As people know I have been doing some biohacking work with people who have PD. As a consequence I have come to a hypothesis as to the cause of PD and I wrote a post on this here:
I have been doing a bit more work on that post today and have added the following text:
Obviously night time levels of melatonin are higher. ChatGPT gives a level of between 500 and 3,000 pg/ml.
There has been quite a bit of burbling in the medical profession about serum levels of melatonin that result from supplementation. Melatonin pharmacokinetics following two different oral surge-sustained release doses in older adults and Chronic Administration of Melatonin: Physiological and Clinical Considerations are both papers that look at this.
Summarising the research, however, if people take something like 0.1 to 0.5mg then the peak serum level is in the normal range. If people take 4mg the peak serum level is around 4000 pg/ml. There is a problem, however, which is that normally during the night the brain is exposed to something like 3,000 pg/ml and during the day looking at the above table something like 300 pg/ml. Hence if the priority is to replicate the brain’s exposure to melatonin then a single dose providing a peak 4000 pg/ml comes nowhere close to the 3,000 mean figure as the half life is around 30 mins. It is obviously hard to know what is going on in the CSF during the night, but replicating physiological figures for melatonin in the brain requires superphysiological figures for the serum.
There are rightly held concerns as to what effects melatonin may have in higher levels in serum and that is not entirely clear. It does appear to hold back puberty (in my view by preventing mtDNA damage). It may increase levels of some molecules such as SHBG. However, if the objective is to concentrate on improving and protecting brain cells having superphysiological levels of melatonin looks right.
I have not tried to calculate AUC for melatonin in the CSF in normal metabolic circumstances at any age. However, I think the figures we now have which indicate a normal level in the CSF during the day of about 300 pg/ml and a night time level of a lot higher than that (perhaps 10-50 times as high) give a solid evidence base that if your priority is to maintain normal physiological levels of melatonin for brain cells you need to supplement to create a superphysiological level of melatonin in serum.
There is in a sense some solid maths to be done here to calculate the supplementation levels needed to replicate the normal diurnal AUC for the brain from the CSF, but in the end people are experimenting with high levels (as am I).
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I understand the rationale for taking a big melatonin dose if I wake up at 1-2am (to help sleep onset and get this boost in nighttime melatonin). Would you assume that if I didn’t wake up that my endogenous melatonin was sufficient? ….that there would be no net benefit to using an alarm to wake up at 2am to take a big dose? (Years ago I stupidly used to wake up to drink a protein shake at 2am; not inclined to repeat that protocol).
As people have lower melatonin levels when they get older I don’t think the endogenous levels are enough. However, I would not set an alarm to wake during the night. The difficulty is that it has a complex interplay with the body and affects people in different ways. If I have not taken all of my melatonin during the night I take the remaining amount when I wake up, but as a rule this does not put me to sleep. Other people it may cause to go back to sleep or at least become very sleepy. Hence I don’t think there is a simple rule on this.
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medaura
#4
In animal studies, melatonin has been shown to delay the onset of puberty. This is because melatonin suppresses the production of gonadotropin-releasing hormone (GnRH), which triggers the release of hormones that initiate puberty — from Google’s AI, with a reference paper
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I think melatonin delays the onset of puberty in humans as well. I think it is probably a splicing issue. That indeed may relate to GnRH, but more than GnRH in isolation.
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adssx
#6
Not PD but ALS: Reduced oxidative damage in ALS by high-dose enteral melatonin treatment 2006
In a clinical safety study, chronic high-dose (300 mg/day) rectal melatonin was well tolerated during an observation period of up to 2 yr. Importantly, circulating serum protein carbonyls, which provide a surrogate marker for oxidative stress, were elevated in ALS patients, but were normalized to control values by melatonin treatment. This combination of preclinical effectiveness and proven safety in humans suggests that high-dose melatonin is suitable for clinical trials aimed at neuroprotection through antioxidation in ALS.
Per ChatGPT, 300 mg rectal is equivalent to about 500 mg oral.
There are retail vendors in the USA of 200 and 400mg suppositories.
Without having done detailed calculations I would think the necessary oral dose to get the AUC for brain cells without CSF contributions would be between 300 and 3000mg. I think it is probably below 1,500 and possibly below 1,000, but I don’t personally want to risk the levels being too low.
