#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.

3 Likes
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.

1 Like
#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.

3 Likes
#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.

2 Likes
#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.

6 Likes
#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.

2 Likes
#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.

4 Likes
#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?

2 Likes
#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.

4 Likes
#358

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

3 Likes
#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.

3 Likes
#362

That’s good news!

Also: Melatonin protects retinal integrity through mediated immune homeostasis in the sodium iodate-induced mouse model of age-related macular degeneration 2023

Melatonin protects RPE cells from necroptosis and NLRP3 activation via promoting SERCA2-related intracellular Ca2+ homeostasis 2024

Melatonin reduces mitochondrial Ca2+ levels and restores mitochondrial membrane potential. Constant mitochondrial Ca2+ overload directly promote cell necroptosis through mitochondrial fission. Inhibition of mitochondrial fission by Mdivi-1 prevent necroptosis induced by SI without altering the level of mitochondrial Ca2+.

1 Like
#363

It may be we should start a new thread on Melatonin

This is one of the key papers on Melatonin
https://academic.oup.com/endo/article-abstract/143/1/84/2988986?redirectedFrom=fulltext

The pineal recess (PR), a third ventricle (IIIV) evagination penetrating into the pineal gland, could constitute a site of melatonin passage to the cerebrospinal fluid (CSF) and explain the high concentrations of melatonin in this fluid. To test this hypothesis, we characterized melatonin distribution in the IIIV of sheep by CSF collection in the ventral part of IIIV (vIIIV) and in PR. At 30μ l/min collection rate, melatonin concentrations were much higher in PR than in vIIIV (19,934 ± 6,388 vs. 178 ± 70 pg/ml, mean ± sem, respectively, P < 0.005), and they increased in vIIIV when CSF collection stopped in the PR (P < 0.05). At 6μ l/min, levels increased to 1,682 ± 585 pg/ml in vIIIV and were not influenced by CSF collection in the PR. This concentration difference between sites and the influence of PR collection on vIIIV levels suggest that melatonin reaches the PR and then diffuses to the IIIV. To confirm the role of PR, we demonstrated that its surgical sealing off decreased IIIV melatonin levels (1,020 ± 305 pg/ml, compared with 5,984 ± 1,706 and 6,917 ± 1,601 pg/ml in shams or animals with a failed sealing off, respectively, P < 0.01) without changes in blood levels. Therefore, this study identified the localization of the main site of penetration of melatonin into the CSF, the pineal recess.

From this paper we get average levels in the 3rd Ventricle of 5984 and 6917 where the pineal recess is not sealed.

I have edited this post as I got some of the maths wrong and am working on revised calculations. I will, however, be posting the results in some other location.

4 Likes
#364

Intranasal and inhaled delivery systems for targeting circadian dysfunction in neurodegenerative disorders, perspective and future outlook 2025

Oral medications often face challenges in achieving the necessary systemic circulation to effectively bypass the blood brain barrier (BBB) and reach the CNS, primarily due to low or variable bioavailability. Advancements in non-invasive delivery methods, such as orally inhaled and intranasal formulations, present promising alternatives for targeting the CNS. Orally inhaled and intranasal drug delivery allows for medications to rapidly achieve high systemic circulation through increased bioavailability and fast onset of action. Additionally, intranasal delivery allows for therapies to bypass the BBB through the olfactory or trigeminal nerve pathways to directly enter the CNS. This review assesses the potential for orally inhaled and intranasal therapies to treat circadian disorders in neurodegenerative conditions. In addition, this review will explore melatonin as an example of enhancing therapeutic outcomes by adopting inhaled or intranasal drug delivery formulations to improve drug absorption and target circadian disorder more effectively.

