Research Group for ME/CFS, Chronic Disease, Ageing and Cancer

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B vitamin support - B6 Paradox?
« on: June 26, 2021, 01:29:18 PM »
In general, the protocol's use of B vitamins to support the added draw on their usage is sound.

However, at least one B-vitamin, B6 (Pyridoxal / Pyridoxine / Pyridoxamine) exhibits a paradoxical reaction in at least a subset of the population.

To that end, it might be best to reduce or eliminate added B6 while performing the protocol and definitely in the maintenance phase as B6 can quickly accumulate and start causing irreversible damage. 

An aside, but there may be evidence that supplementing Pyridoxamine may be a hack to backfill and support normal P5P / Pyridoxamine ratios in cells (Yes, different cells have different homeostatic levels of PL to PM). Though, this is simply not possible in the US.

Really, though, the amount of incoming B6 in the food-based version of the protocol should be more than sufficient (in fact, it *may* even be too much for some).

-----------

A few references:
https://pubmed.ncbi.nlm.nih.gov/28716455/
(Evidence that high amount of Pyridoxine intracellular can block B6 reactions. Quite the opposite one would want on the protocol)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1513048/
(Evidence that high amounts of Pyridoxal-5-Phosphate in the pituitary interrupts proliferation, and hormones)

https://www.sciencedirect.com/science/article/pii/S221343442030013X
(Evidence that most individuals will not tolerate Pyridoxine based supplements over-running PL Kinase, and evidence that a small subset of people will still accumulate Pyridoxine if only supplementing Pyridoxal in 7 short days on 50mg)



Re: B vitamin support - B6 Paradox?
« Reply #1 on: June 26, 2021, 02:03:48 PM »
Rodent and cell studies might be meaningless. Usually only pyridoxine causes neuropathy, not pyridoxal. Used in average 160 mg per day of a mix of both for the last 13 years.

2 years ago the EU disallowed any B6 above 20mg per dose. Therefore relyed more heavily on pyridoxine upto 120 mg/d, Which for the first time caused some tingling in my left arm only neuropathy. Reversed by using higher pyridoxal again.

Needs are highly individual, therefore not helpful to give such general warnings. Best way with any new supplement is to start with lowest possilble doses, and increase gradually over weeks, months and years, whlie monitoring lab-testing and symptoms.

However, even that precaution is actually in complete contradiction of whats this experimental protocol is about.
« Last Edit: June 26, 2021, 02:07:41 PM by pamojja »


Re: B vitamin support - B6 Paradox?
« Reply #2 on: June 26, 2021, 07:17:07 PM »
In general, the protocol's use of B vitamins to support the added draw on their usage is sound.

However, at least one B-vitamin, B6 (Pyridoxal / Pyridoxine / Pyridoxamine) exhibits a paradoxical reaction in at least a subset of the population.

To that end, it might be best to reduce or eliminate added B6 while performing the protocol and definitely in the maintenance phase as B6 can quickly accumulate and start causing irreversible damage.

An aside, but there may be evidence that supplementing Pyridoxamine may be a hack to backfill and support normal P5P / Pyridoxamine ratios in cells (Yes, different cells have different homeostatic levels of PL to PM). Though, this is simply not possible in the US.

Really, though, the amount of incoming B6 in the food-based version of the protocol should be more than sufficient (in fact, it *may* even be too much for some).

-----------

A few references:
https://pubmed.ncbi.nlm.nih.gov/28716455/
(Evidence that high amount of Pyridoxine intracellular can block B6 reactions. Quite the opposite one would want on the protocol)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1513048/
(Evidence that high amounts of Pyridoxal-5-Phosphate in the pituitary interrupts proliferation, and hormones)

https://www.sciencedirect.com/science/article/pii/S221343442030013X
(Evidence that most individuals will not tolerate Pyridoxine based supplements over-running PL Kinase, and evidence that a small subset of people will still accumulate Pyridoxine if only supplementing Pyridoxal in 7 short days on 50mg)
This is an interesting discussion that I've had with Oleg, also.

My thinking around this is that at least 2 things are possible, here - 

P5P is one of the most used co-factors in metabolism. 

P5P get thoroughly (ab)used in the disease model, once oxidative stress (ROS) reaches a level where the a-KGDH impairment causes methylation issues via [B12, riboflavin, folate] + P5P metabolism as succinate (look for high MCV in blood results). This in turn places larger demands on ferritin, magnesium and zinc. 

