Melatonin megadoses?

That is fine, but it is just anecdotal reports which is contradicting randomized controlled trials. I didn’t make it up that 0.3 - 1 mg is best for sleep. The natural amount released in a healthy person is typically around 0.3 mg, without blue light etc.

Many early studies were done on elderly people, who produce less endogenous melatonin than young people and so are considered especially responsive to the drug. Several lines of evidence determined that 0.3 mg was the best dose for this population. Elderly people given doses around 0.3 mg slept better than those given 3 mg or more and had fewer side effects (Zhdanova et al 2001). A meta-analysis of dose-response relationships concurred, finding a plateau effect around 0.3 mg, with doses after that having no more efficacy, but worse side effects (Brzezinski et al, 2005). And doses around 0.3 mg cause blood melatonin spikes most similar in magnitude and duration to the spikes seen in healthy young people with normal sleep (Vural et al, 2014).

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Perhaps, more than you want to know about melatonin, but it has many more uses than just helping us fall asleep or reducing jet lag.
Example: “melatonin, which experimentally at least, reduces the toxicity of alcohol consumption”

Melatonin as an antioxidant: under promises but over delivers

https://onlinelibrary.wiley.com/doi/full/10.1111/jpi.12360

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Article on the effects of weighted blankets on melatonin:

https://www.washingtonpost.com/wellness/2022/12/06/weighted-blanket-sleep-melatonin-benefit/

Study abstract:

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I know there are speculations about other benefits particularly in higher doses. That’s why I specifically mentioned sleep.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC43034/pdf/pnas01533-0367.pdf

Melatonin has shown that it can extend lifespan in mice, BUT only when administered during the night… The only problem with this is that you do not differentiate between the affects of melatonin and sleep.

Also I would just like to say as an individual who studies sleep:

In adults, studies have found the benefits from melatonin are for people who have sleeping problems related to delayed sleep-wake phase disorder and jet lag. Evidence in small studies have indicated that melatonin may be useful in children with certain conditions including epilepsy and some neurodevelopmental disorders such as autism spectrum disorder and Angelman’s syndrome. High doses of melatonin increase sleep duration during nighttime and daytime sleep episodes in older adults. The Suprachiasmatic Nucleus(SCN) and retina from older mice and humans show a decrease in responsiveness to melatonin, showing that it is not that melatonin decreases in humans as they age but instead it is the responsiveness to melatonin that decreases that might contribute to the some of the issues we see in sleep/circadian rhythms as we age.
Many important physiological processes have circadian rhythmicity with these rhythms playing an important role in biological homeostasis. We can say a characterization of advanced aging is by deterioration of overt circadian patterns (reduced amplitude of many rhythms, earlier timing of endogenous circadian rhythmicity, disorganization of temporal order, loss of entrainment stability and responsiveness to Zeitgebers).
There is a desynchronization of overt rhythms that accompanies aging due to a loss of control of these functions by the SCN, where melatonin is what the body uses to entrain or synchronize these rhythms. The loss of melatonin in advanced age leads to disturbances in the circadian pacemaker, which causes internal temporal desynchronization creating a variety of chronopathologies and leads to generalized deterioration of health. But aging is a multi factorial process , I don’t believe melatonin delays aging, but instead is beneficial in some of the age protection processes.
BUT as I say that,
You also need to understand that although a lot of studies propose a mechanism for how X benefits Y, biology is not simple, especially in complex organisms such as ourselves. There are melatonin receptors found all throughout our bodies, so we may see some benefits in certain controlled conditions in a proposed pathway, but the reality is there are other effects we have not discovered, whether good or bad, that melatonin(especially supraphysiological levels) impacts(i.e. such as the article I posted earlier about melatonin signaling causing potential risks for type 2 diabetes).

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Just as an aside, what is your opinion of the new orexin receptor antagonists?

Depends on what you are using it for. I think its a interesting treatment for insomnia patients. I don’t think it is a first line treatment, due to the potential for substance abuse and addiction. But at the same time, it is still new and I would try other treatments such as CBTI and even trying melatonin/ L theonine first before resorting to Suvorexant, especially as we get longer term studies done on its safety profile.

a) Melatonin is produced in the mitochondria as well as the Pineal gland.

b) Pineal Melatonin is injected directly into the CSF (Third ventricle) either substantially, mainly or totally. This means that calculations purely based upon serum levels are not going to be right.

Hence I am not persuaded by the figure of 0.3mg per person generated by the pineal.

The main thing I argue is not to take melatonin to get to sleep, but ideally to keep you asleep. The suppositories are quite good because they are released over a period of time. I am not clear on the bioavailability of the 200mg to 400mg doses compared to oral (or subligual/buccal). However, there clearly is some.

