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

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00:01:04.340 Welcome to this episode of The Drive. In this episode, I focus on sleep pharmacology. Now,

00:01:10.540 we've had plenty of previous episodes about sleep. We've talked about sleep biology,

00:01:14.720 sleep hygiene, even cognitive behavioral therapy for insomnia, CBTI, and even different sleep

00:01:20.720 supplements, but we've never done anything more than sort of a skim of the surface on sleep

00:01:26.780 medications. And the intention of this episode is to fill that obviously very important void.

00:01:33.840 Sleep is a biological imperative. A pioneer of modern sleep research first put the problem this

00:01:40.720 way. If sleep does not serve an absolutely vital function, then it is the biggest mistake the

00:01:46.820 evolutionary process has ever made. When you're asleep, you can't protect yourself from predators,

00:01:52.400 you can't hunt, you can't find a mate, you are, as the phrase goes, dead to the world.

00:01:57.980 But natural selection insisted that we do it anyway, every single night for our entire lives.

00:02:04.140 That should tell you something. To make this practical, I want to give you a simple way to

00:02:08.660 think about sleep problems, because most people, including most clinicians, don't diagnose them

00:02:13.740 correctly. Almost every sleep issue can be traced back to one or more of four things. First, sleep

00:02:21.320 pressure, that buildup of the drive to sleep the longer you're awake. Second, circadian timing,

00:02:28.760 whether your internal clock is aligned with the light-dark cycle. Third, hyperarousal, a state

00:02:35.860 where your brain is effectively holding the gas pedal down when you're trying to sleep.

00:02:40.840 And fourth, sleep architecture, the quality and structure of the sleep you're actually getting.

00:02:46.760 Every tool we're going to talk about, behavioral, psychological, or pharmacological, works by acting on one or more of these.

00:02:54.860 And most failures happen when you apply a perfectly good tool to the wrong problem.

00:03:00.640 Few organisms in their natural environment have trouble sleeping.

00:03:04.080 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?

00:03:15.240 Where more than half of adults report difficulty sleeping and over 22% actually meet diagnostic criteria for insomnia?

00:03:24.560 The answer is that we've engineered an environment that disrupts all four of those systems at the same time.

00:03:31.180 our sleep is regulated by two processes that were sculpted by over half a billion years of

00:03:37.220 evolutionary experience. The first is the homeostatic process or process S, which is the

00:03:43.940 accumulation of pressure to sleep. Sleep pressure builds as a result of brain activity, though the

00:03:50.380 mechanism for this sleep pressure has not been identified. The longer you're awake, the more it

00:03:55.380 builds until eventually it overwhelms you and you sleep. Think of it like a battery that discharges

00:04:01.440 while you're awake and recharges during sleep. The second process is the circadian process or

00:04:07.920 process C. This is your internal clock anchored to the light-dark cycle, coordinated by melatonin

00:04:14.980 at night and cortisol in the morning. It's not just one clock, it's a central clock in the brain

00:04:20.820 with hierarchical peripheral clocks governing individual cells and organs. We now spend almost

00:04:27.640 all of our time indoors under light that's too dim during the day and too bright at night.

00:04:33.080 We go to bed when our to-do list is finally exhausted, not when our body is biologically

00:04:38.160 ready. We use caffeine to push through the afternoon, alcohol to wind down at night,

00:04:43.980 and then wonder why we sleep like garbage. Jet lag, daylight savings time, and many prescription 0.95

00:04:50.500 drugs further disrupt the natural regulators of sleep. It's our systematic engineering away

00:04:56.760 of these environmental cues that makes sleep a struggle for so many of us. Here's something

00:05:02.200 that might surprise you. Our hunter-gatherer ancestors didn't sleep dramatically more than

00:05:06.980 we do. The data suggest their total sleep time is roughly comparable to ours, and some have even

00:05:14.000 more fragmented sleep. But they have extraordinarily strong circadian rhythms and report almost no

00:05:21.280 difficulty sleeping. Some of their languages don't even have a word for insomnia. That's worth

00:05:27.120 noting. One tool in our toolkit for getting our sleep back in order is sleep medications.

00:05:33.940 I want to be direct about this. Medications are not the foundation of good sleep. The foundation

00:05:38.820 is behavioral. It's aligning our lifestyles, environments, and mental attitudes with the

00:05:44.020 cues our biology needs for good sleep. But sleep medications can be useful tools when used

00:05:51.040 skillfully, matched to the specific problem, and ideally as a short-term bridge rather than a

00:05:57.380 long-term crutch. For people dealing with acute crisis situations, chronic pain, or deeply rooted

00:06:03.680 anxiety, they can often fill a gap that we can't meet through our own efforts. The key word is

00:06:09.800 matched, because these drugs vary enormously in how they work, what they do to your sleep

00:06:15.260 architecture, how long they last, and what their risks are. Reaching for a drug without understanding

00:06:21.540 the problem you're treating is a recipe for tolerance, dependence, worse in sleep architecture,

00:06:26.780 or the all-too-common scenario of needing more to get less.

00:06:31.560 So, in this episode, we'll cover the bare-bones basics of sleep biology and how to support it,

00:06:38.120 and then dig into all the major classes of sleep medications.

00:06:42.480 We'll talk about how they work, what they do to and for your sleep,

00:06:46.980 which ones work best for your problems, their side effects, and the risk of dependence.

00:06:52.860 We'll spend extra time discussing the potential that Dora's, the newest class of sleep medications,

00:06:59.020 might have for Alzheimer's prevention in high-risk patients. And we'll discuss some

00:07:04.140 off-label medications and dietary supplements used for sleep, although that's not our focus.

