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John_Maxwell_IV comments on Case study: Melatonin - Less Wrong

20 Post author: gwern 07 January 2010 06:24PM

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Comment author: John_Maxwell_IV 16 March 2013 12:17:05PM 0 points [-]

"It really amazes me that melatonin is available in any pharmacy," Bentley said. "It is a powerful hormone, and yet people don't realize that it's as 'powerful' as any steroid. I'm sure that many people who take it wouldn't take steroids so glibly. It could have a multitude of effects on the underlying physiology of an organism, but we know so little about how it interacts with other hormone systems."

Popular supplement melatonin found to have broader effects in brain than once thought (2005)

Comment author: gwern 16 March 2013 07:35:10PM 1 point [-]

"So in conclusion: be afraid, be very afraid."

Comment author: John_Maxwell_IV 20 March 2013 08:40:27PM *  0 points [-]

I'm confused... did you update at all on the possibility of harms from long-term melatonin use after reading the article?

Comment author: gwern 20 March 2013 08:55:54PM *  8 points [-]

No. Your excerpt was a poor exposition of the standard precautionary principle I regard as entirely useless.

Reading your link now, I have even less reason to pay attention to it. It's a random press release about a presumably small unreplicated animal study in a species I don't know to be particularly germane to humans (eg. chimps) about changes of unclear importance in a body system with no human analogues ("In birds, switching off GnRH causes the gonads -- testes and ovary -- to shrink as part of the birds' yearly cycle.") with doses potentially high enough to be completely irrelevant to human supplementation (injecting melatonin?). I haven't even read the study!

Combine all the conditionals here (the smallness and lack of replication alone knocks down the chance this means anything about anything to well under 50%), and I don't see why I would update at all (not being an AI or anything which can represent degrees of belief with 64-bit floats).

If anything, I think this sort of study is a good example of why animal studies should be ignored in discussing supplements.

Comment author: John_Maxwell_IV 21 March 2013 10:20:15AM *  1 point [-]

Good points.

Have there been any meta-analyses of how well supplement studies on animals tend to transfer to humans?

Comment author: gwern 22 March 2013 02:21:50AM *  11 points [-]

On the general topic of animal model external validity & translation to humans (with obvious relevance to supplements & nootropics), here are the major systematic reviews, meta-analyses, and articles criticizing the routine failures of animal models to provide any meaningful information about dangers or benefits in humans, and documenting the even lower quality of animal experiments than usual in (human) medicine or psychology:

I spent the day reading up on the topic. The transfer or replication rates range from around 40% on the upper end to zero in some cases involving as many as hundreds of attempts to transfer. The methodological quality of the animal studies are usually terrible with hardly any blinding and randomization rare (and when it is done, one author indicates that researchers surveyed would say it was done as informally as grabbing random mice/rats out of the cages), and the publication biases at play seem to be even larger than in human studies.

(Reading the papers, I found myself disturbed by the ethical implications: when human studies fall to publication bias, 'all' that does is waste many millions of dollars and impede the progress of science and substantially inconvenience many subjects and put them at risk; but when at least a third of all animal experiments never get written up, and half of chimpanzee medical/biological studies never get cited when they do get published, that means that the billions of animals gone through every few years are mutilated and tortured and killed for absolutely nothing at all. This makes me much more sympathetic to the NIH's recent retirement of its research chimpanzees.)

There are some interesting examples, though; from one of the links:

In animal models of acute ischemic stroke, about 500 “neuroprotective” treatment strategies have been reported to improve outcome, but only aspirin and very early intravenous thrombolysis with alteplase (recombinant tissue-plasminogen activator) have proved effective in patients, despite numerous clinical trials of other treatment strategies [8],[9].

From the toxicology paper:

"Karnofsky’s Law, which states ‘Anything can be teratogenic if given in the right dose, to the right species, at the right time’. If every single drug, chemical and indeed substance can be teratogenic in some particular animal at some specific dose, then to produce a positive result one need only find a suitably sensitive species and administer a suitably high dose (Scialli, 1992). This may well explain the inclusion of various everyday substances, some of which are intrinsic components of the mother’s body and/or the developing conceptus and which are essential for life itself, in the list of teratogens in ‘Dangerous Properties of Industrial Materials@ (Lewis, 1989). These include drinking water (Turbow et al., 1971) and table salt (Nishimura and Miyamoto, 1969); oxygen; sugars in the form of sucrose and lactose; palm oil, corn oil and nutmeg oil; other naturally occurring food constituents such as cholesterol and papain (prevalent in pineapples); vitamins such as A, D2, K, B7 and B12 (the B vitamins are frequently found in pregnancy supplements); naturally occurring and essential hormones such as estradiol, progesterone and various prostaglandins; the amino acid methionine, and the DNA constituent adenine."

From my appendix:

Animal models such as mice can simply be irrelevant to humans, leading to cases like <150 sepsis clinical trials all failing - because the drugs worked in mice but humans have a completely different set of genetic reactions to inflammation.

(I imagine that the latter is particularly relevant; how many thousands of mouse studies on inflammation were part of the evidence base for those <150 clinical trials? Probably quite a few. And it seems that they all are essentially irrelevant to anything in humans. Now, imagine the translation rate for bird to primate, based on a bird system which doesn't even exist in humans...)

Comment author: John_Maxwell_IV 24 March 2013 01:27:02AM 2 points [-]

Thanks for doing all this research! You should make a page on gwern.net, you're wasting your talents going in to this kind of depth in an ancient comments thread ;)

Comment author: gwern 24 March 2013 01:29:42AM *  1 point [-]
Comment author: [deleted] 21 March 2013 01:30:29PM 0 points [-]

I suspect it might also depend, among other things, on how closely related those animals are to us. I would likely take your study more seriously if it was done on mammals, and even more so if it was done on primates.

Comment author: wedrifid 16 March 2013 08:20:32PM 1 point [-]

Bentley said. "It is a powerful hormone, and yet people don't realize that it's as 'powerful' as any steroid. I'm sure that many people who take it wouldn't take steroids so glibly.

Unless the quality of the remainder of the article uses an entirely different caliber of reasoning than what you have chosen to excerpt here it should be dismissed as drivel. The (by clear implication, anabolic) steroids that Bentley attempts to equate to melatonin have clear effects that need to be managed or accepted. There has been enough research and practical use of melatonin to reliably establish that whatever the effects of melatonin are they less significant than the effects of anabolic steroids.

Comment author: sboo 25 February 2014 10:09:21PM *  1 point [-]
Comment author: John_Maxwell_IV 28 July 2013 10:50:32PM 0 points [-]

A few cautions: Melatonin is considered generally safe for short-term use. However, there have been concerns about risks of bleeding (especially in people taking blood-thinners like warfarin). There also is increased risk of seizure, particularly in children with brain disorders.

http://www.webmd.com/vitamins-and-supplements/lifestyle-guide-11/natural-good-sleep-tips-on-melatonin-valerian

Also, risky for diabetics?

Comment author: gwern 30 July 2013 02:27:09AM 0 points [-]

First link doesn't include any citations, so...