Likewise, Glutamate + P5P can become GABA, via GAD. GABA + P5P can become succinate. 

With the enhanced nitrogen production, the conversion of glutamate to GABA becomes a relevant balancing and recycling pathway in the model and a lack of P5P (or GAD) could lead to excitotoxicity risk + prevention by enhanced nitrogen disposal via glutamine->phenylacetylglutamine and then the whole cascade of depletions that stem from acetyl-coa depletion, as described in the model, in addition to the P5P being consumed from the 2 pathways to succinate and excreted as nitrogen.

Simultaneously, without sufficient magnesium / zinc, the conversion of pyridoxine -> P5P becomes impaired and if chronic, could lead to peripheral neuropathy via pyridoxine accumulation. https://pathbank.org/view/SMP0000017
NB. I am NOT a doctor and all information provided is for educational purposes only.

Please consult your physician before attempting anything you read here.


Re: B vitamin support - B6 Paradox?
« Reply #3 on: June 26, 2021, 08:47:25 PM »
So glad you guys brought up the B6Toxicity topic (SFNP/PNP symptoms w/high b6 plasma levels)!

The fear of B6 (due to reasons below) is one thing deterring multiple people (including myself) from trying the current protocol (which packs a 100mg p5p and 5mg Pyridoxine HCL in the multivitamin), so would be great if we could figure out the mechanism by which b6toxicity seems to be happening, and how to mitigate it.

Josh has some interesting ideas of why this might be happening  [mentioned 2 of them above].

@Shanman75 can confirm how thousands of B6Toxicity group members on social media can attest to having the same symptoms w/high b6 levels in blood - a bunch of them did megadose B6, many of them Pyridoxine, but there were also many who did P5P supplementation, low dose supplementation, or did not (knowingly at least) supplement at all, but got the symptoms and high blood levels. Most of these people also report to getting flareups when eating foods high in B6.

I want to note, that many (maybe most or more) people in those groups do seem to have some type of underlying chronic issues, which could imply problems with cellular metabolism.

I am personally currently doing an experiment of eating high B6 foods for a few days to see if it induces an onset of symptoms that stay, and if I could lessen those with a certain supplement cocktail, more specifically, if symptoms come on and get worse, stick around I'll take:

NAC - ballpark 500mg each hour
Sodium benzoate - 250mg each hour
Glycine - 250mg each hour
LOLA - 500mg (test dose and increase up to 3-5g for the day)
Forskolin - testing 1/2 cap 1x day
a-GPC - 250-300mg, 1-2x day

And we'll see if those can bring the symptoms down.

Anyway looking forward to your guys' scientific discussion, and hopefully other b6T or b6T worried people can benefit!


hEDS, neuropathy symptoms


Re: B vitamin support - B6 Paradox?
« Reply #4 on: June 26, 2021, 10:44:44 PM »
Hey guys,

I'm also concerned about this - I've been supplementing a B complex for around 2.5 years now. I developed restless leg syndrome (RLS) a few weeks/months after I became severe with my ME/CFS (can't recall the exact timing sadly).

It has been slowly but gradually progressing. I also noticed last winter, and now this winter as it has gotten colder, that I also seem to be having some neuropathy in my toes.

I had my serum p5p tested in March and it was 120 ug/L (range greater than 12 for sufficiency, neuropathy observed generally above 600 ug/L).

I'm not sure if this is potentially contributing to these issues or if they are simply a result of my ME/CFS.

Some discussion about target blood levels of p5p would be very interesting and useful, if anyone has any existing knowledge on this. 


Re: B vitamin support - B6 Paradox?
« Reply #5 on: June 27, 2021, 07:48:53 AM »
Some responses to various thoughts so far

Insufficient co-factors for B6 homeostasis of intracellular Pyridoxal / Pyridoxamine versus Pyridoxine
I have heard this theory proposed by many, but I find it wanting. There are just too many people that can't manage high B6 amounts (albeit a subset of the total population). Additionally, there are many who have upped their Zinc consumption especially during COVID, and there only seem to be more people running into neuropathies from B6 recently than in the past. (but, that could easily be biased)

B6 metabolism also needs B2 (FAD / Flavin) and for conversion to Pyridoxic Acid, Molybdenum. 

B6 Transport (not discussed yet in the thread)
Some individuals have issues with ALPL and Alkaline Phosphatase (ALP) homeostasis. This can make transportation difficult because of the need to phosphorylate and de-phosphorylate for transport.