00:07:09.340 We have lots of content on such tools, and our focus here today will be on prescription

00:07:13.980 medications, which we'll be discussing in detail for the first time. Good sleep is built through

00:07:19.720 sleep hygiene, much of which involves adapting your behaviors to align with the homeostatic

00:07:25.440 and circadian sleep processes I discussed a few moments ago. Align the circadian process

00:07:31.360 through things like regular wake-up, meals, and bedtimes, getting sunlight as soon as you can

00:07:37.680 after waking up, reducing light exposure and stressors in the hours before bed, and making

00:07:43.360 the bedroom cool and dark. Enhancing the homeostatic process is done by cultivating and

00:07:50.060 conserving your sleep pressure by getting higher intensity exercise performed earlier in the day

00:07:55.200 or light exercise in the evening, and avoiding sleeping in, napping, or drinking coffee in the

00:08:01.400 afternoon. Now, if you want to go into much more detail on this, you can check out our AMA with

00:08:08.160 Matt Walker, or the four-part episode that we did with Matt Walker, both of which are going to be

00:08:13.800 available in the show notes, and they provide a great discussion on sleep hygiene. If you're the

00:08:18.840 person who has always found yourself fully awake and alert after everyone else has gone to bed,

00:08:24.660 or conversely, if you're the person who has always woken up spontaneously well before the sun,

00:08:30.760 but find yourself winding down or dozing off when the rest of your life is still calling on you to

00:08:36.420 be awake, or if you're suffering from jet lag, or if you chronically stay up late or sleep in on

00:08:43.400 your days off but then find your sleep is poor during the work week, you likely want to work on

00:08:49.000 circadian alignment. On the other hand, if your problem seems unrelated to your schedule but you

00:08:55.340 find yourself too sleepy during the day or too wakeful at bedtime, especially if you're taking

00:09:01.120 naps or relying heavily on caffeine, or if you fall asleep quickly but have a lot of fragmented

00:09:08.560 non-restorative sleep, you may get more benefit from focusing on consolidating your sleep

00:09:14.660 pressure. What sleep hygiene does not reliably fix is hyperarousal, which is why so many people

00:09:22.100 can do everything right and still lie awake at night. So once a patient's sleep hygiene is in

00:09:28.460 order, but before we start thinking about specific sleep medications, we first want to rule out any

00:09:33.960 medical causes of poor sleep. The big ones include restless leg syndrome, which is a maddening urge

00:09:40.240 to move your legs at night when resting, maybe with crawling, tingling, or even aching sensations

00:09:46.100 that you can temporarily relieve with movement. This frequently disrupts sleep onset and can cause

00:09:53.120 daytime fatigue. It afflicts about 3% of the general population of adults worldwide, although

00:10:00.080 a survey from the American Academy of Sleep Medicine found that as many as 13% of Americans

00:10:06.120 report having been diagnosed with it. Another one to think about is obstructive sleep apnea.

00:10:12.000 If you snore, gasp, or choke during your sleep, or if your partner says you stop breathing at night,

00:10:17.180 then it's possible you have obstructive sleep apnea, especially if you're overweight or obese.

00:10:23.860 Patients typically experience unrefreshing sleep, morning headaches, excessive daytime sleepiness,

00:10:29.320 and difficulty concentrating, despite spending adequate time in bed. Because of the obesity

00:10:34.620 epidemic, about a third of adults in the U.S. are likely to have obstructive sleep apnea,

00:10:40.280 including just over 39% of males and 26% of females. About half of these cases are mild,

00:10:47.180 30% are moderate, and nearly 20% are considered severe. Finally, mood disorders. Persistent

00:10:56.240 depressive disorder can cause either difficulty falling asleep or excessive daytime sleepiness.

00:11:02.480 Anxiety disorders can cause difficulty falling or staying asleep. Bipolar disorder can reduce

00:11:07.660 sleep during hypomanic phases and increase it during depressive dips and is generally

00:11:12.860 characterized by circadian disruption, which acts in a vicious cycle with the disease.

00:11:18.240 About a third of U.S. adults in a given 12-month period suffer from anxiety and or mood disorders,

00:11:24.980 and in turn, about 25 to 45 percent of people with mood or anxiety disorders report having had

00:11:32.940 severe insomnia in the previous year, while it was 42 percent to 63 percent of those with comorbid

00:11:41.140 mood and anxiety disorders. This is roughly twice the rate in people without mood or anxiety

00:11:47.900 disorders. All of these have medical and lifestyle treatments, and addressing them can improve your

00:11:53.420 sleep with multiple downstream benefits. But here's the reality. Even when a patient is working

00:11:58.760 hard on all of these things, some people still struggle to get the sleep they need. They may be

00:12:04.560 dealing with shift work, frequent travel, chronic stress, pain, illness, or a nervous system that's

00:12:10.340 been dysregulated for years. So while medications are not necessarily the foundation of good sleep,

00:12:16.520 they can be valuable tools when used deliberately. Each class of sleep medications we'll discuss

00:12:23.300 acts on one or more of the four sleep mechanisms I described earlier. Some suppress the arousal

00:12:30.640 that overrides the homeostatic drive, others reinforce the circadian timing signal, and some,

00:12:37.140 the most promising, work by quietly reducing the brain's wakefulness drive rather than forcing

00:12:43.620 sedation. Understanding which problem is disrupted in a given patient is what allows you to match the

00:12:50.100 medication to the problem rather than reaching for a blunt instrument. Now, before reaching for

00:12:55.880 anything, you need to understand what kind of sleep problem you're up against. The DSM-5 criteria

00:13:01.740 for insomnia are sleep problems persisting more than three months, at least three nights a week,

00:13:08.760 and, this part matters, causing distress. It's not just about how much you sleep,

00:13:15.240 it's about the suffering component. Except in rare cases, people do not develop insomnia because of

00:13:21.260 a broken sleep system. When it is not caused by other medical or environmental factors,

00:13:27.560 insomnia is most often driven by hyperarousal.

00:13:31.180 There is a high cortical activity,

00:13:33.480 and the stress hormone, corticotropin-releasing hormone,

00:13:37.180 and cortisol are elevated,

00:13:39.560 overriding the normal drive to sleep.

00:13:42.160 It is as if the nervous system wants to slow down,

00:13:45.280 but the gas pedal of wakefulness is being held down at the same time,

00:13:49.480 preventing sleep mechanisms from taking over.

00:13:52.740 Hyperarousal was adaptive when the threats to our survival were physical,

00:13:57.020 immediate, and resolvable by direct and often collective action. The problem in modern insomnia

00:14:04.320 is that the threats are abstract, persistent, individualized, and cognitively mediated.

00:14:10.460 Financial worry, career pressure, social conflict. I might suggest that this is the mechanism by which

00:14:17.320 evolutionary mismatch becomes insomnia. This shift helps explain why Cognitive Behavioral

00:14:23.260 therapy for insomnia, CBTI, is the first-line treatment for insomnia. CBTI works on a different

00:14:30.760 axis than most people expect. It doesn't just try to make you more tired. It targets hyperarousal.

