#394 ‒ Sleep pharmacology： the role of medications in healthy sleep, the promise of emerging therapies, and the evidence for common sleep supplements
00:00:00.000Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Atiyah. This podcast,
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00:01:04.340Welcome to this episode of The Drive. In this episode, I focus on sleep pharmacology. Now,
00:01:10.540we've had plenty of previous episodes about sleep. We've talked about sleep biology,
00:01:14.720sleep hygiene, even cognitive behavioral therapy for insomnia, CBTI, and even different sleep
00:01:20.720supplements, but we've never done anything more than sort of a skim of the surface on sleep
00:01:26.780medications. And the intention of this episode is to fill that obviously very important void.
00:01:33.840Sleep is a biological imperative. A pioneer of modern sleep research first put the problem this
00:01:40.720way. If sleep does not serve an absolutely vital function, then it is the biggest mistake the
00:01:46.820evolutionary process has ever made. When you're asleep, you can't protect yourself from predators,
00:01:52.400you can't hunt, you can't find a mate, you are, as the phrase goes, dead to the world.
00:01:57.980But natural selection insisted that we do it anyway, every single night for our entire lives.
00:02:04.140That should tell you something. To make this practical, I want to give you a simple way to
00:02:08.660think about sleep problems, because most people, including most clinicians, don't diagnose them
00:02:13.740correctly. Almost every sleep issue can be traced back to one or more of four things. First, sleep
00:02:21.320pressure, that buildup of the drive to sleep the longer you're awake. Second, circadian timing,
00:02:28.760whether your internal clock is aligned with the light-dark cycle. Third, hyperarousal, a state
00:02:35.860where your brain is effectively holding the gas pedal down when you're trying to sleep.
00:02:40.840And fourth, sleep architecture, the quality and structure of the sleep you're actually getting.
00:02:46.760Every tool we're going to talk about, behavioral, psychological, or pharmacological, works by acting on one or more of these.
00:02:54.860And most failures happen when you apply a perfectly good tool to the wrong problem.
00:03:00.640Few organisms in their natural environment have trouble sleeping.
00:03:04.080So 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?
00:03:15.240Where more than half of adults report difficulty sleeping and over 22% actually meet diagnostic criteria for insomnia?
00:03:24.560The answer is that we've engineered an environment that disrupts all four of those systems at the same time.
00:03:31.180our sleep is regulated by two processes that were sculpted by over half a billion years of
00:03:37.220evolutionary experience. The first is the homeostatic process or process S, which is the
00:03:43.940accumulation of pressure to sleep. Sleep pressure builds as a result of brain activity, though the
00:03:50.380mechanism for this sleep pressure has not been identified. The longer you're awake, the more it
00:03:55.380builds until eventually it overwhelms you and you sleep. Think of it like a battery that discharges
00:04:01.440while you're awake and recharges during sleep. The second process is the circadian process or
00:04:07.920process C. This is your internal clock anchored to the light-dark cycle, coordinated by melatonin
00:04:14.980at night and cortisol in the morning. It's not just one clock, it's a central clock in the brain
00:04:20.820with hierarchical peripheral clocks governing individual cells and organs. We now spend almost
00:04:27.640all of our time indoors under light that's too dim during the day and too bright at night.
00:04:33.080We go to bed when our to-do list is finally exhausted, not when our body is biologically
00:04:38.160ready. We use caffeine to push through the afternoon, alcohol to wind down at night,
00:04:43.980and then wonder why we sleep like garbage. Jet lag, daylight savings time, and many prescription0.95
00:04:50.500drugs further disrupt the natural regulators of sleep. It's our systematic engineering away
00:04:56.760of these environmental cues that makes sleep a struggle for so many of us. Here's something
00:05:02.200that might surprise you. Our hunter-gatherer ancestors didn't sleep dramatically more than
00:05:06.980we do. The data suggest their total sleep time is roughly comparable to ours, and some have even
00:05:14.000more fragmented sleep. But they have extraordinarily strong circadian rhythms and report almost no
00:05:21.280difficulty sleeping. Some of their languages don't even have a word for insomnia. That's worth
00:05:27.120noting. One tool in our toolkit for getting our sleep back in order is sleep medications.
00:05:33.940I want to be direct about this. Medications are not the foundation of good sleep. The foundation
00:05:38.820is behavioral. It's aligning our lifestyles, environments, and mental attitudes with the
00:05:44.020cues our biology needs for good sleep. But sleep medications can be useful tools when used
00:05:51.040skillfully, matched to the specific problem, and ideally as a short-term bridge rather than a
00:05:57.380long-term crutch. For people dealing with acute crisis situations, chronic pain, or deeply rooted
00:06:03.680anxiety, they can often fill a gap that we can't meet through our own efforts. The key word is
00:06:09.800matched, because these drugs vary enormously in how they work, what they do to your sleep
00:06:15.260architecture, how long they last, and what their risks are. Reaching for a drug without understanding
00:06:21.540the problem you're treating is a recipe for tolerance, dependence, worse in sleep architecture,
00:06:26.780or the all-too-common scenario of needing more to get less.
