CFS/ME, are, though, similar to those with vitamin B12 deficiency. In contrast to nutritional vitamin B12 deficiency, the majority of individuals with CFS have been shown to have functional vitamin B12 deficiency as well as functional vitamin B2 deficiency. This functional B12 deficiency occurred despite elevated serum B12 being found, and hence presents as Paradoxical vitamin B12 deficiency. As such, CFS due to functional B2 deficiency presents as Paradoxical B12 deficiency. Maintenance of vitamin B12 functional activity is critically dependent upon functional B2 sufficiency, and hence resolution of CFS there must first be resolution of functional B2 deficiency before treatment with vitamin B12 can be effective.


The study: https://www.researchgate.net/public...al_Journal_of_Psychiatry_Corresponding_author
 

Wishful

Senior Member
Messages
5,684
Location
Alberta
B12 deficiency might cause fatigue, but ME isn't the same fatigue, and for some PWME, there isn't fatigue at all, but there may be brainfog, lethargy or other such symptoms.

What stood out from a quick check of the paper is that the variation in their measurments tend to exceed the measured value, such as 4.45 +/- 11.68. If you let your variation be large enough, those meaningless numbers can support any hypothesis. Furthermore, their selection of subjects isn't robust; they let in anyone who managed to get a diagnosis of ME. On top of that is the use of healthy controls, rather than controls who suffered from similarly limited activity levels, so if any of the measured differences are valid, it might just be for people who are less active than normal healthy people.

I also noticed that they didn't do anything to test B2 supplementation as a treatment or search for any existing data on the effectiveness of B2 supplementation.

Not impressed. It looks like finding shapes in collections of random spots.
 

Hip

Senior Member
Messages
17,824
I also noticed that they didn't do anything to test B2 supplementation as a treatment or search for any existing data on the effectiveness of B2 supplementation.

Greg's B12 protocol for ME/CFS involves taking B2 along with high doses of active B12 (methylcobalamin + adenosylcobalamin).

His protocol also involves taking molybdenum, iodine and selenium. The protocol is detailed in this post.

Greg has a Facebook group where he promotes this B12 protocol as a treatment for ME/CFS. He claims some people have been cured by his approach.

However, while I did find the very high doses of systemic B12 that you can obtain from Greg's transdermal micro-emulsion B12 oils very helpful for my ME/CFS brain fog (see my report in this post), I did not notice any overall improvements in my ME/CFS, even when taking B2 along with the B12 transdermal oil.

I don't believe Greg's claims that ME/CFS is simply due to a functional deficiency of B12.

Though his B12 oils I have taken once weekly now for some years, as a brain fog treatment.
 

CSMLSM

Senior Member
Messages
973
Issues in methylation cause this as the active form of B12 is methylcobalamin and intracellular B12 is adenosylcobalamin. So entry into cells with methylcobalamin is required to get the intracellular form adenosylcobalamin.
Methionine synthase if I remember correctly is required to gain the methyl to the B12 from 5-Methyl-tetrahydrofolate. Maybe a problem with the transcription of this protein (methionine synthase) from some inhibitory affect of the disease (ME/CFS).
Taking the methyl from the 5-Methyl-tetrahydrofolate is how folate is regenerated and stops folate trap as a result.

1660580793816.png


Methionine synthase also known as MS, MeSe, MTR is responsible for the regeneration of methionine from homocysteine. In humans it is encoded by the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase).[5][6] Methionine synthase forms part of the S-adenosylmethionine (SAMe) biosynthesis and regeneration cycle,[7] and is the enzyme responsible for linking the cycle to one-carbon metabolism via the folate cycle. There are two primary forms of this enzyme, the Vitamin B12 (cobalamin)-dependent (MetH) and independent (MetE) forms,[8] although minimal core methionine synthases that do not fit cleanly into either category have also been described in some anaerobic bacteria.[9]


Lack of methionine synthase reduces the ability to convert homocysteine to methionine which is an important process to epigenetics.

