Melatonin megadoses?

#407

I took every melatonin study in this thread and fed it into ChatGPT and got it to spit out a summary of all of them:

:dna: Core Biological Roles of Melatonin

1. Circadian Regulation

  • Melatonin is primarily secreted by the pineal gland and plays a key role in synchronizing circadian rhythms.
  • It follows a light-dependent cycle, peaking at night and signaling darkness to the body, thereby promoting sleep and regulating hormonal cycles (including cortisol and reproductive hormones).

2. Mitochondrial Health & Energy Metabolism

  • Melatonin is synthesized not only in the pineal gland but also in mitochondria.
  • Studies show it enhances mitochondrial function by:
    • Promoting ATP production.
    • Reducing mitochondrial oxidative stress.
    • Improving mitochondrial calcium homeostasis.
  • It can stimulate muscle fiber conversion (from glycolytic to oxidative) in diabetic models—mimicking some effects of endurance exercise.

3. Antioxidant & Free Radical Scavenging

  • Melatonin directly scavenges reactive oxygen and nitrogen species.
  • It also upregulates endogenous antioxidant enzymes (e.g., SOD, glutathione peroxidase).
  • Unique among antioxidants, it crosses the blood-brain barrier and concentrates in mitochondria and nuclei.

:brain: Neuroprotection & Brain Health

4. Alzheimer’s & Parkinson’s Disease

  • Melatonin reduces tau hyperphosphorylation and Aβ accumulation in animal models.
  • Enhances glymphatic clearance of metabolic waste, possibly reducing risk of neurodegeneration.
  • Supports mitochondrial integrity in neurons and may help counter age-related metabolic shifts in brain cells.

5. Cognitive Function & Memory

  • Improves long-term memory formation in rodents via modulation of protein phosphorylation.
  • Enhances glymphatic function post-intracerebral hemorrhage, resulting in improved cognitive recovery.

:person_in_lotus_position: Sleep and Chronobiology

6. Sleep Quality

  • Meta-analyses show optimal efficacy for:
    • 3–4 mg taken ~3 hours before bedtime.
    • Helps reduce sleep onset latency and increase total sleep time.
  • Especially effective in older adults and those with insomnia or circadian rhythm disorders.

7. Jet Lag, Shift Work, and Chronotherapy

  • Well-suited for shifting circadian phase in cases of jet lag and shift work.
  • Has been studied as a tool in chronotherapy to align medication administration with biological rhythms.

:heartbeat: Cardiovascular & Metabolic Health

8. Blood Pressure Regulation

  • Reduces nocturnal blood pressure (more in “non-dippers”), possibly via improved endothelial function and oxidative stress reduction.

9. Glucose Metabolism and Diabesity

  • In diabetic models:
    • Enhances insulin sensitivity.
    • Supports healthy skeletal muscle function.
    • Promotes metabolic reprogramming of muscle and liver.

:eye: Retinal and Ocular Health

10. Age-Related Macular Degeneration (AMD)

  • Protects retinal pigment epithelial (RPE) cells by:
    • Inhibiting necroptosis.
    • Suppressing NLRP3 inflammasome via the SIRT1/Nrf2 pathway.
  • Preserves retinal structure in AMD models.

:microbe: Immune Modulation

11. Dual Immunoregulation

  • Acts as an immune buffer:
    • Stimulates immunity in immunosuppressed states.
    • Suppresses excessive inflammation during cytokine storms.
  • Reduces IL-6 and TNF-α while promoting IL-10 and T-reg activity.
  • Shown to modulate macrophage activity via NF-κB and AA-NAT upregulation.

12. Applications in Autoimmune and Infectious Disease

  • May help in autoimmune diseases and as an adjunct in viral infections (e.g., COVID-19) by dampening hyperinflammation while preserving immune competence.

:dna: Anti-Aging and Lifespan Extension

13. Lifespan Studies

  • Melatonin extended lifespan in several animal models (e.g., flies, mice, aquatic invertebrates), possibly due to its mitochondrial and antioxidant actions.
  • Highlighted in DrugAge as a candidate longevity agent.

14. Aging Phenotypes

  • Maintains mitochondrial and glymphatic function with age.
  • Prevents pathological metabolic reprogramming in aged neurons.

