Sleep – Now By Prescription

Ramelteon isn’t a bad drug. It’s just that its very existence stands as a condemnation of the entire medical system.

All sleep medications have to straddle a very fine line between “idiotically dangerous” and “laughably ineffective”, and Ramelteon manages better than most. It outperforms placebo, it’s not addictive, it won’t sap your ability to sleep without it, and it doesn’t screw up your brain so badly that its unofficial mascot is a hallucinatory walrus.

How does it do it? Ramelteon is the first melatonergic drug, selectively binding to MT-1 and MT-2 melatonin receptors. Binding to melatonin receptors presumably mimics the effect of the natural hormone melatonin which is believed to serve a sleep-promoting role.

Now, you might ask yourself – the natural hormone melatonin is available as an over-the-counter supplement costing a couple cents per pill in every drug store, and provably quite safe and effective. Why would anyone go through the trouble of creating a drug that mimics its action? Especially if a month’s supply of the drug costs around $100 – which it does.

The answer is: I have no idea and I’m pretty sure no one else does either.

Wikipedia says of Ramelteon that:

In a double-blind multicenter trial, Ramelteon did reduce the time to fall asleep by approximately 15–20 minutes, at 8 mg and 16 mg doses after four weeks compared to placebo (approx. 29-32 versus 48 minutes) Total sleep time improved about 40 minutes, however, this was identical to improvement with placebo at the end of trial

A meta-analysis of melatonin says:

Our meta-analysis demonstrated melatonin had a significant benefit in reducing sleep latency. Subjects randomly assigned to melatonin fell asleep 7 minutes earlier on average than subjects receiving placebo…in the random effects model, sleep latency was reduced by over 10 minutes

Sleep latency is a tough statistic to work with, because it depends a lot on how quickly the people in your trial got to sleep in the first place. If the study population is chronic insomniacs who take an hour to fall asleep each night, a good drug might be able to reduce that by 30 minutes. If the study population is normal youth who fall asleep within ten minutes, needless to say your drug isn’t going to be able to do 30 minutes better.

So, for example, it’s easy to find a melatonin trial that finds a very impressive sleep latency decrease of 34 minutes, or a ramelteon trial that finds a rather anaemic 9 minutes. The only fair way to compare ramelteon and melatonin is to run a head-to-head trial.

The only such trial that has ever been performed was performed on monkeys, and its results were contradicted by other monkey experiments. Also, it was run by the company that sells Ramelteon.

I think we may have enough evidence to conclude that Ramelteon is at least as effective as melatonin. There may even be some very tenuous evidence to suggest it is slightly more effective. But let me tell you a story.

One of my patients ran into the Ambien Walrus the other day and so, make a long story short, she needed a new sleeping pill. She was on a lot of drugs at the time and not all that healthy, and every drug I could think of, the pharmacist had some good reason why that would be a terrible idea in her case. Finally in desperation I remembered Ramelteon, which is safe as houses. Unfortunately Ramelteon is kind of new, and the pharmacy didn’t have it.

“Okay,” I said. “Why don’t we just give her some melatonin? Some studies in monkeys suggest it might be slightly inferior to Ramelteon, but it’s sure better than nothing.”

Let’s see if you are cynical enough to predict what happened next.

That’s right. The hospital pharmacy, which carries thousands of drugs including bizarre experimental concoctions and super-expensive recombinant monstrosities, didn’t have melatonin.

So do you want to know what the plan was, that the pharmacist and I came up with to treat my patient? I would take my lunch break, drive home, go into the cabinet in my bathroom, take the bottle of melatonin I had there, and bring it to the 500-something bed, multi-billion dollar hospital I work at.

This is why the story of Ramelteon scares me so much – not because it’s a bad drug, because it isn’t. But because one of the most basic and useful human hormones got completely excluded from medicine just because it didn’t have a drug company to push it. And the only way it managed to worm its way back in was to have a pharmaceutial company spend a decade and several hundred million dollars to tweak its chemical structure very slightly, patent it, and market it as a hot new drug at a 2000% markup.