Low thresholds for toxicity in some (+anecdote)
There have been many cases of people getting toxic on food (e.g. a high protein diet), or even smaller doses. Anecdotally this seems to be increasing. Though, that just could be an awareness bias (and even a confirmation bias in those that are sharing their stories online).

I myself have been toxic on smaller doses of both P5P and Pyridoxine. Yes, I thought it might be only Pyridoxine as well, but biomarkers and symptoms all showed signs of P5P impairment on a relatively low dose of P5P + mainly B6 from animal products stint I went thru last fall for 7 weeks (averaging 4.8mg/day of B6 for the period). I certainly had all the co-factors on board, as well.

For years, I have consumed very large amounts of Magnesium, and decent added amounts of Zinc/Copper (usually in a Zinc/Copper mix, but not always). I do MgCl + MgSO4 on the skin, Mg Bicarb + Mg Citrate supplements (and sometimes Mg Oxide). And, I definitely get plenty of Vitamin B2.

B6 load from the protocol
Given the potential for impact to a select few having either a physiological barrier to B6 management, or a temporal barrier to B6 management, what is the actual hypothesized load of B6 (PLP/P5P) by the protocol?

So far I've seen the following proposed:
GABA processing: Glutamate -> GABA -> succinate (though, unsure how used this is, and it might trigger a cell to produce Pyridoxine to slow its use??)
Neurotransmitter genesis: Nominal levels (? I can't see where there is significant added load)

Certainly Pyridoxal-5-Phosphate is used up when reactions occur, but how many added reactions occur? And, are they offset by reactions that release P5P (or another vitamer form that can be salvaged back to Pyridoxal / Pyridoxamine)?

PL Reductase activity (conversion of PL to PN in humans)
The PathBank reference is missing the PL Reductase link:
https://pathbank.org/view/SMP0000017

PL Reductase activity is found in humans (though, not yet fully understood):
https://www.sciencedirect.com/science/article/pii/S0304416519300753

This may be a missing link in some as it is probably variable by individual. While it very well could be a co-infection (maybe a virus given the type of research done in the above), PL reductase is hypothesized to slow down reactions in some when P5P levels are high. If so, clearing EBV in an individual that hyper-manages P5P levels may still result in B6 sensitivities.

Do note that the very small sample size (2 individuals) significantly accumulate Pyridoxine in Cerebral Spinal Fluid (CSF). I don't think this is a good thing to do if it indeed happens in a subset of humans.

B6 management in protocol maintenance
@Josh, do you have any hypothesis for what would impair B6 management prior to the protocol that would be alleviated post-protocol / during maintenance and allow for higher levels of B6 to be managed effectively by a body? This is one area I struggle with as I don't yet know all the dysfunctions (HPP / ALPL are certainly one, but others?) whereby one could justify taking such high doses during maintenance. (105mg in version 3.31)

The majority of cells do a really really good job at preserving B6 stores. From what I can see, Pyridoxamine is high in many tissues acting mainly as local storage that is not antagonist like Pyridoxine is. In the brain, it is very high proportional to P5P. To me, this provides a pretty large buffer for homeostasis to only need a small amount to maintain it (say, .8-1.2 absorbed per day....and, absorption is somewhat age dependent which drives the target of 1.3 to 1.7mg/day in different countries).


Re: B vitamin support - B6 Paradox?
« Reply #6 on: June 27, 2021, 01:59:48 PM »
Hey guys,

I'm also concerned about this - I've been supplementing a B complex for around 2.5 years now. I developed restless leg syndrome (RLS) a few weeks/months after I became severe with my ME/CFS (can't recall the exact timing sadly).

It has been slowly but gradually progressing. I also noticed last winter, and now this winter as it has gotten colder, that I also seem to be having some neuropathy in my toes.

I had my serum p5p tested in March and it was 120 ug/L (range greater than 12 for sufficiency, neuropathy observed generally above 600 ug/L).

I'm not sure if this is potentially contributing to these issues or if they are simply a result of my ME/CFS.

Some discussion about target blood levels of p5p would be very interesting and useful, if anyone has any existing knowledge on this.


This sounds a lot like my symptom onset - I had muscle twitching, legs feeling restless, twitchy, tingling, rippling when laying down, and then came things like sensory overload and buzzing etc.

Here's the full list of symptoms that correlated with the B6levels and onset:
https://drive.google.com/file/d/1-1TTfrykhwT9xAqHrZDgCoO_4VMiWjvk/view?usp=sharing

I was not supplementing B6, but my levels were 2x the upper range: 46ng/ml ; Range is 2.1-21.7ng/ml.

