I've wanted to revisit this thread for awhile, but putting together long posts is not my forte anymore (came close to ditching this half-way), and mail failure's set me back. Since
http://forums.phoenixrising.me/inde...function-in-myalgic-encephalopathy-cfs.48446/ I think we have a better perspective on the substances suggested here.
Originally I tried a protocol similar to what Kimsie suggested here and the composition led me to believe purine/pyrimidine synthesis was involved (that was fishing). Kimsie focused more on NAD. I think both pathways were too specific, even though they are low in CFS/ME. The NAD was more likely, and Kimsie focused more on B3 (I seemed to need B2 roughly as much) which is not the wrong direction, because B3 as Niacinamide is strong with broad effects. That's the past now.
So reiterating, what should open more doors is instead targeting and trying to normalize the mTor/AMPK cycle (roughly:
http://suppversity.blogspot.com/2011/09/intermittent-thoughts-on-intermittent_25.html) - or at least try to emulate or coerce a normal one using supplements and medication - with a focus on the mTor side for CFS/ME (the opposite of the recommendations "healthy" people get for life extension and cancer prevention). That approach should most likely overlap and encompass the NAD and purine/pyrimidine synthesis.
To do this, timing and the right combinations of substances should be key. But by default I'd assume the common substances listed here won't target or help enough to counteract the specific signals hijacking mTor in CFS/ME. Which may be part of the why some people don't even react to the shotgun approach, and when you do it's short-lived. But at the other extreme, expecting a single medication to reverse one signal and fix all the cycles automatically and ignoring the rest is a bit naive and probably counterproductive. I for one want to put the odds on my side (that's mostly all I do).
In the Metabolic Profiling thread, the Niacinamide (but maybe not so much niacin) seemed relevant right off the bat because of the skin research showing it to boost sphingolipids (->mTor). There isn't enough information on that, but there is this study on Schizophrenia linking its deranged sphingolipid metabolism to skin expression:
https://academic.oup.com/schizophre...07/Skin-Ceramide-Alterations-in-First-Episode So it's at least plausible that skin could serve as a biomarker, and niacinamide reserving its effects for skin seems unlikely. Coincidentally, as I think Kimsie wrote, B3 is used to treat schizophrenia, so it's hard to ignore all this. Also coincidentally... I have the worst skin in the world! Nevertheless, if it solved the sphingolipids completely on its own in CFS/ME (making some assumptions here), I think some of us would have noticed by now.
That aside, Niacinamide is usually advertised as a SIRT1 inhibitor (I think is at least part of why it inhibits lipolysis). In fact, it's a dual SIRT1 inhibitor/activator. Taking a high dose, the blood level of Niacinamide stays elevated for a number of hours, and during this time it should primarily inhibit SIRT1 overall. When the blood levels fall enough, you're left with elevated NAD which upregulates SIRT1 (this process promoted by rising AMPK which increases NAMPT and the Niacinamide->...->NAD conversion).
The SIRT1 inhibition promotes mTor, and SIRT1 is friend of AMPK, so the net effect of Niacinamide is to act as an amplifier of the mTor/AMPK cycle. Which is reduced or otherwise broken in CFS/ME, so it seems like a reasonable adjunct to take based on that alone.
That said, at first glance Niacinamide does appear outright contraindicated in CFS/ME because of the PDH inhibition. Niacinamide basically requires carb metabolism because of the lipolysis inhibition. So definitely other substances are needed (for mTor and/or PDH) and caution warranted.
The time to take Niacinamide is definitely at the beginning of a meal or feeding period, including enough carbs. The dose matters, because the higher doses could inhibit SIRT1 for too long. Therapeutically a popular dose of Niacinamide is 1500mg, and it maximizes its effects, but I think it may lead to blood levels lingering excessively (nevermind being too strong), depending on daily routine and eating pattern (intermittent fasting, etc.). There are some research and articles on its half-life which I haven't read in depth yet, but I think the prudent approach is to start with and/or stick to 100-300mg.