Role of methionine on epigenetic modification of DNA methylation and gene expression in animals - ScienceDirect
Abstract
DNA methylation is one of the main epigenetic phenomena affecting gene expression. It is an important mechanism for the development of embryo, growth and health of animals. As a key nutritional factor limiting the synthesis of protein, methionine serves as the precursor of S-adenosylmethionine (SAM) in the hepatic one-carbon metabolism. The dietary fluctuation of methionine content can alter the levels of metabolic substrates in one-carbon metabolism, e.g., the SAM, S-adenosylhomocysteine (SAH), and change the expression of genes related to the growth and health of animals by DNA methylation reactions. The ratio of SAM to SAH is called ‘methylation index’ but it should be carefully explained because the complexity of methylation reaction. Alterations of methylation in a specific cytosine-guanine (CpG) site, rather than the whole promoter region, might be enough to change gene expression. Aberrant methionine cycle may provoke molecular changes of one-carbon metabolism that results in deregulation of cellular hemostasis and health problems. The importance of DNA methylation has been underscored but the mechanisms of methionine affecting DNA methylation are poorly understood. Nutritional epigenomics provides a promising insight into the targeting epigenetic changes in animals from a nutritional standpoint, which will deepen and expand our understanding of genes, molecules, tissues, and animals in which methionine alteration influences DNA methylation and gene expression.
 

Hip

Senior Member
Messages
17,824
Sorry this is wrong.

What do you believe is wrong with the statement?



@CSMLSM, when you are posting quotations from other websites, the usual thing is to place it in an orange quote box, in order to distinguish it from text written by you.

Also, when posting text, or writing your own text, it's good etiquette to break the text up in to paragraphs of no longer than 4 or 5 lines, and then spaced by a blank line. This is because many ME/CFS patients have neurological issues which makes it very hard for them to read walls of text.
 

CSMLSM

Senior Member
Messages
973
Methionine synthase also known as MS, MeSe, MTR is responsible for the regeneration of methionine from homocysteine. In humans it is encoded by the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase).[5][6] Methionine synthase forms part of the S-adenosylmethionine (SAMe) biosynthesis and regeneration cycle,[7] and is the enzyme responsible for linking the cycle to one-carbon metabolism via the folate cycle. There are two primary forms of this enzyme, the Vitamin B12 (cobalamin)-dependent (MetH) and independent (MetE) forms,[8] although minimal core methionine synthases that do not fit cleanly into either category have also been described in some anaerobic bacteria.[9]
Do you mean this that I forgot to add the link to sorry very new to forums and this is the only one I have ever used. could you tell me how?

Also, when posting text, or writing your own text, it's good etiquette to break the text up in to paragraphs of no longer than 4 or 5 lines, and then spaced by a blank line. This is because many ME/CFS patients have neurological issues which makes it very hard for them to read walls of text.
I did this when I first joined and people seemed to be bothered by it somehow and did not do it themselves.

What is wrong about the statement is the fatigue in severe B12 deficiency is indistinguishable from severe ME/CFS. Maybe they have had neither, I have had both.

So have you now got a problem with me like others?
 
Messages
600
Greg's B12 protocol for ME/CFS involves taking B2 along with high doses of active B12 (methylcobalamin + adenosylcobalamin).

[...]

But what is meant by "functional" deficiency which is what he is mostly talking about in this paper. Are you sure he just means to supplement B2 and then B12? Im thinking that what is meant by "functional" is conversion to active form. So pwme dont lack B2 but active forms of B2. For example he mentions that 35p of pwme have hypothyriodism, and from what i understand thyroxine is supposed to regulate conversion of B2 to active form. I wonder if he thinks there could be other issues in the body that hinders active B2 conversion sort of like the hypothyroidism example.
 

