Random, interesting studies
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Why haven't y'all started superdosing melatonin yet instead of wasting lifetime and effort on quinones and saturating cardiolipins etc.?
Melatonin precedes the importance of quinones as it binds to and activates quinone reductase type 2 (NOQ2) to degrade oxidized, i.e. toxic quinones. Thus, clearly of top priority before adding any K2 (Mk-4) etc.
Melatonin reverses the Warburg-type (glycolytic) metabolism of cells.
This effect is self-enhancing, as reinstated OXPHOS enables intracellular melatonin synthesis.
Just as, without such exogenous intervention, the opposite development is a self-sustaining vicious cycle.Pathological neurons often exhibit Warburg type metabolism and redirect pyruvate into the mitochondria restores mitochondrial redox homeostasis; examples of diseases where this aberrant metabolism occurs include Alzheimer’s, Parkinsonism, amyotrophic lateral sclerosis and others (Reiter et al., 2021b). The ability of melatonin to interfere with Warburg type metabolism presumably relates to its inhibitory action of hypoxia inducible factor 1α (HIF1α), which suppresses the activity of pyruvate dehydrogenase kinase (PDK) which disinhibits PDC allowing pyruvate to enter the mitochondria followed by its conversion to acetyl CoA such that the limited availability of acetyl CoA no longer is a factor in the amount of melatonin synthesized in the mitochondria (Fig. 3) (Mota et al., 2019). These actions of melatonin are reminiscent of those using dichloroacetate, a pharmacological agent that also reverses Warburg type metabolism, perhaps by the same signaling pathway as melatonin and has generated interest as a useful pharmaceutical drug to treat several diseases (Chen et al., 2024b, Kakafika et al., 2024). It has limitations regarding its side effects, actions that do not accompany melatonin use (Bianchi et al., 2024).
Here you get a picture to go along with this:
https://journals.physiology.org/doi/full/10.1152/physiol.00034.2019And here's a table with clinical observations on melatonin relevance in metabolic syndrome (humans):
https://pmc.ncbi.nlm.nih.gov/articles/PMC11107716/table/Tab2/
And a table with experimentally shown effects of melatonin in animal models of metabolic syndrome:
https://pmc.ncbi.nlm.nih.gov/articles/PMC11107716/table/Tab1/Even better: Postmitotic cells aren't doomed to be left by themselves with their inherited pool of malfunctioning mitochondria because melatonin stimulates the transfer of mitochondria from healthy cells to damaged cells via tunneling nanotubes (TNTs)!
If you're now wondering what are tunneling nanotubes, here are pictures of them. They can form between mitochondria of the same cell as a precursor step to fusion and they can form between cells:
Disturbingly and one the downside of this spectacular mechanism, even cancerous cells may use nanotubes to steal mitochondria from T-cells:
t-cell-nanotube-cancer
(I reckon those cancer types can't be running Warburg metabolism - or do they just steal the mitos and their ATP from the immune cells only to then crush them?)And as yet another media of presentation, here's the timestamp (approx. 4mins) of an video interview with Prof. Russel Reiter, Ph.D. on this very topic of metabolism:
![https://youtu.be/t4SuIUtCSLY?t=2825] -
@CrumblingCookie Yeah you cooking us here ngl
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Yeah you cooking us here ngl
No cap fr fr?
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Yeah you cooking us here ngl
No cap fr fr?
Peat was generally suspicious of melatonin, especially as a darkness/stress-associated hormone. In one article, he grouped melatonin with “nocturnal/stress hormones” and argued it could make the retina more vulnerable under certain conditions
Peat cited A.V. Sirotkin’s porcine ovary work, saying melatonin inhibited progesterone and stimulated estradiol. He then interpreted that pattern as similar to low thyroid: higher estrogen, lower progesterone, lower resistance to stres
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@lobotomize Lol you are proving the crumbling cookie right. Muh darkness hormone.
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@CrumblingCookie what dose maybaps u may know
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@sunsunsun The very minimum metabolically effective dose over the long-run appears to be 20mg pd.
The HED from animal experiments suggest 5-10mg/kg BW as the range where optimal/maximal effects set in and Prof. R Reiter mentions that several of his diabetic peers have accordingly been taking 500-1000mg pd.
He himself is more conservative and reckons that 50-100mg should do most of the job and says one may consider body surface area instead of body weight as a perhaps more suitable benchmark for inter-species dosing conversions. The 50-100mg range is what he's been taking. Usually split up to c. 2hrs and c. 30mins before bedtime.