:test_tube: Cancer and Cell Growth

15. Anticancer Activity

  • Shown to inhibit proliferation in some cancer cell lines.
  • May sensitize tumors to chemotherapy while protecting normal cells from side effects (radioprotective and antioxidant roles).

:warning: Safety, Risks, and Considerations

16. Generally Safe — But Not Always Benign

  • Very high doses (up to 200 mg/day) used in research with minimal side effects reported.
  • Most common mild side effects: vivid dreams, morning grogginess, headaches.

17. Rare Case Reports

  • One case report linked melatonin to ventricular arrhythmias (PVCs), which resolved after stopping supplementation — indicates rare individual susceptibility.

18. Hormonal & Developmental Considerations

  • Low melatonin levels in children with hypothalamic hamartomas were linked to precocious puberty, suggesting a role in reproductive timing.

Summary: The Case for Melatonin

Melatonin is a pleiotropic molecule:

  • Antioxidant, immunomodulator, chronobiotic, and neuroprotective agent.
  • It impacts systems far beyond sleep, including metabolism, immunity, cognition, mitochondrial health, and aging.
  • Therapeutically, it is among the most underrated low-toxicity compounds with broad potential — though rare risks exist and personalization is warranted.
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#408

Which tends to demonstrate both the strengths and weaknesses of LLMs. The LLM does not have a model of reality so cannot easily identify what is really important. On the other hand most human beings don’t have the knowledge to analyse the input.

#409

I spoon a 1/4 teaspoon of powder into my mouth, drink some water, swish it around, swallow, and drink a bit more water.

Seems to get it down without too much terrible taste exposure.

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#411

how many mg is a quarter teaspoon?

#412

I tried to down 1/2 teaspoon… Hoping to increase to 1 teaspoon. (About 1.5g)

It will take be a while to tolerate it. It doesn’t dissolve in water. Maybe I’ll try evoo.

#413

I estimate 775 mg to 800 mg.

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#414

Mine dissolves in water enough to swallow, and it’s from two different sources. I put the dose in a small amount of water (less than a shot) stir it well with a teaspoon, leave it for 30 mins then stir again, and it goes down fine. There is usually some residue left that I swill another small amount of water and swallow it down, which also helps with any slight burning sensations. This is about 40 mins before bedtime.

#415

I got 100g from Pure Bulk. I’m not noticing any particularly bad taste. It’s slightly bitter. Maybe I’m just used to eating horrible tasting herbs (tongkat ali for instance).

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#416

I’ve just bumped up to 1/2 tsp (eat 1500mg - 1600 mg) about 1/2 hour before bed.

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#417

Still on fertility: The protective effects of melatonin on testis, sperm parameters quality, and in-vitro fertilization in mice following treatment with aflatoxin B1: An experimental study 2025

These findings demonstrated that MLT can compensate for the adverse effects of AFB1 on the quality of testicular tissue, sperm parameters, sperm DNA, and in vitro fertilization outcomes.

#418

I was checking out different molecules in the DrugAge database and melatonin has impressive results in different species.

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#419

On fertility again: Dose–Response Effects of Oral Melatonin on Reproductive Parameters in Intact Male Pomeranian Dogs With Alopecia X: A Controlled Study 2025

This study investigates the dose–response effects of oral melatonin on reproductive parameters in intact male Pomeranian dogs diagnosed with Alopecia X. Given melatonin’s potential therapeutic effects on hair regrowth and reproductive health, this study aimed to evaluate its impact on semen quality, hormonal profiles and testicular haemodynamics. A total of 16 intact male Pomeranian dogs were randomly assigned to four groups: a control group receiving a placebo and three treatment groups receiving melatonin at low (0.1 mg/kg), medium (0.3 mg/kg) and high (0.5 mg/kg) doses, administered twice daily for 45 days. Reproductive parameters, including semen volume, sperm concentration, total sperm count, sperm motility and levels of testosterone and oestradiol 17-ß, were assessed biweekly. Testicular haemodynamics were evaluated using pulsed Doppler ultrasonography. The results showed dose-dependent improvements in semen quality and testicular blood flow, with the highest dose group demonstrating the most significant improvements. However, analysis of the testosterone-to-oestradiol ratio revealed a decrease in the treatment groups, highlighting a complex hormonal response. Although semen quality improved, the study’s short duration may not have captured the full spermatogenesis cycle. These findings suggest that melatonin may enhance reproductive function in male dogs with Alopecia X, but further research is needed to clarify its long-term endocrine effects and optimize treatment protocols.