00:14:37.040 It reduces the cognitive and physiological activation that keeps the brain in a wakeful

00:14:42.500 state, and it retrains the association between your bed and being awake. That's why it often

00:14:49.000 works when sleep hygiene alone doesn't. We'll put a link in our show notes to the episode

00:14:54.700 with Ashley Mason for a deep dive into the practice of CBTI. There's another concept here

00:15:00.340 that's incredibly important and often missed, which is paradoxical insomnia, also called sleep

00:15:06.500 state misperception. These are people who are convinced they've been awake all night. They've

00:15:13.160 gotten two or three hours of sleep at most. But when you actually measure their sleep, they've

00:15:17.900 gotten significantly more than that. You'll often see this clinically. Someone says they're awake

00:15:23.100 all night, but they're functioning far better the next day than that would suggest. This matters

00:15:28.940 because these patients are especially vulnerable to certain medications. Drugs that impair memory,

00:15:34.820 like benzodiazepines or Z-drugs, can make it feel like sleep is improved simply because the person

00:15:40.800 no longer remembers waking up, but the underlying sleep hasn't actually improved. Most sleep

00:15:47.660 problems fall into four buckets, which actually correspond directly to the four mechanisms of

00:15:53.900 insomnia. Trouble falling asleep, which is often a hyper arousal situation overriding homeostatic

00:16:00.120 drive. Trouble staying asleep, and in my experience with my patients, this second bucket is far more

00:16:07.280 common than the first. Early morning awakenings, which is often a circadian misalignment. Or

00:16:13.700 fragmented non-restorative sleep, which is often inadequate slow wave generation. And this is where

00:16:20.920 people get into trouble. They treat all of these as the same problem. But of course they're not.

00:16:27.140 Trouble falling asleep, waking up in the middle of the night, waking up too early, and getting

00:16:32.500 non-restorative sleep are often driven by completely different mechanisms. And a drug that

00:16:38.440 helps one can make the other worse. Reaching for a drug at random without understanding the

00:16:43.480 problem you're trying to solve or the property of the drugs often leads to tolerance, dependence,

00:16:49.640 worsening sleep architecture, or a cycle of needing more to get less benefit. This is why

00:16:55.200 working with a clinician who understands sleep matters. And part of that understanding actually

00:17:00.960 comes down to understanding the difference between sedation and physiologic sleep. See,

00:17:06.620 here's something I think most people don't appreciate, and it should inform how you think

00:17:11.000 about every sleep medication. Sleep is not just a loss of consciousness. It's an orchestrated

00:17:17.620 biological process cycling through four stages, light non-REM, deeper non-REM, deep non-REM,

00:17:27.340 also called N3 or slow wave sleep, and REM sleep. Each stage does something specific. Slow wave

00:17:35.840 sleep handles physical restoration, declarative memory consolidation, and, this is a big one,

00:17:42.720 waste clearance from the brain, a critical housekeeping function with implications we're

00:17:47.800 only beginning to understand for long-term neurologic health. REM handles emotional

00:17:53.080 processing and procedural memory. Most of the commonly used sleep medications don't deliver

00:17:59.540 this. They create unconsciousness. They flatten the architecture rather than supporting it.

00:18:05.840 That's not a small distinction. As I think we joked on a previous podcast on this topic,

00:18:12.160 if someone came up to me and hit me over the head with a baseball bat and left me unconscious on

00:18:16.980 the sidewalk, nobody would assume I was simply sleeping. The agents we're more comfortable with

00:18:23.900 tend to support the body's own sleep mechanisms rather than overriding them. Different drugs vary

00:18:30.820 in how quickly they work, how long they last, and which sleep problems they target. So we need to

00:18:37.820 match the medication's pharmacology to the patient's specific sleep challenges. For example,

00:18:43.620 short-acting agents are better for sleep-onset insomnia, while longer-acting agents are better

00:18:49.200 for frequent nighttime awakenings. Let's start with benzodiazepines, temazepam, lorazepam,

00:18:56.380 alprazolam, diazepam, clonazepam, and others. They also go by brand names you've probably

00:19:02.960 heard of like Xanax, Ativan, and Valium. These are some of the oldest sedative hypnotics.

00:19:10.000 They work by dampening excitatory neurotransmitter systems, pressing the brakes on the hyperarousal

00:19:16.480 that modern life promotes and that drive insomnia. Specifically, benzodiazepines enhance

00:19:22.060 signaling through GABA, the brain's main inhibitory neurotransmitter. These drugs are

00:19:27.880 particularly active in the cortex and thalamus, where GABA-A receptors are especially abundant.

00:19:33.720 The thalamus serves as a sensory gate between the outside world and the cortex, where gabanergic

00:19:39.980 signaling is increased in the thalamus, the gate closes more tightly, so fewer signals reach the

00:19:46.260 cortex, and conscious perception fades, producing sedation. Different benzodiazepines vary in

00:19:53.520 receptor subtype affinity, onset, and half-life, which leads to some being more sedating and others

00:20:00.400 being more anxiolytic, or muscle-relaxing in practice. Benzodiazepines reduce sleep latency,

00:20:07.400 the time it takes to fall asleep, and may increase total sleep time, but they significantly alter

00:20:13.920 sleep architecture, often decreasing slow-wave sleep, which is that deep N3 sleep we talked about,

00:20:21.620 and suppressing REM sleep. They're also powerful anxiolytics, so they can quickly quiet ruminative

00:20:28.600 thoughts and muscle tensions in patients whose insomnia is driven by anxiety. But the trade-offs

00:20:34.880 are significant. In addition to the disruption of sleep architecture, they carry real risks of

00:20:41.000 physiologic dependence, and withdrawal, including rebound insomnia, anxiety, and even in severe cases,

00:20:48.160 seizures. They also increase fall risk by causing dizziness, ataxia, and impaired balance, which in

00:20:55.020 older adults can be catastrophic. Co-administration with alcohol or opioids, which also enhance

00:21:01.680 gabanergic signaling or depress respiratory centers, markedly increases the risk of respiratory

00:21:07.640 depression and death, particularly in people with undiagnosed or untreated obstructive sleep apnea.

