#394 ‒ Sleep pharmacology: the role of medications in healthy sleep, the promise of emerging therapies, and the evidence for common sleep supplements

0:10Peter Attia:Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free.

0:46Peter Attia:If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of a subscription. If you want to learn more about the benefits of our premium membership, head over to peteratiamd.com forward slash subscribe. Welcome to this episode of The Drive. In this episode, I focus on sleep pharmacology. Now, we've had plenty of previous episodes about sleep. We've talked about sleep biology, sleep hygiene, even cognitive behavioral therapy for insomnia, CBTI, and even different sleep supplements, but we've never done anything more than sort of a skim of the surface on sleep medications.

1:28And the intention of this episode is to fill that obviously very important void.

1:33Peter Attia:Sleep is a biological imperative. A pioneer of modern sleep research first put the problem this way. If sleep does not serve an absolutely vital function, then it is the biggest mistake the evolutionary process has ever made. When you're asleep, you can't protect yourself from predators, you can't hunt, you can't find a mate, you are, as the phrase goes, dead to the world. But natural selection insisted that we do it anyway, every single night for our entire lives. That should tell you something. To make this practical, I want to give you a simple way to think about sleep problems, because most people, including most clinicians, don't diagnose them correctly.

2:14Peter Attia:Almost every sleep issue can be traced back to one or more of four things. First, sleep pressure, that buildup of the drive to sleep the longer you're awake. Second, circadian timing, whether your internal clock is aligned with the light-dark cycle. Third, hyperarousal, a state where your brain is effectively holding the gas pedal down when you're trying to sleep. And fourth, sleep architecture, the quality and structure of the sleep you're actually getting. Every tool we're going to talk about, behavioral, psychological, or pharmacological, works by acting on one or more of these. And most failures happen when you apply a perfectly good tool to the wrong problem.

3:00Peter Attia:Few organisms in their natural environment have trouble sleeping. So how did we get to a place where 36 % of U.S. adults fail to get the seven hours of sleep that most people need each day for optimal health and functioning? Where more than half of adults report difficulty sleeping and over 22 % actually meet diagnostic criteria for insomnia? The answer is that we've engineered an environment that disrupts all four of those systems at the same time. Our sleep is regulated by two processes that were sculpted by over half a billion years of evolutionary experience. The first is the homeostatic process, or process S, which is the accumulation of pressure to sleep.

3:46Peter Attia:Sleep pressure builds as a result of brain activity, though the mechanism for this sleep pressure has not been identified. The longer you're awake, the more it builds until eventually it overwhelms you and you sleep. Think of it like a battery that discharges while you're awake and recharges during sleep. The second process is the circadian process or process C. This is your internal clock anchored to the light-dark cycle, coordinated by melatonin at night and cortisol in the morning. It's not just one clock. It's a central clock in the brain with hierarchical peripheral clocks governing individual cells and organs.

4:25Peter Attia:We now spend almost all of our time indoors under light that's too dim during the day and too bright at night. We go to bed when our to-do list is finally exhausted, not when our body is biologically ready. We use caffeine to push through the afternoon, alcohol to wind down at night, and then wonder why we sleep like garbage. Jet lag, daylight savings time, and many prescription drugs further disrupt the natural regulators of sleep. It's our systematic engineering away of these environmental cues that makes sleep a struggle for so many of us. Here's something that might surprise you. Our hunter-gatherer ancestors didn't sleep dramatically more than we do.

5:07Peter Attia:The data suggest their total sleep time is roughly comparable to ours, and some have even more fragmented sleep. But they have extraordinarily strong circadian rhythms and report almost no difficulty sleeping. Some of their languages don't even have a word for insomnia. That's worth noting. One tool in our toolkit for getting our sleep back in order is sleep medications. I want to be direct about this. Medications are not the foundation of good sleep. The foundation is behavioral. It's aligning our lifestyles, environments, and mental attitudes with the cues our biology needs for good sleep. But sleep medications can be useful tools when used skillfully, matched to the specific problem, and ideally as a short-term bridge rather than a long-term crutch.