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Light, Water, and Melatonin: The Synergistic Regulation of Phase Separation in Dementia
https://www.crsociety.org/topic/17877-middle-of-the-night-melatonin-supplementation-better-sleep-improved-hrv-and-rhr/

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I am considering trying high-dose melatonin. Can you help me answer a few questions:

  1. I’ve read that some people take 50mg - 180mg per day for antioxidant and anti-aging effects. What is your experience? What dosage do you take?

  2. Some people suggest that a person should not take large-dose melatonin before bed or even at bedtime, but in the middle of the night or immediately upon awaking. Do you agree with this? What is the ideal time to take a large dose of melatonin?

  3. Since one effect seems to be better sleep, do you set an alarm to take your dosage in the middle of the night? If you sleep through the night do you skip that dose?

  4. I’ve read that melatonin is a fragile molecule that is easily damaged in production. I have no knowledge in this area, but what I read was suggesting that you should be very careful about your source for melatonin. What source do you use? Ahem, not interested in the suppository.

  5. What else would you say to someone who is considering high-dose melatonin?

  6. I’ve read nothing about health risks, only warnings that it might affect circadian functioning. Are there health risks that you are concerned about?

  7. From what I understand, high-dose melatonin helps… what? re-energize your cells’ mitochondria? Is this the primary positive effect of high dose melatonin?

  8. When you take a high dose of melatonin for a period of time, is there some effect on your body that you feel? What do you experience while taking high-dose melatonin?

  9. Is this something you plan to take for the rest of your life or does it have a re-balancing effect that allows you to stop after some period of time?

  10. How did you learn about the practice of taking high doses of melatonin?

Thank you!

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A lot of this may have been prompted by me. I am using my phone at the moment and intend to respond when i have a keyboard.

  • I’ve read that some people take 50mg - 180mg per day for antioxidant and anti-aging effects. What is your experience? What dosage do you take?
    Mine varies between 10mg and 990mg.
  • Some people suggest that a person should not take large-dose melatonin before bed or even at bedtime, but in the middle of the night or immediately upon awaking. Do you agree with this? What is the ideal time to take a large dose of melatonin?
    That’s my view. I think the receptors on the SCN reduce pineal production of melatonin when it hits a threshold. There is uncertainty as to the proportion of pineal melatonin that is injected directly into the CSF. Some ovine experiments imply 100%. That affects the feedback system,
  • Since one effect seems to be better sleep, do you set an alarm to take your dosage in the middle of the night? If you sleep through the night do you skip that dose?
    I start with issues with sleep maintenance. Hence this is not an issue, but you can take time release melatonin as long as it delays for a while.
  • I’ve read that melatonin is a fragile molecule that is easily damaged in production. I have no knowledge in this area, but what I read was suggesting that you should be very careful about your source for melatonin. What source do you use? Ahem, not interested in the suppository.
    I mainly use biovea’s own brand. I quite like the berry flavour.
  • What else would you say to someone who is considering high-dose melatonin?
    Read the research. It may be different in its impact for different people.
  • I’ve read nothing about health risks, only warnings that it might affect circadian functioning. Are there health risks that you are concerned about?
    The main one raised is that for male golden hamsters their testes reduced in size. I did a video about melatonin that covers some aspects of the issue.
  • From what I understand, high-dose melatonin helps… what? re-energize your cells’ mitochondria? Is this the primary positive effect of high dose melatonin?
    Melatonin is produced in the mitochondria from seratonin and is used as an anti-oxidant. Pineal melatonin that ends up in the serum can from there get into the mitochondria reducing oxidative stress.

?* When you take a high dose of melatonin for a period of time, is there some effect on your body that you feel? What do you experience while taking high-dose melatonin?
If I have that part of hangover that outlasts pantethine and DHM then it does calm that down.

  • Is this something you plan to take for the rest of your life or does it have a re-balancing effect that allows you to stop after some period of time?
    I do intend to stick with it.
  • How did you learn about the practice of taking high doses of melatonin?
    There is quite a bit of research. Russel Reiter has written a lot about it. He also appears in various videos talking about it.
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Melatonin seems really interesting. I am sorry it is controlled and registered as medicine and I am unable to purchase any supplement to be able to try megadose in Europe…

If you have not seen review the link below, this is another thread on this forum, with posting on this subject.

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AFAIK Melatonin is OTC in France. It can be imported for personal use in the UK,

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the problem is that it is registered as medicine as well. In most countries up to 0,44mg is considered supplement. Medicines are forbidden to import to EU. The rest is gray area, but all supplements on the market I could find are up to 5mg… if you want to take megadose that means 36 capsules per day… gets really ridiculous not to mention pricey. If someone know how to get melatonin in Europe to try megadose let me know!

In the US a few companies sell 60mg per single capsule. One of the brand names is mentioned in the Shallenberger paper.

unfortunately it would be impossible to import to EU.

Melatonin Products | Vitasunn Nutritionals

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That’s a shame. I got it in bulk powder in the US. I still use time released as well so I can stay asleep though.