#87

I think it depends on your tolerance, if you don’t drink coffee regularly it will have a stronger effect.

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#88

haha. I don’ get really get psychedelic effect from coffee (sure would like to :sweat_smile: the way Pollan enthusiastically describes it), but sure I never got why people like caffeine so much… I just get fidgety/buzzed/anxious. Dinking in the afternoon usually does not have such a prnounced effect, but I am awake till late if I drink it too late in the afternoo. This must be tolerance or lack of…
As my blood pressure is at it highest right upon waking probably cortisol spike before waking has something to do with it too in the morning.

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#89

A gene called CYP1A2 determines the rate at which caffeine is broken down in the liver. People who have a variant of this gene that results in faster caffeine metabolism may have a higher tolerance to caffeine. In comparison, those with a variant that leads to slower caffeine metabolism may have a lower tolerance.
Apparently, I have the gene. I remember smelling coffee in the morning as a child and thought that it smelled wonderful and I couldn’t wait until I was old enough to be allowed to drink it. I metabolize it quickly, and my tolerance is high. I can drink two cups of coffee and then immediately take a nap. I have drunk coffee, at least two cups a day since I was eighteen. Coffee just doesn’t make me jittery in any amount. The best coffee is made in Europe. During my travels there I sampled the coffee in several countries it is very hard to get the same good taste in the U.S. I grind my own coffee and drink it black. The only additive I use is 5mg of creatine in my first cup and creatine does not significantly affect the taste.

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#90

I do love my coffee and chocolate!

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#91

Can anyone recommend a good coffee that has all of the best longevity chemicals yet still packs a punch?

I had been drinking Starbucks almost exclusively until I found out that their coffee has the least of the good stuff versus all the other brands tested by far.

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#92

I have been taking 60mg of Melatonin nightly for about two weeks.

So as to not double-post, I’ll share the link below where I describe my experience elsewhere on this site.

TL;DR — it takes about 11 hours for large doses of Melatonin to stop affecting me. I found it works best if I take my dose 90-120 minutes before bed. An 8:30pm dose and 11:00pm bedtime keeps me dreaming or daydreaming until around 7:30am.

Here’s the longer version:

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#93

I would be interested in a link to the people who sell 60mg doses of melatonin. I have not managed to have the same effect myself, but I am careful not to take melatonin before I go to sleep.

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#94

I bought two jars of 60mg capsules. I figured I would compare the product and its effects and choose the one I liked best. Lo and behold both “companies” were located in the same city and state, both were 60mg capsules, both capsules looked precisely the same, and both had batch numbers printed on the bottom of the bottle that were quite literally the same batch. So much for product diversity.

Here’s an Amazon listing for one of the two that I purchased. It’s $32 for 60 capsules. I guess that means I bought 120 capsules. Looks like I’ll be using Melatonin for a while.

Regarding the difference in our reactions to Melatonin, perhaps it could be due to age? I’m just shy of 50 yo.

https://www.amazon.com/Melatonin-Ensures-Important-Hormone-Capsules/dp/B06XP47682

#95

I am 63 and historically quite a bad sleeper.

I may have adjusted to higher cortisol and also to high dose melatonin.

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#96

A member of my group asked whether melatonin can attenuate diabetes. This is a fascinating question because you will get opposite results with different amounts and duration.

For example, in 2022 there were two peer-reviewed studies showing opposite results when melatonin is used in the context of diabetes. One study administered 10 mg of MEL to human subjects with type 2 diabetes over the course of 12 weeks in a double ‐blinded, randomized, placebo‐controlled, crossover study. Compared to controls who received placebos, patients receiving melatonin exhibited a REDUCTION in insulin sensitivity by 12%.

However, another peer-reviewed study on diabetic rats conducted last year showed opposite results when melatonin was administered orally at 10 mg/kg body weight to rats at 6 weeks of age (emerging adulthood). The rats injected with streptozotocin to induce diabetes all exhibited a significant reduction in fasting blood glucose (FBG) and increased insulin secretion indicating β cells regeneration in the pancreas. Why would melatonin reduce hyperglycemia, hyperlipidemia and oxidative stress in diabetic rats but not humans?

The key to the controversial puzzle is in dosage and duration.

➡️ The rats were given 10 mg/kg whereas humans were given 10 mg regardless of weight

➡️ Melatonin was administered to rats for 8 weeks; whereas melatonin was given to humans for 12 weeks.

Is there a difference with these study parameters? You bet, and these differences may contribute to the opposite results obtained.

➡️ At emerging adulthood (days 70-150), one human year = 13.3 rat days [2]. That means, the rats were treated with melatonin for a duration (56 days/8 weeks) that is equivalent to ~4.2 human years. The human study gave melatonin to diabetic patients for only 3 months.

