Yesterday I wrote about melatonin, mentioning that most drugstore melatonin supplements were 10x or more the recommended dose. A commenter on Facebook pointed me to an interesting explanation of why.
Dr. Richard Wurtman, an MIT scientist who helped discover melatonin’s role in the body and pioneer its use as a sleep aid, writes:
MIT was so excited about our research team’s melatonin-sleep connection discovery that they decided to patent the use of reasonable doses of melatonin—up to 1 mg—for promoting sleep.
But they made a big mistake. They assumed that the FDA would want to regulate the hormone and its use as a sleep therapy. They also thought the FDA wouldn’t allow companies to sell melatonin in doses 3-times, 10-times, even 15-times more than what’s necessary to promote sound sleep.
Much to MIT’s surprise, however, the FDA took a pass on melatonin. At that time, the FDA was focusing on other issues, like nicotine addiction, and they may have felt they had bigger fish to fry.
Also, the FDA knew that the research on melatonin showed it to be non-toxic, even at extremely high doses, so they probably weren’t too worried about how consumers might use it. In the end, and as a way of getting melatonin on to the market, the FDA chose to label it a dietary supplement, which does not require FDA regulation. Clearly, this was wrong because melatonin is a hormone, not a dietary supplement.
Quickly, supplement manufacturers saw the huge potential in selling melatonin to promote good sleep. After all, millions of Americans struggled to get to sleep and stay asleep, and were desperate for safe alternatives to anti-anxiety medicines and sleeping pills that rarely worked well and came with plenty of side effects.
Also, manufacturers must have realized that they could avoid paying royalties to MIT for melatonin doses over the 1 mg measure. So, they produced doses of 3 mg, 5 mg, 10 mg and more! Their thinking–like so much else in our American society–was likely, “bigger is better!” But, they couldn’t be more wrong.
So he’s saying that…in order to get around a patent on using the correct dose of melatonin…supplement manufacturers…used the wrong dose of melatonin? I enjoy collecting stories of all the crazy perversities created by our current pharmaceutical system, but this one really takes the cake.
Assuming it’s true, that is. Commenter Rodrigo brings up some reasons to be suspicious:
1. Who would patent a drug only up to a certain dose? Isn’t this really dumb?
2. To avoid the patent on the correct dose, drugstores just have to sell more than 1 mg – for example, 2 mg. But they actually sell up to 10 mg.
To these I would add:
3. Lots of supplements are very high dose. When I Google Vitamin C, the first product that comes up advertises that it has 1111% of the recommended daily allowance, which seems better optimized for numerological purposes than medical ones.
4. A few companies do sell melatonin at the right dose range, and MIT hasn’t sued them yet.
Normally I would find these considerations pretty persuasive, but I feel like the guy who discovered melatonin and ran a pharmaceutical company for a while knows more about the history of melatonin and pharmaceutical regulations than I do.
From last week:
This kind of thing is the endless drudgery of rationality training…questions like “How much should you discount a compelling-sounding theory based on the bias of its inventor?” And “How much does someone being a famous expert count in their favor?” And “How concerned should we be if a theory seems to violate efficient market assumptions?” And “How do we balance arguments based on what rationally has to be true, vs. someone’s empirical but fallible data sets?”
Here I’m just really skeptical of the MIT patent story. Wurtman seems to admit that “bigger is better” played a role. Maybe the patent thing was a very small issue, around the beginning of melatonin sales, and was soon forgotten – but the tradition of expecting melatonin to be very high dose stuck around forever, mostly for other reasons?
EDIT: Commenters, including a patent lawyer, have filled in the rest of the story. Because melatonin is a natural hormone and not an invention, patents can only cover specific uses of it. The MIT patent covered the proper way to use it for sleep; a broader patent might not have been granted. The patent probably guided supplement companies, but expired about five years ago. It’s now legal to produce melatonin 0.3 mg pills, but people are so used to higher doses that few people do.
This debate is pretty easily settled simply by looking up the answer.
US 5449683 Methods of inducing sleep using melatonin
Filed July 16, 1993.
Issued September 12, 1995.
1. A method of inducing sleep in an individual comprising orally administering to the individual, within about two hours of when sleep is desired, an acute single dose of melatonin, said single dose being less than 1 mg and effective to raise the peak plasma level of melatonin in the individual to within normal physiological nocturnal levels.