I’m not knocking the pharmaceutical companies – they didn’t do a thing to suppress melatonin. All they did was notice that doctors were too dumb to use melatonin on their own and figure out a way around that problem.

And this is not an isolated incident. For example, on the rare occasions psychiatrists remember that folic acid exists at all they prescribe Deplin ($100/month, prescription only) instead of the chemically identical l-methylfolate ($5/month, over the counter).

While we’re on the subject of melatonin, here are some Fun Melatonin Facts you may not have known (courtesy of Melatonin and Melatonergic Drugs as Therapeutic Agents: Ramelteon and Agomelatine, the Two Most Promising Melatonin Receptor Agonists):

Melatonin’s sleep promoting effects might be related to its ability to decrease core body temperature, which seems tantalizingly related to the finding that cooling caps are highly effective against insomnia.

Smith-Magenis Syndrome is a rare genetic condition among whose effects are disruptions in the melatonin system. People with this syndrome wake at night and sleep during the day, meaning we can add this to porphyria, anemia, and rabies on the List Of Diseases That People With More Desire To Explain Away Ancient Folktales Than Sense Use As A Factual Basis For Vampirism.

Many people use melatonin at night to try to hack their own circadian rhythms, but this is only mildly effective because they still have their own endogenous melatonin doing their own thing. The nuclear version of this strategy is to use melatonin at night to increase melatonin levels and beta-blockers in the morning to decrease melatonin levels; the combination can give you almost complete control over your own circadian rhythm.

Melatonin seems to play a role in fat metabolism and has been found to decrease weight gain associated with overfeeding in rats.

Agomelatine is a melatonergic antidepressant that has been found to be approximately as effective as SSRIs with fewer side effects which is available in Europe. However, attempts to sell it in the USA were cut short when it failed to clearly differentiate from placebo in clinical trials (see: “found to be approximately as effective as SSRIs”)

Melatonin appears to slow the growth of tumors, and a possible role as an adjuvant to classical chemotherapy drugs in cancer treatment is just one of the exciting areas of melatonin biology doctors are completely failing to explore.

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49 Responses to Sleep – Now By Prescription

  1. Dorikka says:

    “beta-blockers in the morning to decrease melatonin levels; the combination can give you almost complete control over your own circadian rhythm.”

    This sounds useful and I know nothing about it. Is there a link where I can learn about this?

  2. Is marinol (a drug version of marijuana) something of the same sort?

    • gwern says:

      Going by Wikipedia, Marinol is just purified THC. I don’t think it’s that analogous because it may be perfectly useful to avoid consuming all the other substance in marijuana, which varies from strain to strain and batch to batch. The analogy here would be marijuana-leaves:Marinol :: cow-pineal-glands:Melatonin.

  3. Does your hospital stock fish oil? I was pessimistically assuming not at all, my housemate was cynically betting on them just having Lovaza.

    • Scott Alexander says:

      I’m off today so I can’t check; I’ll try to let you know tomorrow.

    • Eric Rall says:

      I’ve had a doctor recommend fish oil pills to me for dry eyes. But this was a post-LASIK follow-up appointment at a surgery center that specializes in elective vision correction, so they’re operating in a very different business environment than most US doctors.

  4. yli says:

    Hey, it’s a positive surprise that they even allowed you give the patient melatonin. Thought the story would end with you having to choose between nothing and an expensive prescription medication due to insurance and liability and whatnot.

  5. Deiseach says:

    Scott, I am always fascinated by the glimpses you give into the American medical profession.

    Are prescriptions given out so easily over there? Europeans tend to be fascinated/horrified by American TV advertisements pushing drugs and telling people “Do you get pins and needles sometimes? Ask your doctor to prescribe NewStuff!” Try that over here and you’ll get the “Which one of us went to medical school for seven years, remind me again?” treatment.

    Even when you do get a prescription, doctors are very slow to give out one and tend to give it for the shortiest time possible, which is why I’ve never asked for sleeping tablets (though I’ve been what I now see from your post is “chronically insomniac” all my life – taking an hour or longer to go to sleep) because I know if I ask for them, I’ll be told “Ah, try a cup of warm milk and some gentle exercise before you go to bed each evening” instead.

