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

Episode Date: June 1, 2026

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter In this episode, Peter dives into the pharmacology of sleep, exploring where sleep medications fit within the broader framework of achieving healthy, restorative sleep. He explains why sleep is a biological imperative, why behavioral and environmental interventions must remain the foundation of good sleep, and how medications can serve as useful tools when carefully matched to a person's specific sleep problem. Peter examines the major classes of prescription sleep medications, including how they work, their effects on sleep architecture, their duration of action, side effects, and risks of tolerance and dependence. He also discusses the dangers of using sleep drugs without a clear understanding of the underlying problem being treated, the role of medications as short-term bridges during periods of acute stress, pain, or anxiety, and the promise that newer drugs like DORAs may hold for Alzheimer's prevention in high-risk individuals. Finally, Peter reviews the evidence for select off-label medications and supplements commonly used for sleep. We discuss: The biological foundations of sleep, the major drivers of sleep dysfunction, and the role sleep medications can play when appropriately matched to specific sleep problems [1:00]; Sleep hygiene, circadian alignment, and the medical causes of insomnia: building the foundation for effective sleep treatment [7:15]; Understanding insomnia: hyperarousal, CBT-I, paradoxical insomnia, and why different sleep problems require different treatments [12:45]; The difference between sedation and physiologic sleep: sleep architecture, restorative sleep stages, and matching medications to specific sleep problems [17:00]; Benzodiazepines for insomnia: mechanisms, effects on sleep architecture, and the risks of long-term use [18:45]; Z-drugs for insomnia: how Ambien, Sonata, and Lunesta work, and the ongoing risks of sleep medications targeting GABA systems [23:00]; Dual orexin receptor antagonists (DORAs) and the future of sleep medicine: orexin signaling, sleep architecture, and the emerging connection between sleep and Alzheimer's disease [27:15]; Melatonin for circadian timing: how timing signals differ from sedatives in the treatment of sleep disorders [36:30]; Trazodone for insomnia: preserving deep sleep while minimizing the risks of traditional sedative-hypnotics [42:00]; First-generation antihistamines for sleep: short-term sedation, anticholinergic risks, and concerns about long-term cognitive health [44:00]; Sleep supplements and the evidence behind them: glycine, magnesium, ashwagandha, phosphatidylserine, and more [45:45]; Takeaways: supplement quality, individualized sleep treatment, and the importance of matching interventions to the biology of insomnia [52:00]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

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. 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 the subscription. If you want to learn more about the benefits of our premium membership, head over to peteratia-md.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 or CBTI, and even different sleep supplements. But we've never done anything more than sort of a skim of the surface on sleep

medications. And the intention of this episode is to fill that obviously very important void. 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. Almost every sleep issue can be traced back to one or more of four things. First, sleep pressure. That build up 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, hyper arousal, 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. 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. 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. 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. 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. 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, worsen 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. 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. 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. 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-restortive sleep, you may get more benefit from focusing on consolidating your sleep pressure. What sleep hygiene does not reliably fix is hyperarousal, which is my 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. 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. 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% of people with mood or anxiety disorders report having had severe insomnia in the previous year. 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. 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 disregulated for years. So while medications are not necessarily the foundation of good sleep, they can be valuable tools when used deliberately. Each class of sleep medications will 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 insulin. Now, before reaching for anything, you need to understand what kind of sleep problem you're up against. 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. 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. 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 significant.

more than that. 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 hyperarousal 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-restortive sleep, which is often inadequate slow wave generation. 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.

And 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 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. They 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 medications pharmacology to the patient's patient's specific sleep challenges. For 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, tamazepam, larazepam, 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. These 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 gabinergic signals, 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 N-3 sleep we talked about, and suppressing REM sleep. They'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 risk by causing dizziness, ataxia, and impaired balance, which

in older adults can be catastrophic. Co-administration with alcohol or opioids, which also enhance gabinergic signaling or depressed 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 antaragrate 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. Interagrate 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. The 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 hyperarousal 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. 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. Lunesta 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.

But 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 and teregrate 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. Z 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. In 2019, the FDA issued a black box warning about these behaviors, which can sometimes lead to injury. 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, duration and only with a plan for addressing underlying causes of insomnia and offering CBTI. Z 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 Dora's. We have three versions of these at the moment, Cuivic, Davigo, and Belsamra. Dora's are different in a way that I think really

matters. Most traditional sleep medications work by forcing sedation. They broadly suppress brain activity. But Dora's 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. Dora's 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 Dora's had superior tolerability compared to drugs for which there was a enough information to make a comparison. A second meta-analysis that was generally more cautious about sleep medications found that DeVigo specifically had the most favorable profile of any drug examined. One of the things we like about Dora's is that they consistently preserve or minimally alter sleep architecture with little or no effect on slow-wave sleep and even improvements in REM sleep.