00:21:14.180 And there's meaningful signal on cognitive impairment with long-term use, psychomotor

00:21:19.000 speed, executive function, memory, processing speed, though the full magnitude and reversibility

00:21:25.100 are still debated. They can also trigger complex sleep-related behaviors such as sleepwalking

00:21:31.340 and sleep-related eating, and cause anterograde amnesia, that is, the inability to form new

00:21:38.820 memories while under the influence, such that patients perform behaviors with little or no

00:21:44.260 subsequent memory, similar to alcohol-related blackouts. Anterograde amnesia is both a feature

00:21:50.680 and bug of benzos. As I mentioned earlier, these drugs cause you to forget nocturnal awakenings,

00:21:57.080 so patients feel like they slept solidly when objective measures show fragmented sleep.

00:22:03.420 The subjective impression of benefit exceeds the physiological reality. And as you'd expect,

00:22:09.440 this effect is especially powerful in people with paradoxical insomnia. It's an effect that

00:22:15.100 can essentially trap people in the use of a medication that's not doing what they think

00:22:20.640 it's doing. With the growing understanding of the risks of benzodiazepines, especially in older

00:22:26.460 adults and those with comorbidities, prescribing practices have shifted towards more cautious

00:22:31.620 short-term and lower dose uses for insomnia. The labels say two to four weeks of use.

00:22:38.800 Meta-analyses show the average duration is nearly a decade. The way to think about benzodiazepines

00:22:45.400 is this. They are very effective at shutting down hyperarousal in the short term, but they do it at

00:22:51.860 the cost of sleep quality, dependence risk, and cognitive side effects. They solve the immediate

00:22:58.040 problem, but they often create a bigger one if used chronically. The concerns around benzos drove

00:23:05.340 the development of a second generation of non-benzodiazepine hypnotics, also referred to

00:23:11.960 as Z-drugs. These include Ambien, Sonata, and Lunesta. Z-drugs account for over 40% of all

00:23:20.540 sleep medication prescriptions in the U.S., with Ambien accounting for nearly 90% of that.

00:23:26.620 Despite not being structurally related to benzos, Z-drugs also act on GABA-A receptors. As a result,

00:23:33.980 Z-drugs are more targeted for sleep promotion and have less prominent anxiolytic and muscle

00:23:39.400 relaxing effects than classic benzodiazepines. Z-drugs reduce sleep latency and modestly increase

00:23:45.960 sleep time. Z-drugs vary in their pharmacokinetics, which affects the side effect profile and the type

00:23:52.540 of sleep problems for which they're best suited. Lunesta has the longest half-life, six hours,

00:23:58.480 making it suitable for both sleep onset and sleep maintenance. Ambien's intermediate release version

00:24:05.180 is better suited to sleep onset insomnia, while Sonata, with its very short half-life of about an

00:24:12.600 hour can even be used in the middle of the night if you wake up and have enough time left before

00:24:17.780 morning. However, greater receptor selectivity doesn't solve the fundamental issue that we had

00:24:23.920 with benzodiazepines. It is often said that Z-drugs have less impact on sleep architecture

00:24:30.360 than do the classic benzodiazepines, with smaller effects on slow-wave sleep and REM than traditional

00:24:37.260 benzos. But I want to push back on the rosy picture here. A lot of the favorable sleep

00:24:42.940 architecture comes from animal studies and has been contested based on human evidence.

00:24:48.720 Moreover, chronic use of Z-drugs at higher doses is associated with more pronounced disruptions in

00:24:55.140 sleep architecture. And crucially, Z-drugs induce enterograde amnesia. Z-drugs are also perceived

00:25:02.980 to be less prone to lead to abuse and dependence than benzodiazepines, although increasing

00:25:08.980 evidence suggests that this is untrue or exaggerated. In the show notes, we're going

00:25:13.860 to link to a number of publications to support this position. Z-drugs also impair physical and

00:25:20.720 cognitive performance, with detrimental effects on motor function, balance, attention, processing

00:25:26.300 speed and memory. Additionally, Z-drugs still carry risks of complex sleep behaviors that the

00:25:33.400 user does not remember the day following, such as sleepwalking and eating, shopping, driving,

00:25:39.940 making phone calls, and having sex while unconscious or while in a conscious state

00:25:45.040 but strangely dissociated. These effects are most likely to happen at higher doses

00:25:51.620 in older adults or when combined with alcohol or other sedatives. Importantly, more than half of

00:25:58.660 users of sleeping medications use at least one other sedating medication, and 10% take three

00:26:05.540 or more other sedating medications. In 2019, the FDA issued a black box warning about these

00:26:13.220 behaviors, which can sometimes lead to injury. These cases included accidental overdose, falls,

00:26:19.900 burns, near-drowning, exposure to extreme cold temperatures leading to loss of limb,

00:26:25.920 carbon monoxide poisoning, drowning, hypothermia, motor vehicle collision with the patient driving,

00:26:32.880 and self-injuries such as gunshot wounds and apparent suicide attempts. Z-drugs do have some

00:26:39.420 use, especially for dealing with acute disruptions to a person's sleep and where we suspect paradoxical

00:26:46.140 insomnia. For these reasons, we use Z-drugs at the lowest effective dose for the shortest

00:26:52.560 possible duration, and only with a plan for addressing underlying causes of insomnia and

00:26:57.920 offering CBTI. Z-drugs were designed to be a cleaner version of benzodiazepines,

00:27:03.920 but in practice, many of the same issues remain, just slightly attenuated. They can help with

00:27:10.540 sleep onset in the short term, but they still carry risks around memory, behavior, and dependence.

00:27:16.140 This brings us to the next category of sleep medications, which are the newest and arguably

00:27:22.680 most exciting. They're called dual orexin receptor antagonists, or DORAs. We have three versions of

00:27:29.820 these at the moment, Cuvivic, DeVigo, and Balsamra. DORAs are different in a way that I think really

00:27:37.740 matters. Most traditional sleep medications work by forcing sedation. They broadly suppress brain

00:27:45.160 activity. But DORAs don't do that. They work by dialing down one of the brain's primary wakefulness

00:27:51.340 systems, specifically the orexin system. And in doing so, they allow your natural sleep processes

00:27:57.960 to take over. That distinction between forcing sleep and allowing sleep is not just semantic.