When comparing the different doses of melatonin, the dose-dependent improvements in semen parameters suggest that higher doses, such as 0.5 mg/kg, are more effective in optimizing semen quality. However, despite these improvements, the lack of significant changes in the testosterone-to-oestradiol ratio, even at higher doses, raises important questions regarding the long-term safety and efficacy of high-dose melatonin. Prolonged high-dose administration may affect hormonal feedback mechanisms and other endocrine functions. Furthermore, our study provides a deeper understanding of melatonin’s mechanisms, suggesting that melatonin may exert its effects through antioxidant properties and by influencing the hypothalamic–pituitary–gonadal axis, as well as potentially acting locally within the testes (Mogheiseh et al. 2022). The enhancement of testicular blood flow could also play a crucial role in supporting healthy spermatogenesis. However, further research is necessary to explore the long-term effects of melatonin on reproductive health, optimize dosing regimens and investigate its detailed mechanisms, including its role in local hormone modulation and blood flow dynamics within the testes.

And potential for rapa + melatonin combination? Melatonin enhances everolimus efficacy in breast cancer by suppressing mTOR pathway activation and promoting apoptosis and mitochondrial function 2025

To investigate the effects of melatonin and everolimus combination, we divided MCF-7 cells into four experimental groups: the control, Melatonin (3 mM), Everolimus (30 nM), and a combination of Melatonin and Everolimus (3 mM + 30 nM). Cell viability, apoptosis, autophagy activation, and mitochondrial function were evaluated using established techniques.
Based on the cell viability test, the combination of 30 nM everolimus and 3 mM melatonin inhibited phosphorylation of 4E-BP1 and p70S6K, which are downstream effectors of the mTOR pathway, and reduced cell growth. In addition, co-administration of melatonin and everolimus increased apoptosis and led to Sub-G1 phase accumulation. LC3 protein expression and LC3 puncta analysis demonstrated autophagic activity. In terms of mitochondrial function, co-administration of melatonin with everolimus did not cause proton leakage or mitochondrial uncoupling, but did restore everolimus-induced respiratory inhibition.
In conclusion, melatonin is thought to improve the effectiveness of everolimus by inhibiting mTOR downstream effectors, enhancing apoptosis, activating autophagy, improving mitochondrial respiration, and reducing MCF-7 growth.

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#420

Antioxidant and Analgesic Effect of Melatonin Involving Sirtuin 1: A Randomised Pilot Clinical Study 2025

Approximately 1 h before induction of anaesthesia, patients received oral melatonin or placebo. Melatonin‐treated children received a single dose of oral melatonin 0.5 mg/kg (for a max 10 mg).
Melatonin is a potent antioxidant molecule, and its analgesic effects have been observed in children. However, the underlying mechanisms of these effects have not yet been fully explored in clinical studies. We tested the hypothesis that melatonin reduces pain and oxidative stress involving the sirtuin pathway. Forty‐four children were randomly assigned to oral supplementation with melatonin or placebo before induction of anaesthesia for surgery. Plasma levels of 4‐hydroxynonenal (4‐HNE), melatonin, sirtuin 1 (SIRT1) and circulating miR‐34 and miR‐124a were analysed at T0 (pre‐hospitalisation), T1 (before surgery) and T2 (1 h after the end of the surgery). Melatonin decreased 4‐HNE and increased SIRT1 concentrations at T2 in supplemented children. Significant correlations were found between melatonin and pain score (R = −0.404), 4‐HNE and pain score (R = 0.44), melatonin and 4‐HNE (R = 0.42), 4‐HNE and SIRT1 (R = −0.43) and melatonin and SIRT1 (R = 0.41) at T2. Circulating miR‐34 and miR‐124a modulation were also observed. The reduction of oxidative stress and the modulation of circulating miR‐34 and miR‐124a, which target SIRT1 activity, suggest a novel pathway underlying melatonin’s antioxidant and analgesic effects.

