#342

I wouldn’t conclude much based on an n=8 trial without placebo.

#343

You might be interested in trying Tanganil (N-acetyl-DL-leucine) btw: https://www.semanticscholar.org/paper/Acetyl-dl-leucine-improves-restless-legs-syndrome%3A-Fields-Schoser/40a9ebacf24372ca029990e6a4c846b56dd5d72a

I think I saw on forums people “curing” their RLS with it.

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#344

I thought I’d share that with my new bottle of Pure Bulk 100mg pills, I’ve experimented with taking 1200mg on two different nights.

I took 12 pills all at once, right before I went to sleep.

I based this number on watching the Ryker video from above which contained excerpts from Dr Loh. She said if one is 50, take 180mg, and then add 100mg for each additional year. I through in a little extra to be, you know, extra.

She says if you take enough, you wake up full of energy, but I found myself dragging those two days.

On a few other nights, if I didn’t take any at all but woke up in the middle of the night, I’d take 100mg and it does work like a champ in helping me fall back to sleep.

Is there any more experimenting to be done? Meaning, should I be breaking up the 1200mg dose or even adding more? I don’t want to blow through this bottle of pills if high dosing just isn’t for me.

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#345

I have 5 mg dissolve tabs and 20 mg capsules. I’m taking about 40-60 mgs nightly. With melatonin, I sleep better, get up to the bathroom much, much less (which is a true miracle), and I feel less stressed if/when I do wake up.

Sleep is important, so in the past when I would wake up, I used to lightly fret, get up to use the bathroom repeatedly and/or determine what I needed to take to get back to sleep (Sulforaphane, ashwaganda, magnesium, etc). Melatonin seems to take away my anxiety both at night and in the day, so even if I have a more restless night, I’m just not feeling distressed or negative about it.

I’m still fairly new to melatonin, but I will slowly experiment with increased doses because it’s been a game changer for me. Thanks for sharing the formula that you are following, Beth.

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#346

An experiment is to take presleep melatonin say 2-3 hours before bed. I generally only take it on waking during the night

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#347

There is an interesting question as to the pharmacodynamics of high doses. I think the half life gets reduced, but I have not done the testing to know.

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Canagliflozin - Another Top Longevity Drug
#348

I still haven’t found a practical way to take 1000mg a day. Just too many 20mg pills drives me nuts. Maybe one day.

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#349

Incase it helps, I found 100mg pills from pure bulk. Not inexpensive if you are going to take 1000mg per day, but an easy way to experiment with it, as I am. The pills are tiny, too.

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#350

There are 60mg pills. I also tried a few grams during the day I had dissolved in whisky. That did put me to sleep for a few minutes. Not sure it was the melatonin though.

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#351

A few recent papers that might interest you @John_Hemming:

Melatonin Deficits Result in Pathologic Metabolic Reprogramming in Differentiated Neurons 2025

Differentiation from neural progenitor to mature neuron requires a metabolic switch, whereby mature neurons become almost entirely dependent upon oxidative phosphorylation (OXPHOS) for ATP production. Although more efficient with respect to ATP production, OXPHOS produces additional reactive oxygen species, as compared to glycolysis; thus, endogenous mechanisms to quench free radicals are essential for the maintenance of neuronal health. Melatonin is synthesized in neuronal mitochondria and has a dual role as a free radical scavenger and as an inhibitor of mitochondrial-triggered cell death and proinflammatory pathways. Previously, we showed that loss of endogenous melatonin induced mitochondrial DNA (mtDNA) and cytochrome c (CytC) release triggering pathological inflammation and cell death pathways, respectively. Here we find that in mature neurons, but not undifferentiated neuronal cells, melatonin deficiency altered metabolic reprogramming in aralkylamine N-acetyltransferase knockout (AANAT-KO) neurons as compared with neurons expressing AANAT. Interestingly, there are no differences in neural progenitors regardless of AANAT status. In addition, AANAT-KO deficiency elevated BAK and BAX levels in AANAT-KO neurons. Further, we found that exogenous melatonin treatment of AANAT-KO cells during differentiation into mature neurons rescued metabolic reprogramming defects and restored normal BAK/BAX levels. Thus, we demonstrated that the metabolic reprogramming and subsequent consequences of the switch to OXPHOS that normally occurs during neuronal maturation are compromised by melatonin deficiency and rescued by melatonin supplementation.

Thus, melatonin is a key modulator of metabolic reprogramming during neuronal differentiation. In addition, since bioenergetic impairment drives neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease [26-29], melatonin deficiency may alter susceptibility to neurological diseases later in life.

Therapeutic role of melatonin on acrylamide-induced neurotoxicity via reducing ER stress, inflammation, and apoptosis in a rat model 2025

MEL treatment also suppressed proinflammatory cytokines (TNF-α, IL-1β, IL-6) and neuronal nitric oxide synthase (nNOS), demonstrating anti-inflammatory effects. Furthermore, MEL mitigated ACR-induced neurotoxicity by reducing acetylcholinesterase (AChE) and monoamine oxidase (MAO) levels. ER stress markers (GRP78, ATF4, ATF6, sXBP1, CHOP) and apoptotic markers (Bax, Caspase-3) were elevated following ACR exposure but were suppressed by MEL. Additionally, MEL reduced ACR-induced increases in 8-hydroxy-2-deoxyguanosine (8-OHdG) and glial fibrillary acidic protein (GFAP), markers of DNA damage and astrocyte activation, respectively.