Despite its widespread use, oral melatonin has limited bioavailability, typically around 15 %, due to poor absorption from the gastrointestinal tract or extensive first-pass metabolism in the liver. Bioavailability also varies greatly between individuals, influenced by factors such as gender, caffeine and smoking, oral contraceptive use, age and the co-administration of fluvoxamine. In addition, pharmacokinetic studies have shown substantial variability in the time to reach maximal concentration (Tmax) following oral administration. Rapid release formulations have been found to range from 46 to 90 min with doses of 2 and 25 mg, respectively. Two different 10 mg oral extended-release formulations, from the same study, demonstrated Tmax values of 45 and 210 min. The variability in patient melatonin uptake may limit the effectiveness of oral melatonin as a therapy and could hinder research into oral melatonin formulations.

Although not currently commercially available, intranasal melatonin was first examined in 1981, whereby a small placebo-controlled crossover study of healthy adults (n = 10) reported that an intranasal dose of 1.7 mg of melatonin could effectively induce sleep.
Merkus and colleagues reported a Tmax of 5 min for intranasal melatonin administration (compared to 10 min for intravenous) in a crossover study of three individuals.

While intranasal administration demonstrates promising bioavailability and therapeutic potential, given melatonin readily passes the BBB and accumulates in the CNS at higher levels than in the blood, there may be a more straightforward route for delivering melatonin to the brain—via oral inhalation. Orally inhaled melatonin delivery could offer a direct path to the CNS while avoiding the drawbacks of intranasal delivery, such as limited dose size or reduced absorptive surface area of the nasal mucosa compared to that of the lung.
Given the absence of human studies on inhaled melatonin, a recent modelling study showed the pharmacokinetics of inhaled melatonin, demonstrating that a 2 mg dose of inhaled melatonin would reach a theoretical maximal plasma concentration (Cmax) 26.8 times higher than that of a 2 mg oral dose of melatonin. Furthermore, the theoretical Tmax of inhaled and orally delivered melatonin were found to be 0.2 min and 35.6 min, respectively, demonstrating that inhaled melatonin could provide a considerable improvement in the onset of action, thus, assisting with the management of circadian disorders.
Despite the scarcity of information to verify the safety and efficacy of delivering melatonin via oral inhalation, several ‘vape’ and ‘diffuser’ e-cigarette products, containing highly variable dosages of melatonin, have become commercially available; often marketed as sleep aids
The popularity of melatonin e-cigarettes can be inferred from a recent cross-sectional study of United States residents that found that over a quarter of their 6131 participants (56.3 % female; 43.7 % male; mean age 21.9 years) reported using melatonin vapes

To help address the gap in the literature surrounding the efficacy and safety of inhaled melatonin, the authors of this review have recently registered a randomised open-label crossover human clinical trial comparing the effects of an orally inhaled formulation of melatonin delivered by MDI against oral melatonin tablets (CTR No.). This trial aims to investigate the pharmacokinetic profile of melatonin delivered by orally inhaled administration, as well as examine the effect on sleep architecture measured by overnight polysomnography in older adults with insomnia disorder. A validated air–liquid interface model of the alveolar epithelial layer was used to gather currently unpublished, preliminary data examining the safety of depositing inhaled melatonin within the lung periphery. Thus far, both the trans-epithelial electrical resistance and the apparent permeability (measured by sodium fluorescein assay) of air–liquid interface model have not indicated that inhaled melatonin delivery compromises epithelial integrity, suggesting it will be well tolerated by the human lung.

image
image1656×886 121 KB

Did you know about melatonin e-cigarettes @John_Hemming?

2 Likes
Parkinson's disease
#365

I have not heard about melatonin e-cigarettes, I would not think there is much of an advantage to them as melatonin gets through cell membranes quite easily.

. It readily passes through the blood-brain-barrier and accumulates in the central nervous system at substantially higher levels than exist in the blood. As a result, this molecule exhibits strong neuroprotective effects, especially under the conditions of elevated oxidative stress or intensive neural inflammation.

#366

The advantage is that you could imagine continuous delivery during the night with a diffuser in the room or a mask. Would that make sense?

2 Likes