So why does this matter? Well, here's the thing that gets me really interested, and I want to spend some time on this because I think it could matter a lot for how we think about these drugs in higher risk patients. During slow-wave sleep, the brain activates what's called the glymphatic system, essentially a specialized waste clearance mechanism. Neurons and their support cells shrink slightly during sleep, opening up about 60% more space between cells, which allows CSF to be in the system. to circulate more freely and exchange with the fluid immediately around brainstells, called the interstitial fluid. The mixed fluid travels along pathways surrounding the outside

of cerebral arteries and veins, heading out into the blood for disposal. In the process, the CSF carries away toxins, such as beta amyloid and abnormal forms of the protein tau that contribute to Alzheimer's disease and other neurodegenerative diseases of aging. Animal studies have shown that glymphatic clearance of beta emuloid roughly doubles during sleep, particularly during deep non-REM sleep, with similar increases in clearance of aberrant tau. Human studies show that a night of sleep deprivation impairs glymphatic clearance, as does targeted disruptions of slow-wave sleep. If that disruption becomes chronic, there appears to be long-term consequences. Sleep architecture impairment in older adults predicts the extent of beta amyloid and age-related aberrant tau burden in the future.

Conversely, patients with Alzheimer's disease and so-called mild cognitive impairment exhibit both non-REM and REM sleep disturbances. In fact, the progression of Alzheimer's disease includes selective degeneration of specific neurons in the brain stem and basal forebrain that regulate REM sleep. This suggests a vicious cycle in which poor sleep accelerates damaged beta amyloid and aberrant tau accumulation, and the accumulation of these damaged proteins further impairs sleep. Because orexin levels rise during the day and fall at night, in rough parallel with beta amyloid levels in the CSF, David Holtsman suspected that there might be a relationship between orexin and glymphatic clearance. So he and his colleagues, in fact, he and his colleagues, in fact,

fused orexin into the hippocampi of a mouse model of Alzheimer's. As expected, orexin increased the level of beta amyloid in the animal's interstitial fluid. When Holtzman's group then tried the opposite, infusing an early dora called almeorexent into their brains, interstitial fluid beta amyloid levels went down. Sustained treatments reduced plaque accumulation in several brain regions. He got similar results with DeVigo in transgenic muis. that bear a tau mutation that causes neurodegenerative disease in humans. De Vigo prevented some changes in their tau protein and in male but not female mice ameliorated brain atrophy. The researchers saw similar protective effects when they seeded tau aggregates into the brains of wild type mice.

Importantly, Ambien did not have these neuroprotective effects, indicating that simple unconsciousness isn't doing this. isn't doing this. It's specific to the mechanism of Dora's. Now, of course, let's start with some caveats. First, few of these benefits were observed in the female mice, which the investigators chocked up to their having less severe tau pathology in the first place. Second, the investigators only performed limited cognitive testing, and the observed effects were themselves quite modest. These animal results were supported by a small, short-term human clinical trial in 2023. 38 cognitively unimpaired adults with good sleep, aged 45 to 65, were randomly assigned to take 10 milligrams of balsamra, 20 milligrams of balsamra, or a placebo for two nights

in a row, starting at 11 p.m. Surprisingly, neither dose of balsamra had any effect on sleep parameters compared with placebo. However, 20 milligrams of balsamra, but not 10 milligrams, decreased CSF amyloid beta by roughly 20% starting about five hours after administration, with a rebound during the day and a second reduction after the next dose. It also lowered one form of pathological tau, though not ptow 217, which is the most sensitive and specific marker for Alzheimer's progression. Now, it's important to be very clear about what this does and doesn't mean. These findings are intriguing and even hypothesis generating, but they are early. Most of the compelling data are still in animals, and the human studies are small and short term. So while this

is a signal worth watching closely, it is not yet a reason to use these drugs for preventing neurodegenerative disease outside of a research setting. But we should know a lot more about these effects soon. Three new clinical trials, two of which include around 200 subjects apiece, are currently underway and expect to be completed between this year and 2029. I will certainly be watching these closely. The pharmacokinetics of the various Doras differ, which influences how long their effects persist into the next day. Balsamra has a half-life of around 12 hours, De Vigo, around 17 to 19 hours, and quivivic around 6 to 10 hours. Their relatively long half-lives mean they can cause residual sedation and impaired performance