Improving effects of melatonin on memory and synaptic potentiation in a mouse model of Alzheimer’s-like disease: the involvement of glutamate homeostasis and mGluRs receptors 2025

Melatonin (10 mg/kg) was administered intraperitoneally, starting either two weeks (early intervention) or four weeks (late intervention) post-induction.
Key molecular targets in glutamate signaling pathways were identified using bioinformatics. AD-like mice displayed memory deficits and synaptic dysfunction. Melatonin improved cognitive function, especially with early intervention, as confirmed by behavioral tests. Histological studies revealed reduced neuronal loss, improved myelin integrity, and decreased tau hyperphosphorylation. Molecular findings showed restored mGluR expression and reduced GSK3 activity. Early intervention yielded superior outcomes, with partial restoration of synaptic plasticity observed in LTP recordings.
These findings underscore the neuroprotective properties of melatonin, mediated by its ability to modulate glutamate signaling and mGluR activity, offering new insights into its potential as a therapeutic agent for AD. Additionally, the results suggest that earlier administration of melatonin may significantly enhance its efficacy, highlighting the importance of timely intervention in neurodegenerative diseases.

Melatonin enhances neurogenesis and neuroplasticity in long-term recovery following cerebral ischemia in mice 2025

Post-acute melatonin treatment significantly reduced striatal and callosal atrophy.
Melatonin modulated neuronal plasticity and restoration via acting on key molecules.
Melatonin indicated a role in promoting neurogenesis and synaptic remodeling.
Melatonin treated animals had improvements in behavioral outcomes after stroke.
This study provided evidence for functionally restorative effects of melatonin.

Melatonin Regulates Glymphatic Function to Affect Cognitive Deficits, Behavioral Issues, and Blood–Brain Barrier Damage in Mice After Intracerebral Hemorrhage: Potential Links to Circadian Rhythms 2025

Melatonin restored GS transport after ICH, promoting hematoma and edema absorption, reducing BBB damage, and improving cognitive and behavioral outcomes. However, luzindole partially blocked these benefits and reversed the neuroprotective effects.

Data Mining Approach to Melatonin Treatment in Alzheimer’s Disease: New Gene Targets MMP2 and NR3C1 2025

In Cluster 2, the GO enrichment analysis also indicated that melatonin can interfere with dopaminergic and catecholaminergic neurotransmission.

A Proteomics Profiling Reveals the Neuroprotective Effects of Melatonin on Exogenous β-amyloid-42 Induced Mitochondrial Impairment, Intracellular β-amyloid Accumulation and Tau Hyperphosphorylation in Human SH-SY5Y Cells 2025

Pretreatment with melatonin protected the cells against Aβ42-induced cellular damages by regulating the expression of several proteins underpinning these biological processes, including the suppression of mitochondrial ROS generation and mitigation of mitochondrial membrane depolarization.

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#352

One of the worst things that happened to me recently was that they changed the taste of one of the melatonin pills that I eat - just after that I bought about 10 bottles of 60 pills. The other ones still taste nice though.

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#353

I just managed to place an order of 250g of melatonin powder … I still have plenty of capsules left and would be interesting to see if I manage to fit 1g to each capsule. I hope it gets into Australia… thank you for the suggestions Beth. I ended up buying from Amazon as they are the easiest to ship to Australia. I hope there are no issues coming in because most companies will not ship to Australia. It says delivery on the 2nd April, fingers crossed.

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#354

Melatonin seems to cause or worsen benign PVCs (Premature Ventricular Contractions) in some people:

I wonder: is it dose–dependent? Does it get better over time? Can one start at a very low dose and slowly increase while the body adapts to exogenous melatonin without triggering PVCs?

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#355

I would feel it but maybe the dosage is not high enough.

#356

Any concerns about this @John_Hemming: Impact of oral melatonin on the electroretinogram cone response 2009

The study was composed of a placebo-controlled, double-blind, crossover, and counterbalanced-order design. The subjects were tested on 2 sessions separated by 2-7 days (median = 5 days). Each session lasted two hours beginning with a baseline electroretinography (ERG) followed by one of the two treatments (placebo or melatonin) then a second ERG. Half of the subjects began with the placebo whereas half began with 15 mg of melatonin (Natrol® Chatsworth, CA). On the second sessions, the baseline was repeated followed by the other treatment. All sessions were performed between 12:30 and 16:30.
Following oral melatonin administration, a significant decrease of about 8% of the cone maximal response was observed (mean 6.9 μV ± SEM 2.0; P = 0.0065) along with a prolonged b-wave implicit time of 0.4 ms ± 0.1, 50 minutes after ingestion.

#357

I’m not John Hemming and I didn’t read the whole study, but it’s strange the study tested melatonin in the daytime rather than at night (when most people would normally take it). A small decrease in retinal response measured in bright afternoon conditions might not be that meaningful when you’re in bed at night, in the dark, trying to sleep. Maybe I’m missing something.

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#358

The argument is that melatonin promotes night vision. That suggests it is best taken at night.

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#359

Incidentally looking at my records I think I started taking more than 1g of melatonin a night last year in March. Hence I have been doing this now for a year.

#360

Do you regularly test your vision?

#361

I go to the opticians and also they take photographs of my retinas which I keep. My vision was I think possibly slightly better than 20/20 last time and I am less myopic than I used to be. I don’t have any hypermetropia now. I had a bit in the past. I used to need to use special glasses for reading music, but I don’t use those now.

That, however, is not necessarily a response to any changes in the sensitivity of my cones. I think the iPRGCs are functioning as expected and I have no problem with night vision.

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