00:06:31.560So, in this episode, we'll cover the bare-bones basics of sleep biology and how to support it,
00:06:38.120and then dig into all the major classes of sleep medications.
00:06:42.480We'll talk about how they work, what they do to and for your sleep,
00:06:46.980which ones work best for your problems, their side effects, and the risk of dependence.
00:06:52.860We'll spend extra time discussing the potential that Dora's, the newest class of sleep medications,
00:06:59.020might have for Alzheimer's prevention in high-risk patients. And we'll discuss some
00:07:04.140off-label medications and dietary supplements used for sleep, although that's not our focus.
00:07:09.340We have lots of content on such tools, and our focus here today will be on prescription
00:07:13.980medications, which we'll be discussing in detail for the first time. Good sleep is built through
00:07:19.720sleep hygiene, much of which involves adapting your behaviors to align with the homeostatic
00:07:25.440and circadian sleep processes I discussed a few moments ago. Align the circadian process
00:07:31.360through things like regular wake-up, meals, and bedtimes, getting sunlight as soon as you can
00:07:37.680after waking up, reducing light exposure and stressors in the hours before bed, and making
00:07:43.360the bedroom cool and dark. Enhancing the homeostatic process is done by cultivating and
00:07:50.060conserving your sleep pressure by getting higher intensity exercise performed earlier in the day
00:07:55.200or light exercise in the evening, and avoiding sleeping in, napping, or drinking coffee in the
00:08:01.400afternoon. Now, if you want to go into much more detail on this, you can check out our AMA with
00:08:08.160Matt Walker, or the four-part episode that we did with Matt Walker, both of which are going to be
00:08:13.800available in the show notes, and they provide a great discussion on sleep hygiene. If you're the
00:08:18.840person who has always found yourself fully awake and alert after everyone else has gone to bed,
00:08:24.660or conversely, if you're the person who has always woken up spontaneously well before the sun,
00:08:30.760but find yourself winding down or dozing off when the rest of your life is still calling on you to
00:08:36.420be awake, or if you're suffering from jet lag, or if you chronically stay up late or sleep in on
00:08:43.400your days off but then find your sleep is poor during the work week, you likely want to work on
00:08:49.000circadian alignment. On the other hand, if your problem seems unrelated to your schedule but you
00:08:55.340find yourself too sleepy during the day or too wakeful at bedtime, especially if you're taking
00:09:01.120naps or relying heavily on caffeine, or if you fall asleep quickly but have a lot of fragmented
00:09:08.560non-restorative sleep, you may get more benefit from focusing on consolidating your sleep
00:09:14.660pressure. What sleep hygiene does not reliably fix is hyperarousal, which is why so many people
00:09:22.100can do everything right and still lie awake at night. So once a patient's sleep hygiene is in
00:09:28.460order, but before we start thinking about specific sleep medications, we first want to rule out any
00:09:33.960medical causes of poor sleep. The big ones include restless leg syndrome, which is a maddening urge
00:09:40.240to move your legs at night when resting, maybe with crawling, tingling, or even aching sensations
00:09:46.100that you can temporarily relieve with movement. This frequently disrupts sleep onset and can cause
00:09:53.120daytime fatigue. It afflicts about 3% of the general population of adults worldwide, although
00:10:00.080a survey from the American Academy of Sleep Medicine found that as many as 13% of Americans
00:10:06.120report having been diagnosed with it. Another one to think about is obstructive sleep apnea.
00:10:12.000If you snore, gasp, or choke during your sleep, or if your partner says you stop breathing at night,
00:10:17.180then it's possible you have obstructive sleep apnea, especially if you're overweight or obese.
00:10:23.860Patients typically experience unrefreshing sleep, morning headaches, excessive daytime sleepiness,
00:10:29.320and difficulty concentrating, despite spending adequate time in bed. Because of the obesity
00:10:34.620epidemic, about a third of adults in the U.S. are likely to have obstructive sleep apnea,
00:10:40.280including just over 39% of males and 26% of females. About half of these cases are mild,
00:10:47.18030% are moderate, and nearly 20% are considered severe. Finally, mood disorders. Persistent
00:10:56.240depressive disorder can cause either difficulty falling asleep or excessive daytime sleepiness.
00:11:02.480Anxiety disorders can cause difficulty falling or staying asleep. Bipolar disorder can reduce
00:11:07.660sleep during hypomanic phases and increase it during depressive dips and is generally
00:11:12.860characterized by circadian disruption, which acts in a vicious cycle with the disease.