in the morning, including while driving. This is especially likely at higher doses in older adults or combined with other CNS depressants. Several less common side effects of Duras resemble type 1 narcolepsy, a deficiency of erexin signaling that is often caused by the loss of orexogenic neurons. Because Dora's blunt orexin signaling, their side effects can resemble a mild drug-induced narcolepsy-like state, including excessive daytime sleepiness, sleep paralysis, hypnagogic hallucinations, and in rare cases, daytime sleep attacks or sudden loss of muscle tone, which can cause a standing, conscious person to suddenly collapse onto the floor. 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. From a misuse standpoint, Dora's 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. but they're still psychoactive agents that alter consciousness, so physiological misuse is always possible. If you step back, Dora's are attractive because they target wakefulness directly rather than forcing sedation, and they tend to preserve the underlying structure of sleep. That doesn't make them perfect, but it does make them fundamentally different. Okay, let's pivot to a hormone slash supplement that everyone is heard of.

Melatonin. This is of course a hormone that is released by the pineal gland in response to darkness. Thus, for most of evolutionary history, it was a reliable and precise signal that the sun had gone down and circadian night had begun. Artificial light at night, especially but not only blue spectrum light from screens and LED bulbs, suppresses melatonin release. Melatonin produced by your pineal gland, melatonin supplements, and drugs called melatonin receptor agonists act primarily on the superkismatic nucleus, the SCN, the brain's circadian center,

and their main effect is to shift or reinforce the circadian timing of sleep, not to directly sedate you. Specifically, melatonin promotes sleepiness by both inhibiting wake-promoting orexin neurons and activating gabinergic neurons in different regions, collectively reducing the arousal state and aligning the internal clock with circadian appropriate sleep timing. In other words, melatonin is not a sedative. It doesn't knock you out by suppressing neuronal activity. It's a circadian signal. It prepares the brain and body for sleep. Metaphorically, these agents are nighttime encapsulated. That's a meaningful distinction. The best use case for these molecules is circadian realignment. Jet lag, sheds,

shift work, adjusting to daylight savings time, night owls trying to adapt to an earlier schedule. They are not primarily treatments for general insomnia. A dose response meta-analysis found the optimal dose to shorten sleep latency is four milligrams. Of course, many people are taking way more than that, often five and even 10 milligrams, which can actually disrupt circadian alignment rather than support it. Timing also matters. One to three hours before bed appears to enhance its effects and minimize morning sleep hangovers. This same meta-analysis also found that melatonin is less effective at promoting sleep in people with insomnia compared to healthy volunteers. Melatonin is regulated as a dietary supplement, not a drug, which means that product content and purity are not

rigorously controlled. Analysis of commercial preparations have found that the actual melatonin content can range from minus 80% to plus almost 500% of what is stated on the label. And some products may contain additional unlabeled substances. This is especially a problem with gummies in which melatonin is hard to distribute evenly and can degrade more quickly, leading some companies to overcompensate by adding too much active ingredient. Further complicating dosing, studies of melatonin supplements have reported bioavailabilities ranging from 1% to 74%, which is in part due to inter-individual differences in metabolism and in part due to other properties of the specific supplement, such as the dose, the dosage form, or even the other compounds that are used

as fillers in the supplement. A strong point in favor of melatonin supplements is their safety profile compared to other classes of sleep aids. However, taking excessive melatonin can cause hangover effects, residual daytime sleepiness, or further disrupt circadian alignment instead of correcting it. Melatonin receptor agonists are a distinct class of sleep aids that target the MT1 and MT2 melatonin receptors in the SCN. They include Rameltyon and others.

Unlike melatonin supplements, prescription melatonin receptor agonists are manufactured under quality control standards established as part of FDA licensing, so the dose and pharmacokinetics are consistent and predictable. Rameltion, the first melatonin agonist, is usually taken about 30 minutes before bedtime. High fat meals can delay its absorption and therapeutic effect. Like melatonin itself, melatonin receptor agonists are most useful in patients with circadium, rhythm, disorders rather than as direct sleep aids. In these cases, they help advance the internal circadian clock, so sleep occurs earlier. What initially appears to be insomnia improves because the circadian misalignment is corrected. They are therefore not usually helpful for this scenario where someone

falls asleep easily, but wakes up repeatedly at 3 a.m. The abuse and dependence potential of melatonin receptor agonists appears to be minimal. There is no evidence that they cause physiologic withdrawal the way true sedatives can, although long-term outcome data are more limited than for older sleeping medications. Melatonin receptor agonists are generally well tolerated with side effects such as headache, mild next morning sleepiness, dizziness, and nausea, most of which are transient. They're useful for circadian realignment and more benign for long-term use. than classical hypnotics, especially for older people or people at risk for dependence, or for those who get too much sleep hangover from other meds.