    Irish doctors seem to go the route of the warnings on this tablet: “Special precautions: Identify cause of insomnia wherever possible and treat underlying factors before a hypnotic is prescribed.”

    I’m astounded as to what you say about folic acid: wouldn’t the easiest thing be to tell the people to either eat more fortified foods (bakeries have been voluntarily adding it to bread over here ) or recommend they buy vitamin supplements, rather than write out a prescription?

    That makes me wonder whether it’s not so much the pharmaceutical companies to blame, as it is the medical profession’s (justified) scepticism about “alternative treatment”. If Doctor X thinks that it’s all a load of mystical hogwash, along the lines of telling a patient to take more ginseng to clear out your chakras, then he or she may not tell someone “Go down to your local healthfood store, ignore the biodynamically-planted by the phases of the moon, astrological sign co-ordinated stuff, and buy a bottle of melatonin”, whereas he or she will have more confidence in prescribing “Drug rep from Big Pharma company recommended medicine properly vouched for by SCIENCE”?

    And thanks for the recommendation about melatonin: I had no idea that helped with sleep problems, so I’ll be heading down to my local biodynamic, Anthroposophic, organic and vegan health food shop (just three streets away) to see if it’s on the shelves and try it out 🙂

    • Scott Alexander says:

      I can’t remember if melatonin is illegal/prescription-only in Ireland. It certainly is in some EU countries.

      I didn’t remember Irish doctors being especially responsible with prescriptions, although I was seeing the medical system from a different viewpoint there. And doctors here don’t seem especially irresponsible – patients can suggest medications, but depending on the doctor they might or might not comply. In a lot of cases it’s “Let’s give you some random pain medication” “I heard a commercial for Medication X, can I get that one?” “Okay, sure, whatever.”

      There’s some reasons why pharmaceutical grade l-methylfolate could be more effective than food-grade folic acid, but the studies haven’t been done. Given the lack of good information, I think it’s justifiable to suggest generic l-methylfolate supplementation above and beyond the stuff you get in food, but not justifiable to suggest prescription Deplin l-methylfolate.

      • Andrew Rettek says:

        Melatonin is prescription only in England. I spent a few weeks in cambridge and wanted some, went to a pharmacy and was told I would need a prescription.

  6. Deiseach says:

    One enterprising small dairy producer over here is selling melatonin-rich milk!

    So if anyone knows a dairy farmer and is an insomniac, try if you can get milk from the morning’s first milking, as that will apparently be full of melatonin 🙂

    • Scott Alexander says:

      Cool! Drink it with breakfast, become drowsy, have your circadian rhythm disrupted all day! And build dangerous levels of tolerance to one of your own endogenous hormones while you’re at it!

      • Deiseach says:

        Ah no, they’re recommending that you drink it at bedtime (since it’s called Lullaby Milk).

        So how is buying a carton of this stuff and drinking a glass before going to bed different from the bottle of melatonin you had in your bathroom cabinet?

      • Lee Wang says:

        “build dangerous levels of tolerance to one of your own endogenous hormones”.

        After reading this article I’m taking one mg of melatonine each evening. I’m not an insomniac but I’m sleeping much better and longer. Now this comment makes me reevaluate my practices? Do you recommend taking melatonin to someone without a serious sleeping disorder?

        • Douglas Knight says:

          In general, for any drug, you should try reducing the dose and finding the smallest that works. For melatonin, 1mg is probably 10x too big. Try the smallest you can find, eg 0.2mg, 0.3mg, or if you’re in the Netherlands, 0.1mg available in your local pharmacy. If I could get 0.01mg, I’d try it. It works in the lab.

  7. Douglas Knight says:

    Why did you go home, rather than to a drug store? In my experience, all drug stores carry melatonin, although usually in huge doses, like 3mg, or more recently 10mg. (I assume you didn’t send the patient to a drug store because she was an in-patient, which is also why she was still in the hospital after lunch.)

    I’m not sure how doctors see it, but I think American patients conflate several dichotomies: prescription / over the counter; risky / safe; covered by insurance / out of pocket; and I think I’m forgetting some. So when loratadine went off patent, Schering made it over the counter and started pushing d-loratadine.