00:11:18.240About a third of U.S. adults in a given 12-month period suffer from anxiety and or mood disorders,
00:11:24.980and in turn, about 25 to 45 percent of people with mood or anxiety disorders report having had
00:11:32.940severe insomnia in the previous year, while it was 42 percent to 63 percent of those with comorbid
00:11:41.140mood and anxiety disorders. This is roughly twice the rate in people without mood or anxiety
00:11:47.900disorders. All of these have medical and lifestyle treatments, and addressing them can improve your
00:11:53.420sleep with multiple downstream benefits. But here's the reality. Even when a patient is working
00:11:58.760hard on all of these things, some people still struggle to get the sleep they need. They may be
00:12:04.560dealing with shift work, frequent travel, chronic stress, pain, illness, or a nervous system that's
00:12:10.340been dysregulated for years. So while medications are not necessarily the foundation of good sleep,
00:12:16.520they can be valuable tools when used deliberately. Each class of sleep medications we'll discuss
00:12:23.300acts on one or more of the four sleep mechanisms I described earlier. Some suppress the arousal
00:12:30.640that overrides the homeostatic drive, others reinforce the circadian timing signal, and some,
00:12:37.140the most promising, work by quietly reducing the brain's wakefulness drive rather than forcing
00:12:43.620sedation. Understanding which problem is disrupted in a given patient is what allows you to match the
00:12:50.100medication to the problem rather than reaching for a blunt instrument. Now, before reaching for
00:12:55.880anything, you need to understand what kind of sleep problem you're up against. The DSM-5 criteria
00:13:01.740for insomnia are sleep problems persisting more than three months, at least three nights a week,
00:13:08.760and, this part matters, causing distress. It's not just about how much you sleep,
00:13:15.240it's about the suffering component. Except in rare cases, people do not develop insomnia because of
00:13:21.260a broken sleep system. When it is not caused by other medical or environmental factors,
00:13:27.560insomnia is most often driven by hyperarousal.
00:14:23.260therapy for insomnia, CBTI, is the first-line treatment for insomnia. CBTI works on a different
00:14:30.760axis than most people expect. It doesn't just try to make you more tired. It targets hyperarousal.
00:14:37.040It reduces the cognitive and physiological activation that keeps the brain in a wakeful
00:14:42.500state, and it retrains the association between your bed and being awake. That's why it often
00:14:49.000works when sleep hygiene alone doesn't. We'll put a link in our show notes to the episode
00:14:54.700with Ashley Mason for a deep dive into the practice of CBTI. There's another concept here
00:15:00.340that's incredibly important and often missed, which is paradoxical insomnia, also called sleep
00:15:06.500state misperception. These are people who are convinced they've been awake all night. They've
00:15:13.160gotten two or three hours of sleep at most. But when you actually measure their sleep, they've
00:15:17.900gotten significantly more than that. You'll often see this clinically. Someone says they're awake
00:15:23.100all night, but they're functioning far better the next day than that would suggest. This matters
00:15:28.940because these patients are especially vulnerable to certain medications. Drugs that impair memory,
00:15:34.820like benzodiazepines or Z-drugs, can make it feel like sleep is improved simply because the person
00:15:40.800no longer remembers waking up, but the underlying sleep hasn't actually improved. Most sleep
00:15:47.660problems fall into four buckets, which actually correspond directly to the four mechanisms of
00:15:53.900insomnia. Trouble falling asleep, which is often a hyper arousal situation overriding homeostatic
00:16:00.120drive. Trouble staying asleep, and in my experience with my patients, this second bucket is far more
00:16:07.280common than the first. Early morning awakenings, which is often a circadian misalignment. Or
00:16:13.700fragmented non-restorative sleep, which is often inadequate slow wave generation. And this is where
00:16:20.920people get into trouble. They treat all of these as the same problem. But of course they're not.
00:16:27.140Trouble falling asleep, waking up in the middle of the night, waking up too early, and getting
00:16:32.500non-restorative sleep are often driven by completely different mechanisms. And a drug that
00:16:38.440helps one can make the other worse. Reaching for a drug at random without understanding the
00:16:43.480problem you're trying to solve or the property of the drugs often leads to tolerance, dependence,
00:16:49.640worsening sleep architecture, or a cycle of needing more to get less benefit. This is why
00:16:55.200working with a clinician who understands sleep matters. And part of that understanding actually
00:17:00.960comes down to understanding the difference between sedation and physiologic sleep. See,
00:17:06.620here's something I think most people don't appreciate, and it should inform how you think
00:17:11.000about every sleep medication. Sleep is not just a loss of consciousness. It's an orchestrated
00:17:17.620biological process cycling through four stages, light non-REM, deeper non-REM, deep non-REM,
00:17:27.340also called N3 or slow wave sleep, and REM sleep. Each stage does something specific. Slow wave
00:17:35.840sleep handles physical restoration, declarative memory consolidation, and, this is a big one,
00:17:42.720waste clearance from the brain, a critical housekeeping function with implications we're
00:17:47.800only beginning to understand for long-term neurologic health. REM handles emotional
00:17:53.080processing and procedural memory. Most of the commonly used sleep medications don't deliver
00:17:59.540this. They create unconsciousness. They flatten the architecture rather than supporting it.