00:28:05.100 It shows up in the outcomes. DORAs outperformed other drugs on sleep efficiency, which is the

00:28:11.620 amount of time you're sleeping relative to how much time you're in bed, and total sleep time.

00:28:17.040 And DORA's had superior tolerability compared to drugs for which there was enough information to

00:28:22.860 make a comparison. A second meta-analysis that was generally more cautious about sleep medications

00:28:28.780 found that DeVigo specifically had the most favorable profile of any drug examined.

00:28:35.000 One of the things we like about DORA's is that they consistently preserve or minimally alter

00:28:40.280 sleep architecture with little or no effect on slow-wave sleep and even improvements in REM

00:28:46.380 sleep. So why does this matter? Well, here's the thing that gets me really interested, and I want

00:28:53.580 to spend some time on this because I think it could matter a lot for how we think about these

00:28:58.340 drugs in higher-risk patients. During slow-wave sleep, the brain activates what's called the

00:29:05.280 glymphatic system, essentially a specialized waste clearance mechanism. Neurons and their support

00:29:11.660 cells shrink slightly during sleep, opening up about 60% more space between cells, which allows

00:29:18.960 CSF to circulate more freely in exchange with the fluid immediately around brain cells, called the

00:29:24.980 interstitial fluid. The mixed fluid travels along pathways surrounding the outside of cerebral

00:29:31.580 arteries and veins, heading out into the blood for disposal. In the process, the CSF carries

00:29:37.880 away toxins such as beta amyloid and abnormal forms of the protein tau that contribute to

00:29:43.560 Alzheimer's disease and other neurodegenerative diseases of aging. Animal studies have shown

00:29:49.260 that glymphatic clearance of beta amyloid roughly doubles during sleep, particularly during deep

00:29:56.280 non-REM sleep, with similar increases in clearance of aberrant tau. Human studies show that a night

00:30:04.780 of sleep deprivation impairs glymphatic clearance, as does targeted disruptions of slow-wave sleep.

00:30:13.020 If that disruption becomes chronic, there appears to be long-term consequences. Sleep architecture

00:30:18.560 impairment in older adults predicts the extent of beta amyloid and age-related aberrant tau

00:30:25.100 burden in the future. Conversely, patients with Alzheimer's disease and so-called mild cognitive

00:30:31.660 impairment exhibit both non-REM and REM sleep disturbances. In fact, the progression of

00:30:39.120 Alzheimer's disease includes selective degeneration of specific neurons in the brainstem

00:30:44.560 and basal forebrain that regulate REM sleep. This suggests a vicious cycle in which poor sleep

00:30:51.660 accelerates damaged beta amyloid and aberrant tau accumulation, and the accumulation of these

00:30:58.400 damaged proteins further impairs sleep. Because orexin levels rise during the day and fall at

00:31:05.260 night, in rough parallel with beta amyloid levels in the CSF, David Holtzman suspected that there

00:31:13.180 might be a relationship between orexin and glymphatic clearance. So he and his colleagues

00:31:18.140 infused orexin into the hippocampi of a mouse model of Alzheimer's.

00:31:23.700 As expected, orexin increased the level of beta-amyloid in the animal's interstitial fluid.

00:31:29.760 When Holtzman's group then tried the opposite, infusing an early Dora called almorexin into

00:31:35.880 their brains, interstitial fluid beta-amyloid levels went down.

00:31:41.200 Sustained treatments reduced plaque accumulation in several brain regions.

00:31:45.060 He got similar results with DeVigo in transgenic mice that bear a tau mutation that causes

00:31:51.460 neurodegenerative disease in humans. DeVigo prevented some changes in their tau protein

00:31:57.620 and, in male but not female mice, ameliorated brain atrophy. The researchers saw similar

00:32:04.860 protective effects when they seeded tau aggregates into the brains of wild-type mice.

00:32:11.360 Importantly, Ambien did not have these neuroprotective effects, indicating that simple

00:32:16.960 unconsciousness isn't doing this. It's specific to the mechanism of DORA's. Now, of course,

00:32:23.880 let's start with some caveats. First, few of these benefits were observed in the female mice,

00:32:29.800 which the investigators chalked up to their having less severe tau pathology in the first place.

00:32:35.500 Second, the investigators only performed limited cognitive testing, and the observed effects

00:32:41.820 were themselves quite modest. These animal results were supported by a small,

00:32:47.740 short-term human clinical trial in 2023. 38 cognitively unimpaired adults with good sleep,

00:32:56.100 aged 45 to 65, were randomly assigned to take 10 milligrams of balsamira, 20 milligrams of

00:33:03.940 Balsamra or a placebo for two nights in a row, starting at 11 p.m. Surprisingly, neither dose

00:33:10.000 of Balsamra had any effect on sleep parameters compared with placebo. However, 20 milligrams

00:33:15.680 of Balsamra, but not 10 milligrams, decreased CSF amyloid beta by roughly 20% starting about

00:33:23.720 five hours after administration, with a rebound during the day and a second reduction after the

00:33:30.500 next dose. It also lowered one form of pathological tau, though not p-tau-217, which is the most

00:33:38.360 sensitive and specific marker for Alzheimer's progression. Now, it's important to be very clear

00:33:43.800 about what this does and doesn't mean. These findings are intriguing and even hypothesis

00:33:48.700 generating, but they are early. Most of the compelling data are still in animals, and the

00:33:54.800 human studies are small and short-term. So while this is a signal worth watching closely,

00:34:00.480 it is not yet a reason to use these drugs for preventing neurodegenerative disease

00:34:05.260 outside of a research setting. But we should know a lot more about these effects soon.

00:34:12.260 Three new clinical trials, two of which include around 200 subjects apiece, are currently underway

00:34:19.360 and expect to be completed between this year and 2029. I will certainly be watching these closely.

00:34:26.900 The pharmacokinetics of the various Doras differ, which influences how long their effects persist

00:34:33.420 into the next day. Balsamra has a half-life of around 12 hours, De Vigo around 17 to 19 hours,

00:34:41.300 and Quivivic around 6 to 10 hours. Their relatively long half-lives mean they can cause

00:34:48.380 residual sedation and impaired performance in the morning, including while driving. This is

00:34:53.740 especially likely at higher doses in older adults or combined with other CNS depressants.