  8. John Maxwell IV says:

    Speaking of cancer, it seems marijuana is looking good for cancer in rodents:

    • g says:

      My impression is that to a good first approximation, just about everything causes cancer in rodents and just about everything cures cancer in rodents, because (maybe on account of usually having short lifespans for other reasons such as predation) they lack all kinds of protective mechanisms that, e.g., people have. So it’s really easy to give cancer to lab mice, and pretty easy to find things that make them less susceptible, but these findings very frequently don’t transfer to humans.

      So being able to cure or prevent cancer in rodents is a nice first step but is only very weak reason to expect a beneficial effect on humans.

      • Aside from that, there are strains of lab mice and lab rats which are bred to get cancer.

        I hope someone is looking at which genes the cancer-prone rodents have.

        I tried to subscribe to this thread, but it didn’t work. Anyone else having problems?

  9. I wonder if there’s money to be made exploiting the market inefficiencies you describe. Like, set up a consulting business where you charge hospitals (insurance companies?) thousands of dollars a pop to tell them to stock melatonin (or steer patients towards the cheaper drug nobody uses in the case of insurance companies, or whatever).

    • Eric Rall says:

      My first thought was for a nutritional supplement manufacturer or distributor to figure out what products they have that have strong clinical evidence of effectiveness, do full-out Big Pharma style marketing to doctors and hospitals, and charge a 50%-ish markup over regular retail price.

      • Douglas Knight says:

        I’m pretty sure that’s illegal. It is definitely illegal for drug companies to give medical research about their drugs to doctors, except statements that have been vetted by the FDA. In particular, they can’t talk about off-label uses.

        So the consultant would have to be paid for the information, not the drugs.

        • Eric Rall says:

          That fits in with my understanding of how FDA drug regulations work, and if you’re right, it goes a long way towards explaining why this particular $20 bill hasn’t been picked up.

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  11. Error says:

    > And this is not an isolated incident. For example, on the rare occasions psychiatrists remember that folic acid exists at all they prescribe Deplin ($100/month, prescription only) instead of the chemically identical l-methylfolate ($5/month, over the counter).

    I’m curious: What would folic acid be used for in this context?

    I’ve been taking metalonin since being pointed to Gwern’s tome on the subject, and it more or less cured my insomnia. Wondering if your reference here is to something similarly cheap-but-effective, for a different problem.

    • @johnwbh says:

      I’m not an expert, but here’s what I got from a mnute with google

    • Douglas Knight says:

      You could look it up. This context is a treatment for depression, whether alone or in combination with SSRIs. Pregnant women probably should take folic acid, but ObGyns don’t forget it exists.

      Folic acid in multivitamins is a synthetic form that 10% of the population can’t metabolize to mefolic acid, the form Scott mentioned. I don’t know if he meant to draw attention to that difference. This ability is determined by a SNP on the MTHFR gene, presumably tested by 23andme. I think this is the second useful test I’ve heard of from 23andme (after the non-SNP test for BRCA, useful to 1% of Ashkenazim). Dietary sources probably don’t require a functioning gene, so it’s not so important.

      • Error says:

        Thanks, that’s interesting and possibly useful (not so much for me, but for someone I care about). Is the mefolic form available over the counter as well, or just the synthetic form? (from his quote it sounds like it is, from yours it sounds like it isn’t)

        Also, while not related, is 23-and-me worth the cost? I’ve run into it a time or two, it sounds like an interesting service, but I’ve never been inclined to cough up.

        • Douglas Knight says:

          When I search google for “methylfolate” it offers me amazon, so, yes, it is easily available. I suppose that doesn’t prove that it’s legal.

          I did not mean to imply that mefolic acid is not available over the counter. My main point was that folic acid is so not a secret that it’s in multivitamins. The distinction between the synthetic and methylated forms might be a cheap secret.

          I have not done 23andme, so that’s my revealed preference. It bombards you with lots of useless information that you’re 30% more likely to get disease X. Even if this were true (which I doubt), a relative risk of 1.3 is not going to move a disease from a rare disease that you shouldn’t think about to a common one that you should. For a common disease, say, blood pressure, this may affect your life expectancy, but it shouldn’t change your behavior; you should already be worrying about it.