00:18:05.840That's not a small distinction. As I think we joked on a previous podcast on this topic,
00:18:12.160if someone came up to me and hit me over the head with a baseball bat and left me unconscious on
00:18:16.980the sidewalk, nobody would assume I was simply sleeping. The agents we're more comfortable with
00:18:23.900tend to support the body's own sleep mechanisms rather than overriding them. Different drugs vary
00:18:30.820in how quickly they work, how long they last, and which sleep problems they target. So we need to
00:18:37.820match the medication's pharmacology to the patient's specific sleep challenges. For example,
00:18:43.620short-acting agents are better for sleep-onset insomnia, while longer-acting agents are better
00:18:49.200for frequent nighttime awakenings. Let's start with benzodiazepines, temazepam, lorazepam,
00:18:56.380alprazolam, diazepam, clonazepam, and others. They also go by brand names you've probably
00:19:02.960heard of like Xanax, Ativan, and Valium. These are some of the oldest sedative hypnotics.
00:19:10.000They work by dampening excitatory neurotransmitter systems, pressing the brakes on the hyperarousal
00:19:16.480that modern life promotes and that drive insomnia. Specifically, benzodiazepines enhance
00:19:22.060signaling through GABA, the brain's main inhibitory neurotransmitter. These drugs are
00:19:27.880particularly active in the cortex and thalamus, where GABA-A receptors are especially abundant.
00:19:33.720The thalamus serves as a sensory gate between the outside world and the cortex, where gabanergic
00:19:39.980signaling is increased in the thalamus, the gate closes more tightly, so fewer signals reach the
00:19:46.260cortex, and conscious perception fades, producing sedation. Different benzodiazepines vary in
00:19:53.520receptor subtype affinity, onset, and half-life, which leads to some being more sedating and others
00:20:00.400being more anxiolytic, or muscle-relaxing in practice. Benzodiazepines reduce sleep latency,
00:20:07.400the time it takes to fall asleep, and may increase total sleep time, but they significantly alter
00:20:13.920sleep architecture, often decreasing slow-wave sleep, which is that deep N3 sleep we talked about,
00:20:21.620and suppressing REM sleep. They're also powerful anxiolytics, so they can quickly quiet ruminative
00:20:28.600thoughts and muscle tensions in patients whose insomnia is driven by anxiety. But the trade-offs
00:20:34.880are significant. In addition to the disruption of sleep architecture, they carry real risks of
00:20:41.000physiologic dependence, and withdrawal, including rebound insomnia, anxiety, and even in severe cases,
00:20:48.160seizures. They also increase fall risk by causing dizziness, ataxia, and impaired balance, which in
00:20:55.020older adults can be catastrophic. Co-administration with alcohol or opioids, which also enhance
00:21:01.680gabanergic signaling or depress respiratory centers, markedly increases the risk of respiratory
00:21:07.640depression and death, particularly in people with undiagnosed or untreated obstructive sleep apnea.
00:21:14.180And there's meaningful signal on cognitive impairment with long-term use, psychomotor
00:21:19.000speed, executive function, memory, processing speed, though the full magnitude and reversibility
00:21:25.100are still debated. They can also trigger complex sleep-related behaviors such as sleepwalking
00:21:31.340and sleep-related eating, and cause anterograde amnesia, that is, the inability to form new
00:21:38.820memories while under the influence, such that patients perform behaviors with little or no
00:21:44.260subsequent memory, similar to alcohol-related blackouts. Anterograde amnesia is both a feature
00:21:50.680and bug of benzos. As I mentioned earlier, these drugs cause you to forget nocturnal awakenings,
00:21:57.080so patients feel like they slept solidly when objective measures show fragmented sleep.
00:22:03.420The subjective impression of benefit exceeds the physiological reality. And as you'd expect,
00:22:09.440this effect is especially powerful in people with paradoxical insomnia. It's an effect that
00:22:15.100can essentially trap people in the use of a medication that's not doing what they think
00:22:20.640it's doing. With the growing understanding of the risks of benzodiazepines, especially in older
00:22:26.460adults and those with comorbidities, prescribing practices have shifted towards more cautious
00:22:31.620short-term and lower dose uses for insomnia. The labels say two to four weeks of use.
00:22:38.800Meta-analyses show the average duration is nearly a decade. The way to think about benzodiazepines
00:22:45.400is this. They are very effective at shutting down hyperarousal in the short term, but they do it at
00:22:51.860the cost of sleep quality, dependence risk, and cognitive side effects. They solve the immediate
00:22:58.040problem, but they often create a bigger one if used chronically. The concerns around benzos drove
00:23:05.340the development of a second generation of non-benzodiazepine hypnotics, also referred to
00:23:11.960as Z-drugs. These include Ambien, Sonata, and Lunesta. Z-drugs account for over 40% of all
00:23:20.540sleep medication prescriptions in the U.S., with Ambien accounting for nearly 90% of that.
