[Edit: probably not as bad as it first looks. See comment for more thoughts.]
Long-term melatonin usage for insomniacs was associated with doubling of all-cause mortality*
New article from the American Heart Association seems pretty damning for long-term melatonin usage safety:
In a large, multinational real-world cohort rigorously matched on >40 baseline variables, long-term melatonin supplementation in insomnia was associated with an 89% higher hazard of incident heart failure, a three-fold increase in HF-related hospitalizations, and a doubling of all-cause mortality over 5 years.
*Caveats:
we just have the abstract, not the full article
observational study, not experimental
their sample is only of insomniacs, not of the general population
Responses to the caveats:
we’ll get the full article soon-ish (probably a month or so?)
it seems they did quite a bit of controlling? though we won’t know how good their controlling was until the full article comes out
I can’t imagine that the validity of their results for non-insomniacs is many orders of magnitude less than for insomniacs — like, maybe a factor of two or five, but that’d still be a huge effect size
All things considered — this seems like a crazily high effect size. Am I missing something?
(Warning: relatively hot take and also not medical advice.)
Firstly, there’s a major underlying confounder effect here which is the untracked severity of insomnia and it’s correlation with the prescription of melatonin. If these are majorly coupled it could amount to most of the effect?
Secondly, here’s a model and a tip for melatonin use as most US over the top pills I’ve seen are around 10mg which is way too much. I’ll start with the basic mental model for why and then say the underlying thing we see.
TL;DR:
If you want to be on the safe side don’t take more than 3mg of it per night. (You’re probably gonna be fine anyway due to the confounder effects of long-term insomnia having higher correlation with long-term melatonin use but who knows how that trend actually looks like.)
Model:
There’s a model for sleep which I quite like from Uri Alon (I think it’s from him at least) and it is mainly as the circadian rhythm and sleep mechanism as a base layer signal for your other bodily systems to sync to.
The reasoning goes a bit like: Which is the most stable cycle that we could stabilise to? Well we have a day rhythm that is coupled to 24 hours a day each day, very stable compared to most other signals. That’s the circadian rhythm which is maintained by your system’s sleep.
What sleep does is that it is a reset period for the biological version of this as it sends out a bunch of low-range stable signals that are saying “hey gather around let’s coordinate, the time is approximately night time.” These brain signals don’t happen in non-sleep and so they are easy to check.
Melatonin is one of the main molecules for regulating this pattern and you actually don’t need more than 0.3 mg (remember bioavaliability here) to double your existing amount that you already have in the body. Most over the counter medicine is around 10mg which is way too much. Imagine that you change one of the baseline signals of your base regulatory system and just bloop it the fuck out of the stratosphere for a concentrated period once everyday. The half life of melatonin is also something like 25-50 minutes so it decays pretty quickly as well which means that the curve ends up looking like the following:
If you don’t do this then your more natural curve looks something more like this:
So if you stratosphere your melatonin with 10 mg then your REM sleep will be fine but the sensitivity to your MT2 receptor will be a bit fucked which means worse deep sleep (which is important for your cardiovascular system!). Hence you will fall asleep but with worse deep sleep (Haven’t checked if this is true but this could probably be checked pretty easily experimentally).
The bioavaliability of melatonin varies between 10 and 30% so if you aim for approximately your own intragenous generation of melatonin you should take 10 to 3x the amount existent in the system. For my own optimal sleep that is 0.5 mg of melatonin but that’s because my own system already works pretty well and I just need a smaller nudge. The area under the curve part of the model is also a good reason to take slow release melatonin as it better approximates your normal melatonin curve.
(I need to get back to work lol but hopefully this helps a bit)
(1) just spoke with a doctor[1] who’d looked into it a bit. he basically wasn’t worried about it at all — his take was (paraphrasing quite a bit):
causes of heart failure are numerous & complex — it’d be really confusing mechanistically if melatonin affected a sufficiently large subset of those causes sufficiently strongly to have this strong of an effect.
also, because they’re so numerous & complex, it seems pretty implausible that they could’ve done even close to a sane job of manually controlling for all of the right variables.
