Melatonin and spermidine protect early mouse embryos from ethylparaben toxicity by restoring histone modifications and subcellular structures 2025

Ethylparaben exposure induces early embryonic development arrest in mice.
Ethylparaben alters histone modifications and compromises zygotic genome activation.
Ethylparaben exposure causes mitochondrial dysfunction and DNA damage in embryos.
Melatonin and spermidine partially restores ethylparaben-induced embryonic damage.

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If you mess up the mitochondria then the acetylation will be lesser which I think is upstream of methylation (as in acetylation reduces methylation). I don’t think melatonin has direct effects on acetylation. (or methylation)

Dark-phase melatonin administration does not reduce blood pressure but induces changes in parameters related to the control of the cardiovascular system in spontaneously hypertensive rats 2025

Melatonin is synthesised during the dark phase of the day, and its biosynthesis is inhibited by light. Exogenously supplied melatonin has been reported to have hypotensive effects. However, in animal experiments, melatonin is usually administered in one high dose and blood pressure (BP) is almost exclusively measured by plethysmography during the light phase of the day. We tested the effects of melatonin administration in drinking water during the dark phase of the day at different concentrations (2–45 mg/kg/12 h) for three weeks and telemetrically measured haemodynamic variables in spontaneously hypertensive rats (SHR). We measured gene and protein expression in the hypothalamus, brainstem, kidney and adrenal gland. We did not observe a BP decrease even at the highest melatonin concentration. We observed a dose-dependent increase in the percent recovery point and a decrease in dP/dtmax, particularly during the light phase at lower doses. The effects on the autonomic nervous system and baroreflex were equivocal, with changes observed in both experimental and placebo groups. Melatonin dose-dependently decreased vasopressin expression in the supraoptic nuclei. In the adrenal gland, melatonin increased tyrosine hydroxylase expression. In the kidney, low melatonin doses increased endothelial nitric oxide synthase, while higher doses decreased CD68 levels. Our results do not confirm the hypotensive effects of melatonin in SHR. The potential beneficial effects of melatonin could result from a long-term impact on various organs involved in BP regulation and interaction with multiple molecular pathways, some of which may manifest in improved cardiovascular health in the long term.

By contrast, in the adrenal gland, we observed an increase in tyrosine hydroxylase expression only in the group with a lower dose of melatonin. This could indicate improved synthesis of catecholamines in the adrenal gland.

Weird dose-response relationship @John_Hemming ?

You might also like this article: Adaptation under constant light or dark: a challenge to the pineal

This study is particularly curious to me (just read the bolded text in the post, tbh), because I have the consistent experience of taking moderate doses of melatonin at night and no longer having the need or urge to get up to urinate. Melatonin has completely changed my decades long nocturia.

Given my personal experience, I would have thought that melatonin would actually increase my vasopressin/antidiuretic hormone, however it sounds like this study shows the opposite. Granted I am neither a rat nor hypertensive, so perhaps this doesn’t apply to me.

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I personally take a high dose of melatonin (> 100 mg) daily, and don’t see any negative effects. It doesn’t make me groggy during the day or impair sleep or cause unwanted bodily changes (I’m a man in my early 50s).

Interestingly, melatonin use has risen tremendously over the past few decades, and so has the percent of the population taking > 5 mg / day; and I imagine the same is true of people taking > 30 mg / day, say:

https://jamanetwork.com/journals/jama/fullarticle/2788539

I was interested once in finding antioxidants that don’t cause “reductive stress”, and melatonin was one of the few that came up when I posed the question to OpenAI’s o3 model (along with Astasanthin, ergothioneine, molecular hydrogen, and various hormetic polyphenols):

On a separate occasion I asked Google’s Gemini 2.5 Pro about supplements that prevent mitochondrial DNA damage, and it mentioned melatonin, saying “Unlike many antioxidants that act primarily in the cytoplasm or cell membrane, melatonin readily enters mitochondria”:

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What is your protocol? Do you take it before going to bed (how much) and when you wake up at night (how much)? Thanks

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Melatonin mitigates ovarian aging through regulation of the YTHDF2/m6A/UBE3C axis 2025

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Hi Tom. It kind of varies, but I usually take about 10-15 mgs dissolvable tabs an hour before bed. Then when I’m getting into bed I will take a 20 mg capsule or a 10 mg slow release combo pill with melatonin, l theonine, and chamomile. If I wake up, I may take a 20 mg capsule a few nights a week or just another 5 mg dissolve tab. In all, I probably take between 30-50 mgs, but I’ve taken more and less. I really no longer feel that there is a strict way I have to take melatonin anymore to get improved sleep. I did buy 60 mg capsules, but I’ve been lax in trying them.

