Melatonin megadoses?

#166

I wonder myself if melatonin increases SHBG.

I did spend some time studying the literature on whether melatonin is likely to affect puberty in older human beings. Although it is higher prior to puberty I don’t think the literature support it having a causal effect.

I do think it acts to reduce mitochondrial heteroplasmy.

The most I have taken in a night is around 1.4g. I may experiment with Doris Loh’s approach. I do weekly blood tests so should see any impact reasonably quickly.

In the end keeping heteroplasmy under control is IMO a good idea.

#167

Age might be a factor in regards to sleep cycles, as melatonin has helped combat some of the age related issues one experiences with sleep.
This is due to some depletion of melatonin receptors or decrease sensitivity of these receptors,

#168

No doubt there are lots of benefits. If taken at night no light period especially as we age I do not think the negatives are a concern even at large dosages. But during the day having raised melatonin levels and its effects when you consume food I think is about the absolute worst time. If you consider how bad late night eating is and the natural melatonin release pattern and its effect it seems in line with similar negative effects seen with late night eating. Higher BG reduced insulin sensitivity, etc…

#169

I don’t know. I have used daytime melatonin recently to reduce the harm from alcohol. I know it works overnight because I can sense the effects and I have tried 100 or 200mg when drunk, but at least one HPA/Sleep cycle before going to bed to avoid any effect on sleeping.

I cannot say particularly if this has helped. I have put in an order for 100g of Bulk Supplements melatonin and may try some higher doses cf Doris Loh. (probably a couple of days before a broad spectrum blood tests so I can see any impact on SHBG.

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#170

After taking relatively high doses of melatonin for decades I, (N=1), I have not noticed any discernable negative effects.
I read the 5 studies and one chapter that you cite. They are generally very small studies or poorly done. None of the studies appear in the top 25 most prestigious medical journals.

  1. Small sample size (n=17) limits generalizability
    Only included male participants, so results may not apply to females
    Short duration of treatment (3 months)
    Didn’t measure HbA1c, so the clinical significance is unclear
    “Still, it was not the individuals with the highest melatonin levels that had the largest reduction in insulin sensitivity”

  2. The limitations of small sample size, single dose, and lack of long-term data are acknowledged.

  3. Small sample size (n=6) limits generalizability
    Short study duration
    Lack of dose-response data
    No measurement of downstream effects on sperm or fertility

“These data indicate that an evening melatonin administration decreases the next-day LH secretion in normal adult males without altering testosterone levels or the endogenous nocturnal melatonin secretory pattern.”

  1. Very small sample size (n=8)
    No measurement of baseline semen quality prior to treatment
    No measurement of testicular volume.
    Lack of dose-response data

  2. This chapter provides a limited overview of studies on melatonin/norethisterone contraception from 1993. There are currently no medical guidelines to recommend the use of melatonin as a contraceptive.

  3. The last one is irrelevant or pro-melatonin as it relates to this thread.
    "The results of this study did not support our hypothesis that melatonin would improve sleep and suppress hot flashes among symptomatic postmenopausal women, but there were no significant adverse effects, and LH was possibly suppressed’

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#171

Thank you for this connection. I need to look into this now.

#172
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#173

This seemed to have interesting elements

#174

I decided not to take Melatonin. I routinely see a fasting (morning) blood glucose (BG) of 150-185, which would say that I’m diabetic. Yet, my A1C is at the top end of normal, therefore I am not (yet) diabetic. (Yes, I do work at keeping it that way with fasting/keto).

I did some reading and it’s paradoxical. Some research indicates that it’s good for BG levels. Yet, others indicate that it may elevate BG levels.

Since I tend to work out at a gym from 8:30 to 10pm and eat dinner after, I decided that it was not for me since I have read that timing of meals versus timing of Melatonin intake is a factor.

The take-away: If you are diabetic, or “pre-diabetic,” do your research and either watch your BG with a glucose meter or better, use a CGM (Continuous Glucose Monitor) to see what happens to your BG

I liked this article: How does melatonin affect metabolic health? - Levels

“The researchers found that higher nighttime melatonin levels were linked to greater insulin sensitivity and a lower prevalence of insulin resistance. Other research suggests melatonin can have a negative impact on metabolic health. For example, one study published in Cell Metabolism that used both mouse and human models found that increasing levels of melatonin negatively impact the ability of beta cells to produce insulin. The researchers determined that the effect is stronger in people with a variant in the melatonin receptor gene MTNR1B, which is linked to a higher risk of Type 2 diabetes. But the study also found that insulin inhibition may also have a positive effect in some cases. The authors concluded that reduced insulin release at night when melatonin levels are high but metabolic demand is low (because food hasn’t been consumed recently) may be a protective mechanism against nocturnal hypoglycemia, or low blood sugar levels at night.”

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#175

I have just taken 200mg of melatonin. Earlier today I drank 3 pints of beer and 0.5l of red wine. I know from personal experience that melatonin reduces the negative effects of alcohol (for me personally). I will probably go out for some more drink later an also take more melatonin during the night (it is 17.46 where I am).

I do also take pantethine and DHM to deal with alcohol.

My last HbA1c was 24.47 mmol/L which is 4.4%. However, the previous week was a lot higher.