This is pretty common in the B6T groups (people experiencing neuropathy without being close to the “official“ potential neuropathy levels). It’s as if the body messed something up and started miss managing the B6, or maybe something else happened and the high B6 levels were just a side effect… no idea.

I’ve been trying to get to the bottom of this for months, and been afraid to try the protocol because of this. It completely messed up what was left of my prior life where I already had chronic issues (HEDS), and put a lot more limits on me. Including dietary, and being scared to try protocol :/


« Last Edit: June 27, 2021, 02:03:33 PM by HealthnHappiness »


Re: B vitamin support - B6 Paradox?
« Reply #7 on: June 28, 2021, 04:29:45 AM »
... (trimmed for space) 
B6 management in protocol maintenance
@Josh, do you have any hypothesis for what would impair B6 management prior to the protocol that would be alleviated post-protocol / during maintenance and allow for higher levels of B6 to be managed effectively by a body? This is one area I struggle with as I don't yet know all the dysfunctions (HPP / ALPL are certainly one, but others?) whereby one could justify taking such high doses during maintenance. (105mg in version 3.31)

The majority of cells do a really really good job at preserving B6 stores. From what I can see, Pyridoxamine is high in many tissues acting mainly as local storage that is not antagonist like Pyridoxine is. In the brain, it is very high proportional to P5P. To me, this provides a pretty large buffer for homeostasis to only need a small amount to maintain it (say, .8-1.2 absorbed per day....and, absorption is somewhat age dependent which drives the target of 1.3 to 1.7mg/day in different countries).
Good conversation points! So, setting the scene -

P5P is a cofactor used in possibly 140+ reactions. 
In this manner, we could think of it as an "enabler" of other things (reactions). 
If some of those reactions are part of runaway pathways / processes from virally altered metabolism, we come back to the old "things that help healthy cells also help unhealthy cells", as discussed in cancer research (androgen/estrogen/b12 depletion therapies, etc).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1326353/

Some of these pathways are really important and related to many of the symptoms being discussed, albeit further down the cascade (we'll come back to this article):
https://pubmed.ncbi.nlm.nih.gov/29204749/

Too much B6/pyridoxine is associated with acutely decreased P5P, although the mechanism isn't clear. It could be that that high levels of P5P directly inhibit the B6 metabolism, as indicated, however it could be that additional P5P-related metabolism depletes a common cofactor for pyridoxine metabolism:
https://pubmed.ncbi.nlm.nih.gov/28716455/

A deficiency of B6 (and presumably P5P) is generally associated with the diseases in the spectrum being discussed:
https://pubmed.ncbi.nlm.nih.gov/17260529/
https://www.researchgate.net/publication/225042504_Plasma_Pyridoxal-5-Phosphate_Is_Inversely_Associated_with_Systemic_Markers_of_Inflammation_in_a_Population_of_US_Adults
https://www.researchgate.net/publication/49826424_Low_Plasma_Vitamin_B-6_Status_Affects_Metabolism_through_the_Kynurenine_Pathway_in_Cardiovascular_Patients_with_Systemic_Inflammation

(Although this may have some explanations from high homocysteine:)
https://pubmed.ncbi.nlm.nih.gov/17260529/

However, high P5P is associated with sensory neuropathy in some people.. as you no doubt have unpleasantly experienced way too often:
http://www.viapath.co.uk/articles-and-papers/the-prevalence-of-low-and-very-high-vitamin-b6-pyridoxal-5%E2%80%99-phosphate

In other people, the P5P upper limit seems unknown -
RCTs showing 250mg, 750mg/day of P5P weren't associated with SFPN or the other symptoms we regularly discuss that are common to multiple diseases in the spectrum.
https://pubmed.ncbi.nlm.nih.gov/18381567/
https://pubmed.ncbi.nlm.nih.gov/17532963/

Now, the article you linked also shows pyridoxine accumulation in the CSF and plasma of some acutely ill people who were given P5P, however I was also interested to see the accompanying VAST increases of pyridoxal, suggesting an issue with either phosphorylation.. (seems rare).. or, as you said - FAD/flavin deficiency, despite "normal" riboflavin consumption (good old MTHFR / C677 territory).. perhaps suggesting depletion and excretion elsewhere, as we regularly see in CFS/ME people (look at homocysteine, high MCV, low ferritin) .. as such, this might be driven by the high ROS "nitrogen drain" I've been describing.
https://www.sciencedirect.com/science/article/pii/S0304416519300753

Overall, what I'd be suggesting for anyone in this rather unfortunate situation is that if they've checked their serology, found high titres of a HHV and were now considering self-experimenting with the research I've been describing, 2 things might be appropriate:

1. Starting the protocol by performing the GDH knock-down water fast. This would likely allow for a thorough reset of problematic metabolite levels.
and/or
2. Leaving out any additional B vitamins until after the induction phase has been completed and then "testing the waters" appropriately.

