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- [00:05]
Caroline
Well, I. I was single, living on my own, and I would just lay in my bed in agony. And this was really before smartphones, but I would just lay there, tossing and turning. Then, of course, I would look at the clock.
- [00:24]
Thomas Goetz
This is Caroline. She has insomnia.
- [00:28]
Caroline
I have lived my entire life in Columbus, Ohio, and I am 42 years old. I think many people have sort of described insomnia and the mental anguish it causes in this way that if I fall asleep now, I still have an opportunity to get six solid hours. And it gets to a point where once the clock whittles down to, you know, maybe four hours, or you see the sunlight coming up, but then it's time for work, and you have to go into work just depleted, looking terrible, feeling terrible, and not on your game. But of course, that night, you're thinking, I'm going to get a good night's sleep tonight. But then it just happens again.
- [01:16]
Thomas Goetz
And do you remember that first night that you took an Ambien? Do you remember what that was like?
- [01:24]
Caroline
You know, it's funny, I actually do. I had taken the dose maybe 20 minutes prior, and all of a sudden, the laptop scream was wavy and everything was great. Life was great. You couldn't say anything to get me down. At that point, I was not full of energy. I was very mellowed out. I was happy. I was relaxed. It was a euphoria that lasted maybe 15, 20 minutes before I was like, wow, I'm really tired. I slept better than I had in quite some time, because the next day I thought, I'm going to sleep tonight because that medication was fantastic.
- [02:16]
Thomas Goetz
But then Caroline started to notice strange things.
- [02:20]
Caroline
I found myself, though, quickly waking up to pans and boxes of pasta that I had cooked, and I did not remember it progressed into making phone calls and texts that I didn't remember. And so that was a bit frightening. It impacted some romantic relationships that I was in. I had been seeing a man for around six months. I really liked him, and he had ended the relationship because one night I had taken an Ambien and I apparently had said something, and I don't even know what I had said to him. And I had explained to him that Ambien can sometimes cause that. And he was, I guess, didn't believe it.
- [03:16]
Thomas Goetz
Right. I mean, it sounds like they were very clear pros and cons to. To taking this drug, that there were benefits that you. You needed to sleep, but all these kind of side effects that were quite significant.
- [03:31]
Caroline
Absolutely. And there was a time, one instance, one instance where I wanted to drive and I don't want to think about what would have happened because I don't even remember it. And my neighbor was there and stopped me. I just felt like a bad person, I think because of the reactions that others were having, expressing concern or, or even discussed. And I, yet I just kept taking it. And I thought, wow, this is, this is disgusting. Or it's dirty because you're, you've lost two relationships because of this. Your own mother's worried. So, yeah, it just made me feel like a not great person. It was probably two years after that I started to taper off of it.
- [04:35]
Thomas Goetz
This is DRUG story. I'm Thomas Goetz. Today's drug STORY is about Ambien, also known by the generic name Zolpidem. Zolpidem is a sleeping pill, the most popular sleeping pill ever invented. It has helped millions of people over the years. But just like sleep is something of a mystery, Zolpidem also turned out to be a lot more curious and concerning than originally thought. Caroline's story is much more common than you might think. Her struggles with insomnia and the way that her anxiety made it harder to sleep, many, many people have the same troubles. And the Ambien that's on Also common, about 2 million Americans take it to help them sleep. And those side effects, they happen much more frequently than was expected back when the drug was approved by the FDA in 1992. What Caroline was searching for is what a lot of people want, a medicine that helps them get some rest. And about one in three people suffer from sleeplessness every once in a while. And you know what that's like, not getting a good night's sleep, it can make for a really horrible next day. You're sluggish, irritable. It just feels bad. But chronic insomnia, that can be truly miserable. It can be profoundly destructive to daily life. And if there's a drug like Ambien that gives even a few hours of rest, well, for many people, the risks seem worth it.
- [06:08]
Dr. Andrew Crystal
I think it's hard for people to relate to that because they think of the people suffering from insomnia as the same as them when they have a bad night here or there.
- [06:16]
Thomas Goetz
This is Dr. Andrew Crystal. He is our resident expert on insomnia and treating sleeplessness in this episode. He is a professor of psychiatry and neurology at ucsf, the University of California, San Francisco, where he leads programs in sleep research.