00:23:26.620Despite not being structurally related to benzos, Z-drugs also act on GABA-A receptors. As a result,
00:23:33.980Z-drugs are more targeted for sleep promotion and have less prominent anxiolytic and muscle
00:23:39.400relaxing effects than classic benzodiazepines. Z-drugs reduce sleep latency and modestly increase
00:23:45.960sleep time. Z-drugs vary in their pharmacokinetics, which affects the side effect profile and the type
00:23:52.540of sleep problems for which they're best suited. Lunesta has the longest half-life, six hours,
00:23:58.480making it suitable for both sleep onset and sleep maintenance. Ambien's intermediate release version
00:24:05.180is better suited to sleep onset insomnia, while Sonata, with its very short half-life of about an
00:24:12.600hour can even be used in the middle of the night if you wake up and have enough time left before
00:24:17.780morning. However, greater receptor selectivity doesn't solve the fundamental issue that we had
00:24:23.920with benzodiazepines. It is often said that Z-drugs have less impact on sleep architecture
00:24:30.360than do the classic benzodiazepines, with smaller effects on slow-wave sleep and REM than traditional
00:24:37.260benzos. But I want to push back on the rosy picture here. A lot of the favorable sleep
00:24:42.940architecture comes from animal studies and has been contested based on human evidence.
00:24:48.720Moreover, chronic use of Z-drugs at higher doses is associated with more pronounced disruptions in
00:24:55.140sleep architecture. And crucially, Z-drugs induce enterograde amnesia. Z-drugs are also perceived
00:25:02.980to be less prone to lead to abuse and dependence than benzodiazepines, although increasing
00:25:08.980evidence suggests that this is untrue or exaggerated. In the show notes, we're going
00:25:13.860to link to a number of publications to support this position. Z-drugs also impair physical and
00:25:20.720cognitive performance, with detrimental effects on motor function, balance, attention, processing
00:25:26.300speed and memory. Additionally, Z-drugs still carry risks of complex sleep behaviors that the
00:25:33.400user does not remember the day following, such as sleepwalking and eating, shopping, driving,
00:25:39.940making phone calls, and having sex while unconscious or while in a conscious state
00:25:45.040but strangely dissociated. These effects are most likely to happen at higher doses
00:25:51.620in older adults or when combined with alcohol or other sedatives. Importantly, more than half of
00:25:58.660users of sleeping medications use at least one other sedating medication, and 10% take three
00:26:05.540or more other sedating medications. In 2019, the FDA issued a black box warning about these
00:26:13.220behaviors, which can sometimes lead to injury. These cases included accidental overdose, falls,
00:26:19.900burns, near-drowning, exposure to extreme cold temperatures leading to loss of limb,
00:26:25.920carbon monoxide poisoning, drowning, hypothermia, motor vehicle collision with the patient driving,
00:26:32.880and self-injuries such as gunshot wounds and apparent suicide attempts. Z-drugs do have some
00:26:39.420use, especially for dealing with acute disruptions to a person's sleep and where we suspect paradoxical
00:26:46.140insomnia. For these reasons, we use Z-drugs at the lowest effective dose for the shortest
00:26:52.560possible duration, and only with a plan for addressing underlying causes of insomnia and
00:26:57.920offering CBTI. Z-drugs were designed to be a cleaner version of benzodiazepines,
00:27:03.920but in practice, many of the same issues remain, just slightly attenuated. They can help with
00:27:10.540sleep onset in the short term, but they still carry risks around memory, behavior, and dependence.
00:27:16.140This brings us to the next category of sleep medications, which are the newest and arguably
00:27:22.680most exciting. They're called dual orexin receptor antagonists, or DORAs. We have three versions of
00:27:29.820these at the moment, Cuvivic, DeVigo, and Balsamra. DORAs are different in a way that I think really
00:27:37.740matters. Most traditional sleep medications work by forcing sedation. They broadly suppress brain
00:27:45.160activity. But DORAs don't do that. They work by dialing down one of the brain's primary wakefulness
00:27:51.340systems, specifically the orexin system. And in doing so, they allow your natural sleep processes
00:27:57.960to take over. That distinction between forcing sleep and allowing sleep is not just semantic.
00:28:05.100It shows up in the outcomes. DORAs outperformed other drugs on sleep efficiency, which is the
00:28:11.620amount of time you're sleeping relative to how much time you're in bed, and total sleep time.
00:28:17.040And DORA's had superior tolerability compared to drugs for which there was enough information to
00:28:22.860make a comparison. A second meta-analysis that was generally more cautious about sleep medications
00:28:28.780found that DeVigo specifically had the most favorable profile of any drug examined.