Someone may also see benefits from an unpublished "lite" version of the older v2 protocol, which addresses the same hot-spots in a different way.

Something I have been looking into recently, which I think is going to be more appropriate for some of the B6 toxicity subgroup are metabolic alterations from enterovirus / coxsackie infections. These bolt into the disease model in slightly different places to HHV (so far - serotonin, dopamine/catecholamine metabolism, GABA metabolism), however has the same downstream cascade. (reference to that earlier link)

This area is very much a WIP, although we have some specific biomarkers that can be tested which may infer positive serology for one or more of these other viruses.


Re: B vitamin support - B6 Paradox?
« Reply #8 on: June 28, 2021, 08:47:54 AM »
... (trimmed for space)
... (trimmed for space)

Overall, what I'd be suggesting for anyone in this rather unfortunate situation is that if they've checked their serology, found high titres of a HHV and were now considering self-experimenting with the research I've been describing, 2 things might be appropriate:

1. Starting the protocol by performing the GDH knock-down water fast. This would likely allow for a thorough reset of problematic metabolite levels.
and/or
2. Leaving out any additional B vitamins until after the induction phase has been completed and then "testing the waters" appropriately.

Someone may also see benefits from an unpublished "lite" version of the older v2 protocol, which addresses the same hot-spots in a different way.

Something I have been looking into recently, which I think is going to be more appropriate for some of the B6 toxicity subgroup are metabolic alterations from enterovirus / coxsackie infections. These bolt into the disease model in slightly different places to HHV (so far - serotonin, dopamine/catecholamine metabolism, GABA metabolism), however has the same downstream cascade. (reference to that earlier link)

This area is very much a WIP, although we have some specific biomarkers that can be tested which may infer positive serology for one or more of these other viruses.
Great points!!!

I like the suggestion to go down the water-fast / GDH knockout method alone. The risk and the journey is a bit off-putting even for someone like me...who has done some pretty risky things in the past (like my multi-gram Niacin flushes that did NOT end well!)

Perhaps the protocol without the added P5P/Pyridoxine in the mix would also work out well...unless someone can point out that the PLP/P5P requirements might be and that they exceed what one gets by the added B6 in food (the suggested diet in the protocol more than doubles the normal B6 burn rate of .8-1.2mg/day)

Adding back B6
I'm very apprehensive in suggesting adding back B6 to anyone that has experienced B6 hypervitaminosis (including myself). If we had a real-time, or even fairly accessible way of evaluating B6 function, this may be a valid idea. However, the only tests I know of are:
- B6 Plasma (which doesn't break down the vitamers, and is really poor at predicting CSF and Intracellular levels)
- OAT B6 markers (XA / KA ratios...perhaps with a Tryptophan challenge, and corroborating one-carbon metabolites). Trouble is, this takes at least 3 weeks to get results.

I did an experiment on P5P only in a complex by measuring the contents out on a mg scale last fall, and ran into low B6 function (overnight heart rate started increasing) fairly quickly with latent issues taking a few more weeks (Thyroid blockage ~2-3 weeks in, Bile disruption ~8 weeks in...near when I stopped). Average intake was 4.8mg B6/day (Food + Supplement) over 50 days.

I took several plasma samples (and CBC / CMP's) during that do show my total B6 moving up and exceeding the Quest range. I have all my food and supplement intake logged since last August along with these samples.

Link to complex:

Note: I do realize now that Benfotiamine isn't the ideal form for maintaining total body Thiamine status as it fails to raise Brain levels of Thiamine
Note: I was also taking lots of Mg and pulsed Zinc before and during this period.

Concurrent infections
This is an interesting area, as well. Both viruses that modify cellular function, and SIBO (or even enteric bacterial infections) can modify cell function thru the mass load of various substances (certain Clostridia overgrowth manufacturing HPHPA and inhibiting conversion of Dopamine to Norepinephrine, Yeast/Candida possibly disrupting Kreb in subsets of cells, etc.). 

