(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!

1. ^{^}

   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?

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

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.)

observational study, not experimental

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.)

This seems to be a nice observational study which analyses already available data, with an interesting and potentially important finding.

They didn't do "controlling" in the technical sense of the word, they matched cases and controls on 40 baseline variables in the cohort with "demographics, 15 comorbidities, concomitant cardiometabolic drugs, laboratories, vitals, and health-care utilization"

The big caveat here is that these impressive observational findings often disappear, or become much smaller when a randomised controlled trial is done. Observational studies can never prove causation. Usually that is because there is some silent feature about the kind of people that use melatonin to sleep, that couldn't be matched for or was missed in the matching. A speculative example here could be that some silent, unknown illnesses could have caused people to have poor sleep - which lead to melatonin use. Also what if poor sleep itself led to poor cardiovascular health not the melatonin itself?

This might be enough initial data to trigger a randomised placebo control trial using melatonin. It might be hard to sign enough people up to detect an effect on mortality - although a smaller study could still at least pick up if melatonin caused cardiovascular disease.

I agree with their conclusion which I think is a great takeaway

"These findings challenge the perception of melatonin as a benign chronic therapy and underscore the need for randomized trials to clarify its cardiovascular safety profile."

I second that.

If you take caffeine regularly, I also recommend experimenting with tolerance build-up, which the pill form makes easy. You want to figure out the minimal number of days N such that if you don't take caffeine every N days, you don't develop tolerance. For me, N turned out to be equal to 2: if I take 100 mg of caffeine every second day, it always seems to have its full effect (or tolerance develops very slowly; and you can "reset" any such slow creep-up by quitting caffeine for e. g. 1 week every 3 months).

You can test that by taking 200 mg at once^[1] after 1-2 weeks of following a given intake schedule. If you end up having a strong reaction (jitteriness, etc., it's pretty obvious, at least in my experience), you haven't developed tolerance. If the reaction is only about as strong as taking 100 mg on a toleranceless stomach^[2], then you have.

(Obviously the real effects are probably not so neatly linear, and it might work for you differently. But I think the overarching idea of testing caffeine tolerance build-up by monitoring whether the rather obvious "too much caffeine" point moved up or not, is an approach with a much better signal/noise ratio than doing so via e. g. confounded cognitive tests.)

Once you've established that, you can try more complicated schemes. E. g., taking 100 mg on even days and 200 mg on odd days. Some caffeine effects are plausibly not destroyed by tolerance, so this schedule lets you reap those every day, and have full caffeine effects every second day. (Again, you can test for nonlinear tolerance build-up effects by following this schedule for 1-2 weeks, then taking a larger dose of 300-400 mg^[3], and seeing where its effect lies on the "100 mg on a toleranceless stomach" to "way too much caffeine" spectrum.)

1. ^{^}

   Assuming it's safe for you, obviously.

2. ^{^}

   You can establish that baseline by stopping caffeine intake for 3 weeks, then taking a single 100 mg dose. You probably want to do that anyway for the N-day experimentation. 

3. ^{^}

   Note that this is even more obviously dangerous if you have any health problems/caffeine contraindications, so this might not work for you.

One question I'm curious about: do these pills have less or no effects on your bowels compared to what a coffee cup can? Is it something about the caffeine in itself, something else, or the mode of absorption? If they ditch those effects then I'm genuinely interested.

[insert joke about how publishing fresh JVN tokens will accelerate AGI timelines]

which one is your favorite?

Glad somebody finally made a post about this. I experimented with the distinction in my trio of posts on photographic memory a while back.

Useful clarification and thanks for writing this up!

Inspired by and building on this, I decided to clean up some thoughts of my own in a similar direction. Here they are on my short forum: What are the actual use cases of memory systems like Anki?

I've sometimes used "crux weight" for a related but different concept - how important that crux is to a decision.  I'd propose "crux belief strength" for your topic - that part of it fits very well into a Bayesean framework for evidence.

Most decisions (for me, as far as I can tell) are overdetermined - there are multiple cruxes, with different weights and credences, which add up to more than 51% "best".  They're inter-correlated, but not perfectly, so it's REALLY tricky to be very explicit or legible in advance what would actually change my mind.