00:34:59.680 Several less common side effects of DORA's resemble type 1 narcolepsy,

00:35:03.740 a deficiency of orexin signaling that is often caused by the loss of orexigenic neurons.

00:35:11.300 Because DORA's blunt orexin signaling, their side effects can resemble a mild drug-induced

00:35:17.440 narcolepsy-like state, including excessive daytime sleepiness, sleep paralysis, hypnogotic

00:35:24.640 hallucinations, and in rare cases, daytime sleep attacks or sudden loss of muscle tone,

00:35:31.120 which can cause a standing conscious person to suddenly collapse onto the floor.

00:35:36.800 For this reason, package inserts and clinical guidelines caution against use in patients with narcolepsy and recommend careful counseling about the risk of abnormal sleep-related experiences and next-day impairment.

00:35:50.320 From a misuse standpoint, DORAs appear to have a lower abuse potential than benzodiazepines or Z-drugs, and controlled studies have generally found low scores on drug-liking instruments at therapeutic doses.

00:36:04.780 but they're still psychoactive agents that alter consciousness, so physiological misuse is always

00:36:10.800 possible. If you step back, Doras are attractive because they target wakefulness directly rather

00:36:16.940 than forcing sedation, and they tend to preserve the underlying structure of sleep. That doesn't

00:36:22.940 make them perfect, but it does make them fundamentally different. Okay, let's pivot to

00:36:28.440 a hormone-slash-supplement that everyone has heard of, melatonin. This is, of course, a hormone that

00:36:34.820 is released by the pineal gland in response to darkness. Thus, for most of evolutionary history,

00:36:40.460 it was a reliable and precise signal that the sun had gone down and circadian night had begun.

00:36:47.040 Artificial light at night, especially but not only blue-spectrum light from screens and LED

00:36:51.800 bulbs suppresses melatonin release. Melatonin produced by your pineal gland, melatonin

00:36:57.960 supplements, and drugs called melatonin receptor agonists act primarily on the suprachiasmatic

00:37:05.100 nucleus, the SCN, the brain's circadian center, and their main effect is to shift or reinforce

00:37:13.080 the circadian timing of sleep, not to directly sedate you. Specifically, melatonin promotes

00:37:20.160 sleepiness by both inhibiting wake-promoting orexin neurons and activating gabanergic neurons

00:37:27.280 in different regions, collectively reducing the arousal state and aligning the internal clock

00:37:33.440 with circadian-appropriate sleep timing. In other words, melatonin is not a sedative. It doesn't

00:37:39.560 knock you out by suppressing neuronal activity. It's a circadian signal. It prepares the brain

00:37:46.820 and body for sleep. Metaphorically, these agents are nighttime encapsulated. That's a meaningful

00:37:54.040 distinction. The best use case for these molecules is circadian realignment, jet lag, shift work,

00:38:01.680 adjusting to daylight savings time, night owls trying to adapt to an earlier schedule. They are

00:38:08.060 not primarily treatments for general insomnia. A dose response meta-analysis found the optimal

00:38:14.960 dose to shorten sleep latency is 4 milligrams. Of course, many people are taking way more than

00:38:20.220 that, often 5 and even 10 milligrams, which can actually disrupt circadian alignment rather than

00:38:25.740 support it. Timing also matters. One to three hours before bed appears to enhance its effects

00:38:32.340 and minimize morning sleep hangovers. This same meta-analysis also found that melatonin

00:38:39.420 is less effective at promoting sleep in people with insomnia compared to healthy volunteers.

00:38:46.200 Melatonin is regulated as a dietary supplement, not a drug, which means that product content

00:38:52.280 and purity are not rigorously controlled. Analyses of commercial preparations have found

00:38:58.200 that the actual melatonin content can range from minus 80% to plus almost 500% of what is stated

00:39:07.540 on the label, and some products may contain additional unlabeled substances. This is

00:39:14.000 especially a problem with gummies, in which melatonin is hard to distribute evenly and

00:39:19.700 can degrade more quickly, leading some companies to overcompensate by adding too much active

00:39:25.400 ingredient. Further complicating dosing, studies of melatonin supplements have reported bioavailabilities

00:39:31.900 ranging from 1% to 74%, which is in part due to inter-individual differences in metabolism

00:39:39.800 and in part due to other properties of the specific supplement, such as the dose,

00:39:45.100 the dosage form, or even the other compounds that are used as fillers in the supplement.

00:39:51.700 A strong point in favor of melatonin supplements is their safety profile compared to other classes

00:39:57.620 of sleep aids. However, taking excessive melatonin can cause hangover effects, residual daytime

00:40:03.840 sleepiness, or further disrupt circadian alignment instead of correcting it. Melatonin receptor

00:40:09.280 agonists are a distinct class of sleep aids that target the MT1 and MT2 melatonin receptors in the

00:40:15.220 SCN. They include Rameltion and others. Unlike melatonin supplements, prescription melatonin

00:40:22.680 receptor agonists are manufactured under quality control standards established as part of FDA

00:40:28.060 licensing, so the dose and pharmacokinetics are consistent and predictable. Ramaltion,

00:40:34.280 the first melatonin agonist, is usually taken about 30 minutes before bedtime. High-fat meals

00:40:40.440 can delay its absorption and therapeutic effect. Like melatonin itself, melatonin receptor agonists

00:40:46.140 are most useful in patients with circadian rhythm disorders rather than as direct sleep aids.

00:40:52.680 In these cases, they help advance the internal circadian clock, so sleep occurs earlier.

00:40:58.840 What initially appears to be insomnia improves because the circadian misalignment is corrected.

00:41:05.700 They are therefore not usually helpful for the scenario where someone falls asleep easily but wakes up repeatedly at 3 a.m.

00:41:13.740 The abuse and dependence potential of melatonin receptor agonists appears to be minimal.

00:41:18.740 There is no evidence that they cause physiologic withdrawal the way true sedatives can, although

00:41:25.120 long-term outcome data are more limited than for older sleeping medications.

00:41:30.020 Melatonin receptor agonists are generally well-tolerated with side effects such as headache,

00:41:35.600 mild next morning sleepiness, dizziness, and nausea, most of which are transient.