The key point here is that melatonin is not a sleeping pill. It's a timing signal. It works when the problem is timing. It does very little of use when the problem is something else. This brings us to another favorite of mine for clinical use along with Dora's, which is a drug called Trasadone. Trasadone was originally developed as an antidepressant, approved at doses of 300 milligrams for major depressive disorder. But approximately half of the patients taking trazodone for depression develop excessive daytime sleepiness compared to 19% of those receiving a placebo. That side effect

became the drug's second career. It's now prescribed off-label at doses typically between 50 and 100 milligrams as a sleep aid far more often than it's prescribed for depression. It's popular because it's inexpensive, it's not controlled, and it's quite safe. A 22 meta-analysis confirmed that it increases total sleep time and that it has a very favorable property that most sleep medications don't. It increases slow wave n3 sleep rather than suppressing it with minimal effects on other aspects of sleep architecture. This appears to come from Trazodone's more precise targeting of receptors involving wakefulness and sympathetic activity. It inhibits 5H2 receptors, which are a subset of serotonin receptors, histamine H1 receptors, and alpha-1 adrenergic receptors. Common side effects include morning

groginess, nasal congestion, dizziness, and orthostatic hypotension, which is an important risk for falls. Rarer side effects include priapism, which are erections that don't go down for several hours, and potential cardiac arrhythmias. Next to Dora's, trazodone is one of the best options as a sleep medication, especially for longer-term use, and it's less likely to cause a morning hangover. Trazadone is interesting because unlike most sedatives, it tends to preserve or even increase deep sleep. This makes it one of the most reasonable options for long-term use, assuming patients can tolerate it. Well, this brings us to some of the most commonly used medications for sleep, which are the first

generation antihistamins, such as Benadryl, Nyquil, and Unisome. Like Trazodone, they block central histamine H-1 receptors, reducing histamine-mediated arousal and causing drowsiness, which is why the PM formulations of pain relievers and many over-the-counter cold remedies include them. Now, because they're not controlled substances and are easy to obtain over the counter, they're widely used as sleep aids, but tolerance develops fast, often within days to weeks, so the benefits erode quickly. And these drugs have significant anticholinergic properties, meaning they inhibit signaling by the neurotransmitter acetycholine,

which is a key signal in the autonomic nervous system. As a result, they can cause dry mouth, constipation, urinary retention, blurred vision, and cognitive slowing. They can also potentially worsen angle closure glaucoma, also called narrow angle glaucoma, by causing the pupil to dilate, which may trigger an acute angle closure crisis. Additionally, with long-term use, there's some observational data suggesting that anticholinergic burden may increase the risk of dementia. This is a topic we'll probably cover in the future. There's a real irony here. The cheapest, most accessible sleep aids carry exactly the kind of long-term neurological risks that the modern Dora's may help prevent. The bottom line is,

these have a role for very short-term use only. Okay, let's talk about dietary supplements. Now we've already mentioned one briefly, which is melatonin, but there's actually a number of other supplements that are talked about for sleep. Before we get into specifics, let me say what I say every time we talk about supplements. They are not regulated like drugs. Companies don't have to prove their product does something, and while they aren't permitted to say things that they prevent, treat, or cure, there's plenty of room for weasel wording to suggest that they do almost anything a company wants to claim they do. And there's often an enormous gap between what's on the label and what's in the bottle.

There is an enormous variety of supplements out there that are marketed for sleep, and we couldn't possibly review all of them. So here I'm going to focus on the ones where some mixture of the popularity and the evidence makes them rise to the top of our attention. Let's start with glycine. It's a non-essential amino acid found in high concentrations in collagen. It also acts as an inhibitory neurotransmitter, in the central nervous system where it plays a role in shutting down motor activity during REM sleep.