5:58Peter Attia:For people dealing with acute crisis situations, chronic pain, or deeply rooted anxiety, they can often fill a gap that we can't meet through our own efforts. The key word is matched because these drugs vary enormously in how they work, what they do to your sleep architecture, how long they last, and what their risks are. Reaching for a drug without understanding the problem you're treating is a recipe for tolerance, dependence, worsened sleep architecture, or the all-too-common scenario of needing more to get less. So, in this episode, we'll cover the bare-bones basics of sleep biology and how to support it, and then dig into all the major classes of sleep medications.

6:42Peter Attia:We'll talk about how they work, what they do to and for your sleep, which ones work best for your problems, their side effects, and the risk of dependence. We'll spend extra time discussing the potential that Dora's, the newest class of sleep medications, might have for Alzheimer's prevention in high-risk patients. And we'll discuss some off-label medications and dietary supplements used for sleep, although that's not our focus. We have lots of content on such tools, and our focus here today will be on prescription medications, which we'll be discussing in detail for the first time. Good sleep is built through sleep hygiene, much of which involves adapting your behaviors to align with the homeostatic and circadian sleep processes I discussed a few moments ago.

7:29Peter Attia:Align the circadian process through things like regular wake-up, meals, and bedtimes, getting sunlight as soon as you can after waking up, reducing light exposure and stressors in the hours before bed, and making the bedroom cool and dark. Enhancing the homeostatic process is done by cultivating and conserving your sleep pressure by getting higher intensity exercise performed earlier in the day or light exercise in the evening, and avoiding sleeping in, napping, or drinking coffee in the afternoon. Now, if you want to go into much more detail on this, you can check out our AMA with Matt Walker or the four-part episode that we did with Matt Walker, both of which are going to be available in the show notes, and they provide a great discussion on sleep hygiene.

8:18Peter Attia:If you're the person who has always found yourself fully awake and alert after everyone else has gone to bed, or conversely, if you're the person who has always woken up spontaneously well before the sun but find yourself winding down or dozing off when the rest of your life is still calling on you to be awake, or if you're suffering from jet lag, or if you chronically stay up late or sleep in on your days off but then find your sleep is poor during the work week, you likely want to work on circadian alignment. On the other hand, if your problem seems unrelated to your schedule, but you find yourself too sleepy during the day or too wakeful at bedtime, especially if you're taking naps or relying heavily on caffeine, or if you fall asleep quickly, but have a lot of fragmented non-restorative sleep, you may get more benefit from focusing on consolidating your sleep pressure.

9:15Peter Attia:What sleep hygiene does not reliably fix is hyperarousal, which is why so many people can do everything right and still lie awake at night. So once a patient's sleep hygiene is in order, but before we start thinking about specific sleep medications, we first want to rule out any medical causes of poor sleep. The big ones include restless leg syndrome, which is a maddening urge to move your legs at night when resting, maybe with crawling, tingling, or even aching sensations that you can temporarily relieve with movement. This frequently disrupts sleep onset and can cause daytime fatigue. It afflicts about 3 % of the general population of adults worldwide, although a survey from the American Academy of Sleep Medicine found that as many as 13 % of Americans report having been diagnosed with it.

10:09Peter Attia:Another one to think about is obstructive sleep apnea. If you snore, gasp, or choke during your sleep, or if your partner says you stop breathing at night, then it's possible you have obstructive sleep apnea, especially if you're overweight or obese. Patients typically experience unrefreshing sleep, morning headaches, excessive daytime sleepiness, and difficulty concentrating, despite spending adequate time in bed. Because of the obesity epidemic, about a third of adults in the U.S. are likely to have obstructive sleep apnea, including just over 39 % of males and 26 % of females. About half of these cases are mild, 30 % are moderate, and nearly 20 % are considered severe.

10:53Peter Attia:Finally, mood disorders. Persistent depressive disorder can cause either difficulty falling asleep or excessive daytime sleepiness. Anxiety disorders can cause difficulty falling or staying asleep. Bipolar disorder can reduce sleep during hypomanic phases and increase it during depressive dips and is generally characterized by circadian disruption, which acts in a vicious cycle with the disease. About a third of U.S. adults in a given 12-month period suffer from anxiety and or mood disorders, and in turn, about 25 to 45 percent of people with mood or anxiety disorders report having had severe insomnia in the previous year.