CSMLSM

Senior Member
Messages
973
This is because many ME/CFS patients have neurological issues which makes it very hard for them to read walls of text.
I know I have had ME/CFS all my life almost, why I did this when I first joined.
@CSMLSM, when you are posting quotations from other websites, the usual thing is to place it in an orange quote box, in order to distinguish it from text written by you.
You are the first person in 6 months to tell me this thank you.

I know you are involved in the site I hope we can get along. It seems anything cannabis turns people against me normally. I see from some of your posts you likely do not feel this way about cannabis related stuff so am hopeful.

Your post to me appears slightly attacking finding faults as much as possible, defending your friend? I just added my thoughts like others do to me. Then I get this reaction.
 

CSMLSM

Senior Member
Messages
973
Im thinking that what is meant by "functional" is conversion to active form
Yes from memory (10 approx years ago) this is indeed what is a functional deficiency. So you have high levels of B12 in the blood but are unable to convert and thus utilise B12 in processes. I assume it is the same for other vitamins such as B2.
 

Wishful

Senior Member
Messages
5,684
Location
Alberta
Sorry this is wrong.

Wrong in what way? There's been plenty of discussion of how ME's feeling of fatigue is not the same as the fatigue caused by overexertion or lack of sleep. When I do exert myself enough to feel normal fatigue, I do notice that it feels different from my ME symptoms. The combination of symptoms of ME feel something like fatigue, and the lack of proper definition of 'fatigue' leads to quite reasonable confusion of what it is.

"Chronic Malaise Syndrome" is no better defined, but I think more of us would agree that we feel lousy rather than fatigued.
 

Hip

Senior Member
Messages
17,824
But what is meant by "functional" deficiency which is what he is mostly talking about in this paper. Are you sure he just means to supplement B2 and then B12? Im thinking that what is meant by "functional" is conversion to active form.

Yes, that is right, my understanding is that a "functional deficiency" of a vitamin is where the vitamin is not being sufficiently converted into active forms, or is not being adequately transported to where it is needed. So blood levels look normal, but symptoms of deficiency are still present.

In my email conversations with Greg, he told that by functional B2 deficiency, he means where B2 has not been converted to its active forms FMN and FAD. And presumably by functional B12 deficiency, he means where this vitamin is not being converted into active forms of methylcobalamin and adenosylcobalamin.

The B12 oil Greg recommends for ME/CFS contains both methylcobalamin and adenosylcobalamin, so the oil would deal with any B12 functional deficiency.


I looked to see if both the active forms of B2 were available, to deal with B2 functional deficiency, but unfortunately only FMN can be bought as a supplement (it is usually called riboflavin-5′-phosphate, R5P). But for some reason FAD is not available as a supplement.

I asked Greg whether it was worth taking riboflavin-5′-phosphate (R5P) in addition to B2, but according to Greg, oral R5P gets broken down in the stomach back to B2, so he says R5P supplements are a waste of money. I am not sure if that is true, but if it is, I guess one could try R5P sublingually, or possibly as a suppository.

But that still does not get any FAD into the body. Perhaps it is not safe to supplement with FAD; maybe that is why no FAD supplements are available.

This article says FAD "is approved for use in Japan under the trade name Adeflavin as an ophthalmic treatment for vitamin B2 deficiency". But I don't think Adeflavin is intended for oral use.



In any case, the idea that ME/CFS is due to functional B12 and B2 deficiency seems implausible to me. ME/CFS is triggered by viral infection; how would a virus cause a functional deficiency in these vitamins?

The virus would have to affect the process of vitamin conversion into the active forms, or would have to affect the transport of these vitamins into the places where they are needed.
 
Last edited:

CSMLSM

Senior Member
Messages
973
First please do not take offence at anything I say as none is intended.
Wrong in what way?
This is what you said-
B12 deficiency might cause fatigue, but ME isn't the same fatigue, and for some PWME, there isn't fatigue at all, but there may be brainfog, lethargy or other such symptoms.
I was unaware of the term PWME until just now and that it is a milder form than severe less likely to have fatigue (had a quick search just now). Much of my research is from many many years ago before having to stop treatment and go severe many times.