00:41:40.040 They're useful for circadian realignment and more benign for long-term use than classical

00:41:46.260 hypnotics, especially for older people or people at risk for dependence or for those who get too

00:41:52.120 much sleep hangover from other meds. The key point here is that melatonin is not a sleeping pill.

00:41:58.180 It's a timing signal. It works when the problem is timing. It does very little of use when the

00:42:05.240 problem is something else. This brings us to another favorite of mine for clinical use along

00:42:12.640 with Dora's, which is a drug called trazodone. Trazodone was originally developed as an

00:42:17.740 antidepressant, approved at doses of 300 milligrams for major depressive disorder.

00:42:23.580 But approximately half of the patients taking trazodone for depression develop excessive

00:42:28.280 daytime sleepiness, compared to 19% of those receiving a placebo. That side effect became

00:42:34.400 the drug's second career. It's now prescribed off-label at doses typically between 50 and 100

00:42:41.060 milligrams as a sleep aid far more often than it's prescribed for depression. It's popular

00:42:46.820 because it's inexpensive, it's not controlled, and it's quite safe. A 2022 meta-analysis confirmed

00:42:52.960 that it increases total sleep time and that it has a very favorable property that most sleep

00:42:58.940 medications don't. It increases slow-wave N3 sleep rather than suppressing it, with minimal effects

00:43:06.420 on other aspects of sleep architecture. This appears to come from trazodone's more precise

00:43:12.260 targeting of receptors involving wakefulness and sympathetic activity. It inhibits 5-HT2 receptors,

00:43:20.400 which are a subset of serotonin receptors, histamine H1 receptors, and alpha-1 adrenergic

00:43:26.640 receptors. Common side effects include morning grogginess, nasal congestion, dizziness,

00:43:32.340 and orthostatic hypotension, which is an important risk for falls. Rarer side effects include

00:43:39.080 priapism, which are erections that don't go down for several hours, and potential cardiac

00:43:44.920 arrhythmias. Next to Dora's, trazodone is one of the best options as a sleep medication,

00:43:51.720 especially for longer-term use, and it's less likely to cause a morning hangover. Trazodone

00:43:57.980 is interesting because unlike most sedatives, it tends to preserve or even increase deep sleep.

00:44:04.460 This makes it one of the most reasonable options for long-term use, assuming patients can tolerate

00:44:09.740 it. Well, this brings us to some of the most commonly used medications for sleep, which are

00:44:16.000 the first-generation antihistamines, such as Benadryl, NyQuil, and Unisom. Like trazodone,

00:44:23.980 they block central histamine H1 receptors, reducing histamine-mediated arousal and causing

00:44:30.780 drowsiness, which is why the PM formulations of pain relievers and many over-the-counter cold

00:44:36.940 remedies include them. Now, because they're not controlled substances and are easy to obtain

00:44:42.120 over-the-counter, they're widely used as sleep aids. But tolerance develops fast, often within

00:44:48.160 days to weeks, so the benefits erode quickly. And these drugs have significant anticholinergic

00:44:55.020 properties, meaning they inhibit signaling by the neurotransmitter acetylcholine, which is a key

00:45:01.220 signal in the autonomic nervous system. As a result, they can cause dry mouth, constipation,

00:45:07.420 urinary retention, blurred vision, and cognitive slowing.

00:45:11.240 They can also potentially worsen angle-closure glaucoma, also called narrow-angle glaucoma,

00:45:18.160 by causing the pupil to dilate, which may trigger an acute angle closure crisis.

00:45:23.720 Additionally, with long-term use, there's some observational data suggesting that

00:45:28.220 anticholinergic burden may increase the risk of dementia. This is a topic we'll probably cover

00:45:33.800 in the future. There's a real irony here. The cheapest, most accessible sleep aids

00:45:39.300 carry exactly the kind of long-term neurological risks that the modern DORAs may help prevent.

00:45:45.780 The bottom line is these have a role for very short-term use only.

00:45:51.660 Okay, let's talk about dietary supplements.

00:45:54.340 Now, we've already mentioned one briefly, which is melatonin, but there's actually a

00:45:58.780 number of other supplements that are talked about for sleep.

00:46:02.260 Before we get into specifics, let me say what I say every time we talk about supplements.

00:46:07.260 They are not regulated like drugs.

00:46:09.840 Companies don't have to prove their product does something, and while they aren't permitted

00:46:13.960 to say things that they prevent, treat, or cure, there's plenty of room for weasel wording to

00:46:19.980 suggest that they do almost anything a company wants to claim they do. And there's often an

00:46:25.380 enormous gap between what's on the label and what's in the bottle. There is an enormous variety

00:46:31.700 of supplements out there that are marketed for sleep, and we couldn't possibly review all of

00:46:37.960 them. So here I'm going to focus on the ones where some mixture of the popularity and the evidence

00:46:44.380 makes them rise to the top of our attention. Let's start with glycine. It's a non-essential

00:46:49.960 amino acid found in high concentrations in collagen. It also acts as an inhibitory

00:46:55.940 neurotransmitter in the central nervous system where it plays a role in shutting down motor

00:47:00.940 activity during REM sleep. The three human studies on glycine for sleep show modest benefits

00:47:07.820 on sleep. Their effect size is not large, but the safety profile is excellent and it's cheap.

00:47:14.140 Magnesium is one of the most popular supplements taken for sleep. Magnesium is required for

00:47:19.000 melatonin synthesis and gabanergic signaling, and circadian fluxes in intracellular magnesium

00:47:25.500 coordinate cyclical metabolic processes. So despite the fact that deficiencies and insufficiencies

00:47:32.560 are quite common for magnesium, the evidence for magnesium's use in sleep is frankly underwhelming

00:47:39.960 by comparison. There's a systematic review on the use of magnesium for sleep and a meta-analysis

00:47:46.300 specifically on magnesium for insomnia in older people, both of which are kind of lukewarm.

00:47:52.480 Three trials that were published after the cutoff dates of these two analyses and were therefore not

00:47:58.900 included, haven't changed the picture that much. If there is a real benefit of magnesium on sleep,

00:48:05.240 then mechanistically you would expect magnesium L3 and 8 to be the most likely to show it.

