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Saul Munn

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[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?

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.
- [t... (read more)

5Seth Herd1y

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.

9Mateusz Bagiński1y

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?