2. The method of claim 1 wherein said oral single dose of melatonin is administered at night.
3. The method of claim 1 wherein said oral single dose of melatonin is 0.3 mg.
4. The method of claim 1 wherein said oral single dose of melatonin is 0.1 mg.
5. A method of inducing sleep in an individual comprising orally administering to the individual, when sleep is desired, an acute single dose of melatonin sufficient to result in peak melatonin blood levels of the individual within normal physiological nocturnal melatonin levels, thereby inducing sleep, said single dose being less than 1 mg.
6. The method of claim 5 wherein said single dose of melatonin is 0.3 mg.
7. The method of claim 5 wherein said single dose of melatonin is 0.1 mg.
8. The method of claim 1 which further comprises allowing the individual to fall asleep within about two hours of administration of said single dose.
9. The method of claim 5 which further comprises allowing the individual to fall asleep within about two hours of administration of said single dose.
http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=12&f=G&l=50&co1=AND&d=PTXT&s1=5449683&OS=5449683&RS=5449683
That has definitely expired, though.
A million times this. Questions about bias and whether to trust arguments from expertise are super interesting, but none of those things is even the weakest substitute for simply doing your own research.
Edit: In case I seem a bit irritated about this, it’s frustrating to see an intelligent group of people saying things like “reasons to be suspicious include…who would patent a drug up to a specific dose?”. This question is not a “reason to be suspicious”, it is a factual question that one can easily answer in less than 30 seconds using a search engine keyed off the information given in Wurtman’s comment. The answer is that MIT and Wurtman would, and did. That’s literally 1/4th of the “reasons to be suspicious” of the expert explanation eliminated with the most basic research, rather than pontificating about whether we should trust experts.
As a person who works as an expert in my own field I am continually gobsmacked by the idea that people feel that “should we believe experts” is a binary question that only has two answers: believe or disbelieve. The right answer is that when good experts present verifiable claims, you verify them or at least mark them as worth checking before you hold them up as valid reasons to disbelieve anyone.
Pardon me. Now I’m going to go shout at some clouds.
I give you honor and internet points for doing the right thing and actually looking up the patent.
Thanks, came here to post this.
As far as I can tell, this is the first-filed application by Wurtman on the use of melatonin as a sleep aid. It was followed by a few more in the US and a half dozen other countries (see patent family here: https://patents.google.com/patent/US5449683/en17 ).
The reasons for claiming less than 1 mg may be complicated. Generally, you want to claim dosages showing efficacy and low side effects — this can help in clearing various hurdles to patentability.
If you look at the data in the patent, say at FIG. 9A, it shows that only the dosages below 1.0 mg have sleep latency effects that differed from the placebo. (See PDF of the patent here https://patentimages.storage.googleapis.com/2f/0a/72/621ec8501f9eb0/US5449683.pdf, at page 15). So if you’re claiming use of melatonin to reduce sleep latency and your claim includes dosages that have no statistically significant effect, that claim is likely to be invalid for lack of utility.
Pharma patent claiming is an art. Unlike other fields of technology where you’re often describing a device or method that has components or steps that are different from the prior art, pharma patents often try to claim a family of previously-known compounds, or the use of known compounds, defined in such a way that the selected family or the method of use differs from other families or methods in some demonstrably useful effect.
Thanks, came here to post this.
To answer the question about why the claims are narrow: the claimed dosage of a known drug has to be specific enough that it has a demonstrable utility that differs from an arbitrary dose. Figure 9A of the patent (linked above) shows that only dosages under 1.0 mg differed from placebo in sleep latency effects. Hence, Claim 1 is directed to use of dosages of less than 1 mg.
Also: this appears to be the earliest filed application by Wurtman, but it was followed by several related applications in the US and in a half dozen other countries. You can explore the family here: https://patents.google.com/patent/US5449683/en17
Thanks for posting patent. +1
I don’t think that settles it. What if we looked up a time-series of commercial melatonin supplements and found that they never tended to offer low-dose melatonin and there was definitely no increase in average dosage around the time of publication of those patents?
Yes, I saw that last night when I was researching this post.
The question isn’t whether a patent exists – the argument isn’t that Dr. Wurtman is a liar – it’s whether the patent had any effect on the later development of melatonin doses.
