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

“side effects, and the risk of dependence. We'll spend extra time discussing the potential that DORAs, 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.”

“But DORAs don't do that. They work by dialing down one of the brain's primary wakefulness systems, specifically the orexin system. And in doing so, they allow your natural sleep processes to take over.”

“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.”

“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. So why does this matter?”

“It's specific to the mechanism of DORAs. Now, of course, let's start with some caveats. First, few of these benefits were observed in the female mice, which the investigators chalked up to their having less severe tau pathology in the first place.”

“adults or combined with other CNS depressants. Several less common side effects of DORAs resemble type 1 narcolepsy, a deficiency of orexin signaling that is often caused by the loss of orexigenic neurons.”

“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.”

“misuse is always possible. If you step back, DORAs are attractive to patients with narcolepsy, but they can also be effective because they target wakefulness directly rather than forcing sedation. And they tend to preserve the underlying structure of sleep.”

“cheapest, most accessible sleep aids carry exactly the kind of long-term neurological risks that the modern DORAs may help prevent. The bottom line is these have a role for very short-term use only. Okay, let's talk about dietary supplements. Now, we've already mentioned one briefly, which is melatonin, but there's actually a number of other supplements that are talked about for sleep.”

“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.”

“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 suprachiasmatic nucleus , the brain's circadian center,”

“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.”

“Further complicating dosing, studies of melatonin supplements have reported bioavailabilities ranging from 1% to 74%, which is in part due to inter-individual dosing.”

“in the supplement. A strong point in favor of melatonin supplements is their safety profile compared to other classes of sleep aids. However, taking excessive melatonin can cause hangover effects, residual daytime sleepiness, or further disrupt circadian alignment instead of correcting it.”

“This matters because these patients are especially vulnerable to certain medications. Drugs that impair memory, like benzodiazepines or Z drugs, can make it feel like sleep is improved simply because the person no longer remembers waking up. But the underlying sleep hasn't actually improved.”

“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 to prevent insomnia.”

“insomnia. 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.”

“or Z-drugs, and controlled studies have generally found low scores on drug-liking instruments at therapeutic doses. But they're still psychoactive agents that alter consciousness, so physiological misuse is always possible.”

“hypnotics, also referred to as Z drugs. These include Ambien, Sonata, and Lunesta. Z drugs account for over 40% of all sleep medication prescriptions in the U.S., with Ambien accounting for nearly 90% of them.”

Also filed under Z-Drugs

“maintenance. Ambien's intermediate release version is better suited to sleep onset insomnia, while Sonata, with its very short half-life of about an hour, can even be used in the middle of the night if you wake up and have enough time left before morning.”

“effects when they seeded tau aggregates into the brains of wild-type mice. Importantly, Ambien did have these neuroprotective effects, indicating that simple unconsciousness isn't doing this.”

“Ashwagandha 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”

“ashwagandha supplements vary widely in quality. Consumer lab testing found that only five of 13 tested ashwagandha supplements contained the amount of standardized, bioactive, withanolides stated on the label.”

“hypnotics, also referred to as Z drugs. These include Ambien, Sonata, and Lunesta. Z drugs account for over 40% of all sleep medication prescriptions in the U.S., with Ambien accounting for nearly 90% of them.”

Also filed under Z-Drugs

“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.”

Also filed under Z-Drugs

“called Trazodone. Trazodone was originally developed as an antidepressant approved at doses of 300 milligrams for major depressive disorder. But approximately half of the patients taking Trazodone for depression develop excessive daytime sleepiness compared to 19% of those receiving a placebo.”

“it's prescribed for depression. It's popular because it's inexpensive, it's not controlled, and it's quite safe. A 2022 meta-analysis confirmed that it increases total sleep time and that it has a very favorable property that most sleep medications don't. It increases slow wave N3 sleep rather than suppressing it, with minimal effects on other aspects.”

“which are the first-generation antihistamines, such as Benadryl, NyQuil, and Unisom. Like Trazodone, they block central histamine H1 receptors”

“In the show notes, we'll discuss three more sleep supplements that I didn't really have time to get into here. L-tryptophan for its long and controversial history, tart cherry juice, because it seems to be talked about nonstop on social media, and Japanese sake yeast extract because of its intriguing mechanism of action.”

“Let's start with glycine. It's a non-essential amino acid found in high concentrations in collagen. It also acts as an inhibitory neurotransmitter in the central nervous system, where it plays a role in shutting down motor activity during REM sleep. The three human studies on glycine for sleep show modest benefits on sleep.”

“In the show notes, we'll discuss three more sleep supplements that I didn't really have time to get into here. L-tryptophan for its long and controversial history, tart cherry juice, because it seems to be talked about nonstop on social media, and Japanese sake yeast extract because of its intriguing mechanism of action.”

“Let's start with benzodiazepines. Temazepam, lorazepam, alprazolam, diazepam, clonazepam, and others. They also go by brand names you've probably heard of, like Xanax, Ativan, and Valium. These are some of the oldest sedative hypnotics.”

“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.”

“effects, residual daytime sleepiness, or further disrupt circadian alignment instead of correcting it. Melatonin receptor agonists are a distinct class of sleep aids that target the MT1 and MT2 melatonin receptors in the SCN. They include Ramelteon and others. Unlike melatonin supplements,”

“circadian misalignment. In practice, I typically use 400 to 600 milligrams alongside melatonin when I need to force sleep at an otherwise inappropriate biological time. For example, if I need to force sleep at 2 p.m.”

“They include Ramelteon and others. Unlike melatonin supplements, prescription melatonin receptor agonists are manufactured under quality control standards”

“which are the first-generation antihistamines, such as Benadryl, NyQuil, and Unisom. Like Trazodone, they block central histamine H1 receptors”

“Let's start with benzodiazepines. Temazepam, lorazepam, alprazolam, diazepam, clonazepam, and others. They also go by brand names you've probably heard of, like Xanax, Ativan, and Valium. These are some of the oldest sedative hypnotics.”

“Let's start with benzodiazepines. Temazepam, lorazepam, alprazolam, diazepam, clonazepam, and others. They also go by brand names you've probably heard of, like Xanax, Ativan, and Valium. These are some of the oldest sedative hypnotics.”