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#176

I am currently trying a high dose of melatonin protocol.
I take 500mg in the morning with my coffee and 500mg about 90 minutes before bedtime. I have only been doing this for ~1 week

So far I am impressed with the results. lt seems contrary to the conventional wisdom surrounding melatonin. I have much better sleep and I don’t wake up drowsy and I have no daytime sleepiness. Oddly it seems to improve my energy level. I go to the gym earlier now, maybe because of improved sleep quality.

Signs and Symptoms of Melatonin Overdose
Excessive daytime sleepiness
Headache
Dizziness
Irritability
Confusion
Stomach cramps
Anxiety

These are almost all anecdotal reports of melatonin at much lower doses than 1 gram a day.
So, I must conclude from my experience of taking what is considered high doses of melatonin for decades that the conventional medical wisdom about melatonin is BS, at least as it applies to me.

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#177

I am now in the pub having taken 200mg

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Lots of things are said about melatonin without evidence

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#178

Adjuvant melatonin for the prevention of recurrence and mortality following lung cancer resection (AMPLCaRe): A randomized placebo controlled clinical trial, 2021

709 patients across eight centres were randomized to melatonin (n = 356) versus placebo (n = 353).

There is potential evidence to support its use in patients with late stage resected NSCLC; however, confident conclusions cannot be made based on the results of our study and other available evidence. Another placebo-controlled, blinded RCT designed around patients with late stage resected NSCLC is needed to confirm these results.

#179

IMO: Recent evidence of the benefits of high-dose melatonin suggests that they should have used higher doses.

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#180

Can MRI detect calcification of pineal gland?

#181

What evidence are you referring to?

I do think taking 200 mg melatonin during the day (around meals), seem like it is lacking evidence of safety and efficacy. Not acutely, I am aware of the toxicology studies, but rates of diabetes and increases in HbA1C.

#182

N=1
I have been taking what was considered very high doses of melatonin at the time, 10 to 20mg daily. The amount of melatonin produced varies by individual but generally ranges from 10-80 micrograms (0.01-0.08 mg) per night. So yes, 10 to 20 mg daily was considered a very high dose.

A1c levels tend to increase with age, even in people without diabetes. This age-related increase in A1c is considered a normal part of aging.
My current A1c is 5.4 which is good for my age and I don’t think melatonin has had an adverse effect.

Those such as Doris Loh who has extensively studied melatonin for many years has offered guidelines for high-dose melatonin based on such studies involving melatonin and viral diseases.

No, there are no quality studies involving high-dose melatonin in humans and I am not suggesting or advocating for anyone to experiment with extremely high doses of melatonin. Those who are, are Guinea pigs doing a self-experiment in healthspan and longevity. By the time you reach my age, I am sure you will know much more about extending lifespan than we do now.

Below are Doris Loh’s guidelines and you will see that the 1 gram daily that I am taking
is about 1/4 the dose she is suggesting. (Though I am going to slowly titrate my dose upward while checking my blood work. I monitor my glucose levels daily and have not noticed a daily fasting increase in glucose levels)

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#183

I have weekly values of HbA1c the last was 4.4%. I am 64.

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#184

Subjective report of the effects of taking high dose melatonin 800-1000 mg total after 10 days in divided doses taken morning and evening. N=1

It’s always possible that there is some placebo effect, but I don’t think so, because the benefits only started to show up after 7 days of taking high doses and some benefits were unexpected.

The benefits I have experienced so far: Improved sleep cycle ie., deep sleep to rem sleep is closer to the ideal. This is also subjective because I can’t rely on my “smartwatch” to give accurate readings. Though it says this is so. So, it would certainly be a relative improvement over previous readings.

Noticeably improved energy levels noticed through faster gait speed and the amount of work I do during the day. It has also improved my mood, which was good to begin with.

I don’t know how this occurs, but it is probably through improved mitochondrial function and antioxidant properties.

“In specific reference to the brain, melatonin also has an advantage over some other antioxidants given that it readily passes through the blood-brain-barrier. This, coupled with the fact that it and its by-products are particularly efficient detoxifiers of reactive species, make these molecules of major importance in protecting the brain from oxidative/nitrosative abuse.”

“The measurement of the subcellular distribution of melatonin has shown that the concentration of this indole in the mitochondria greatly exceeds that in the blood. Melatonin presumably enters mitochondria through oligopeptide transporters, PEPT1, and PEPT2.”

“Melatonin is capable of directly scavenging a variety of toxic oxygen and nitrogen-based reactants, stimulates antioxidative enzymes, increases the efficiency of the electron transport chain thereby limiting electron leakage and free radical generation, and promotes ATP synthesis. Via these actions, melatonin preserves the integrity of the mitochondria and helps to maintain cell functions and survival.”

“For example, melatonin has established effects as an antioxidant and free radical scavenger both in vitro and in animal models. This is also evident in melatonin’s prominent role in mitochondria, which is reviewed in the next section. Melatonin is synthesized in, taken up by, and concentrated in mitochondria, the powerhouse of the cell.”

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#185

@desertshores, Thank you kindly sir. I greatly appreciate you sharing your experiences and perspective. I’ve been a pretty consistent user of higher dose melatonin for many years averaging 10-20 mg extended release nightly and definitely feel it’s been helpful for me as a former shift worker. I’m going to look into Loh’s approach now as I suspect I’m dealing with some mild long covid from being mandated to work two 12 hour shifts back to back in the hospital while positive and symptomatic last November. Hopefully this helps since there doesn’t currently seem to be many options available.

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