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#422

@Brandon can you please tell us more?

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#423

Another paper on melatonin and fertility, for whatever reason this is a recurring topic these days: Melatonin receptor 1a alleviates sleep fragmentation-aggravated testicular injury in T2DM by suppression of TAB1/TAK1 complex through FGFR1 2025

A major obstacle in type 2 diabetes mellitus (T2DM) is sleep fragmentation (SF), which negatively affects testicular function. However, the underlying mechanisms remain to be elucidated. In this study, we demonstrate that SF induces testicular damage through a mechanism involving lipid metabolism, specifically mediated by melatonin (MEL) receptor 1a (MT1). T2DM mice with SF intervention displayed several deleterious phenotypes such as apoptosis, deregulated lipid metabolism, and impaired testicular function. Unexpectedly, sleep recovery (SR) for 2 consecutive weeks could not completely abrogate SF’s detrimental effects on lipid deposition and testicular function. Interestingly, MEL and MT1 agonist 2-iodomelatonin (2IM) effectively improved lipid homeostasis, highlighting MEL/2IM as a promising therapeutic drug for SF-trigged testicular damage. Mechanistically, MEL and 2IM activated FGFR1 and sequentially restrained the crosstalk and physical interaction between TAB1 and TAK1, which ultimately suppressed the phosphorylation of TAK1 to block lipid deposition and cell apoptosis caused by SF. The ameliorating effect of MEL/2IM was overtly nullified in Fgfr1 knockout (Fgfr1-KO+/–) diabetic mice. Meanwhile, testicular-specific overexpression of Tak1 abolished the protective effect of FGF1691 on diabetic mouse testis. Our findings offer valuable insights into the molecular mechanisms underlying the testicular pathogenesis associated with SF and propose a novel therapeutic approach for addressing male infertility in T2DM.
Sleep fragmentation in T2DM impairs the testes by disrupting lipid metabolism. Melatonin and its agonist protect by activating FGFR1 to inhibit TAK1 phosphorylation, reducing lipid deposition and apoptosis.

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#424

Chinese paper from Tonji University: Nanoplastics exposure exacerbates Aβ plaque deposition in Alzheimer’s disease mice by inducing microglia pyroptosis

Melatonin treatment ameliorated cognitive deficits and reduces Aβ plaque deposition caused by NPs exposure.
Our study addresses the critical issue of environmental relevant dose nanoplastics (NPs) exposure and their neurotoxic effects, highlighting a significant environmental health concern. Using APP/PS1 transgenic mice and BV2 microglial cells, we examined the impact of NPs on cognitive function and Alzheimer’s disease (AD) pathology. Our findings reveal that environmental relevant dose NPs exposure aggravated cognitive dysfunction, and exacerbated amyloid-beta (Aβ) plaque formation. NPs cause lysosomal damage and trigger pyroptosis in microglia, impairing their phagocytic function and reducing their ability to clear Aβ plaques. We investigated melatonin as a therapeutic agent, finding it significantly ameliorated cognitive deficits and reduced Aβ plaque deposition, restoring microglial function. This study highlights the significant neurotoxic potential of NPs and suggests targeting pyroptosis as a therapeutic strategy. Our work underscores the urgent need to understand the neurological consequences of NPss exposure and develop strategies to mitigate their health risks.
For melatonin treatment, melatonin was administered via intraperitoneal injection (10 mg/kg) once daily for 28 consecutive days.

The equivalent dose in a 70 kg human adult in tablets would be 57 mg/day.

Poke @AlexKChen as you’re interested in the topic.

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#425

This (a paper from 2018) is news to me:

Interestingly I found this whilst trying to find melatonin concentrations in lymph fluid and chatGPT told me of sufficient to find the paper

I have separately asked chatGPT where melatonin is secreted and it said

What I am curious about is the extent to which melatonin is circulated from the pineal gland via the CSF into the lymphatic system.

I didn’t really get an answer there

I have also done some more general questions looking at blockages in the CSF and unsurprisingly it seems to report motor neurone problems from spinal chord blockages (which would occur by blocking pineal melatonin).