- [06:33]
Dr. Andrew Crystal
And you know, it's never pleasant to have a bad night, but when it's persistent and going on for years for people. It takes a very significant toll on them. There are some people who are particularly prone to having disturbed sleep under settings of stress or health issues or other kinds of problems. And they have persistent disturbance, difficulty, and impairs their lives in significant ways. But it's only about 15% that has this kind of protracted difficulty with sleeping that is associated with impairment in their ability to function during the day. And that really make up the group we think of as having insomnia.
- [07:18]
Thomas Goetz
In this episode of Drug Story, we're going to step into that sweet oblivion called sleep and that infernal torment called insomnia. We're going to learn why insomnia is such a part of our modern world, and we're going to explore that riddle called the placebo effect, which is a vexing part of figuring out whether a medication actually works and just how much of that medication is truly a safe dose. That's all coming up on Drug Story. And to set the mood, here's a bit of a of Brahms lullaby. Drug Story is sponsored by GoodRx. Every prescription has a story, and for many patients, affordability is a defining chapter. Goodrx makes it easier to find lower prices on prescriptions from GLP1s to flu meds, so cost isn't a barrier to care. Trusted by nearly 30 million Americans and over 1 million healthcare professionals each year, Goodrx offers savings at more than 70,000 pharmacies nationwide, helping people start and stay on the therapies that keep them healthy. To start saving, go to goodrx.com drugstore that's goodrx.com drugstory GoodRx is not insurance. Each episode of Drug Story has three the diagnosis, the prescription, and side effects. This is part one, the Diagnosis, where we explore the underlying condition behind the drug. In today's episode, that condition is insomnia.
- [09:14]
Caroline
Foreign
- [09:18]
Thomas Goetz
trouble sleeping is surely as old as humanity itself. In the Old Testament, the Book of Job has an apt description of the struggle. When I lie down, I say, when shall I arise and the night be gone, And I am full of tossings to and fro unto the dawning of the day. But the medical condition we call insomnia, which is just Latin for no sleep, that is a much more recent creation and the word for people who suffer from chronic sleeplessness. Insomniacs. That is an altogether modern idea. In fact, the disorder of insomnia is intertwined with the very idea of a modern life, a modern age, a time, and a condition that I will argue emerge in a very specific window of history from 1875 to 1900. A list of inventions from those years serves as an inventory of the toolbox for modern life. The telephone, the light bulb, the dishwasher, the bicycle and the automobile, the radio, the paperclip, the zipper, matches and drinking straws, and dozens more. All of these modern tools were invented in a brave burst of innovation unprecedented in human history. And these were improvements at the human scale. Each of these inventions, even zippers, came with the promise of making life's daily toil a little less complicated and a little more comfortable. These things offered an irresistible step into the future when life maybe wouldn't be quite so much work. An advertisement for one of the era's most marvelous creations promised, if once tried, this will always afterwards be used. That great invention was perforated toilet paper. Patented in 1891. These amazing inventions created a world buzzing with electricity and motion. It was an era of machines and noise and light. All this modernity created a whole new malady of the modern age. Neurasthenia. This was a nervous disorder brought on, it was believed, by the stress and hubbub of the modern city. Neurasthenia was caused by too much tension, too little sleep, and too much frenzy in everyday urban life. Neurasthenia seemed especially bad in America, where the pursuit of happiness increasingly meant a pursuit of stuff like those inventions promising to make life easier. In fact, neurasthenia was often called americanitis, a term popularized in the 1890s by the philosopher William James. James described it as the American over tension and jerkiness and breathlessness and intensity and agony of expression. And the primary symptoms of this disorder were chronic fatigue and insomnia. Neurasthenia was, to be sure, largely a white upper class malady. After all, to participate in this modern world, to enjoy the fruits of invention, well, you had to buy all those gadgets. Neurasthenia was not just an American problem. The British Medical Journal in 1906 noted that there is no human disorder which so doggedly shadows the advance of civilization as neurosthenia. It was around then that the word insomniac entered popular discourse, and insomnia was pegged as an exceptionally modern condition. One article in a woman's magazine said,
- [13:00]
Caroline
we live too much in an electric glare by night.