00:48:11.960 Mag 3 and 8 has better blood-brain barrier penetration in animal studies than other

00:48:17.200 forms of magnesium, and yet the one trial that directly tested the question found no effects

00:48:23.600 on sleep variables in adults aged 50 to 70 with cognitive impairment. If there's a real effect

00:48:30.160 somewhere in there, it might be beneficial in people who are actually deficient in magnesium,

00:48:34.840 as was hinted in the largest trial to date, which we'll link to in the show notes.

00:48:39.700 I take magnesium for other reasons, but I wouldn't hang my sleep strategy on it.

00:48:44.860 Ashwagandha is an herb used in traditional Indian medicine. It modestly lowers cortisol in several

00:48:50.540 human studies, which would tend to promote sleep and circadian rhythms if it occurred in the

00:48:56.300 evening, and animal studies suggest it modulates GABA signaling. A meta-analysis of five randomized

00:49:03.420 control trials in about 400 participants found a small but statistically significant positive

00:49:08.340 effect on sleep with stronger effects in people with diagnosed insomnia at doses of at least

00:49:14.060 600 milligrams per day and with a treatment duration of at least eight weeks. It's worth

00:49:19.600 pointing out that even amongst highly established supplement brands, ashwagandha supplements vary

00:49:26.160 widely in quality. Consumer lab testing found that only 5 of 13 tested ashwagandha supplements

00:49:34.080 contained the amount of standardized bioactive withanolides stated on the label. Also, there are

00:49:42.100 safety concerns around ashwagandha. Although few side effects have been reported in clinical trials,

00:49:47.440 case studies have reported severe GI side effects, allergic reactions, burning, itching,

00:49:53.100 and discoloration of the skin, worsening and new-onset hyperthyroidism, and numerous reports

00:49:59.360 of liver injury. None of these are from randomized trials, but the pattern is consistent enough that

00:50:05.140 I'd encourage monitoring thyroid and liver markers if you're going to use it regularly.

00:50:09.380 Phosphatidylserine, or PS, is reputed to lower levels of the stress hormone cortisol and ACTH.

00:50:18.960 Since cortisol plays a role in morning circadian signaling, PS is sometimes used as a sleep aid,

00:50:24.560 particularly when you're under stress or undergoing circadian disruption, including

00:50:29.740 as part of a jet lag protocol. However, the most positive evidence for this use comes from two

00:50:36.800 small trials using PS derived from bovine cortex, which is no longer available due to concern about

00:50:43.380 mad cow disease. Most recent trials used soy-based PS, which is what's in most of every supplement

00:50:50.280 you'll see of this on the market. And these trials have been largely negative, including

00:50:54.420 one trial that tested its effects on sleep. Despite limited formal data, I often recommend

00:51:01.060 phosphatidylserine as part of a jet lag protocol, as I've consistently seen it help patients

00:51:06.140 initiate sleep at times when they would otherwise be fully awake. Mechanistically, its likely role

00:51:12.360 is blunting HPA axis activity and lowering cortisol, which can reduce physiologic alert

00:51:18.540 signaling that resists sleep during circadian misalignment. In practice, I typically use 400

00:51:25.600 to 600 milligrams alongside melatonin when I need to force sleep at an otherwise inappropriate

00:51:32.580 biological time. For example, if I need to force sleep at 2 p.m. because it's 10 p.m. in my

00:51:39.400 destination time zone while I'm traveling. In the show notes, we'll discuss three more sleep

00:51:45.420 supplements that I didn't really have time to get into here. L-tryptophan for its long and

00:51:50.420 controversial history, tart cherry juice because it seems to be talked about non-stop on social

00:51:56.040 media, and Japanese sake yeast extract because of its intriguing mechanism of action. When

00:52:02.140 considering taking any supplement, remember that regardless of how good the evidence is for a

00:52:06.600 supplement, it doesn't matter if what's in the bottle isn't what's used in the trial. Supplement

00:52:11.980 companies don't have to demonstrate the reliable quality of their supplements before marketing them,

00:52:17.060 and there are many, many examples of dietary supplements not containing what they say

00:52:22.100 they contain on the label, or containing too much or too little bit, or containing

00:52:26.220 contaminants or banned drugs altogether. So for any supplement you take, quality control matters

00:52:32.200 as much as the underlying evidence. Look for USP verified or NSF certified for sport certifications

00:52:39.360 on products and check independent testing organizations like Consumer Lab and Labdoor

00:52:44.940 before buying. Okay, so how do we put this all together? Sleep problems are not a single entity.

00:52:51.960 They reflect breakdowns in one or more of those four systems we talked about, sleep pressure,

00:52:57.860 circadian timing, hyperarousal, and sleep architecture. Most of the time when people

00:53:03.280 continue to struggle with sleep, despite working on the problem, it's because they're targeting

00:53:08.320 the wrong mechanism. The foundation is always the same. Align your environment with your biology,

00:53:14.520 reduce hyperarousal, and restore confidence in sleep. Medications can help, but only when

00:53:20.360 they're used precisely and only when they're matched to the problem you're actually trying

00:53:24.680 to solve. If you skip this step, you're just guessing. And in sleep medicine, guessing is

00:53:30.500 where most problems begin. Thank you for listening to this week's episode of The Drive. Head over to

00:53:37.180 peteratiamd.com forward slash show notes if you want to dig deeper into this episode. You can also

00:53:44.860 find me on YouTube, Instagram, and Twitter, all with the handle Peter AtiyahMD. You can also leave

00:53:50.640 us review on Apple podcasts or whatever podcast player you use. This podcast is for general

00:53:56.900 informational purposes only and does not constitute the practice of medicine, nursing,

00:54:00.920 or other professional healthcare services, including the giving of medical advice.

00:54:05.600 No doctor patient relationship is formed. The use of this information and the materials linked to

00:54:11.260 this podcast is at the user's own risk. The content on this podcast is not intended to be

00:54:16.700 a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard

00:54:21.940 or delay in obtaining medical advice from any medical condition they have, and they should

00:54:26.200 seek the assistance of their healthcare professionals for any such conditions. Finally, I take all

00:54:32.140 conflicts of interest very seriously. For all of my disclosures and the companies I invest in

00:54:37.140 or advise, please visit peteratiamd.com forward slash about where I keep an up-to-date and active

00:54:44.220 list of all disclosures.

The Peter Attia Drive - June 01, 2026

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

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