The HPHPA impacted me last year, but I was able to clear Clostridia and HPHPA levels are now nominal. 

And, there are so many other potential confounders.


Re: B vitamin support - B6 Paradox?
« Reply #9 on: June 28, 2021, 01:21:54 PM »
Hey guys,

I'm also concerned about this - I've been supplementing a B complex for around 2.5 years now. I developed restless leg syndrome (RLS) a few weeks/months after I became severe with my ME/CFS (can't recall the exact timing sadly).

It has been slowly but gradually progressing. I also noticed last winter, and now this winter as it has gotten colder, that I also seem to be having some neuropathy in my toes.

I had my serum p5p tested in March and it was 120 ug/L (range greater than 12 for sufficiency, neuropathy observed generally above 600 ug/L).

I'm not sure if this is potentially contributing to these issues or if they are simply a result of my ME/CFS.

Some discussion about target blood levels of p5p would be very interesting and useful, if anyone has any existing knowledge on this.

The discussion between Joshua and Shannon is one of the best B6T discussion I've witnessed. Hopefully the back and forth can eventually help find a resolution for b6T and how those w/B6"issues" can safely do the protocol. 

I wonder if there's any advice for now for people in GlassCannonLife position? 

GlassCannon if you are presently doing the protocol and taking the multi (containing 100mgp5p, 5mgpyrodoxine) - perhaps you can keep us updated on your symptoms and b6 levels, if anything is resolving? 

(obviously if you keep getting SFNP symptoms and link it to high b6 levels, I'm def not saying to experiment for our sake)


Re: B vitamin support - B6 Paradox?
« Reply #10 on: June 28, 2021, 05:59:25 PM »
Hey guys,

I'm also concerned about this - I've been supplementing a B complex for around 2.5 years now. I developed restless leg syndrome (RLS) a few weeks/months after I became severe with my ME/CFS (can't recall the exact timing sadly).

It has been slowly but gradually progressing. I also noticed last winter, and now this winter as it has gotten colder, that I also seem to be having some neuropathy in my toes.

I had my serum p5p tested in March and it was 120 ug/L (range greater than 12 for sufficiency, neuropathy observed generally above 600 ug/L).

I'm not sure if this is potentially contributing to these issues or if they are simply a result of my ME/CFS.

Some discussion about target blood levels of p5p would be very interesting and useful, if anyone has any existing knowledge on this.

The discussion between Joshua and Shannon is one of the best B6T discussion I've witnessed. Hopefully the back and forth can eventually help find a resolution for b6T and how those w/B6"issues" can safely do the protocol.

I wonder if there's any advice for now for people in GlassCannonLife position?

GlassCannon if you are presently doing the protocol and taking the multi (containing 100mgp5p, 5mgpyrodoxine) - perhaps you can keep us updated on your symptoms and b6 levels, if anything is resolving?

(obviously if you keep getting SFNP symptoms and link it to high b6 levels, I'm def not saying to experiment for our sake)

I'm taking a half dose of the life extension B complex, which at that dose has 50 mg of pyridoxine hcl/p5p. It doesn't specify the amount of each form on the bottle..

Not sure if I'll try and get a b6-free b complex or continue with this for the moment. 


Re: B vitamin support - B6 Paradox?
« Reply #11 on: June 28, 2021, 06:17:25 PM »
I did an experiment on P5P only in a complex by measuring the contents out on a mg scale last fall, and ran into low B6 function (overnight heart rate started increasing) fairly quickly with latent issues taking a few more weeks (Thyroid blockage ~2-3 weeks in, Bile disruption ~8 weeks in...near when I stopped). Average intake was 4.8mg B6/day (Food + Supplement) over 50 days.

I took several plasma samples (and CBC / CMP's) during that do show my total B6 moving up and exceeding the Quest range. I have all my food and supplement intake logged since last August along with these samples.
Sorry, could you clarify what you did? I don't quite follow what you're saying.

Do you mean that you took a B complex and weighed out small amounts to deliver calculated amounts of P5P?

By "low B6 function" do you then mean that your chosen dose gave you symptoms of B6 deficiency? And this occurred despite a 4.8 mg daily intake (multiple times the RDA)?