- [13:05]
Thomas Goetz
The New York Times suggested that New York City was the insomnia capital of the world. It estimated that the city was home to nearly 700,000 insomniacs. That would have been a whopping 20% of the city's entire population. In time, neurasthenia faded as a diagnosis, as modern life just became, well, life. But insomnia? That was here to stay. Today we live in a 24 7, 365 culture where civilization doesn't just contribute to insomnia. It has become downright antagonistic to the idea of sleep itself. Sleep is an irrational weakness of frail humans, a failure to optimize productivity over biology. But you don't have to be a Marxist to believe that capitalism is the enemy of sleep. Just take a peek inside Hustle culture, where sleep is considered a friction, an inefficiency that should be minimized and resisted. Here's just a few of our favorite rise and grinders People ask me all the time how much I sleep. Hustlers don't sleep. We nap. I wake up at 4am most days during the week. It's not that easy all the time. It does take some getting used to and takes a couple of tricks. The first one set a bunch of alarms. My first alarm goes off at 4am I then have one go off at 4:15, 4:16, 4:17, 4:18, 4:19 and 4:20. In fact, sleep a lot of times just becomes annoying because it's just one more thing. It's almost a necessary evil that we have to get through in order to get to the next day where we can hopefully get some things done. Because honestly, you can run on four hours. You can run on four hours of sleep just fine. All of that is just yuck. The whole premise of Hustle culture says that the road to success is paved with personal pain and sacrifice. And the first thing to sacrifice is sleep. It's deeply entwined, not surprisingly, with cliches about masculinity and weakness. It's all very bro bro. Hustle culture isn't the only attack on sleep these days. Consumer technology itself is intentionally designed to optimize for daos and houzz. That's tech speak for daily active users and hourly active users, which is just a way to measure how much time out of 24 hours a company or product can can suck out of our lives. On average, these things are made to keep us awake with autoplay and endless scrolling and whatever other tricks they can muster. To Facebook and TikTok and Netflix. Sleep is what stands between us and their maximum profit. In fact, a few years ago, Netflix CEO Reed Hastings was talking with Wall street analysts and he admitted as much as you know, think about it. When you watch a show from Netflix and you get addicted to it, you
- [16:09]
Caroline
know, you Stay up late at night,
- [16:11]
Thomas Goetz
you really were competing with sleep on the margin. And so it's a very large pool of time. Reed Hastings said it out loud. Sleep is the enemy of commerce. It is just crazy. Of course, it's not news that social media and screens make it harder to sleep. But what is surprising is how even insomnia has been commercialized and commodified. One of the weird corners of the Internet that I found while researching this episode was the world of supplements made exclusively for gamers. That is people who spend all day, you know, playing video games, many of them professionally. I know today many companies make various supplements designed for gamers. There are nootropics, which claim to enhance cognitive function. And of course there are energy supplements which usually just contain caffeine and taurine. And then there are also supplements made to help gamers sleep after a long binge with names like Cutscene and Zen. Their magic ingredients typically stuff like melatonin and chamomile, but, you know, for gamers. But do these products work as intended? We have no idea. Since supplements are not regulated by the fda. Do these products even include the ingredients they claim to include? We have no idea because again, they are not regulated by the fda. Sleep supplements for gamers are just one sliver of what's been called the insomnia industry. The booming business of REM tracking wearables and sunrise alarm clocks and special mattresses, and so many supplements and so many sleep science gurus, psychologists and neuroscientists and psychiatrists who make the rounds on optimization podcasts. They offer the latest breakthroughs from the frontiers of sleep science. They promise to reveal the seven secrets to better sleep. This is an industry that, that profits from its own problem. There is apparently no end to it. I think part of the reason why sleep is such an area of fascination and vexation for people is that sleep is both physical and psychological. Sleep clearly serves a biological function. We get tired, we sleep and we wake up refreshed. That's how it's supposed to work. And for most people, it usually does. We could get into cellular repair and antibody production, but we just won't. That's a different show. Basically, our bodies need sleep and it's good for us. And then there's the psychology. Sleep processes our fears and