00:28:35.000One of the things we like about DORA's is that they consistently preserve or minimally alter
00:28:40.280sleep architecture with little or no effect on slow-wave sleep and even improvements in REM
00:28:46.380sleep. So why does this matter? Well, here's the thing that gets me really interested, and I want
00:28:53.580to spend some time on this because I think it could matter a lot for how we think about these
00:28:58.340drugs in higher-risk patients. During slow-wave sleep, the brain activates what's called the
00:29:05.280glymphatic system, essentially a specialized waste clearance mechanism. Neurons and their support
00:29:11.660cells shrink slightly during sleep, opening up about 60% more space between cells, which allows
00:29:18.960CSF to circulate more freely in exchange with the fluid immediately around brain cells, called the
00:29:24.980interstitial fluid. The mixed fluid travels along pathways surrounding the outside of cerebral
00:29:31.580arteries and veins, heading out into the blood for disposal. In the process, the CSF carries
00:29:37.880away toxins such as beta amyloid and abnormal forms of the protein tau that contribute to
00:29:43.560Alzheimer's disease and other neurodegenerative diseases of aging. Animal studies have shown
00:29:49.260that glymphatic clearance of beta amyloid roughly doubles during sleep, particularly during deep
00:29:56.280non-REM sleep, with similar increases in clearance of aberrant tau. Human studies show that a night
00:30:04.780of sleep deprivation impairs glymphatic clearance, as does targeted disruptions of slow-wave sleep.
00:30:13.020If that disruption becomes chronic, there appears to be long-term consequences. Sleep architecture
00:30:18.560impairment in older adults predicts the extent of beta amyloid and age-related aberrant tau
00:30:25.100burden in the future. Conversely, patients with Alzheimer's disease and so-called mild cognitive
00:30:31.660impairment exhibit both non-REM and REM sleep disturbances. In fact, the progression of
00:30:39.120Alzheimer's disease includes selective degeneration of specific neurons in the brainstem
00:30:44.560and basal forebrain that regulate REM sleep. This suggests a vicious cycle in which poor sleep
00:30:51.660accelerates damaged beta amyloid and aberrant tau accumulation, and the accumulation of these
00:30:58.400damaged proteins further impairs sleep. Because orexin levels rise during the day and fall at
00:31:05.260night, in rough parallel with beta amyloid levels in the CSF, David Holtzman suspected that there
00:31:13.180might be a relationship between orexin and glymphatic clearance. So he and his colleagues
00:31:18.140infused orexin into the hippocampi of a mouse model of Alzheimer's.
00:31:23.700As expected, orexin increased the level of beta-amyloid in the animal's interstitial fluid.
00:31:29.760When Holtzman's group then tried the opposite, infusing an early Dora called almorexin into
00:31:35.880their brains, interstitial fluid beta-amyloid levels went down.
00:31:41.200Sustained treatments reduced plaque accumulation in several brain regions.
00:31:45.060He got similar results with DeVigo in transgenic mice that bear a tau mutation that causes
00:31:51.460neurodegenerative disease in humans. DeVigo prevented some changes in their tau protein
00:31:57.620and, in male but not female mice, ameliorated brain atrophy. The researchers saw similar
00:32:04.860protective effects when they seeded tau aggregates into the brains of wild-type mice.
00:32:11.360Importantly, Ambien did not have these neuroprotective effects, indicating that simple
00:32:16.960unconsciousness isn't doing this. It's specific to the mechanism of DORA's. Now, of course,
00:32:23.880let's start with some caveats. First, few of these benefits were observed in the female mice,
00:32:29.800which the investigators chalked up to their having less severe tau pathology in the first place.
00:32:35.500Second, the investigators only performed limited cognitive testing, and the observed effects
00:32:41.820were themselves quite modest. These animal results were supported by a small,
00:32:47.740short-term human clinical trial in 2023. 38 cognitively unimpaired adults with good sleep,
00:32:56.100aged 45 to 65, were randomly assigned to take 10 milligrams of balsamira, 20 milligrams of
00:33:03.940Balsamra or a placebo for two nights in a row, starting at 11 p.m. Surprisingly, neither dose
00:33:10.000of Balsamra had any effect on sleep parameters compared with placebo. However, 20 milligrams
00:33:15.680of Balsamra, but not 10 milligrams, decreased CSF amyloid beta by roughly 20% starting about
00:33:23.720five hours after administration, with a rebound during the day and a second reduction after the
00:33:30.500next dose. It also lowered one form of pathological tau, though not p-tau-217, which is the most
00:33:38.360sensitive and specific marker for Alzheimer's progression. Now, it's important to be very clear
00:33:43.800about what this does and doesn't mean. These findings are intriguing and even hypothesis
00:33:48.700generating, but they are early. Most of the compelling data are still in animals, and the
00:33:54.800human studies are small and short-term. So while this is a signal worth watching closely,
00:34:00.480it is not yet a reason to use these drugs for preventing neurodegenerative disease
00:34:05.260outside of a research setting. But we should know a lot more about these effects soon.
00:34:12.260Three new clinical trials, two of which include around 200 subjects apiece, are currently underway
00:34:19.360and expect to be completed between this year and 2029. I will certainly be watching these closely.
00:34:26.900The pharmacokinetics of the various Doras differ, which influences how long their effects persist
00:34:33.420into the next day. Balsamra has a half-life of around 12 hours, De Vigo around 17 to 19 hours,
00:34:41.300and Quivivic around 6 to 10 hours. Their relatively long half-lives mean they can cause
00:34:48.380residual sedation and impaired performance in the morning, including while driving. This is
00:34:53.740especially likely at higher doses in older adults or combined with other CNS depressants.
