Dietary Supplements for Sleep

Hey everyone, welcome to the Drive podcast. I'm your host, Peter Aa 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 meembers get back much more than the price of a subscription If you want to learn more about the benefits of our premium membership, head over to PeterataMd d. 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 aoid 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 build upp 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 thirty six percent 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 twenty two percent 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 notot 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 aligning our lifestyles, environments, and mental attitudes with the cues our biology needs for good sleep. Sleep medications can be useful tools when used skillfully match to this specific problem. and ideally as a short term bridge rather than a long term crutch. peopleeople 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 keyword is matched becausecause 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 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 talk about how they work what they do to and for your sleep whichich ones work best for your problems? There' side effects and the risk of dependence We'll spend extra time discussing the potential that DorAas, 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. gettinget 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. 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. bothoth 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 orr if you're suffering from jet lag Or if you chronically stay up late or sleep in on your days off, but then find your sleep is poor during the work week you likely want to work on circadian alignment. On the other hand, if your problem seems unrelated to your schedule, but you find yourself too sleepy during the day or too wakeful at bedtime, especially if you're taking naps or relying heavily on caffeine. or if you fall asleep quickly but have a lot of fragmented non restorative sleep You may get more benefit from focusing on consolidating your sleep pressure What sleep hygiene does not reliably fix is hyper arousal which is why so many people can do everything right and still lie awake at night 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 three percent of the general population of adults worldwide Although a survey from the American Academy of Sleep Medicine found that as many as thirteen percent 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 stopp 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 thirty nine percent of males and twenty six percent of females About half of these cases are mild, thirty percent are moderate And nearly twenty percent 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 twelve month period suffer from anxiety and or mood disorders and in turn About twenty five to forty five percent of people with mood or anxiety disorders report having had severe insomnia in the previous year while it was forty two percent to sixty three percent 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 dysregulated 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 we'll discuss acts on one or more of the four sleep mechanisms I described earlier Some suppress the arousal that overrides the homeostatic drive Others reinforce the circadian timing signal. And some, the most promising work by quietly reducing the brain's wakefulness drive rather than forcing sedation Understanding which problem is disrupted in a given patient is what allows you to match the medication to the problem rather than reaching for a blunt instrument Now, before reaching for anything, you need to understand what kind of sleep problem you're up against The DSM five criteria for insomnia Are sleep problems persisting more than three months at least three nights a week. And this part matters caausing 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 hyper arousal 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 Hyper arousal 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 targets hyper arousal. It reduces the cognitive and physiological activation that keeps the brain in a wakeful state And it retrains the association between your bed and being awake That's why it often works when sleep hygiene alone doesn't We'll put a link in our show notes to the episode with Ashley Mason for a deep dive into the practice of CBTI. There's another concept here that's incredibly important and often missed, which is paradoxical insomnia, also called sleep state misperception These are people who are convinced they've been awake all night They've gotten two or three hours of sleep at most. But when you actually measure their sleep, they've gotten significantly more than that 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. underlying sleep hasn't actually improved Most sleep problems fall into four buckets, which actually correspond directly to the four mechanisms of insomnia trouble falling asleep, which is often a hyper arousal situation overriding homeostatic drive trouble staying asleep And in my experience with my patients, this second bucket is far more common than the first Ely morning awakenings, which is often a circadian misalignment or fragmented non restorative 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 kneading 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 non REM Dep non REM, also called N three 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 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. Agents we're more comfortable with tend to support the body's own sleep mechanisms rather than overriding them Different drugs vary in how quickly they work how long they last and which sleep problems they target So we need to match the medication's pharmacology to the patient's specific sleep challenges 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 Mazepam, Lazapam Alprazleam, Diazepam, Canazepam, and others. They also go by brand names you've probably heard of like Xanax, Aavan, and Valium These are some of the oldest sedative hypnotics. They work by dampening excitatory neurotransmitter systems, pressing the brakes on the hyper arousal that modern life promotes and that drive insomnia spepecifically, 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 gabinergic signaling is increased in the thalmus, the gate closes more tightly, so fewer signals reach the cortex and conscious perception fades, producing sedation Different benzodiazepines vary in receptor subtype affinity onnset and half life which leads to some being more