ideas and memories through dreams. Sleep helps us turn the messiness of our days into meaning and moments. Sleep also lowers our stress and gives us more calm in the morning. It is a once a night psychological reset. That's the whole idea of sleeping on it, we're better able to tackle yesterday's heart problems after we've had some rest. Today, a vicious cycle can set in, though. Lack of sleep makes us stressed, and stress makes it harder to sleep. And lack of sleep, that has been strongly associated with a great many health problems. And many of those problems, well, they make it harder to sleep. Voila. A perpetual insomnia machine of our own creation. How bad can this all get? Well, a recent study in the journal Health Data Science found that poor sleep quality was associated with increased risk for a staggering 172 different diseases. 172. And that included Parkinson's disease and type 2 diabetes. This study was all over the news for a couple days. Sleep linked to 172 diseases. It seemed proof that bad sleep is very, very bad for us in general. But this study, well, it was also sort of absurd because at what point does it become overkill? If insomnia contributes to pretty much every disease you can think of, what does that even mean? Does good sleep then prevent 172 diseases? Is sleep the cure to everything? Of course not. It turns out that this study suffers from a classic correlation is not causation effect. These connections are only statistical associations. They could be entirely coincidental and not causal at all. What's more, the study found almost no effect from sleep duration, how many hours of sleep people got, which is how most people think about sleep quality. So when you read past the misleading headlines sleep linked to 172 diseases, it's actually kind of a disappointment. Like a lot of what passes for science in the insomnia industry. The insomnia industry is like a snake eating its own tail. Hustle culture fetishizes insomnia and optimization culture promises the protocols to cure it. These things feed off of each other, both of them symptoms of our current americanitis. Our twin desires to do more and to do better. That's what living life in the 21st century is all about, right? We are still dealing with the same stuff our forebears were 150 years ago. It's neurasthenia all over again. Modern life is making us all insomniacs. Which brings us to the very simple idea of a sleeping pill. One pill to make it all go away. Is there such a thing really as an effective and safe sleeping pill? It turns out that is a very hard question to answer. And we'll see why. Coming up. To set the stage, here's a very old commercial for a drug called Salmonex. Can't sleep because of simple nervous tension. Take Salmonex to enjoy a good night's sleep and a good bright morning too. Salmonex contains three medical ingredients. Take Salmonex to night and sleep. Safe and restful. Sleep, sleep, sleep, sleep. Take two Salmonex tablets and sleep. Welcome back. This is part two, the Prescription where we look at the arrival of the drug in question, which today is Ambien, the medication also known generically as Solpidem. For decades, pharmaceutical companies have chased the promise of a perfect sleeping pill, one that puts us to sleep and is safe without any side effects. That quest has been a difficult and sometimes perilous journey. In the US Sleep aids have been sold over the counter since the 1950s. Over the counter means a medicine that doesn't require a prescription because the active ingredient is considered reasonably safe. These are the products on the shelves at the grocery store, not the ones behind the pharmacist's counter. That commercial we just heard for Salmonex that is sold over the counter. Salmonex by the way, is a cute play on the word somnolent meaning sleepy. For many years the active ingredient in Salmonex was an antihistamine called Methylpyrlene which was known to cause drowsiness. But it turns out it wasn't all that Safe. In the 1970s it was found to cause liver cancer in rats and it was banned. The active ingredient in Salmonics today is a different antihistamine called Diphenhydramine which is considered generally safe though long term use is associated with dementia. Diphenhydramine is also the active ingredient in other over the counter sleep aids including Unisom, Tylenol, pm, Nital and Zequil. This is the same drug in different packages. Diphenhydramine by the way is also the active ingredient in Benadryl and this is a digression, but it's worth it. If you compare prices you will see that Benadryl often costs about half as much as the sleep aids, even though it's the same drug, just a different package at a different price. In general, when you're buying an over the counter medicine at the pharmacy or grocery store, shop for the active ingredients, not the brand. That is a pro tip from Drug Story. Anyway, antihistamines do make you drowsy, but you don't always wake up refreshed. Antihistamines can make you sluggish