➡️ Rats were given 10 mg/kg melatonin. At an average weight of 195 grams, a rat would have

received 1.95 mg melatonin. The human equivalent dose (HED) for a 70 kg person after adjusting for interspecies differences in metabolic rate would be 160.8 mg. However, this does not account for the difference between rat and human oral bioavailability of 53.5% and 15%. [3]

The final adjusted dosage for the HED used in the successful rat experiment is actually 573.52 mg, or 57.35-fold higher than what was used in the human RCT. Furthermore, this amount was administered at 16.8 times the duration (4.2 human-year equivalent versus 3 months).

Yes, dosage and frequency matters a lot when you are supplementing with melatonin for targeted results. If you want to learn more about dosages, read my peer-reviewed paper on how to calculate HEDs from animal doses used in successful melatonin studies.

https://www.mdpi.com/1422-0067/24/6/5835

References:

[1] Lauritzen, E. S.; Kampmann, U.; Pedersen, M. G. B.; Christensen, L.-L.; Jessen, N.; Møller, N.;

Støy, J. Three Months of Melatonin Treatment Reduces Insulin Sensitivity in Patients with Type 2

Diabetes-A Randomized Placebo-Controlled Crossover Trial. J. Pineal Res. 2022, 73, e12809.

[2] Ghasemi, A.; Jeddi, S.; Kashfi, K. The Laboratory Rat: Age and Body Weight Matter. EXCLI J.

2021, 20, 1431–1445.

[3] Loh, D.; Reiter, R.J. Light, Water, and Melatonin: The Synergistic Regulation of Phase

Separation in Dementia. Int. J. Mol. Sci. 2023, 24, 5835. https://doi.org/10.3390/ijms24065835

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#97

Melatonin being a circadian hormone is best dosed in a circadian manner to go with the circadian cycle rather than conflict with it.

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#98

FWIW

A excellent video on how NIR light generates intracellular melatonin production and effects on mitochondria.

Less than 5% of melatonin produced in the body is at night.

Link’s to papers mentioned in the video

“Melatonin and the Optics of the Human Body” | Melatonin Research

https://www.melatonin-research.net/index.php/MR/article/view/19

“NF-κB Drives the Synthesis of Melatonin in RAW 264.7 Macrophages by Inducing the Transcription of the Arylalkylamine-N-Acetyltransferase (AA-NAT) Gene” | PLOS ONE

“Melatonin: A mitochondrial resident with a diverse skill set” - ScienceDirect

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#99

I’ve been experimenting with 100mg melatonin every other day. Before anyone calls me out, yes, I’m the same one who had a “hangover” from 5mg. But I also like to experiment.

Results:

I sleep deeper and longer. The hangover still exists but it’s not actually much worse than 5-10mg.

I tend to be relaxed the entire next day. But I’m awake enough to feel good.

I find it particularly nice to go to bed quite empty, skipping dinner or being a bit hungry. Normally this makes my sleep a bit more shallow, but with the high dose melatonin I just knock out. That combination of empty stomach + deep sleep feels quite restorative. It also seems quite good for fat loss.

Plan on continuing this schedule for now

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#100

I am wondering myself if the “hangover” is in fact a shortage of cortisol in that the cortisol awakening response is weaker. I am not sure that melatonin itself hangs around that much as it has quite a short half life.

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#101

What I find interesting about melatonin and cortisol is their interplay during the night. What I think happens is that there is an interplay between the sleep cycles and melatonin. The sleep cycle which is governed by the HPA axis is the same as the daily ultradian cycle and last perhaps 90 minutes. If serum melatonin drops then cortisol increases. However, at the start of each ultradian cycle a sufficient level of serum melatonin can prevent the increase in cortisol. When there is an increase in cortisol people get to the state of awakeness. At this point people cannot sleep even with a large amount of melatonin in blood serum.

Melatonin is inhibitory and therefore unless there is a lot of cortisol floating around melatonin can assist with sleep.

Pineal melatonin is the best for sleep because it is injected directly (either mainly, all or partially) into the cerebrospinal fluid (third ventricle) which does not metabolise as quickly and comes slowly out into the blood thereby maintaining a sufficient level in the blood to stop cortisol from increasing. The danger with exogenous melatonin into the blood is that it metabolises quite quickly (or is absorbed into cells) so depending upon the threshold for keeping cortisol low - which varies from person to person - it can cause an early awakening or indeed it can cause the awakening response to be limited.

What would be really interesting is to work out what affects the level at which melatonin suppresses cortisol, this probably does adjust and clearly varies for some reason or other.

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#102

Vitamin E and C can blunt some exercise benefits. Is there a risk that melatonin will do the same? Especially with large doses.

https://physoc.onlinelibrary.wiley.com/doi/epdf/10.1113/jphysiol.2013.267419

#103

Its hard to say. I am now able to do some chinups with an extra 10kg weight on my feet (5kg on each foot). I do take a lot of melatonin. However, there is always the question as to what would have happened had I not taken the melatonin.

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#104

I’m more concerned about endurance training and melatonin. If melatonin reduce mitochondrial biogenesis like c or e vitamin might do.

#105

Superficially this appears to enhance mitochondrial biogenesis, but I have not read the papers.

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#106

The person to ask is Russel Reiter, Ph.D.

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