[this bullet added by saul, not explicitly said by the doctor but he sort-of implied it] in particular, badness of insomnia is comorbid with extent of lots of other bad stuff. i.e. it’d be reasonable to expect having a prescription for melatonin selects for having very bad insomnia, which then seems like a straightforward causal factor for getting heart failures. it’s obviously possible they did some manual controlling for this, but since we don’t have the full paper, we can’t tell (and it seems like it’d be pretty tough to actually effectively control for this).
causes of heart failure typically take quite a while to build up; it’d be surprising if it only took melatonin 5 years to have such a significant effect.
we naturally produce some melatonin, and the amount one would exogenously supplement isn’t (typically, at least for prescribed patients) substantially higher than what you’d expect to see in one’s natural range of endogenous melatonin production.
if the american heart association was actually worried about this, they’d have done some public messaging independent from the paper abstract — it’s possible such a message is forthcoming, but we probably should have expected to see something about it by now.
(2) i’ve emailed the authors asking for the full paper. i’ll aim to keep this thread updated with thoughts if/when the paper arrives in my inbox!
doctor was a psychiatrist, not a cardiologist or internal medicine doctor — so though you should take it with a grain of salt, he did still get an MD. which implies way more medical knowledge than i have, at least!
I also saw this and was curious. It could just be an uncontrolled third correlate, like the severity of insomnia mentioned in other comments, or something else. But I think there are plausible causal mechanisms.
One relevant thing is that the doses they were prescribed were almost certainly far too high.
I think you could make an argument for anything up to 1 mg. Anything beyond that and you’re definitely too high. Excess melatonin isn’t grossly dangerous, but tends to produce tolerance and might mess up your chronobiology in other ways.
So my guess is that the prescribed dose is even higher than the 5-30x too high that’s the standard non-prescription dose. Even with the fast half-life, that melatonin is telling those patients minds and bodies (several metabolic processes I assume) that they should be sound asleep when they shouldn’t. High doses will probably also cause tolerance, as all of the brain is an adaptive system with tons of negative feedback loops that cause tolerance at many scales (citation: me), and I weakly gather that the rest of the body works the same way. The combination of sleep signals out of place and strong tolerance could wreak havoc in a variety of ways.
I suspect the other correlation might be that doctors who ignore all of this and prescribe high-dose melatonin for sleep disorders are bad doctors. But that’s speculation, aside from the above hypothesis.
Alexander continues:
Based on anecdotal reports and the implausibility of becoming tolerant to a natural hormone at the dose you naturally have it, I would guess sufficiently low doses are safe and effective long term, but this is just a guess, and most guidelines are cautious in saying anything after three months or so.
So I continue to take .5mg melatonin nightly as a way to gain voluntary control over my sleep schedule.
There’s also some evidence that the body may not produce melatonin properly if we’re in bright artificial light up to bedtime. So the supplementation I’m doing might actually be doing something that the body would do in its natural environment but doesn’t do now. This evidence was cited by a trustworthy but non-rationalist person and I haven’t tracked it down myself, so I don’t know how likely this really is to be true.
The rest of that essay on melatonin also seems highly useful.
[single anecdatum:] I’ve tried melatonin several times to treat rotating sleep because people won’t talk to you about it without suggesting that, and it never works. More to the point, it makes me feel weird and makes me feel like the resulting sleep is weird and less restful. IDK if related. (Yes I would take 300µg.)
I remember one scientist who pointed out that observational studies were one of the weakest forms of evidence possible. This type of study can detect things like “smoking is bad for you”, because smokers are 30 times more likely to die of lung cancer. But once you get down to smaller effect sizes, you run into the problem that observational studies hopelessly mix up different correlated variables. So for many things, observational studies essentially return random noise. This is allegedly what happened with HRT for post-menopausal women, where the observational studies failed to note that the people taking HRT contained a much larger proportion of nurses and other people who complied with medical advice. And then there’s nutrition, where every study feels like it gets reversed every 5 years.
Or the way that Vitamin D levels are apparently correlated with almost every measure of good health, but Vitamin D supplementation notoriously fails to actually improve any of those measures.
“2x” is a big enough effect size that this may actually be real, and not a spurious correlation. And of course, there’s the underlying history of other sleep medications apparently being cursed to have horrible side effects, so “melatonin is actually terrible for you” wouldn’t be surprising.
(Since we are speaking of observational studies, I suspect that at least two of the things I have claimed in this post are Officially Wrong. Which two things are officially wrong may depend on what year you read it.)