11:35Peter Attia:while it was 42 % to 63 % of those with comorbid mood and anxiety disorders. This is roughly twice the rate in people without mood or anxiety disorders. All of these have medical and lifestyle treatments, and addressing them can improve your sleep with multiple downstream benefits. But here's the reality. Even when a patient is working hard on all of these things, some people still struggle to get the sleep they need. They may be dealing with shift work, frequent travel, chronic stress, pain, illness, or a nervous system that's been dysregulated for years. So while medications are not necessarily the foundation of good sleep, they can be valuable tools when used deliberately.

12:19Peter Attia:Each class of sleep medications we'll discuss acts on one or more of the four sleep mechanisms I described earlier. Some suppress the arousal that overrides the homeostatic drive, others reinforce the circadian timing signal, and some, the most promising, work by quietly reducing the brain's wakefulness drive rather than forcing sedation. Understanding which problem is disrupted in a given patient is what allows you to match the medication to the problem rather than reaching for a blunt instrument. Now, before reaching for anything, you need to understand what kind of sleep problem you're up against.

13:00Peter Attia:The DSM-5 criteria for insomnia are sleep problems persisting more than three months, at least three nights a week, and, this part matters, causing distress. It's not just about how much you sleep, it's about the suffering component. Except in rare cases, people do not develop insomnia because of a broken sleep system. When it is not caused by other medical or environmental factors, insomnia is most often driven by hyperarousal. There is a high cortical activity, and the stress hormone, corticotropin-releasing hormone, and cortisol are elevated, overriding the normal drive to sleep. It is as if the nervous system wants to slow down, but the gas pedal of wakefulness is being held down at the same time, preventing sleep mechanisms from taking over.

13:52Peter Attia:Hyperarousal was adaptive when the threats to our survival were physical, immediate, and resolvable by direct and often collective action. The problem in modern insomnia is that the threats are abstract, persistent, individualized, and cognitively mediated. financial worry, career pressure, social conflict, I might suggest that this is the mechanism by which evolutionary mismatch becomes insomnia. This shift helps explain why cognitive behavioral therapy for insomnia, CBTI, is the first line treatment for insomnia. CBTI works on a different axis than most people expect. It doesn't just try to make you more tired, it targets hyperarousal.

14:37Peter Attia:It reduces the cognitive and physiological activation that keeps the brain in a wakeful state, and it retrains the association between your bed and being awake. That's why it often works when sleep hygiene alone doesn't. We'll put a link in our show notes to the episode with Ashley Mason for a deep dive into the practice of CBTI. There's another concept here that's incredibly important and often missed, which is paradoxical insomnia, also called sleep state misperception. These are people who are convinced they've been awake all night. They've gotten two or three hours of sleep at most. But when you actually measure their sleep, they've gotten significantly more than that.

15:19Peter Attia:You'll often see this clinically. Someone says they're awake all night, but they're functioning far better the next day than that would suggest. This matters because these patients are especially vulnerable to certain medications. Drugs that impair memory, like benzodiazepines or Z-drugs, can make it feel like sleep is improved simply because the person no longer remembers waking up, but the underlying sleep hasn't actually improved. Most sleep problems fall into four buckets, which actually correspond directly to the four mechanisms of insomnia. Trouble falling asleep, which is often a hyper arousal situation overriding homeostatic drive, trouble staying asleep, and in my experience with my patients, this second bucket is far more common than the first, early morning awakenings, which is often a circadian misalignment, or fragmented non-restorative sleep, which is often inadequate slow-wave generation.

16:19Peter Attia:And this is where people get into trouble. They treat all of these as the same problem. But of course they're not. Trouble falling asleep, waking up in the middle of the night, waking up too early, and getting non-restorative sleep are often driven by completely different mechanisms. And a drug that helps one can make the other worse. Reaching for a drug at random without understanding the problem you're trying to solve or the property of the drugs often leads to tolerance, dependence, worsening sleep architecture, or a cycle of needing more to get less benefit. This is why working with a clinician who understands sleep matters.