and foggy headed the next day, what they call a hangover effect and people quickly develop a tolerance meaning the drug loses effectiveness at a normal dose after a few days. So the search for something Better continued. And that means prescription drugs, stronger drugs that only a doctor can prescribe. In 1982, the FDA approved a new prescription drug called Halcyon for the treatment of insomnia. Halcyon was a benzodiazepine, a class of drugs that was widely used at the time to treat anxiety. If you heard our episode on Xanax, that's also a benzodiazepine. Today we know that these drugs can be very dangerous. People can develop tolerance and dependence issues and they have side effects including confusion, sleep, behavior problems, even amnesia. At the time, though, Halcyon was considered safer than other sleeping pills, especially barbiturates, which turned out to be very dangerous drugs. Soon, Halcyon was the world's best selling sleeping pill. As many as 11 billion prescriptions were dispensed worldwide in the 15 years after it reached the market. But in less than a decade after FDA approval, the dark side of Halcyon started to emerge. In his 1990 memoir, Darkness Visible, William Styron said Halcyon caused suicidal thoughts. Philip Roth blamed Halcyon for his mental coming apart. It was as distinctly physical a reality as a tooth being pulled, he said. In 1991, Upjohn, the maker of Halcyon, settled a lawsuit brought by a woman who had shot and killed her 82 year old mother after taking the drug. By this point, questions started to emerge. Had Upjan deliberately concealed evidence regarding the serious psychological side effects of the drug? 60 Minutes did a segment on the controversy. And while the company denied hiding any data, the drug was banned in the UK in 1991. In the US the FDA began a systematic review of all the clinical data about Halcyon. The perfect sleeping pill had become a nightmare. And just then, along came Ambien, a new drug with perfect timing. Just as the market for Halcyon collapsed, Ambien seemed to offer a safer alternative with none of the scary side effects. Ambien was developed by the French pharmaceutical company Sanofi. What made the drug so exciting was how it worked and how it was marketed. Here's Dr. Andrew Kristol again.
- [27:44]
Dr. Andrew Crystal
It was very clear that their goal was to differentiate the drug from benzodiazepines because it was such a negative view that the practitioners have had of it. The reality is that the word benzodiazepine refers to a chemical structure and all those drugs called benzodiazepines have that chemical structure. Dopinem doesn't have it, so it's technically not a benzodiazepine, but its action has a lot in common, it binds to the same site in the brain. But they worked really hard to differentiate it from other drugs. They said, we want to call this a non benzodiazepine, which, I mean, with just simply a marketing idea, you know, you could also say it's a non opioid, it's a non. Non steroidal anti inflammatory agent. It's a non, you know, chemotherapeutic agent.
- [28:38]
Thomas Goetz
It's a non. Aspirin.
- [28:40]
Dr. Andrew Crystal
Aspirin, Exactly. And that's all true. It's not false advertising. It's just, you know, in this case, it. It really led people to differentiate the drug from the benzodiazepines in a way that I think is maybe more than was merited.
- [29:00]
Thomas Goetz
So there it was. Ambien arrived in 1992, and it was a huge hit. Prescriptions took off even more in 1997 after the FDA allowed direct to consumer advertising. TV commercials made Ambien seem like the perfect sleeping pill. By 2006, it was the ninth most prescribed drug in the United States. That same year, it was even approved for use in children. So what could go wrong? Well, we'll get to that coming up. But first, here's a commercial for Ambien from 2000. As we always say, this is not a paid ad. This is journalism. Take a listen.
- [29:47]
Ambien Commercial Narrator
There is a rhythm to life. We sleep at night and wake in the morning. It's this sleep cycle that helps keep us in a healthy balance. But for millions of Americans, sleep doesn't always come easy. Fortunately, there's Ambien. Ambien is a prescription sleep aid that can help you get a full night's sleep. With Ambien, you fall asleep fast, stay asleep longer, and generally wake without feeling groggy the next morning. No wonder Ambien is the number one prescribed sleep aid in America. Until you know how Ambien will affect you, you shouldn't drive or operate machinery. Side effects may include drowsiness, dizziness, and diarrhea. You shouldn't take it with alcohol. Patients who abuse prescription sleep aids may become dependent. Prescription sleep aids are most often taken for seven to ten days as needed. Your doctor will advise you about taking them longer. Take Ambien only when you can devote a full night to sleep and wake up rested and ready to start your day. Talk to your doctor about Ambien. Ambien works like a dream.