As Steven Kaas says: “Why get stuck in ARGUING and DEBATING when you can just LOOK UP the answer to a superficially similar sounding question SCIENTIFICALLY?”
This isn’t an honest response. The original post says (quoting an earlier comment, sure):
I submit that less than a second of consideration will show that reason (1) is not a reason to be suspicious of the idea that an existing patent had any effect on the development of commercial melatonin doses. It is clearly a reason to be suspicious of the idea that a patent exists at all. And that’s not a matter for speculation or insinuation; there is an authoritative record listing all patents that exist. That record is the purpose of the patent system!
If you want to argue that “the question is whether a patent had any effect on the later development of melatonin doses”, you have no business at all mentioning that “the story about this patent is suspicious because there is no earthly reason to patent only certain doses of a medication”. That argument is not relevant to the question of the development of prices, because — if a patent exists — the stipulated fact that there was no good reason to file it is irrelevant to whatever effect it may or may not have had on commercial doses. The effect is drawn from the fact that it exists.
Well, because Kevin answered the same question you implicitly asked. This looks like a case of you being publicly humiliated and claiming post facto that you meant to ask a different question, only superficially similar to the one you actually asked. How was Kevin supposed to know that?
I object to an arguing methodology of (1) asking a stupid question; (2) getting a straight answer; and then (3) making fun of your respondent for answering a stupid question.
In every other medication I’ve read about, there’s no such thing as patenting a certain dose. You patent the medication, and you mention the dose on the patent. For example, no one would ever patent “Prozac 20 mg”. You either have the patent on Prozac or you don’t.
The melatonin patent mentions the dose, but I didn’t realize until seeing some of the responses below that because it’s the use of a natural hormone rather than a medication itself, the patent is on the method of use rather than on the chemical.
Look, I’m an idiot, and I admit I’m an idiot, and I’m sorry, I just wish people would stop accusing me of being lazy and dishonest to boot.
Scott, this still isn’t quite right. Drugs are often patented for certain doses; they’re also often patented as methods of use. For example, in one case, I successfully represented Actavis in invalidating a method of treatment patent for providing specific doses of extended-release oxymorphone to renally impaired patients. I also was involved in cases on Novartis’s transdermal rivastigmine patent, which specifies ranges of drug and other ingredients in the composition, and this patent on extended-release mixed amphetamine salts for ADHD treatment that specifies a 20 mg total dose or amounts of the relative salts proportional to that for a 20 mg total dose.
The reason you don’t see companies avoiding patented dose ranges for drugs by selling overdoses is FDA regulation. The FDA allows companies to get generic drugs approved with significantly smaller clinical tests to show that the generic works the same as the branded product; they don’t have to run separate clinical tests to compare the generic to a placebo. So if, for example, Novartis goes out and patents a cure for the common cold by providing a 5 mg to 100 mg dose of unobtanium, and gets that treatment approved by the FDA for 5 mg to 100 mg ranges, a competitor that wanted to avoid the patent would have to run their own clinical efficacy tests to show that a 200 mg dose was effective and not harmful.
But for dietary supplements, no clinical efficacy tests are required to sell the product, so it’s easy to design around the patent by providing a dose outside the claimed effective range–as long as you know the larger dose isn’t harmful so you don’t get sued for an ordinary product liability claim.
(Added: I’d agree that people should not call you an idiot, lazy, or dishonest for not knowing this–pharma patent law is really confusing because all its weird effects are the result of interaction between patent and FDA law. Since the two areas of law developed independently, Congress didn’t have a great idea of what unintended consequences would result, which is why it’s such a messy field. The Epipen mess, which I commented on in that threat, is another great example.)
I’m going to have to push on this lazy/dishonest thing. Last night when you were doing research, you saw the patent, and then you wrote a post asking “Who would patent a drug only up to a certain dose?” MIT would, you saw the patent!
Either you saw the patent but didn’t bother to read the part mentioning specific dose (lazy), or you never saw it at all (dishonest).
I took your post as still being at least somewhat confused about the true patent situation. The fact that you didn’t post a reference to the patent yourself or forward chain solely from the fact that such a patent had existed and been in force seemed to support this interpretation.
The explanation of anchoring on higher doses due to patent circumvention seemed fairly obvious if one assumed the patent. The fact that much weight was given to other hypotheses at your level of rationality yielded a low Bayesian probability calculation that you were fully aware of it.