[Edit: probably not as bad as it first looks. See comment for more thoughts.]
Long-term melatonin usage for insomniacs was associated with doubling of all-cause mortality*
New article from the American Heart Association seems pretty damning for long-term melatonin usage safety:
*Caveats:
we just have the abstract, not the full article
observational study, not experimental
their sample is only of insomniacs, not of the general population
Responses to the caveats:
we’ll get the full article soon-ish (probably a month or so?)
it seems they did quite a bit of controlling? though we won’t know how good their controlling was until the full article comes out
I can’t imagine that the validity of their results for non-insomniacs is many orders of magnitude less than for insomniacs — like, maybe a factor of two or five, but that’d still be a huge effect size
All things considered — this seems like a crazily high effect size. Am I missing something?
(Warning: relatively hot take and also not medical advice.)
Firstly, there’s a major underlying confounder effect here which is the untracked severity of insomnia and it’s correlation with the prescription of melatonin. If these are majorly coupled it could amount to most of the effect?
Secondly, here’s a model and a tip for melatonin use as most US over the top pills I’ve seen are around 10mg which is way too much. I’ll start with the basic mental model for why and then say the underlying thing we see.
TL;DR:
If you want to be on the safe side don’t take more than 3mg of it per night. (You’re probably gonna be fine anyway due to the confounder effects of long-term insomnia having higher correlation with long-term melatonin use but who knows how that trend actually looks like.)
Model:
There’s a model for sleep which I quite like from Uri Alon (I think it’s from him at least) and it is mainly as the circadian rhythm and sleep mechanism as a base layer signal for your other bodily systems to sync to.
The reasoning goes a bit like: Which is the most stable cycle that we could stabilise to? Well we have a day rhythm that is coupled to 24 hours a day each day, very stable compared to most other signals. That’s the circadian rhythm which is maintained by your system’s sleep.
What sleep does is that it is a reset period for the biological version of this as it sends out a bunch of low-range stable signals that are saying “hey gather around let’s coordinate, the time is approximately night time.” These brain signals don’t happen in non-sleep and so they are easy to check.
Melatonin is one of the main molecules for regulating this pattern and you actually don’t need more than 0.3 mg (remember bioavaliability here) to double your existing amount that you already have in the body. Most over the counter medicine is around 10mg which is way too much. Imagine that you change one of the baseline signals of your base regulatory system and just bloop it the fuck out of the stratosphere for a concentrated period once everyday. The half life of melatonin is also something like 25-50 minutes so it decays pretty quickly as well which means that the curve ends up looking like the following:
If you don’t do this then your more natural curve looks something more like this:
Section 3 of the following talk about a desentisation of the MT2 part of melatonin as something that happens quite quickly: https://www.sciencedirect.com/topics/neuroscience/melatonin-receptor
So if you stratosphere your melatonin with 10 mg then your REM sleep will be fine but the sensitivity to your MT2 receptor will be a bit fucked which means worse deep sleep (which is important for your cardiovascular system!). Hence you will fall asleep but with worse deep sleep (Haven’t checked if this is true but this could probably be checked pretty easily experimentally).
The bioavaliability of melatonin varies between 10 and 30% so if you aim for approximately your own intragenous generation of melatonin you should take 10 to 3x the amount existent in the system. For my own optimal sleep that is 0.5 mg of melatonin but that’s because my own system already works pretty well and I just need a smaller nudge. The area under the curve part of the model is also a good reason to take slow release melatonin as it better approximates your normal melatonin curve.
(I need to get back to work lol but hopefully this helps a bit)
some updates:
(1) just spoke with a doctor[1] who’d looked into it a bit. he basically wasn’t worried about it at all — his take was (paraphrasing quite a bit):
causes of heart failure are numerous & complex — it’d be really confusing mechanistically if melatonin affected a sufficiently large subset of those causes sufficiently strongly to have this strong of an effect.
also, because they’re so numerous & complex, it seems pretty implausible that they could’ve done even close to a sane job of manually controlling for all of the right variables.