- [30:49]
Thomas Goetz
Welcome back. This is part three. Side effects. Usually, we meet side effects broadly. We typically explore the wider social and economic consequences of using medications to treat disease. But in this episode, we want to dig in on the actual side effects caused by Ambien, because those side effects are what eventually caused fairly significant social consequences for Caroline and so many other users. So you know this, but when we sleep, we're pretty much unconscious. We don't really know what's happening. Even people with insomnia, they are not usually awake 24 hours a day. Insomniacs typically do sleep off and on fitfully during the night, but they may not be aware that they're sleeping or they're so anxious when they are awake that they don't notice when they drop off. It's not always everyone is different. But my point is that the subjective experience of insomnia can be different from the actual objective measure of sleep during the night. So for many insomniacs, the night to night reality can be all mixed up with the idea that they're not sleeping again. So amid this muddle, how does science actually measure sleep? And how does a drug company with a new drug validate that it is helping people who are basically sometimes unconscious? Here's the first answer. In a sleep experiment, subjects with insomnia report to a sleep lab. They are put in a room with a bed and outfitted with a dozen or more electrodes and monitors that measure brain activity, body movements and breathing and airflow rates. There is a lot of tape and wires. It does not look comfortable at all. The patient is then given a dose of drug or a placebo, which is a sugar pill, no medicine, and then nighty night the next morning. All that data offers an objective measure of sleep, including duration and stages. Since this is awkward and expensive, patients typically will only report to a lab once or twice over the course of an experiment. Otherwise, they are asked to record their own experiences at home. And that is subjective data. Okay, so that's the scientific process for measuring sleep. But what about the second question? How does the FDA determine that a drug provides a real and true benefit and not just that the study subjects nodded off on their own. The answer is they use a placebo as the benchmark for many kinds of drugs. The the FDA requires drug companies to set up an experiment where patients are randomly assigned to a test group or a placebo group. If the new drug works better than the placebo, that suggests a true benefit. The challenge here, though, is that the placebo effect is especially strong for psychological conditions like anxiety or pain or, yes, insomnia. One study suggested that 82% of the response from antidepressants was due to the placebo effect. For insomnia, it's not uncommon for 50% of people taking a placebo to report that it helped them sleep, because, again, they didn't know it was a placebo, that it had no real medicine in it. 50%. That's a lot of people. So a drug company testing a new insomnia drug will want to use a dose that has a strong chance of beating the placebo effect without creating too many side effects or safety issues. It's threading a needle between the highest possible dose for potency while still keeping side effects to a minimum. But ultimately, you really want your drug to win. In their trials, Sanofi tested Zolpidem in doses from 1.25 milligrams all the way up to 90 milligrams. Eventually, the company zeroed in on 10 milligrams as the ideal effective dose. At that amount, about 90% of people taking Ambien reported that it helped them sleep, versus around 51% of those taking a placebo. So it clearly beat the placebo success. And in 1992, Ambien was approved by the FDA. Now, once a medicine is approved, a drug company still needs to pay attention to what happens to patients in the real world. The term for this is pharmacovigilance, which is just a lovely piece of jargon. The whole premise of pharmacovigilance rests on the vigilance. When many millions of people take a drug that had previously been tested only on thousands, new things can show up. And at that scale, sometimes exceedingly rare side effects can turn up frequently enough to raise concerns. The FDA catalogs reports of real world side effects in a database called faers, which stands for FDA Adverse Event Reporting System. Now, it's not a perfect system. Not all side effects enter the FAERS database, only those reported back to the FDA using an official form. Drug companies are required to report adverse events to the fda, but doctors or hospitals are not. Still, the FAERS dataset is the best system. We have to see what happens in the real world after a drug is released. The most common side effects reported in the clinical trials for Ambien were drowsiness the next day and some dizziness. After the drug hit the market, though, other kinds of events began to trickle into the FAERS database. Reports of amnesia, confusion, sleep talking, sleep walking, sleep sex. People were getting up and cooking meals with no memory of it in the morning. And the majority of these cases involved women. This was the same stuff that Caroline, who we introduced at the start of this episode, that she was Talking about
- [37:03]
Caroline
maybe once every few weeks, once a month, where I would call my mother or call my best friend or text a relationship partner and something just utterly embarrassing, something out of a hallucination or something about, I see all these elephants in my room.