C. 70mg pd is also the mean/median (40-200mg) of the two Argentinian human study populations with the good cardiovascular and neurological benefits.I had started off with 10 + 20 +10mg last week but noticed that I need to stay in bed for at least 3hrs (which is also about the duration of a notably decreased body temp) after another 10mg in the early morning and will still be groggy all day (I was awake at 6am and thought: What a waste of nighttime; better take some more).
Now I've made capsules with 80mg MEL along with 220mg Na-R-ALA, which is synergistic in many ways.
(I'm going to make a small batch with also 40-50mg methylene blue in them as a complete acute ischaemia/reperfusion infarct remedy to have at hand for the elderly since still nobody's being indulged in receiving the medicinal Proveblue i.v. by the EMS despite all the evidence for it).Jeff T. Bowles was one of the early adopters of MEL in the 2010s and wrote to have taken 300-500mg for a long time and that on this dose he was very tired for three months but then it lifted. Which I find very interesting! Doris Loh endorses high-dose melatonin especially in acute inflammatory phases (cytokine storms, viral infections like Covid) and you'll see that her dosing recommendations reach well up to 4000mg pd for an adult, split up all throughout the day and night.
(Apart from such acute cases it's however likely prudent to keep MEL intake away from daylight/artificial light/screentime hours because those rodent experiments showing acutely heightened potosensitivity of the retina by elevated melatonin concentrations may also hold true in humans.)
On we go: Doris Loh suggested that higher-dose MEL (500-1000mg) may quickly overcome grogginess by lower-doses MEL. This notion possibly supports a kind of a drop-in-the-bucket scenario. It is noteworthy that reports on SS-31, the peptide which fixes broken mitochondrial membranes, also reveal that many people become extra tired from it and that this resolves either over time or by much increased dosages.
Such a particular groggy feeling of (calm, relaxed) tiredness may thus indeed be a marker of mitochondrial/metabolic healing and a good sign to continue or double-down.It's astonishing to me that all this info has already been around since the late nineties (in its earliest hints) and confirmed over and over througout the 2000s, 2010s and 2020s. I'm sure there are plenty of people who take >40mg pd melatonin but they are certainly not spread over the publicly accessible internet. Reddit and youtube is filled with bots and naysaying government agents pushing their instructions for obfuscation and scaremongering hogwash. RP's rant on MEL was blatant hogwash. There's a funny comment by someone under the YT video interview with Prof. R Reiter linked above:
Georgi has said melatonin can have a feedback loop and convert back to serotonin. (Maybe that's what put Mercola off from taking it.) .....I wrote to Russell about that and he said, "That's incorrect. Georgi doesn't know what he's talking about." He also asked me for Georgi's contact details.Duh. Higher-dose MEL hasn't even been embraced by the CFS folks on the phoenixrising forums. It's like we're all being deliberately guided to being both forcedly and voluntarily blind and deaf-mute. I certainly feel like I have been kept stupid and sent around in circles always away from crucial keystones.
My stack for mitochondrial fusion (PGC-1α, Opa1, Mfn1/2) and against excessive fission (Drp1 or most crucially Fis1) also includes echinacoside 220mg pd (from Cistanche tubulosa extract), kaempferol 25mg pd (from Kaempferia galanga extract), trans-resveratrol 500mg pd and SS-31 in yet to be determined doses (0.5-10mg pd probably; will start with 2mg pd). Also expecting delivery of Gastrodia elata rhizomes for the gastrodin as their active ingredient – the traditional Korean/Chinese way is to boil the root or its powder over 15mins and consume it as a brew/tea. And there's more research to find and dissect about morin.
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@CrumblingCookie nice…
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Melatonin inhibits cardiolipin peroxidation in mitochondria and prevents the mitochondrial permeability transition and cytochrome c release
https://pubmed.ncbi.nlm.nih.gov/19577639/ -
at those high doses is there actually any time that light won't potentially negatively interact with retina ? methylene blue and riboflavin are also not a great idea apparently to take at high doses and go in strong sunlight unless an antimicrobial or anti tumour effect is desired with some risk of damaging healthy cells.
anyways since you're taking ss-31 maybe also look into ghk. there is a published paper by Lorne pickhardt (sp?) using it on a constant drip for 7-10 days and it is something like 10-100x more effective than taking a singe larger dose everyday. it's something like use a 100mg vial on a constant drip over a week, or maybe it was 3 days or something, but the data on it shows it is way more effective than a larger dose taken everyday. can use an insulin pump or just do 10 shots a day. if you use ghk-cu (the blue one) if you also put bpc 157 in the shot it apparently doesn't sting. ghk by itself doesn't sting.
tb4 (1-43) also synergizes with antibiotics so maybe it syngerizes with antifungals too. there's ll-37 which is an antimicrobial peptide as well.
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