At the risk of sounding like a melatonin evangelist, I will share the way it’s helped me. Besides the help with my nocturia, and improved sleep, melatonin seems to greatly decrease my anxiety. I take waking up in stride now which usually allows me to roll over and fall back asleep. If I do wake up, it usually allows me to not get in my head about sleep or life’s problems, and I also no longer tell myself or feel the urge to just go to the bathroom one more time so that the urge doesn’t wake me up later. I still do have an occasional night of poor sleep, which I think is pretty normal, but the crazy thing about it is that I no longer fret about it or feel despair, instead I am able stay relaxed and take it all in stride. Last thing I will add is that I sometimes will take a sulforaphane pill instead of melatonin if I wake up and it reliably gets me back to sleep.

Hope all this helps you or someone else!

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Thanks for such a thorough response! Really appreciate you breaking down not just the dosages but also how it’s helped with your anxiety and overall sleep quality. Definitely doesn’t sound like evangelizing, just genuinely helpful info!

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Paraquat model of PD, so shit but still: Melatonin protects dopaminergic neurons in paraquat-induced Parkinson in rats through PI3K/AKT/Nrf2 pathway 2025

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Melatonin Supplementation Enhances Next-Day High-Intensity Exercise Performance and Recovery in Trained Males: A Placebo-Controlled Crossover Study 2025

Background/Objectives: Sleep and recovery are critical for optimising exercise performance. However, the efficacy of melatonin supplementation in improving sleep quality and next-day physical performance remains unclear. This study examined the effects of melatonin ingestion on sleep and performance-related outcomes the following day in trained males.
Methods: In a randomised, double-blind, placebo-controlled crossover study, 12 trained males (age: 21.92 ± 2.84 years) ingested 6 mg of melatonin (MEL) or a placebo (PLA) the night before performing the 5 m shuttle test (5mSRT). Before and after the 5mSRT, blood samples were collected. Peak heart rate (HRpeak) and rating of perceived exertion (RPE) were recorded throughout the test. Perceived recovery status (PRS) and delayed onset muscle soreness (DOMS) were measured before, 5 min, 24 h, 48 h, and 72 h after the test. The sleep/wake cycle was monitored during the night after ingestion.
Results: Data were analysed using paired t-tests, Wilcoxon tests, and two-way ANOVAs, with significance set at p < 0.05. Compared to PLA, MEL did not modify any sleep parameters or blood markers (all p > 0.05). However, MEL improved total distance, fatigue index, the percentage decrement between sprints, and HRpeak (all p < 0.05) in the 5mSRT compared to PLA. MEL also enhanced PRS values up to 72 h post-exercise and reduced DOMS (all p < 0.05).
Conclusion: In summary, 6 mg of melatonin taken at night enhanced next-day high-intensity exercise performance and improved perceived recovery up to 72 h post-exercise.

Impact of oral melatonin supplementation on sperm quality and testicular artery hemodynamics in the bull 2025

Yearling Angus bulls (n = 21) were randomly allocated into two groups, either melatonin fed (MEL; n = 11) or control fed (CON; n = 10) for 90 days of treatment. MEL bulls were supplemented with 200 mg/kg of body weight of melatonin dissolved in ethanol, while CON bulls were supplemented with an equivalent ethanol vehicle control.
Melatonin supplementation increased sperm motility (P = 0.0496) in MEL (82.52 ± 2.41) compared to CON bulls (75.52 ± 2.22) and wobble tended to decrease (P = 0.051) in MEL (51.93 ± 0.36) compared to CON bulls (53.03 ± 0.32). Progressive motility, beat cross frequency, average path velocity, curvilinear velocity, and straight-line velocity improved (P < 0.05) over time. In contrast, distal droplet count, linearity, and straightness decreased (P < 0.05) over time. There was no effect (P > 0.05) of treatment on testicular artery hemodynamics. However, PI, RI, S/D TBF, and BF/BW changed (P < 0.05) over time. PI, RI, and S/D decreased (P < 0.05) from d 14 to 56. In contrast, TBF and BF/BW increased (P < 0.05) from d 14 to d 56. MnV tended (P = 0.0687) to increase and DIA tended (P = 0.0576) to decrease from d 14 to d 70. Melatonin supplementation from fall to winter resulted in a notable increase in sperm motility despite the lack of alterations to testicular artery hemodynamics due to treatment.