I also realise now you were more talking about the views of one of the researchers maybe when you said
B12 deficiency might cause fatigue, but ME isn't the same fatigue
However I have had severe ME/CFS and severe B12 deficiency. At the end of both severities of both these conditions it is indistinguishable the fatigue from one another.

My B12 deficiency did have me with lost feeling in limbs, pins and needles in my feet, unable to feel socks on my feet, very bad dementia type symptoms, bolts of lighting type feelings through my body, hyper sensitive to cold, heat, light and everything else, major bowel issues and fatigue just like severe ME/CFS. Thats what I can remember.

So when I said what you wrote was wrong it was from this perspective and also having discovered and treated myself the B12 deficiency approximately 10 years ago but still had ME/CFS until in the last few months after finally getting the materials needed to act on the knowlegde gained from over 20 years of experimenting on myself with cannabis and understanding why it worked.

I am now virtually symptom free.

I am sorry if I have caused offence in any way.

MODERATOR NOTE: Posts on a continued discussion of cannabis / caryophyllene / CBD and its benefit in ME/CFS were moved from this thread to the "A place to ask questions about caryophyllene and related stuff" thread. You may continue that discussion at the following link:
https://forums.phoenixrising.me/thr...llene-related-stuff.87175/page-9#post-2409852
 
Last edited by a moderator:

hapl808

Senior Member
Messages
2,052
At the end of both severities of both these conditions it is indistinguishable the fatigue from one another.

I think both b12 deficiency symptoms and ME/CFS symptoms have many different presentations, so it's impossible to say if something is definitely due to one thing or another. As ME/CFS itself is a syndrome with criteria, there isn't much agreement on definitive symptoms. If there were, diagnosis would be easier.

For me, there are numerous versions of fatigue. The PEM crashes after mild cognitive exertion - where I feel great while the exertion is ongoing, but within a few hours to a day or two, a crash comes. Then there's the PEM crashes after physical exertion - where I feel physically tired but mentally a bit better while exerting, but a similar (but not identical) crash follows. Then there's the unrefreshing sleep, where I never feel rested or recharged - I wake up exhausted. Then there's the poisoned heat stroke feeling fatigue during PEM crashes. Then there's the fully body exhaustion and myoclonus during periods where my symptoms are worse overall. Then there's the constant brain fog. Then there's the slight fatigue dizziness and lack of proprioception. Then there's the muscle weakness.

That's not even getting into the digestive issues, etc.

I thought pwME just refers to the generic People with ME. Therefore they could be mild or severe or any other version. I could be wrong, but that was my understanding of the term.
 

CSMLSM

Senior Member
Messages
973
@hapl808 Excellent description of those. When at the extreme ends of both you do not have ups and downs you just have impossible and confusion. As you move away from the extreme ends of both the differences would show, but the fatigue from both are not like normal person fatigue which is all I have now so can compare I think.

Normal person fatigue feels good and helps me sleep. Before I was a weak, wired, tired and confused insomniac.
Now I have tiredness lead to sleep and sleep lead to bounds of energy and no confusion. All my life I have struggled to sleep, get up and focus without cannabis and it was still a massive struggle and could not build routine into my life but now I can and I love it all finally.

I am one person with an experience and others that have been in the same position may percieve these things differently.
 

Wishful

Senior Member
Messages
5,684
Location
Alberta
I was unaware of the term PWME until just now and that it is a milder form than severe less likely to have fatigue

I'm not sure what definition you found, but here on PR PWME means People With ME, whether it's severe or mild. Acronyms are useful, but occasionally confusing.


However I have had severe ME/CFS and severe B12 deficiency. At the end of both severities of both these conditions it is indistinguishable the fatigue from one another.

When either condition is severe, isn't your brain malfunctioning so badly that your judgement of such things is questionable? I suppose it's similar to intoxication.