The three human studies on glycine for sleep show modest benefits on sleep. Their effect size is not large, but the safety profile is excellent and it's cheap. Magnesium is one of the most popular supplements taken for sleep. Magnesium is required for melatonin synthesis and gabinergic signaling, and circadian fluxes in intracellular magnesium coordinate cyclical metabolic processes. So despite the fact that deficiencies and insufficiencies are quite common for magnesium, the evidence for magnesium's use in sleep is frankly underwhelming by comparison. There's a systematic review on the use of magnesium for sleep and a meta-analysis, specifically on magnesium for insomnia and older people, both of which are kind of lukewarm.

warm. Three trials that were published after the cutoff dates of these two analyses and were therefore not included haven't changed the picture that much. If there is a real benefit of magnesium on sleep, then mechanistically you would expect magnesium L3 and 8 to be the most likely to show it. Mag 3 and 8 has better blood-brain-barrier penetration in animal studies than other forms of magnesium. And yet, the one trial that directly tested the question found no effects on sleep variables in adults aged 50 to 70 with cognitive impairment. If there's a real effect somewhere in there, it might be beneficial in people who are actually deficient in magnesium, as was hinted in the largest trial to date, which we'll link to

in the show notes. I take magnesium for other reasons, but I wouldn't hang my sleep strategy on it. Ashriganda is an herb used in traditional Indian medicine. It modestly lowers cortisol in several human studies, which would tend to promote sleep and circadian rhythms if it occurred in the evening. And animal studies suggest it modulates GABA signaling. A meta-analysis of five randomized control trials in about 400 participants found a small but statistically significant positive effect on sleep with stronger effects in people with diagnosed insomnia at doses of at least 600 milligrams per day, and with a treatment duration of at least eight weeks. weeks. It's worth pointing out that even amongst highly established supplement brands, ashriganda supplements vary widely in quality. Consumer lab testing found that only five of 13

tested asheraganda supplements contained the amount of standardized bioactive with analydes stated on the label. Also, there are safety concerns around aschwaganda. Although few side effects have been reported in clinical trials, case studies have reported severe GI side effects, allergic reactions, burning, itching, and discoloration of the skin, worsening and new onset hyperthyroidism, and numerous reports of liver injury. None of these are from randomized trials, but the pattern is consistent enough that I'd encourage monitoring thyroid and liver markers if you're going to use it regularly. Phosphotidyl serine, or PS, is reputed to lower levels of, and liver markers. I'd encourage levels of the stress hormone, cortisol, and ACTH.

Since cortisol plays a role in morning circadian signaling, PS is sometimes used as a sleep aid, particularly when you're under stress or undergoing circadian disruption, including as part of a jet lag protocol. However, the most positive evidence for this use comes from two small trials using PS derived from bovine cortex, which is no longer available due to concern about mad cow disease. Most recent trials used soy-based PS, which is what's in most of every supplement you'll see of this on the market. And these trials have been largely negative, including one trial that tested its effects on sleep. Despite limited formal data, I often recommend phosphatidilcureen as part of a jet lag protocol,

as I've consistently seen it help patients initiate sleep at times when they would otherwise be fully awake. Mechanistically, its likely role is blunting HPA access activity, and lowering cortisol, which can reduce physiologic alert signaling that resists sleep during circadian misalignment. In practice, I typically use 400 to 600 milligrams alongside melatonin when I need to force sleep at an otherwise inappropriate biological time. For example, if I need to force sleep at 2 p.m. because it's 10 p.m. in my destination time zone while I'm traveling. In the show notes, we'll discuss three more sleep supplements that I didn't really have time to get into here. L-tryptophan for its long and controversial history, tart cherry juice, because it seems to be talked about nonstop on social media,

and Japanese sake yeast extract because of its intriguing mechanism of action. When considering taking any supplement, remember that regardless of how good the evidence is for a supplement, it doesn't matter if what's in the bottle isn't what's used in the trial. Supplement companies don't have to demonstrate the reliable quality of their supplements before marketing them. And there are many, many examples of dietary supplements not containing what they say they contain on the label or containing too much or too little bit or containing contaminants or banned drugs altogether.

So for any supplement you take, quality control matters as much as the underlying evidence. Look for USP verified or NSF certified for sport certifications on products and check independent testing organizations like Consumer Lab and Labdor before buying. Okay, so how do we put this all together? Sleep problems are not a single entity. They reflect breakdowns in one or more of those four systems we talked about, sleep pressure, circadian timing, hyperarousal, and sleep architecture. Most of the time when people continue to struggle with sleep, despite working on the problem,

it's because they're targeting the wrong mechanism. The foundation is always the same. Align your environment with your biology, reduce hyperarousal, and restore confidence in sleep. Medications can help, but only when they're used precisely and only when they're matched to the problem you're actually trying to solve. If you skip this step, you're just guessing. And in sleep medicine, guessing is where most problems are. problems begin. Thank you for listening to this week's episode of The Drive. Head over to peter

atia md.com forward slash show notes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter, all with the handle Peter Atia MD. You can also leave us review on Apple Podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional health care services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice,

diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their health care professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peteratia-md.com forward slash about where I keep an up-to-date and active list of all disclosures.