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I’ve been experimenting with high dose melatonin since April. I didn’t feel groggy the next day but I think it was interrupting my sleep.

I think cycling these high doses is a better path forward.

I still take 1.5mg combo of instant release and extended release and I’m finding I’m sleeping better.

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I have not looked not looked into this, but perhaps there are studies out there exploring the impact, if any, on the sleep architechture of supplementation with high doses of melatonin.

One day soon, I’ll have to do a deep dive on melatonin as my sleep is trash, and I should do something about that at some point.

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I noticed I became sleepy a lot earlier in the night when on the small dose of melatonin.

I feel like high dose melatonin acts in a completely different manner and could be useful for other purposes.

My view about high dose melatonin is that it acts to protect mtDNA much more so than lower dose, but you won’t sense anything immediate from that.

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Same. 2 mg melatonin makes me sleep well throughout the night whereas with 5, 10 or 20 mg I wake up in the middle of the night (around 6 hours after taking the pill?) and I have to take a second pill. Very weird.

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Its because it combines with endogenous melatonin.

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How to take melatonin for sleep and mitochondrial health at the same time, if a small dose helps with sleep, but large dose is effective for all other purposes, but interferes with sleep?

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This is all anecdotal but I’ve been doing something similar and taking a 10mg extended release with a 60mg immediate release and like it. I’ve done much higher doses in the past but ran out of the powder and haven’t bothered to reorder it yet. I’ve also intuitively cycled higher doses over the years. When I get to the point where I feel it’s possibly negatively impacting my sleep I’ll back off for a bit. I don’t have any rationale for this other than noticing it seems to help. I definitely love how I feel on melatonin and it seems anti inflammatory for me personally.

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N=1. I started having sleeping issues about one year ago (waking up at 2-3AM) every night and having hard time going to sleep. So, I started taking Melatonin 1mg and did help me go to sleep after about an hour. The sleep was not the best quality, but it was sleep (at least). Then. kept reading people in here (mainly @John_Hemming) suggesting taking mega doses and decided to give it a go. so initially started taking 3mg before bed then 3mg when I’d wake up at 2. After couple days went to 5mg, then 10, then 20 and now 40 evening about 7-8pm, 40 if I wake up at 2-3, and another 40mg when i wake up in the morning, sometimes even another 40mg mid-day. Initially when I started ramping up the dosage I’d experience some negative effect, such as irregular sleep, grogginess in the AM etc. but after a week or so (on high doses) everything changes for the better, and quality of sleep was way better than before, plus less frequent waking up at 2=3Am (though still do at times maybe 30-40% of time as opposed to 100% of the time)

It is by far one of the best supplements that I have ever taken (together with taurine, which I think work synergistically), no more brain fog, no more tiredness during the day, way faster recovery after exercise, great skin complexion, better sleep in general (still not as good as I’d like) and healthier looking hair (for some reason). Inflammation kept at bay, not totally gone though, and an overall sense of wellbeing and relaxation (again I anecdotally I split the positive effects 50/50 between taurine and mega doses of melatonin).

A side note, I have been doing Tirze for last few months and it totally destroyed my stomach (though did lose most of weight I wanted to lose) and literally two hours after I took 2000mg of Taurine my stomach was in best shape it’s ever been. As luck would have it. one evening I open my youtube and a doctor with British accent popped up suggesting taking taurine for muscle spasms/shoulder pain (was having sharp right shoulder blade pain). So, the fixing of stomach was accidental but a very welcome effect. BTW, my shoulder blade pain is 95% gone, and again I believe mega doses of melatnonin+taurine helped for that also (as these two were the only two substances I added about one month ago)

So. that’s my two cents, but thanks to @John_Hemming for insisting on benefits of the high dosage melatonin because I was very skeptical initially.

Mega doses of melatonin (not taurine in this case) is having also an interesting positive side effect as it seems to do something good to male hormonal balance (clearly visible when waking up each morning). Don’t know the mechanism’s of it but anecdotally it might increase testosterone? (have not tested yet but I will in next 3-4 months when my annual tests are due)

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