- [37:27]
Thomas Goetz
So Caroline was clearly not the only one having these strange behaviors. But it took years for these reports to amount to a signal that something was going on. And it's worth noting here that Ambien went off patent in the US in 2006. The original drug got a lot cheaper now that it was available in generic form. The price went from about $300 to about $30 for a 30 pill supply. The upshot was, was that prescriptions for Zolpidem went up after 2006. Millions of people who had trouble sleeping now had an affordable way to find their Zs. But as prescriptions rose, so did visits to the emergency room. From 2005 to 2010, Zolpidem related visits to the ER tripled, with women accounting for two thirds of those visits. Further studies showed that the morning after taking a dose, significant amounts of the drug were still present in women's bodies, far longer than in men. Zolpidem began to show up in courtrooms, too. Dozens of people accused of a range of crimes from reckless driving to assault to murder, blamed Zolpidem in their defense.
- [38:46]
Caroline
I remember getting on the highway, and
- [38:49]
Thomas Goetz
then I have no memory. Kerry Kennedy took Ambien and sideswiped a truck.
- [38:53]
Caroline
It was also in the system of her cousin, former Congressman Patrick Kennedy, when he crashed into a concrete barrier. In 2006 in Texas, a woman who mixed Ambien and alcohol had no memory
- [39:05]
Thomas Goetz
of running over two young girls and their mother. A Southern Illinois man took four Ambien
- [39:11]
Caroline
just 12 hours before he drove into
- [39:14]
Thomas Goetz
a highway construction crew, killing one man and injuring three. Three others. In 2007, the FDA issued a warning cautioning about sleep driving and other odd behaviors. And In February of 2013, the FDA issued new guidance to prescribers. It cut the recommended dose for women in half to just 5 milligrams. In 2019, the agency went even further. It required a new warning label on all products containing Zolpidem and two similar drugs. The new language cautioned patients of what it called complex sleep behaviors, including sleepwalking and sleep driving, some of which resulted in death. These cases included accidental overdoses, falls, burns, near drowning, carbon monoxide poisoning, hypothermia, self injuries such as gunshot wounds, and apparent suicide attempts. Patients usually did not remember these events. By that time, though, Zolpidem use had already begun to drop off. The total number of prescriptions fell from more than 40 million in 2010 to just 31 million in 2017. In 2023, there were just over 11 million prescriptions written for zolpidem. Today, zolpidem is still out there, but it is no longer the sleeping pill of choice. Surprisingly, perhaps the most prescribed drug for insomnia these days is trazodone. It is an antidepressant, and, oddly, there's actually no strong evidence that it is effective in treating insomnia. In fact, trazodone is not even approved for insomnia by the fda. It's prescribed off label. And both the American Academy of Sleep Medicine and the American association of Family Physicians recommend against prescribing trazodone for sleep. Nonetheless, millions of people are taking it, hoping that it works, which shows just how far away we still are from a perfect sleeping pill.
- [41:17]
Dr. Andrew Crystal
We've got a bunch of insomnia medications. There are, you know, let's say 20, probably more. People say to me, which is the drug you use to treat insomnia? And my answer is, I use the drug that is best suited to the particular patient's needs. It's kind of like asking a person who treats infectious diseases, what antibiotic do you use? Well, it depends what kind of infection it is. Right. You know, you use ampicillin for one thing, you use penicillin for something else.
- [41:48]
Thomas Goetz
And this means you really have to unpack or understand or characterize a person's insomnia in a much more granular way.
- [41:57]
Dr. Andrew Crystal
Exactly. Which has not been the history.
- [42:00]
Thomas Goetz
It turns out that maybe the whole idea of one perfect sleeping pill, it's probably misguided. After all, sleep is a complicated thing. It is unlikely to ever have a simple solution. The best approach these days is probably to rethink the whole issue of sleep from the ground up.