[this bullet added by saul, not explicitly said by the doctor but he sort-of implied it] in particular, badness of insomnia is comorbid with extent of lots of other bad stuff. i.e. it’d be reasonable to expect having a prescription for melatonin selects for having very bad insomnia, which then seems like a straightforward causal factor for getting heart failures. it’s obviously possible they did some manual controlling for this, but since we don’t have the full paper, we can’t tell (and it seems like it’d be pretty tough to actually effectively control for this).
causes of heart failure typically take quite a while to build up; it’d be surprising if it only took melatonin 5 years to have such a significant effect.
we naturally produce some melatonin, and the amount one would exogenously supplement isn’t (typically, at least for prescribed patients) substantially higher than what you’d expect to see in one’s natural range of endogenous melatonin production.
if the american heart association was actually worried about this, they’d have done some public messaging independent from the paper abstract — it’s possible such a message is forthcoming, but we probably should have expected to see something about it by now.
(2) i’ve emailed the authors asking for the full paper. i’ll aim to keep this thread updated with thoughts if/when the paper arrives in my inbox!
doctor was a psychiatrist, not a cardiologist or internal medicine doctor — so though you should take it with a grain of salt, he did still get an MD. which implies way more medical knowledge than i have, at least!
Does anyone have any plausible models (~ causal pathways) for how long-term melatonin usage could have this effect?
Like: Assume it’s true. Then, what’s the most likely mechanism that makes it true?
May be related: OTC melatonin dosage is way above what is recommended. It’s easy to find 10mg when the recommended dose is more like 0.3 mg.
The study only looked at patients who were prescribed melatonin (though they indeed do not detail what the dosages are).
I also saw this and was curious. It could just be an uncontrolled third correlate, like the severity of insomnia mentioned in other comments, or something else. But I think there are plausible causal mechanisms.
One relevant thing is that the doses they were prescribed were almost certainly far too high.
Scott Alexander claims and argues convincingly that the evidence for this is clear and overwhelming in his essay Melatonin: Much More Than You Wanted To Know
So my guess is that the prescribed dose is even higher than the 5-30x too high that’s the standard non-prescription dose. Even with the fast half-life, that melatonin is telling those patients minds and bodies (several metabolic processes I assume) that they should be sound asleep when they shouldn’t. High doses will probably also cause tolerance, as all of the brain is an adaptive system with tons of negative feedback loops that cause tolerance at many scales (citation: me), and I weakly gather that the rest of the body works the same way. The combination of sleep signals out of place and strong tolerance could wreak havoc in a variety of ways.
I suspect the other correlation might be that doctors who ignore all of this and prescribe high-dose melatonin for sleep disorders are bad doctors. But that’s speculation, aside from the above hypothesis.
Alexander continues:
So I continue to take .5mg melatonin nightly as a way to gain voluntary control over my sleep schedule.
There’s also some evidence that the body may not produce melatonin properly if we’re in bright artificial light up to bedtime. So the supplementation I’m doing might actually be doing something that the body would do in its natural environment but doesn’t do now. This evidence was cited by a trustworthy but non-rationalist person and I haven’t tracked it down myself, so I don’t know how likely this really is to be true.
The rest of that essay on melatonin also seems highly useful.
[single anecdatum:] I’ve tried melatonin several times to treat rotating sleep because people won’t talk to you about it without suggesting that, and it never works. More to the point, it makes me feel weird and makes me feel like the resulting sleep is weird and less restful. IDK if related. (Yes I would take 300µg.)
I remember one scientist who pointed out that observational studies were one of the weakest forms of evidence possible. This type of study can detect things like “smoking is bad for you”, because smokers are 30 times more likely to die of lung cancer. But once you get down to smaller effect sizes, you run into the problem that observational studies hopelessly mix up different correlated variables. So for many things, observational studies essentially return random noise. This is allegedly what happened with HRT for post-menopausal women, where the observational studies failed to note that the people taking HRT contained a much larger proportion of nurses and other people who complied with medical advice. And then there’s nutrition, where every study feels like it gets reversed every 5 years.
Or the way that Vitamin D levels are apparently correlated with almost every measure of good health, but Vitamin D supplementation notoriously fails to actually improve any of those measures.
“2x” is a big enough effect size that this may actually be real, and not a spurious correlation. And of course, there’s the underlying history of other sleep medications apparently being cursed to have horrible side effects, so “melatonin is actually terrible for you” wouldn’t be surprising.
(Since we are speaking of observational studies, I suspect that at least two of the things I have claimed in this post are Officially Wrong. Which two things are officially wrong may depend on what year you read it.)