Oh, I see what you're getting at: that the 'fatigue-like' symptoms of B12 deficiency and ME are hard to distinguish between, but you'r agreeing that neither is 'normal' fatigue. I can't comment on how B12 deficiency feels, since I haven't experienced it. I do agree that during my ME, I've experienced normal fatigue and it does feel good in its own way, quite unlike ME's fatigue-like symptom.
 

Hip

Senior Member
Messages
17,824
You are the first person in 6 months to tell me this thank you.

Lots of ME/CFS patients have reading difficulties and short attention spans due to brain fog. So it's best to try to make posts that are simple and readable, using paragraphs no longer than 3 or 4 lines, and a blank line between each paragraph. When I am quoting material from other websites, I will also add in this paragraph spacing, to make it easier to read.

I notice that you post large extracts from Wikipedia articles and the like to support your points; it's good to providing supporting evidence; but whether ME/CFS patients here have the stamina to read such long excerpts of complex material is another question.

You can create more readable and useful posts on PR by writing more succinctly in your own words the points that you want to get across. And then you can provide a weblink to any supporting material, or place that supporting material in an orange quote box, quoting the relevant paragraphs from the material. Usually less is more.

That way the knowledge you have to offer can be better understood by readers of this forum.

An orange quote box can be inserted using this menu option:
Quote box.png


I hope you find these suggestions about posting style useful.



I know you are involved in the site I hope we can get along. It seems anything cannabis turns people against me normally. I see from some of your posts you likely do not feel this way about cannabis related stuff so am hopeful.

You may personally get benefits from Cannabis, but given how common this drug is, if it were the cure for ME/CFS, we would know it by now.

Some people use Cannabis as a PEM buster (see the PEM busters thread). I suspect Cannabis helps alleviate PEM via its effects on mitochondria; see this quote from the PEM busters thread:
In terms of why cannabis has this anti-PEM effect, this article says the THC and CBD active principles in cannabis can affect mitochondria: cannabinoid type 1 receptors (CB1) are found on mitochondria, and THC is an agonist of the CB1 receptor, whereas CBD is an antagonist of this receptor. So maybe that is how cannabis helps avoid PEM, by modulating mitochondrial function.




Your post to me appears slightly attacking finding faults as much as possible, defending your friend? I just added my thoughts like others do to me. Then I get this reaction.

I was not attacking, I just thought that statement made by Wishful looked correct, so I wondered why you thought his statement was wrong.
 

Jadzhia

Senior Member
Messages
148
Location
England, UK
I'm in Greg's Facebook group(s) re B12 deficiency. I joined a couple of years ago when I stumbled across them by chance, and was immediately attracted by the Kreb's Cycle of the group's banner! Anyway I have been (attempting to) follow his protocol during that time and still do so.

There's a lot to unpack, really. The group consists of a large mix of people, some have CFS/ME, many have hypo (or occasionally hyper) thyroidism (I am hypo with Hashi's and think I have some degree of CFS, am still investigating that). Others there have autistic children whom they are trying to help or are diagnosed with B12 deficiency but can't get well.

The protocol has a very definite 'order' to it, in terms of the 'cascade of energy' - from Iodine through Selenium, Molybdenum, B2 and B12. The thyroid is crucial to this as it requires both Iodine and Selenium, and Greg monitors the thyroid by using TSH along with total T4 and T3 measurements (rather than the 'frees').

As doctors misuse TSH all the time to assess one's thyroid function (by using it on its own without looking at thyroid hormone levels), I am very resistant to monitoring one's thyroid via TSH (which is a pituitary hormone after all), and aiming to get it to a value of 1.0 in lab tests. Not everyone's TSH 'set point' is the same, plus there is diurnal variation in TSH, plus some folk have problems with their pituitary that causes their TSH to not respond properly. I have never seen any of those points mentioned. I do see people post how their TSH is, say, 1.3 and they can't seem to get it lower, how much more Iodine do they need to take. I feel there can be an over-emphasis on TSH which doesn't help.