From what Nandixon posted, we know Glutamine is quite relevant to mTor function. The only comment I can make further on it, is from experimentation, sometimes it seemed more effective to take 30-60 mins prior to eating, rather than exactly at the same time as other aminos like Leucine. Perhaps for preloading the cells.
Obviously now, the general protocol calls for Leucine, which there was little focus on, and in my own attempts, regularly my protein sources at that time were not optimal sources. Lysine is also known to be able to contribute to mTor. So Whey is no doubt quite a powerhouse in this respect (even with ketogenesis aspect aside), and comes with enough Tyrosine to offset the common depressive effect of BCAAs (advantaged vs taking separate aminos), and fast assimilation being the closest possible to isolate aminos as you can get.
A bit surprisingly, Glycine can also rescue mTor, in a relevant way to disease:
https://www.ncbi.nlm.nih.gov/pubmed/27225947
Glycine enhances muscle protein mass associated with maintaining Akt-mTOR-FOXO1 signaling and suppressing TLR4 and NOD2 signaling in piglets challenged with LPS.
Pro-inflammatory cytokines play a critical role in the pathophysiology of muscle atrophy. We hypothesized that glycine exerted an anti-inflammatory effect and alleviated lipopolysaccharide (LPS)-induced muscle atrophy in piglets. Pigs were assigned to four treatments including the following: 1) nonchallenged control, 2) LPS-challenged control, 3) LPS+1.0% glycine, and 4) LPS+2.0% glycine. After receiving the control, 1.0 or 2.0% glycine-supplemented diets, piglets were treated with either saline or LPS. At 4 h after treatment with saline or LPS, blood and muscle samples were harvested. We found that 1.0 or 2.0% glycine increased protein/DNA ratio, protein content, and RNA/DNA ratio in gastrocnemius or longissimus dorsi (LD) muscles. Glycine also resulted in decreased mRNA expression of muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1) in gastrocnemius muscle. In addition, glycine restored the phosphorylation of Akt, mammalian target of rapamycin (mTOR), eukaryotic initiation factor 4E binding protein 1 (4E-BP1), and Forkhead Box O 1 (FOXO1) in gastrocnemius or LD muscles. Furthermore, glycine resulted in decreased plasma tumor necrosis factor-α (TNF-α) concentration and muscle TNF-α mRNA abundance. Moreover, glycine resulted in decreased mRNA expresson of Toll-like receptor 4 (TLR4), nucleotide-binding oligomerization domain protein 2 (NOD2), and their respective downstream molecules in gastrocnemius or LD muscles. These results indicate glycine enhances muscle protein mass under an inflammatory condition. The beneficial roles of glycine on the muscle are closely associated with maintaining Akt-mTOR-FOXO1 signaling and suppressing the activation of TLR4 and/or NOD2 signaling pathways.
Anyway, protein is obviously important, but also the fast digestibility and absorption of aminos I think is a bigger factor than I originally thought, for the purpose of modulating mTor/AMPK and exploit window of activation.
But high protein is also a burden on the liver to regulate and metabolize, and the Glutamate, Glutamine, and Glycine all have negatives as neurotransmitters, in and of themselves and by producing ammonia, like Adreno and others pointed out in these threads. I do think TUDCA has a notable value specifically in helping the liver process high protein (Mario's thread has the links), and although Nandixon made a good counterpoint in the other thread, I still think (pure) NMDA antagonists could be a useful workaround if you don't mind their effects. Long story short, I worry about high protein protocols failing needlessly or backfiring without proper support to handle the protein.
Of course none of this is written intending to address the specific derangements in CFS/ME being investigated in the other thread. It's all supporting protocol and revisiting why some of these substances may have or could make a difference.
But these did help me before, and so now my interest is in repurposing them for mTor/AMPK cycle normalization, to combine with the more targeted interventions being looked at and/or known to revert or force these processes, such as the Cemetidine, NMDA/AMPA antagonists/agonists, etc. Wishfully something that could be used 4-5/7 days of the week perpetually.