Re: B vitamin support - B6 Paradox?
« Reply #12 on: June 28, 2021, 07:46:09 PM »
Perhaps the protocol without the added P5P/Pyridoxine in the mix would also work out well...unless someone can point out that the PLP/P5P requirements might be and that they exceed what one gets by the added B6 in food (the suggested diet in the protocol more than doubles the normal B6 burn rate of .8-1.2mg/day)

Well this is the interesting part - it really varies by person. The core levers in the HHV-related protocol revolve around normalising GDH and a-KGDH.

Depending on the 'traps' that each person has found themselves in, different metabolites / pathways may be affected, which influence these two reactions.

With that in mind, the protocol is largely aimed to be a "catch-all" for each trap that has been observed, including many instances we've seen large hints of P5P related depletion.. this might be appropriate for a large number of people and inappropriate for another group of people. It's possible that dietary P5P may be appropriate for that group.

Quote
I did an experiment on P5P only in a complex by measuring the contents out on a mg scale last fall, and ran into low B6 function (overnight heart rate started increasing) fairly quickly with latent issues taking a few more weeks (Thyroid blockage ~2-3 weeks in, Bile disruption ~8 weeks in...near when I stopped). Average intake was 4.8mg B6/day (Food + Supplement) over 50 days.

Now this appears to be where your journey and the model converges - P5P enables reactions which "bypass" the a-KGDH mitochondrial limiter at succinate.

The additional nitrogen waste created, on top of the already high nitrogen waste lead to the cascade of metabolite depletions being discussed in the model.

Phenylalanine, Tyrosine are depleted for
- Acetyl-CoA regeneration, which is needed for (https://www.ncbi.nlm.nih.gov/books/NBK22453/)
      - nitrogen disposal via phenylacetylglutamine
      - mitochondrial energy production
      - beta-oxidation / fatty acid oxidation
      - histone acetylation, to prevent DNA damage, etc
      - acetylation of metabolites, such as
            - acetylcholine (brain fog, muscle contraction issues, inflammation)
            - acetyl-l-carnitine (muscle activity and brain function, etc)
            - n-acetylserotonin (neurotransmitter and precursor to metatonin production)
            - a very, very long list of other pathways, eg.

               

Tyrosine is needed for Thyroxine, Dopamine (and downstream Norepinephrine, Epinephrine) production, so without tyrosine, you can expect downstream problems.

eg.
Hypothyroidism and
Resting heart rate increases, which could be from catecholamine dysregulation, along with localised acetyl-CoA depletion, eg. hepatic, leading to a difference in beta-oxidation rates between eg. hepatic and cardiac tissues.

The bile disruption is also a key feature in SIBO, IBD and ME/CFS. I've seen markers showing significant disruption to both primary and secondary bile acid metabolism.
   

.. in a nutshell, I think your own research overlaps heavily with ours.
« Last Edit: June 28, 2021, 08:00:11 PM by joshua.leisk »


Re: B vitamin support - B6 Paradox?
« Reply #13 on: June 29, 2021, 09:39:09 AM »


In other people, the P5P upper limit seems unknown -
RCTs showing 250mg, 750mg/day of P5P weren't associated with SFPN or the other symptoms we regularly discuss that are common to multiple diseases in the spectrum.
https://pubmed.ncbi.nlm.nih.gov/18381567/
https://pubmed.ncbi.nlm.nih.gov/17532963/

.....

These studies are pretty interesting and follow what I've seen so far generally. The majority of people seem to be able to manage higher amounts of Pyridoxal versus Pyridoxine. There is a subset of individuals that cannot for various reasons, but they are definitely <10%, and probably <1% of the population.

If that understanding holds, one wouldn't expect to see statistically significant adverse events at large with P5P. Similarly, you wouldn't expect to find as many adverse events with interventions involving Potassium in a large random population even though ~15% have CKD and would certainly be impacted due to their lowered GFR. (Though, the 15% *might* be enough to trigger statistical significance) 

It is interesting that in the second study where adverse events were recorded, the investigator was allowed to summarily dismiss unrelated SAE/AEs.

They did take blood samples, but the only reported marker was the ckMB. Why did they also not gather simple CBC / CMB's as well as B6 assays (since, after all, they were dosing 250 and 750mg!!!)

Pyridoxamine alternative one day?
A bit of a sidebar, but related. The form Pyridoxamine may help one of the subgroups that cannot manage B6 vitamers by:
A) Being inactive, but non-competitive in P5P dependent reactions
B) Purportedly supporting PNPO in the B6 Salvage tree (meaning more P5P, and less or no PN)

I have seen many studies in the US involving the drug "Pyridorin" (nothing more than Pyridoxamine). There are many involving 300mg/day and 600mg/day levels.