sedating and others being more angxiolytic 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. Oen decreasing slow wave sleep, which is that deep N three sleep we talked about and suppressing REemsle They're also powerful angxiolytics so they can quickly quiet ruminative thoughts and muscle tensions in patients whose insomnia is driven by anxiety But the trade offffs 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, aaxia, and impaired balance, which in older adults can be catastrophic. P administration with alcohol or opioids, which also enhance gabinergic signaling or depress respiratory centers, markedly increases the risk of respiratory depression and death, particularly in people with undiagnosed or untreated obstructive sleep apnea. And there iss 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 antteriggrrade 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. Inttergrrade 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 Pcribing 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 hyper arousal in the short term But they do it at the cost of sleep quality dependence risk and cognitive side effects They solve the immediate problem. 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 Ambian, Sonata, and Lunesta Z drrugs account for over forty percent of all sleep medication prescriptions in the US, with Abien accounting for nearly ninety percent of that Despite not being structurally related to benz'es, Z drugs also act on GABAA receptors As a result, Z drugs are more targeted for sleep promotion and have less prominent angioottic 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 Ambiian'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 tergrade amnesia The 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 that strangely dissociated These effects are most likely to happen at higher doses 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 ten percent take three or more other sedating medications In twenty nineteen, 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 Exosure to extreme cold temperatures leading to loss of limb Carbon monoxide poisoning, drowning, hypothermia, motor vehicle collision with the patient driving and self injuries such as gunshot wounds and apparent suicide attempts Z drugs do have some use, especially for dealing with acute disruptions to a person's sleep. and where we suspect paradoxical insomnia. For these reasons, we use Z drugs at the lowest effective dose for the shortest possible duration, and only with a plan for addressing underlying causes of insomnia and offering CBTI 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 erexin receptor antagonists, or Doras We have three versions of these at the moment Q Vivic Dave Vigo and Bel Sama Doras are different in a way that I think really matters. Most traditional sleep medications work by forcing sedation they broadly suppress brain activity But doas don't do that. They work by dialing down one of the brain's primary wakefulness systems, specifically the erexin system And in doing so, they allow your natural sleep processes to take over distinction between forcing sleep and allowing sleep is not just semantic It shows up in the outcomes Doras outperformed other drugs on sleep efficiency, which is the amount of time you're sleeping relative to how much time you're in bed and total sleep time Andoras had superior tolerability compared to drugs for which there was enough information to make a comparison A second meta analysis that was generally more cautious about sleep medications found that D Vigo specifically had the most favorable profile of any drug examined One of the things we like about Doras 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. Why does this matter? 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 sixty percent more space between cells which allows CSF to circulate more freely in exchange with the fluid immediately around brain cells, 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 gymphatic clearance of beta amyloid roughly doubles during sleep particularly during deep non REM sleep with similar increases in clearance of a barnt towel Human studies show that a night of sleep deprivation impairs gymphatic 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 abarrant 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 brainstemem and basal forebrain that regulate REMs sleep This suggests a vicious cycle in which poor sleep accelerates damaged beta amyloid and a barrnt toauer accumulation And the accumulation of these damaged proteins further impairs sleep Because erectin levels rise during the day and fall at night in rough parallel with beta amyloid levels in the CSF. David Holzman suspected that there might be a relationship between erexin and glyymphatic clearance So he and his colleagues infused erexin into the hippocampi of a mouse model of Alzheimer's As expected, Erexin 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 alarexin into their brains, interstitial fluid beta amyloid levels went down. Sustained treatments reduce plaque accumulation in several brain regions He got similar results with D Vigo in transgenic mice that bear a tau mutation that causes neurodegenerative disease in humans Dave 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, Ambian did not have these neuroprotective effects, indicating that simple unconsciousness isn't doing this. It's specific to the mechanism of Doras Now of course St start with some caveats First, few of these benefits were observed in the female mice, which the investigators chalked up to there having less severe tu 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 twenty twenty three thirty eight cognitively unimpaired adults with good sleep, aged forty five to sixty five were randomly assigned to take ten milligrams of belsomera twentywenty milligrams of balssoma or a placebo for two nights in a row, starting at eleven PM Surprisingly, neither dose of balssomera had any effect on sleep parameters compared with placebo However, twenty milligrams of Balssamra, but not ten milligrams, decreased CSF amyloid beta by roughly twenty percent 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 P Tau two hundred seventeen, which is the most sensitive and specific marker for Alzheimer's progression 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 two hundred subjects apiece, are currently underway and expect to be completed between this year and twenty twenty nine I will certainly be watching these closely The pharmaccokinetics of the various doras differ, which influences how long their effects persist into the next day. Balsamra has a half life