00:34:59.680Several less common side effects of DORA's resemble type 1 narcolepsy,
00:35:03.740a deficiency of orexin signaling that is often caused by the loss of orexigenic neurons.
00:35:11.300Because DORA's blunt orexin signaling, their side effects can resemble a mild drug-induced
00:35:17.440narcolepsy-like state, including excessive daytime sleepiness, sleep paralysis, hypnogotic
00:35:24.640hallucinations, and in rare cases, daytime sleep attacks or sudden loss of muscle tone,
00:35:31.120which can cause a standing conscious person to suddenly collapse onto the floor.
00:35:36.800For 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.
00:35:50.320From 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.
00:36:04.780but they're still psychoactive agents that alter consciousness, so physiological misuse is always
00:36:10.800possible. If you step back, Doras are attractive because they target wakefulness directly rather
00:36:16.940than forcing sedation, and they tend to preserve the underlying structure of sleep. That doesn't
00:36:22.940make them perfect, but it does make them fundamentally different. Okay, let's pivot to
00:36:28.440a hormone-slash-supplement that everyone has heard of, melatonin. This is, of course, a hormone that
00:36:34.820is released by the pineal gland in response to darkness. Thus, for most of evolutionary history,
00:36:40.460it was a reliable and precise signal that the sun had gone down and circadian night had begun.
00:36:47.040Artificial light at night, especially but not only blue-spectrum light from screens and LED
00:36:51.800bulbs suppresses melatonin release. Melatonin produced by your pineal gland, melatonin
00:36:57.960supplements, and drugs called melatonin receptor agonists act primarily on the suprachiasmatic
00:37:05.100nucleus, the SCN, the brain's circadian center, and their main effect is to shift or reinforce
00:37:13.080the circadian timing of sleep, not to directly sedate you. Specifically, melatonin promotes
00:37:20.160sleepiness by both inhibiting wake-promoting orexin neurons and activating gabanergic neurons
00:37:27.280in different regions, collectively reducing the arousal state and aligning the internal clock
00:37:33.440with circadian-appropriate sleep timing. In other words, melatonin is not a sedative. It doesn't
00:37:39.560knock you out by suppressing neuronal activity. It's a circadian signal. It prepares the brain
00:37:46.820and body for sleep. Metaphorically, these agents are nighttime encapsulated. That's a meaningful
00:37:54.040distinction. The best use case for these molecules is circadian realignment, jet lag, shift work,
00:38:01.680adjusting to daylight savings time, night owls trying to adapt to an earlier schedule. They are
00:38:08.060not primarily treatments for general insomnia. A dose response meta-analysis found the optimal
00:38:14.960dose to shorten sleep latency is 4 milligrams. Of course, many people are taking way more than
00:38:20.220that, often 5 and even 10 milligrams, which can actually disrupt circadian alignment rather than
00:38:25.740support it. Timing also matters. One to three hours before bed appears to enhance its effects
00:38:32.340and minimize morning sleep hangovers. This same meta-analysis also found that melatonin
00:38:39.420is less effective at promoting sleep in people with insomnia compared to healthy volunteers.
00:38:46.200Melatonin is regulated as a dietary supplement, not a drug, which means that product content
00:38:52.280and purity are not rigorously controlled. Analyses of commercial preparations have found
00:38:58.200that the actual melatonin content can range from minus 80% to plus almost 500% of what is stated
00:39:07.540on the label, and some products may contain additional unlabeled substances. This is
00:39:14.000especially a problem with gummies, in which melatonin is hard to distribute evenly and
00:39:19.700can degrade more quickly, leading some companies to overcompensate by adding too much active
00:39:25.400ingredient. Further complicating dosing, studies of melatonin supplements have reported bioavailabilities
00:39:31.900ranging from 1% to 74%, which is in part due to inter-individual differences in metabolism
00:39:39.800and in part due to other properties of the specific supplement, such as the dose,
00:39:45.100the dosage form, or even the other compounds that are used as fillers in the supplement.
00:39:51.700A strong point in favor of melatonin supplements is their safety profile compared to other classes
00:39:57.620of sleep aids. However, taking excessive melatonin can cause hangover effects, residual daytime
00:40:03.840sleepiness, or further disrupt circadian alignment instead of correcting it. Melatonin receptor
00:40:09.280agonists are a distinct class of sleep aids that target the MT1 and MT2 melatonin receptors in the
00:40:15.220SCN. They include Rameltion and others. Unlike melatonin supplements, prescription melatonin
00:40:22.680receptor agonists are manufactured under quality control standards established as part of FDA
00:40:28.060licensing, so the dose and pharmacokinetics are consistent and predictable. Ramaltion,
00:40:34.280the first melatonin agonist, is usually taken about 30 minutes before bedtime. High-fat meals
00:40:40.440can delay its absorption and therapeutic effect. Like melatonin itself, melatonin receptor agonists
00:40:46.140are most useful in patients with circadian rhythm disorders rather than as direct sleep aids.