I apologize for my error.
Maybe the dose specificity was the only way to get a patent? If the claim was “Any method where melatonin is administered to induce sleep” it would likely have been too broad to be granted. I’m not a huge fan of allowing patents on hormones or gene therapies, although I recognize there would be little incentive to research them if the money couldn’t be recouped. I think the FDA did everyone a favor in this case.
Echoing your point, it isn’t like melatonin was a novel drug that MIT invented, it is a naturally occurring hormone. The way to make the patent viable was to patent the *method* of dosing X for treating Y, instead of patenting melatonin itself.
Yes. You are both right. The claimed dosage of a known drug has to be specific enough that it has a demonstrable utility that differs from an arbitrary dose. Figure 9A of the patent (linked above) show that only dosages under 1.0 mg differed from placebo in sleep latency effects. Hence, Claim 1 is directed to use of dosages of less than 1 mg.
Vitamin C is perhaps not the best example, superstition has it that huge doses of it has various health benefits, including curing viral infections like the common cold. (Some of it might be real, for instance it may have an effect on UTI by lowering the pH of urine).
See Linus Pauling.
Well, there you go: let’s ask the Kabbalah for the correct dose.
FWIW, here in Europe most melatonin pills have somewhere around 1 or 2 mg. (The first five non-sponsored hits on amazon.fr for “melatonine” have 1.8 mg, 1 mg, 1.8 mg, 1 mg, and 1.9 mg respectively.)
Checking with NICE, in the UK you can only get one brand of malatonin, Circadian, with a 2mg dosage, matching the French picture pretty well. Note though that it is only licensed for use of over 55s as a sleep aid, although online pharmacies seem to be selling it for jetlag noting it is not licensed for this.
Is it normal for European agencies to be more restrictive on licensing than the FDA?
I don’t know about drugs, but I have heard that European agencies tend to be more restrictive about food additives. This is just one link I found after a brief googling.
Another thing that has been around for a long time, but resurfaced with Brexit, is the chlorination of chicken, which is banned in the EU.
The story is plausible. MIT does have patents on the use of melatonin up to 1 mg to induce sleep, with Wurtman listed as the inventor. The US patents are 5,641,801 and 5,449,683. Re whether it is dumb to limit the dose, there are a variety of reasons this might be done. One is that an invention must be useful, which means, more or less, that it works. As explained in the story linked to, high doses may actually impede sleep. So the claim might have been limited to satisfy the utility requirement. However, the most likely explanation for the limit turns on the requirements that an invention must be new and non-obvious (inventive). According to the patent, prior studies had studied the sleep-inducing effects of very high doses of melatonin in the belief that rapid metabolization of melatonin would render low doses ineffective. So a claim to very high doses would not have been “new.” Also, according to the patent, the surprising (inventive) aspect of the patent is that low doses actually are effective. In short, they couldn’t patent high doses because that had been tried before and didn’t work; their discovery was that low doses actually work, which is why they patented low doses.
With that said, it is a bit surprising that they didn’t patent up to 10mg, since the very high doses previously studied were in the 100s of mg. But it may be that the patent examiner objected to a higher dose claim, and often you want to just get your patent granted rather than fighting with the examiner at the margins.
Since those patents are now expired, low-dose melatonin is now allowed.
Because it’s a supplement, not a medicine, the specific pill manufacture doesn’t have to be licensed, so lower doses can be made.
But, if the “traditional” dose is 3mg to 10mg, then supplement makers aren’t going to want to move to lower doses because people who are used to high doses will want to carry on with them.
Dosing might trickle down over time, but actually convincing people not to overdose on supplements is hard…
There are still a number of other patents around the composition and manufacture of tablets etc for oral consumption of melatonin. (Check the related/referenced by section to begin with). I’m unsure how troublesome they are in reality though.
Any patent or application referenced by a patent issued in 1995 has since expired.
If someone having sleep troubles is in the pharmacy looking at two potential pills, one of which says ‘1mg melatonin’ and one of which says ’10mg melatonin’ then there’s going to be a certain tendency for them to want to go with the 10mg pill. After all, they wouldn’t be going to the lengths of getting a pill if they only had a small sleeping problem, right? The assumption of linear dose effects is a very natural one even if it isn’t true.