of around twelve hours, D Vigo around seventeen to nineteen hours, and Quavivic around six to ten 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 Doras resemble type one narcolepsy. efficiency of Orexin signaling that is often caused by the loss of orexogenic neurons Because Dor's blunt erexin signaling, their side effects can resemble a mild drug induced, narcolepsy like state including excessive daytime sleepiness sleep paralysis hypnogotic 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, 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. But they's still psychoactive agents that alter consciousness. So physiological misuse is always possible If you step back, Doras 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 has heard of Mellatonin 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 superchismatic 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 erexin neurons 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, shhift 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 ten 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 Analyses of commercial preparations have found that the actual melatonin content can range fromr minus eighty percent to plus almost five hundred percent 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 one percent to seventy four percent which is in part due to inter individual differences in metabolism and in part due to other properties of the specific supplements, such as the dose, the dosage form, or even the other compounds that are used as fillers in this 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 MT one and MT two melatonin receptors in the SCN They include Ramulton 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 Ramulton, the first melatonin agonist, is usually taken about thirty minutes before bedtime High fat meals can delay its absorption and therapeutic effects Like melatonin itself, melatonin receptor agonists are most useful in patients with circadian rhythm disorders rather than as direct sleep aids In these cases, they help advance the internal circadian clock. So sleep occurs earlier initially appears to be insomnia improves because the circadian misalignment is corrected. They are therefore not usually helpful for the scenario where someone falls asleep easily but wakes up repeatedly at three AM. 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. does very little of use when the problem is something else This brings us to another favorite of mine for clinical use along with Doras's which is a drug called trarazodone. The Pident was originally developed as an antidepressant. doses of three hundred milligrams for major depressive disisorder Approximately half of the patients taking trarazodone for depression develop excessive daytime sleepiness comppared to nineteen percent of those receiving a placebo That side effect became the drug's second career It's now prescribed off label at doses typically between fifty and one hundred 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. twenty twenty two 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 N three 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 five HT two receptors, which are a subset of serotonin receptors histamine H one receptors and alpha one adrenergic receptors. Common side effects include morning groiness, nasal congestion, dizziness, and orthostatic hypertension which is an important risk for falls Raarer side effects include priopism, which are erections that don't go down for several hours and potential cardiac arrhythmias Next to Doras, Trazidone 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 Prazidone 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 antihistamines, such as benadryl Niquil and Unisom Like trarazidone, they block central histamine H one 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. meananing they inhibit signaling by the neurotransmitter acetylcholine 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 Doras may help prevent. Bottom line is these have a roll 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 Be we get into specifics, let me say what I say every time we talk about supplements They are not regulated like drugs. compompanies 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 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 nonessential amino acid found in high concentrations in collagens. 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 The 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 in older people Both of which are kind of lukewarm Th 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 L three and eight to be the most likely to show it Mag three and eight 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 fifty to seventy 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 Ashraganda 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 controlll trials in about four hundred participants found a small but statistically significant positive effect on sleep, with stronger effects in people with diagnosed insomnia at doses of at least six hundred milligrams per day and with a treatment duration of at least eight weeks It's worth pointing out that even amongst highly established supplement brands, Ashroaganda supplements vary widely in quality Consumer lab testing found that only five of thirteen tested ashwaganda supplements contained the amount of standardized bioactive withanalides stated on the label Also, there are safety concerns around Ashroal Gando. 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 phhosphatetyl serine or PS is reputed to lower 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 phosphyl sereine 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 four hundred to six hundred milligrams alongside melatonin when I need to force sleep at an otherwise inappropriate biological time. For example, if I need to force sleep at two PM because it's ten PM 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. Ltptophan for its long and controversial history. partart 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 Vverified or NSF certified for sport certifications on products and check independent testing organizations like Consumer Lab and lab door before buying 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, hyper arousal 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 hyper arousal, 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 begin Thank you for listening to this week's episode of the Drive. Head over to Peteratamd dot com forward slash show notes if you want to dig deeper into this episode. 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