          If you’re an Ashkenazi woman, there’s a 1% chance it will tell you that you have a >50% chance of dying of breast cancer. That’s useful to know, in the rare case that it hits. An Ashkenazi woman with breast cancer deaths in the family should do it. A Dutch woman with breast cancer deaths in the family should get the $300 Myriad test. Other women with serious breast cancer in the family should consider the $3,000 Myriad test.

          MTHFR is (a) relevant to many people and (b) maybe useful. Also, in my previous comment I forgot about one or two SNPs that are supposed to affect how fast you metabolize an awful lot of drugs. That seems like it should be more useful than the others, but I’m not sure exactly how to use the information. It just suggests whether you should start doses low or high, which is nice, but the important thing, which almost no one does, is to experiment with doses.

        • Eric Rall says:

          I’ve heard anecdotal reports that it’s useful if you have symptoms for one or more hard-to-diagnose chronic disorders with genetic components: if you also have the genetic risk factors, that increases the confidence that you’ve correctly identified the disorder and makes it much easier to persuade a doctor to confirm it as an official diagnosis; conversely, turning up negative for genetic risk factors is an indicator that you’re likely mistaken in your tentative self-diagnosis.

        • Douglas Knight says:

          What particular diseases? And what are the effect sizes? (I can look them up, if you tell me the disease) Yeah, you can probably use a 50% increase in genetic risk of a rare disease to get your doctor to take you seriously, but that’s an error by the doctor.

  12. Eric Rall says:

    Just checked specifics on one of them: the patient had a diagnosis for depression, and was referred by a doctor to get genetic testing to narrow down specific causes to help evaluate treatment options. The genetic testing showed a double recessive allee for short seratonin receptors.

    • Douglas Knight says:

      The original question was about 23andMe. Except for BRCA, it only tests for common SNPs, not repeat number variation, like short serotonin. Some people on the 23andMe message boards claim, following wikipedia and snpedia, that you can guess short serotonin from common SNPs, but others claim that these misreport the original sources.

      There are dueling meta-analyses, so I doubt there’s much effect size with short serotonin, anyhow.

      • Eric Rall says:

        When I chimed in on the thread, I’d thought the patient in question had used 23andme. I found out I was mistaken when I double-checked the details for you.

  13. Jai says:

    Melatonin was one of the first things my doctor recommended when I went to him with sleep problems; Is that very unusual?

    • Douglas Knight says:

      Every drug store I’ve checked has melatonin, which suggests some level of popularity. But that Scott’s hospital’s pharmacy doesn’t stock it suggests that doctors there don’t prescribe it. I’m not sure how to reconcile these two points.

  14. Douglas Knight says:

    One thing that distinguishes ramelteon from melatonin is that the new drug has a longer half-life. That sounds like a disadvantage to me. When I’m trying to get to sleep, I want the smallest dose that will work. Maybe the lab dose of 0.01mg is so small that it produces too short a window of sleep and a longer half-life is better, but I use 15x that dose because that’s what I can get. If you’re trying to avoid waking up in the middle of the night, the main concern is how much drug is left in the morning, for which this won’t make a difference, but a longer half-life has the advantage of not exposing you to a large dose at bedtime. But extended-release melatonin is probably better than either.

    Probably ramelteon is available in doses that are effectively smaller than melatonin, at least the stuff easily available in the drug store (which is 30x my dose). That’s an advantage, but mainly a result of melatonin being available over the counter.

  15. sleepinguide says:

    I wanted to put in my two cents about how Melatonin has helped me. I am a natural “night owl” and Melatonin is the only thing that puts me’ in control of my bed time. On vacation, I stay up late and sleep late, but when I don’t have flexibility, I take 9 mg 1/2 hour before I want to fall asleep. I read or do crossword puzzles and then a feeling of sleepiness comes over me. I have not had one instance in the past few years that Melatonin did not work. If I ignore the sleepiness and keep reading or doing an activity, it wears off. It seems that the main effect is to produce a temporary sleepy feeling that is probably what “normal” people feel in the evening.

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