Of course there’s the possible problem that if the dose is too high it won’t work right and the customer won’t come back for more of your pills so there’s also a self-limiting aspect to this since I presume most sales are repeat sales.
And some customers are going to be more sophisticated or will have been told by their doctors what the right dose is.
But I could certainly believe that the patents are a big explanation for our current equilibrium.
As a counterpoint, when I first went to buy melatonin I went on Amazon, saw 3, 5, and 10 mg doses, and bought the 3 mg pills. I had no idea about the lower dose being better, my logic was that I was primarily afraid of developing a dependence so I wanted to start off as low as possible. I figure it’s a lot easier to combine a few 3 mg pills than it is to cut up 10 mg pills, so the lower dose was the least committal purchase.
Perhaps people thinking “I want ALL THE DRUG” will always buy the largest dose available, but I’d imagine at least a decent number of people would think like I was and plan to take multiple pills if needed. This might not generalize down to 0.3 mg doses though, because it’s a lot easier to take 3 pills at 3 mg than 30 pills at 0.3 mg.
Does anyone sell .3 mg melatonin gummies? If not, maybe someone could start – I’d be glad to buy them.
Searching Amazon for ‘melatonin gummies 0.3mg’ gives several results. Sometimes they are listed as “300 mcg” which is the same.
The mention of Vitamin C is very pertinent; I remember the crackpots advising that it could cure everything from the common cold to cancer, but only if you took massive amounts – way more than the RDA. They scoffed at that and maintained that the only effective dosage was a mega dose. Linus Pauling, God rest the man, was responsible for giving a scientific gloss to the idea that 1000mg or more of Vitamin C daily would do you the world of good, and so he is still invoked by those peddling mega dosages. He himself claimed to be taking 18,000mg daily (yes, that’s not an extra zero or two by mistake) where the limits of currently recommended dosages are around a maximum of 250mg daily.
So I wonder if that carried over to other supplements – the kind of customers who frequented health food shops at the beginning, before supplements and natural remedies became mass-market, would have been habituated to the idea that “mega dose is effective dose” and the manufacturers probably hoped to outdo one another – as I still see supplement manufacturers doing today – with “our competitor’s pill only gives you a measly 3mg but we have a gigantic 5mg in every tablet!”
It seems like the moral of the story is: evidence is interesting. Conclusions, not so much. To come to a conclusion from uncertain information, you’re basically assigning weights in a spreadsheet, or the equivalent in your head, and there’s no way to do this that isn’t a bit arbitrary.. Being a little bit better at setting weights isn’t going to help much at resolving uncertainty compared to going out and finding more evidence.
Attempting to come to a conclusion, though, is a good way of gathering and organizing an interesting set of evidence for a blog post.
Regarding Vitamin C, there are several factors which lead to the much greater than RDA dosages:
1. Linus Pauling.
2. Most mammals generate their own vitamin C at rates in the ballpark of taking a gram a day if we scale by animal weights.
3. A diet high in tropical fruits — a possible precursor to the Paleo diet — would likely be much higher than the RDA levels, though likely less than a gram.
Based on the second two arguments, I think getting somewhat more than the RDA makes sense. A few hundred milligrams per day might be optimal. More than that gives me digestive problems.
2. To avoid the patent on the correct dose, drugstores just have to sell more than 1 mg – for example, 2 mg. But they actually sell up to 10 mg.
Based on the discussion, I checked the melatonin gummies we use for our elementary school aged child, and it’s 3mg — split across two gummies. We give him just one (which is too much, based on yesterday’s discussion).
As a patent lawyer with lots of experience in pharma patent litigation, I can answer some of these questions! Of course, the previous commenters found U.S. Patent No. 5,449,683, and confirmed that it does in fact only cover doses up to 1 mg.
One reason this might be done is to avoid anticipating prior art; i.e., if the examiner had found that melatonin tablets were previously being used as sleep aids but only at dosages above 1 mg, the applicant would limit the claim to avoid that prior art. Unfortunately, this patent is old enough that the prosecution history is not available for free online (for most patents slightly more recent than a 1993 filing date, you can get the prosecution history through the PTO’s Public PAIR website). If you look at the prosecution history, you’ll be able to tell whether this was the reason for the limited range.