I think it may be part hallucinating in some of the answers here, however.

The substantive issue which is whether a blockage of CSF can result in motor neurone problems seems to be quite well substantiated.

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#426

Again, one article on male fertility: Melatonin Regulates Clusterin to Reconstruct the Blood–Testis Barrier Disrupted by Atrazine 2025

Atrazine (ATZ), a commonly used triazine herbicide, is known to impair male reproductive function. Melatonin (MLT) is an endogenous hormone synthesized by the pineal gland. Its lipophilic nature enables it to freely penetrate the blood-testis barrier (BTB) and exert direct effects. However, it remains unclear whether MLT can prevent ATZ-induced impairment of BTB function. Pubertal male mice were randomly assigned to four groups and treated via gavage for 21 days: control group (Con), 5 mg/kg melatonin group (MLT), 170 mg/kg atrazine group (ATZ), and cotreatment group (ATZ+MLT). Furthermore, BTB-associated proteins, transepithelial electrical resistance, and cell adhesion assays were performed in TM4 cells treated with siClusterin, pcDNA3.1-Clusterin, and AKT inhibitor VIII to evaluate BTB function in vitro. Our findings demonstrate that MLT effectively restores ATZ-induced reductions in BTB protein levels and function in both in vivo and in vitro models. Moreover, MLT mitigated ATZ-induced BTB damage by reactivating the Clusterin/AKT signaling pathway.

#427

Systemic Melatonin Improves Regeneration After Facial Nerve Crush Injury in a Rat Model 2025

The primary predictor variable was the different doses of systemic melatonin treatment. The animals were randomly divided into three treatment groups (n=8 each): melatonin 5mg/kg/day; melatonin 20mg/kg/day; carrier solution alone (control). The intraperitoneal injections were administered during the 28-day healing period.
Histomorphometric analysis revealed that the number of axons with the optimum g-ratio in the control group (180) was statistically significantly lower than expected (217.33) (p<0.01). The mean axonal density was statistically significantly higher in 5mg/kg (12.99±2.20/1000μ2) (p=0.01) and 20mg/kg (13.47±1.57/1000μ2) (p=0.004) melatonin treatment groups compared to control group(9.43±2.57/1000μ2). Both treatment groups presented higher EMG amplitude (1.59±0.28 for 5mg/kg melatonin group and 1.94±0.31 for 20mg/kg melatonin group) than the control group (1.25±0.15) (p<0.05) and both treatment groups presented shorter duration values (19.16±1.35 for 5mg/kg melatonin group and 20.39±1.62 for 20mg/kg melatonin group) than the control group (24.24±3.80) (p<0.05). Whisking amplitude was statistically significantly higher in 5mg/kg (61.25±14.28) (p=0.009) and 20 mg/kg (63±14.69) (p=0.003) melatonin groups compared to the control group (35.62±8.21) at the end of treatment period.
Both supraphysiological doses of systemic melatonin treatment enhanced regeneration after facial nerve crush injury in an animal model. Our findings invite further research on the clinical potential of melatonin-induced facial nerve regeneration.

@John_Hemming: very interesting if axon regeneration also applies to long dopaminergic axons in the nigrostriatal tract. Dose equivalence (rough estimate):

  • Rat mg/kg injection => ~ 100 mg/day orally in a human adult
  • Rat 20 mg/kg injection => ~ 400 mg/day orally in a human adult

Chinese mouse study: Melatonin modulates mitochondrial function and inhibits atherosclerosis progression through NRF2 activation and OPA1 inhibition 2025

MLT reduces atherosclerotic plaque formation and oxidative stress.
MLT enhances mitochondrial function via NRF2 activation and OPA1 inhibition.
Inhibition of OPA1 ameliorates mitochondrial dysfunction and inflammation in AS.
This study is the first to elucidate that MLT synergistically ameliorates mitochondrial dysfunction through dual mechanisms—activating the NRF2 antioxidant pathway and suppressing OPA1-mediated mitochondrial fusion—providing novel therapeutic targets for AS.

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#428

We don’t know what the optimal melatonin dose is and we know some positive effects go up with dose. I take a simplistic view and err on the high side

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