16:59And part of that understanding actually comes down to understanding the difference between sedation and physiologic sleep. See, here's something I think most people don't appreciate, and it should inform how you think about every sleep medication. Sleep is not

17:14Peter Attia:just a loss of consciousness. It's an orchestrated biological process cycling through four stages, light non-REM, deeper non-REM, deep non-REM, also called N3 or slow wave sleep, and REM sleep. Each stage does something specific. Slow wave sleep handles physical restoration, declarative memory consolidation and, this is a big one, waste clearance from the brain, a critical housekeeping function with implications we're only beginning to understand for long-term neurologic health. REM handles emotional processing and procedural memory. Most of the commonly used sleep medications don't deliver this.

18:00They create unconsciousness. They flatten the architecture rather than supporting it. That's not a small distinction. As I think we joked on a previous podcast on this topic, if someone came up to me and hit me over the head with a baseball bat and left me unconscious on the sidewalk, nobody would assume I was simply sleeping. The agents we're more comfortable with tend to support the body's own sleep mechanisms rather than overriding them. Different drugs vary in how quickly they work, how long they last, and which sleep problems they target. So we need to match the medication's pharmacology to the patient's specific sleep challenges.

18:42For example, short-acting agents are better for sleep-onset insomnia, while longer-acting agents are better for frequent nighttime awakenings. Let's start with benzodiazepines, temazepam, lorazepam, alprazolam, diazepam, clonazepam, and others. They also go by brand names you've probably heard of like Xanax, Ativan, and Valium. These are some of the oldest sedative hypnotics. They work by dampening excitatory neurotransmitter systems, pressing the brakes on the hyperarousal that modern life promotes and that drive insomnia. Specifically, benzodiazepines enhance signaling through GABA, the brain's main inhibitory neurotransmitter.

19:26These drugs are particularly active in the cortex and thalamus, where GABA-A receptors are especially abundant. The thalamus serves as a sensory gate between the outside world and the cortex, where gabanergic signaling is increased in the thalamus, the gate closes more tightly, so fewer signals reach the cortex and conscious perception fades, producing sedation. Different benzodiazepines vary in receptor subtype affinity, onset, and half-life, which leads to some being more sedating and others being more anxiolytic, or muscle-relaxing in practice. Benzodiazepines reduce sleep latency, the time it takes to fall asleep, and may increase total sleep time, but they significantly alter sleep architecture, often decreasing slow-wave sleep, which is that deep N3 sleep we talked about, and suppressing REM sleep.

20:23They're also powerful anxiolytics, so they can quickly quiet ruminative thoughts and muscle tensions in patients whose insomnia is driven by anxiety. But the trade-offs are significant. In addition to the disruption of sleep architecture, they carry real risks of physiologic dependence and withdrawal, including rebound insomnia, anxiety, and even in severe cases, seizures. They also increase fall

20:50Peter Attia:risk by causing dizziness, ataxia, and impaired balance, which in older adults can be catastrophic. Co-administration with alcohol or opioids, which also enhance gabanergic signaling or depress respiratory centers, markedly increases the risk of respiratory depression and death, particularly in people with undiagnosed or untreated obstructive sleep apnea. And there's meaningful signal on cognitive impairment with long-term use, psychomotor speed, executive function, memory, processing speed, though the full magnitude and reversibility are still debated. They can also trigger complex sleep-related behaviors, such as sleepwalking and sleep-related eating, and cause anterograde amnesia, that is, the inability to form new memories while under the influence, such that patients perform behaviors with little or no subsequent memory, similar to alcohol-related blackouts.

21:48Enterograde amnesia is both a feature and bug of benzos. As I mentioned earlier, these drugs cause you to forget nocturnal awakenings, so patients feel like they slept solidly when objective measures show fragmented sleep. The subjective impression of benefit exceeds the physiological reality. And as you'd expect, this effect is especially powerful in people with paradoxical insomnia. It's an effect that can essentially trap people in the use of a medication that's not doing what they think it's doing. With the growing understanding of the risks of benzodiazepines, especially in older adults and those with comorbidities, prescribing practices have shifted towards more cautious, short-term, and lower dose uses for insomnia.