However, the specification of the patent indicates that this is probably the reason for the limited range. It describes a number of prior art studies that used high doses of melatonin, including doses between 1 mg and 10 mg (as well as much higher doses). Then, the specification explains what the real invention was:
So, the advance over the prior art wasn’t using melatonin as a sleep aid, but discovering that low dose melatonin was an effective sleep aid. That would explain why the claim is limited to low dose melatonin; higher doses likely were already in the prior art.
Generic competitors often use patent specifications as guides, either where the patents are expired or invalidated or where the specifications are broader than the claims. The ‘683 patent is one of the latter, explaining:
This pretty much screams at competitors to sell melatonin at doses between 1 mg and 10 mg. For a drug, this would be difficult because FDA clinical testing regulations would limit a generic’s ability to modify dosages without performing their own (very expensive) clinical efficacy tests, but for a dietary supplement, anything goes.
Similar issue, though with Vitamin C it’s not about evading patents as much as it is that it’s cheap and people think more vitamins are always better. With dietary supplements, anything goes that isn’t harmful.
But at what time? The term on a US patent filed in 1993 is the longer of twenty years from the earliest priority date or seventeen years from issuance. The ‘683 patent, a continuation-in-part of an October 1992 application that issued in September 1995, expired in October 2012. I have no idea if any of these companies were selling doses under 1 mg prior to October 2012, but they’re perfectly free to now.
In general, the theory about actual nutritional supplements, is that the FDA’s of the world set the RDA at the minimum dose to avoid serious deficiency symptoms (scurvy etc.), but not enough for general wellness and/or not enough for specific situations. I have at least twice consumed nutritional supplements above the RDA amount on “doctor’s orders” – that would be experienced MDs, members of the AMA, not homeopaths etc.
That theory may or may not make sense, in specific cases. But the high doses make sense, given those theories.
Something like melatonin is another case entirely – it’s not a food, or something normally gotten from food, even if it’s probably travelling in that company legally. Patent restrictions aside, this looks more like “just plain stupid” with a side order of taking advantage of common human error patterns. (Many people will automatically buy the larger dose, or the one with the best price per gram, without engaging their common sense.)
I am not comfortable in the description of the melatonin situation as a “crazy perversity”. Yes, if you assume that the fundamental goal of everyone involved is to sell and use the drug in a way that an M.D. would consider medically well-advised, the situation is perverse. But melatonin isn’t (legally) a drug, it’s not regulated by the FDA, and neither the making, the selling, nor the consumption of it is done by people who have the same opinions and value systems as M.D.s.
In particular, the cost of the melatonin in the product is likely to be a small fraction of the retail price, and the buyers are unlikely to be well-informed as to the point beyond which increased dosages make no difference.
After the previous post, I went out and got me a bottle of liquid melatonin so that I could try it at the “normal” dose and schedule (300 µg, 6pm-ish). The instructions printed on the label recommended a 3 mg dose, to be measured by counting thirty drops.
Thirty drops?
Either they’re figuring most people will fall asleep by the time they’ve ascertained that thirty (not twenty-nine or thirty-one) drops are on the spoon, or this is a sneaky way of actually selling 300 µg doses.
Melatonin is also an antioxidant.
We use 3mg at the hospital. Surprisingly, few patients want it or ask for it, and it is only occasionally prescribed, and then pretty much only for pts who have drug abuse problems and the docs don’t want to start them on another psychoactive.
Had one pt who routinely used 24mg at home. This person was in because couldn’t figure out why kept falling out of bed! I am quite proud of myself for noticing the dose and notifying the doc, who cut the dose to, if I recall, 6mg. The pt did seem a bit more perky after a few days.
I’d be interested in having a general discussion about sleep, if it hasn’t already been done here. A lot of my pts have disturbed sleep, and many claim to be insomniacs. However, when I enter the room at 1 or 4 AM, they are sound asleep, but upon waking in the morning, claim not to have slept all night and don’t believe me when I tell them I came in, took their blood pressure, and they slept right through it.
That’s interesting, my initial hypothesis would be something along the very rough lines of “Although they are physiologically asleep their brains aren’t firing in the correct patterns that one typically expects of sleep, so for all intents and purposes haven’t slept at all”. I’m reasonably certain I’ve heard of a similar phenomena occurring before. Would it be unjustifiable (in the sense of arguably trivial usage of equipment) to attach one of such patients to an EEG machine?