Here's one:
https://www.researchgate.net/publication/51752253_Pyridorin_in_Type_2_Diabetic_Nephropathy

They also don't record any statistically significant adverse impacts with this form of B6. Though, the "drug manufacturer" hasn't been able to prove efficacy in helping CKD.

Oddly enough it just may help people who do have issues with management of B6 *if* the missing link is the PNPO step in the B6 salvage tree. This is an interesting study where they induce PNPO deficiency in Zebrafish and tried various interventions with different vitamers in their water:
https://pubmed.ncbi.nlm.nih.gov/31616300/

I'm not advocating people that do have susceptibility to go out and try...it needs quite a bit more studying, but it could one day be a safer way for all people to move through a protocol like this.


Re: B vitamin support - B6 Paradox?
« Reply #14 on: July 04, 2021, 08:39:11 PM »
Digging deeper into the B6 metabolism and riboflavin connection..

B6 metabolism relies heavily on riboflavin metabolites, as FMN (and cofactors magnesium, zinc):




Therefore, if riboflavin (as FAD, FMN) is being depleted you could expect LARGE bottlenecks in B6 metabolism and accumulation of B6 metabolites.. which leads to neuropathy.. and more.

Some recent metabolomics work that looks ..hauntingly familiar.. to the disease model I've been describing also noted a-KGDH and succinate dehydrogenase (SDH) impairments - https://www.medrxiv.org/content/10.1101/2021.06.14.21258895v1

So let's take another look at the TCA cycle again and examine what may happen if ROS is high and therefore a-KGDH is proportionally low.. and if riboflavin is now decreased:



Riboflavin metabolism consumes magnesium and riboflavin->FAD depletion can further impair a-KGDH, putting more pressure on P5P via [B12, folate + P5P] (and BCAAs)



and [GABA + P5P] (GABA shunt) to fill in the shortfall at succinate, creating a riboflavin-based "metabolic trap" at a-KGDH, by continuing the cycle of depletion involving P5P.

https://www.sciencedirect.com/science/article/pii/S0005272816300597

Riboflavin is particularly difficult to absorb from diet/supplements -


Riboflavin depletion may create a further bottleneck at SDH, which may increase ROS.. which further reduces a-KGDH:



Which then puts more pressure on the urea cycle to perform and "fill in the gap" at fumarate.. which is fine for a while, as we have plenty of nitrogen to get rid of:



However, this then puts more pressure on aspartate and argininosuccinate until that fails also. We now have hypoxia, potential lactate issues + connective tissue disorders downstream of HIF-1a signalling and prolyl hydroxylases.

So in this way, chronically high ROS can becoming a trap that causes B6 toxicity and all of the downstream cascade of issues we see in CFS/ME, if P5P is able to be maintained.

If the initial ROS is being created by viral mTOR activity, the best solution is to turn that off.

For HHV-related activity, the triterpenes and beta-glucans in reishi have provided some rather good early results, as has spironolactone, however these don't do anything useful for other infections that subvert a different energy pathway, eg. fatty acid oxidation (FAO).

If anything, the metabolic patches which normalise HHV behaviour can exacerbate the problems created by these other pathogens.

This is where I'm heavily focused at the moment.

For now, as a temporary patch - aspects of v1 and v2 protocol may be appropriate for managing these other infections.

https://www.hindawi.com/journals/sci/2020/2016809/

Regular small doses of succinate (as also found in high-dose apple cider vinegar capsules) and high dose R-ALA (both 3-4 x day), plus an initial increased frequent intake of riboflavin to help unblock the "metabolic trap" and keep things balanced, may be quite useful in preventing B vitamins was being turned into nitrogen and urine, unblocking other metabolic pathways.

By supplementing succinate directly (and not overdosing on it), this prevents the drain on all of the metabolites.
(This may be around 75-100mg of succinate, 3-4x a day.)

A reportedly successful "lite" of v2 simply consisted of 2-3 high dose ACV capsules + 400mg R-ALA, 3-4x day, some eggs and otherwise maintaining a clean diet.

"Brute-forcing" a-KGDH with "very high" doses of thiamine (reports of 1g/day), or more usually as derivatives such as benfotiamine, sulbutiamine has also been reported by people as very helpful.
« Last Edit: July 05, 2021, 07:32:16 AM by joshua.leisk »