22:35The labels say two to four weeks of use. Meta-analyses show the average duration is nearly a decade. The way to think about benzodiazepines is this. They are very effective at shutting down hyper arousal in the short term, but they do it at the cost of sleep quality, dependence risk, and cognitive side effects. They solve the immediate problem, but they often create a bigger one if used chronically. The concerns around benzos drove the development of a second generation of non-benzodiazepine hypnotics, also referred to as Z-drugs.

23:13Peter Attia:These include Ambien, Sonata, and Lunesta. Z-drugs account for over 40 % of all sleep medication prescriptions in the U.S., with Ambien accounting for nearly 90 % of that. Despite not being structurally related to benzos, Z-drugs also act on GABA-A receptors. As a result, Z-drugs are more targeted for sleep promotion and have less prominent anxiolytic and muscle-relaxing effects than classic benzodiazepines. Z-drugs reduce sleep latency and modestly increase sleep time. Z-drugs vary in their pharmacokinetics, which affects the side effect profile and the type of sleep problems for which they're best suited.

23:55Lunesta has the longest half-life, six hours, making it suitable for both sleep onset and sleep maintenance. Ambien's intermediate release version is better suited to sleep onset insomnia, while Sonata, with its very short half-life of about an hour, can even be used in the middle of the night if you wake up and have enough time left before morning. However, greater receptor selectivity doesn't solve the fundamental issue that we had with benzodiazepines. It is often said that Z-drugs have less impact on sleep architecture than do the classic benzodiazepines, with smaller effects on slow-wave sleep and REM than traditional benzos.

24:38But I want to push back on the rosy picture here. A lot of the favorable sleep architecture comes from animal studies and has been contested based on human evidence. Moreover, chronic use of Z-drugs at higher doses is associated with more pronounced disruptions in sleep architecture. And crucially, Z-drugs induce enterograde amnesia. Z-drugs are also perceived to be less prone to lead to abuse and dependence than benzodiazepines, although increasing evidence suggests that this is untrue or exaggerated. In the show notes, we're going to link to a number of publications to support this position.

25:18Z-drugs also impair physical and cognitive performance, with detrimental effects on motor function, balance, attention, processing speed, and memory. Additionally, Z-drugs still carry risks of complex sleep behaviors that the user does not remember the day following, such as sleepwalking and eating, shopping, driving, making phone calls, and having sex while unconscious or while in a conscious state but strangely dissociated. These effects are most likely to happen at higher doses in older adults or when combined with alcohol or other sedatives. Importantly, more than half of users of sleeping medications use at least one other sedating medication, and 10 % take three or more other sedating medications.

26:08In 2019, the FDA issued a black box warning about these behaviors, which can sometimes lead to injury.

26:16Peter Attia:These cases included accidental overdose, falls, burns, near drowning, exposure to extreme cold temperatures leading to loss of limb, carbon monoxide poisoning, drowning, hypothermia, motor vehicle collision with the patient driving, and self-injuries such as gunshot wounds and apparent suicide attempts. Z-drugs do have some use, especially for dealing with acute disruptions to a person's sleep and where we suspect paradoxical insomnia. For these reasons, we use Z-drugs at the lowest effective dose for the shortest possible duration, and only with a plan for addressing underlying causes of insomnia and offering CBTI.

26:59Z-drugs were designed to be a cleaner version of benzodiazepines, but in practice, many of the same issues remain, just slightly attenuated. They can help with sleep onset in the short term, but they still carry risks around memory, behavior, and dependence. This brings us to the next category of sleep medications, which are the newest and arguably most exciting. They're called dual orexin receptor antagonists, or DORAs. We have three versions of these at the moment, Cuvivic, DeVigo, and Balsamra. DORAs are different in a way that I think really matters. Most traditional sleep medications work by forcing sedation.

27:43They broadly suppress brain activity. But DORAs don't do that. They work by dialing down one of the brain's primary wakefulness systems, specifically the orexin system. And in doing so, they allow your natural sleep processes to take over. That distinction between forcing sleep and allowing sleep is not just semantic. It shows up in the outcomes. DORAs outperformed other drugs on sleep efficiency, which is the amount of time you're sleeping relative to how much time you're in bed, and total sleep time. And DORAs had superior tolerability compared to drugs for which there was enough information to make a comparison.