00:40:52.680In these cases, they help advance the internal circadian clock, so sleep occurs earlier.
00:40:58.840What initially appears to be insomnia improves because the circadian misalignment is corrected.
00:41:05.700They are therefore not usually helpful for the scenario where someone falls asleep easily but wakes up repeatedly at 3 a.m.
00:41:13.740The abuse and dependence potential of melatonin receptor agonists appears to be minimal.
00:41:18.740There is no evidence that they cause physiologic withdrawal the way true sedatives can, although
00:41:25.120long-term outcome data are more limited than for older sleeping medications.
00:41:30.020Melatonin receptor agonists are generally well-tolerated with side effects such as headache,
00:41:35.600mild next morning sleepiness, dizziness, and nausea, most of which are transient.
00:41:40.040They're useful for circadian realignment and more benign for long-term use than classical
00:41:46.260hypnotics, especially for older people or people at risk for dependence or for those who get too
00:41:52.120much sleep hangover from other meds. The key point here is that melatonin is not a sleeping pill.
00:41:58.180It's a timing signal. It works when the problem is timing. It does very little of use when the
00:42:05.240problem is something else. This brings us to another favorite of mine for clinical use along
00:42:12.640with Dora's, which is a drug called trazodone. Trazodone was originally developed as an
00:42:17.740antidepressant, approved at doses of 300 milligrams for major depressive disorder.
00:42:23.580But approximately half of the patients taking trazodone for depression develop excessive
00:42:28.280daytime sleepiness, compared to 19% of those receiving a placebo. That side effect became
00:42:34.400the drug's second career. It's now prescribed off-label at doses typically between 50 and 100
00:42:41.060milligrams as a sleep aid far more often than it's prescribed for depression. It's popular
00:42:46.820because it's inexpensive, it's not controlled, and it's quite safe. A 2022 meta-analysis confirmed
00:42:52.960that it increases total sleep time and that it has a very favorable property that most sleep
00:42:58.940medications don't. It increases slow-wave N3 sleep rather than suppressing it, with minimal effects
00:43:06.420on other aspects of sleep architecture. This appears to come from trazodone's more precise
00:43:12.260targeting of receptors involving wakefulness and sympathetic activity. It inhibits 5-HT2 receptors,
00:43:20.400which are a subset of serotonin receptors, histamine H1 receptors, and alpha-1 adrenergic
00:43:26.640receptors. Common side effects include morning grogginess, nasal congestion, dizziness,
00:43:32.340and orthostatic hypotension, which is an important risk for falls. Rarer side effects include
00:43:39.080priapism, which are erections that don't go down for several hours, and potential cardiac
00:43:44.920arrhythmias. Next to Dora's, trazodone is one of the best options as a sleep medication,
00:43:51.720especially for longer-term use, and it's less likely to cause a morning hangover. Trazodone
00:43:57.980is interesting because unlike most sedatives, it tends to preserve or even increase deep sleep.
00:44:04.460This makes it one of the most reasonable options for long-term use, assuming patients can tolerate
00:44:09.740it. Well, this brings us to some of the most commonly used medications for sleep, which are
00:44:16.000the first-generation antihistamines, such as Benadryl, NyQuil, and Unisom. Like trazodone,
00:44:23.980they block central histamine H1 receptors, reducing histamine-mediated arousal and causing
00:44:30.780drowsiness, which is why the PM formulations of pain relievers and many over-the-counter cold
00:44:36.940remedies include them. Now, because they're not controlled substances and are easy to obtain
00:44:42.120over-the-counter, they're widely used as sleep aids. But tolerance develops fast, often within
00:44:48.160days to weeks, so the benefits erode quickly. And these drugs have significant anticholinergic
00:44:55.020properties, meaning they inhibit signaling by the neurotransmitter acetylcholine, which is a key
00:45:01.220signal in the autonomic nervous system. As a result, they can cause dry mouth, constipation,
00:45:07.420urinary retention, blurred vision, and cognitive slowing.
00:45:11.240They can also potentially worsen angle-closure glaucoma, also called narrow-angle glaucoma,
00:45:18.160by causing the pupil to dilate, which may trigger an acute angle closure crisis.
00:45:23.720Additionally, with long-term use, there's some observational data suggesting that
00:45:28.220anticholinergic burden may increase the risk of dementia. This is a topic we'll probably cover
00:45:33.800in the future. There's a real irony here. The cheapest, most accessible sleep aids
00:45:39.300carry exactly the kind of long-term neurological risks that the modern DORAs may help prevent.
00:45:45.780The bottom line is these have a role for very short-term use only.
00:45:51.660Okay, let's talk about dietary supplements.
00:45:54.340Now, we've already mentioned one briefly, which is melatonin, but there's actually a
00:45:58.780number of other supplements that are talked about for sleep.
00:46:02.260Before we get into specifics, let me say what I say every time we talk about supplements.