- [42:20]
Dr. Andrew Crystal
We have a couple of kinds of therapies. One is called sleep hygiene. And this is simply addressing some of the maladaptive behaviors that people engage in that may cause sleep difficulty. And this is like exercising too close to bedtime, drinking too much caffeine, things of that nature. And that helps some people, but some people, it doesn't. A common thing that people do is when they have trouble sleeping, they start spending more time in bed with the hopes of getting more sleep. So a common strategy that's used by therapists is to cut down the time in bed to about what you're able to sleep. And remarkably, that just having it Be one consolidated period makes people feel more rested and feel and function better during the day. It's remarkable, but it's a quite potent intervention.
- [43:05]
Thomas Goetz
So there was one thing that you also mentioned in it was when people can't sleep, so they get up and they have ice cream or they watch tv. So you're basically unintentionally perhaps rewarding yourself for not being able to sleep.
- [43:16]
Dr. Andrew Crystal
Yeah. And what we try to get people do is don't do something that is enjoyable and engaging and energizing because that will of course be counterproductive. And the cognitive behavioral therapy has become the standard first line therapy for this condition. And the reason for it is because it tends to fix the causes that some people have. The big issue we have now, which is a public health issue, is access to that form of therapy. In our clinic, we have up to a year long waiting list for people to get access to therapists for cognitive behavioral therapy.
- [43:56]
Thomas Goetz
Changing our behavior, changing our habits, that can be really hard. But for people with chronic persistent insomnia, behavior is probably a much better place to get relief than to start a drug that over time brings a material risk for some big issues down the road. For people like Caroline who have experienced the dark side of Ambien, that's a welcome realization.
- [44:20]
Caroline
I don't know that insomnia is taken seriously enough. I think it's just more prevalent with everything being electronic and smartphones and everything being light kind of all the time. But what has helped too is to not look at my phone when I'm in bed and not keep a television in my bedroom. I would be completely lying if I said that my insomnia has been 100% cured by ambient meditation, music, a weighted blanket, and a sleep mask. But there are nights where I lay there and boy, oh boy. But for the most part, yes, they absolutely work. And I like the fact that I don't rely on a pill to fall asleep.
- [45:16]
Thomas Goetz
What Caroline describes, it's really a program for purging modern life from our bedroom. All the gadgets and lights and central heating. So no tv, no phones, no screens, a cool room, a heavy blanket. Shut out the everyday. Shut out everything that screams at us to pay attention, to be concerned. Just one more episode, one more swipe. Maybe we try to turn back the clock to a pre modern world. And maybe tonight you will get some rest. That's it for this episode of Drug Story. Drug Story was created, written and hosted by me, Thomas Goetz. Molly Werner is our research director. From Reasonable Volume, Rachel Swaby produced and Sound designed this episode with assistance from Audrey Ngo. Elise Hu was the editor. Mark Bush is our engineer. Voice acting by Colin Borden. Drugstore was produced with support from the University of California, Berkeley School of Public Health. Special thanks to Claudia Williams and Dean Michael Lu. Thanks also to Caroline and Dr. Andrew Crystal. Also thanks to my old team at Iodine, which over a decade ago actually built the open FDA website that features the Fairs data. That was an amazing project. I learned so much about how the FDA works and how much good that agency does for the world and for public health. Thank you God for the fda. So kudos to Taha Kass Hout, Matt Mohebbi, Adam Baker and Hans Nelson for their work on that project. It's still there@open.fda.gov check it out. Drug Story is an independent production. If you would like to support our work, contact us at drugstory. Co. You can also subscribe to our substack there. And if you want there to be even more episodes of Drug Story, help us make it happen. Rate us on Apple or Spotify or wherever you get your podcasts. Get your friends to listen. Who knows what drug stories remain to be told? For an annotated list of our sources for this episode, visit Drugstory Co. Thank you for listening. Listening to this episode of Drug Story may cause neurasthenia, Americanitis and other 19th century maladies. We recommend that you report any adverse events to the fda. Turn off your phone and try to ignore the modern world as much as possible.