In the context of the escalating global health challenge posed by Alzheimer’s disease (AD), this comprehensive review considers the potential of melatonin in both preventive and therapeutic capacities. As a naturally occurring hormone and robust antioxidant, accumulating evidence suggests melatonin is a compelling candidate to consider in the context of AD-related pathologies. The review considers several mechanisms, including potential effects on amyloid-beta and pathologic tau burden, antioxidant defense, immune modulation, and regulation of circadian rhythms. Despite its promise, several gaps need to be addressed prior to clinical translation. These include conducting additional randomized clinical trials in patients with or at risk for AD dementia, determining optimal dosage and timing, and further determining potential side effects, particularly of long-term use. This review consolidates existing knowledge, identifies gaps, and suggests directions for future research to better understand the potential of melatonin for neuroprotection and disease mitigation within the landscape of AD.
I am very intrigued by possibly including melatonin in my stack. One thing holding me back is the mainstream claim that taking it regularly will shut down the pineal gland’s production, making one dependent on melatonin to get to sleep, which would be a problem if I was traveling, say, and didn’t have access to it for a while.
It depends on quantities and timing really. If you take say up to 100mg during the night after a first sleep using pineal melatonin to get to sleep then I don’t think it will affect generation of pineal melatonin.
On the other hand more recently I have taken over 2g during the night which did push me into a parasympathetic state say about 7am when I am normally in the sympathetic state. That may have reduced endogenous pineal melatonin (remembering pineal melatonin is not the only endogenous source).
I am currently experimenting with various configurations during the day and during the night. For example I tried to dissolve about a gram in some whisky and drink it about noon. That resulted in an enforced nap at about 1pm.
However, I don’t think any of these changes are permanent although they may persist for a few days.
Hence if you are not going for doses over 100mg and you take them after say midnight (on waking at night) I don’t think there is an issue.
However, different people do seem to respond differently. A lot of this is, however, timing because of the interplay between melatonin and the autonomous nervous system. Because it has cycles of roughly 90 minutes when you take melatonin during the cycle really matters in a rather complicated manner.
One thing that complicates things for me is that I am relatively frequent binge drinker and this has effects on sleep that need to be isolated from any effects on washing out MT1 and MT2 receptors.
Thanks. Yeah, I need to get my head around the timing and dosing issues. But all this information I’m learning about melatonin’s many benefits has me ready to try.
Timing and dosing is really hard. I have worked some of it out, but there remains quite a bit to understand.
What I do during the night is to use my fitbit to track when the sleep cycles are. I then time melatonin dosing to ensure that it is at a serum peak (it takes a bit of time to get into serum) just before the start of a new cycle.
There is also an interesting nuance that if you wake at the end of a cycle and which to remain asleep you can take sublingual melatonin (because it needs to get into serum) quickly and stay in the parasympathetic state. Otherwise you are likely to only get 90 mins more sleep and then be back awake (aka in the sympathetic state).
Melatonin actually inhibits CRH and ACTH as well as to some extent Cortisol so it has broad effects on the HPA cycle (aka Sleep Cycle, Ultradian cycle - although that is a non specific name).
I use daridorexant (Quviviq). It usually works quite well for insomnia, but the timing is quite precise, i.e. if you are not in bed when the effect starts, it can pass suddenly and then you won’t fall asleep for a long time. It’s good not to eat 3-4 hours before going to bed so that the daridorexant is well absorbed.
Interesting. Maybe I will try it if I can get insurance to cooperate. I take the Dayvigo about an hour before I want to sleep, with casein and granola, because the increased AUC and delayed tmax due to the food seem to help me stay asleep longer (I have sleep maintenance issues). The reduced Cmax isn’t an issue.
Here’s a new one on melatonin. I’m up to 20mg a night…but I take it 10mg 1hr before sleep and 10mg if I wake up before 4am. I guess I’m out on a limb on this one.
“Our results suggest that advancing the timing of administration (3 h before the desired bedtime) and increasing the administered dose (4 mg/day)“
The one about that taking it earlier helps with an earlier /faster sleep onset makes some logical sense to me.
I was more surprised about that taking it earlier also helps with total sleep time.
Based on those of you who take melatonin what is your experience with optimal time to take if goal is maximizing length of sleep and not focused on falling a sleep fast.
I take a small dose (11 mg) - 5 mg time release before bed, and two 3 mg quick release tabs at around 2 am.
The past weekend (Friday and Saturday night), and last night, I took the nights off from melatonin. Sleep quality did not change. I fall asleep fast, with or without melatonin. But I woke up earlier the mornings after nights off on melatonin, at 5:40 am.
Am trying to chase the nocturnal BP lowering effects of sustained release melatonin. (Not that I have a problem with nocturnal BP). The majority of studies say 5 mg is the effective dose.
Am using the immediate release to increase my dosage, to megadose. Immediate release, because I want the effect to not overflow to the day. Am still on the fence with megadosing. So a middling dose. So far, no noticeable changes.
This protocol really didn’t work for me. Taking 4 mg three hours before bedtime made me feel tired after one hour, but by the three-hour mark, I was already fully alert and barely slept the entire night.
Its all about timing with the HPA cycle. I go for megadoses because i want to protect mtDNA, but in your situation you might find reducing it helps or taking it 90 minutes earlier. What is happening for you is that the first cycle is in parasympathetic mode and you are sleep. But for the next it is metabolised away and you hit sympathetic mode.
This is exactly the problem. I’ve tried all possible timings, but nothing works properly. Melatonin causes me more harm than benefit, except for Circadin (very long-acting melatonin). I can take a small dose (1 mg) of fast-acting melatonin 20 minutes before going to bed. This combination (1mg + 2mg circadian) has worked reasonably well in the past, but on its own, it’s not enough for me; unfortunately, other medications are also needed.
This is an important point for me. If I am very alert at 2am then I need to wait to take my big melatonin dose or it will metabolize before my brain is ready to feel sleepy. If I take a slow release dose then the timing isn’t important (but I don’t have big dose extended release).