The 'functional' deficiencies have been nicely covered by @Hip above. You may have a very high top of the reference interval value for B12 in your blood but yet be 'paradoxically' deficient - this is because it is in an inactive form and cannot be utilised, yet you will think you are replete in it and so will your doctor. Greg says that sublingual supplementation is ineffective and serves to increase this paradoxical level in the blood, and he invented his B12 oils for transdermal application to overcome this.

I definitely had signs of B12 deficiency - peripheral neuropathy - despite taking B12 sublingually in large doses. I have been using B12 transdermal oils and was just thinking last night how my feet are now free of neuropathy. I also take B2 as it seems to be the cornerstone of so many enzymes - via FAD.

Greg claims that both histamine intolerance and oxalate issues (which I have) can be remediated via fixing B2 deficiency (as it's needed to metabolise these) but as yet I have not seen the back of these unpleasant conditions. Some in the group have done so, and have gone from only being able to eat a few foods to back to a normal diet. I can't speak to how many have been 'cured' of CFS/ME, I'll have to take his word for it.

The OAT is Greg's favourite analytical tool along with thyroid labs, full blood count and iron panel. He has accumulated hundreds of OAT tests from many people who've contacted him. I don't doubt for a minute that he has helped people, but of course everyone is different. He is not a fan of many supplements (e.g. magnesium) preferring that people get their nutrition from food. This of course can be extremely difficult if you have food intolerances.

I think I will pause here or my post will reach epic proportions, if it hasn't done so already! I do recall Greg mentioning Creatine as important in CFS but will put that in another post. :)
 

Learner1

Senior Member
Messages
6,305
Location
Pacific Northwest
I think I will pause here or my post will reach epic proportions,
Thank you for your epic post. I found it very interesting.
The OAT is Greg's favourite analytical tool along with thyroid labs, full blood count and iron panel. He has accumulated hundreds of OAT tests from many people who've contacted him. I don't doubt for a minute that he has helped people, but of course everyone is different
I have gone the rounds with Greg. He is very formulaic and everything goes back to his pet theory. Though the OAT can be useful, I find it misses many things that are important for ME/ CFS patients, like amino acids, antioxidants, lipids, heavy metals, and mineral cofactors.
Greg monitors the thyroid by using TSH along with total T4 and T3 measurements (rather than the 'frees').

As doctors misuse TSH all the time to assess one's thyroid function (by using it on its own without looking at thyroid hormone levels), I am very resistant to monitoring one's thyroid via TSH. TSH
Agreed.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471951/
He is not a fan of many supplements (e.g. magnesium) preferring that people get their nutrition from food
Over 70% of Americans are short of magnesium. It is virtually impossible to get enough through food and it is an important cofactor for many, many reactions.
Greg claims that both histamine intolerance and oxalate issues (which I have) can be remediated via fixing B2 deficiency (as it's needed to metabolise these) but as yet I have not seen the back of these unpleasant conditions.
That's wishful thinking. Oxalates and histamine intolerance cannot be remedied by taking B2. There are multiple factors that contribute to histamine. Intolerance. Oxalates are an insidious toxin that are in plant-based foods, and microbiome composition is critical for reducing oxalates, as well as lowering oxalate intake, binding them as they come into the body with minerals, supplementing minerals one becomes short of, and ideally, replacing oxalate degrading bacteria in the microbiome, to reduce oxalate load in the body are all critical to improving oxalate problems. Additionally, some people have genetics that cause them to accumulate oxalates, and taking B2 is not going to reverse these genetics.

All of these flaws make me very suspicious of Greg's self-enriching dogma. Oral, sublingual, as well as injectable MB12, AB12, and HB12 have been helpful In many patients, without Greg's oil.
I definitely had signs of B12 deficiency - peripheral neuropathy - despite taking B12 sublingually in large doses. I have been using B12 transdermal oils and was just thinking last night how my feet are now free of neuropathy
There are other factors that can lead to neuropathy. Too much or too little B6, for example.