Hey everyone, welcome back to My Weird Prompts. I am Corn, and I am sitting here in our living room in Jerusalem with my brother, looking out at a surprisingly crisp February morning. The light over the Judean hills is beautiful today, but we are about to spend the next twenty five minutes or so talking about the dark. Specifically, the things we take to make the night actually happen for those of us who struggle with the simple act of falling asleep.
Herman Poppleberry, at your service. It is indeed a beautiful day, Corn, but for many people, the beauty of the day is completely overshadowed by the exhaustion of the night before. We are diving into a topic that hits home for millions of people, but we are looking at it through the lens of early twenty twenty six data. The science of sleep has moved faster in the last three years than it did in the previous thirty.
Our housemate Daniel sent us a really personal and scientifically dense prompt this week. He has been incredibly open about his journey with sleep aids. He started where many do, with the Z-drugs like Ambien, but eventually moved over to low dose Seroquel. Now, he is feeling that classic next day heaviness, that mental fog that feels like you are walking through waist deep water. He wants to know if the sleep we get from these chemicals is actually doing the job, or if we are just knocking ourselves unconscious without the benefits of real rest.
It is the million dollar question in neurology right now. Is sedation the same as sleep? The short answer is a resounding no. Sleep is not just a passive state of being off. It is an incredibly active metabolic and neurological process. It is more like a scheduled maintenance period for a high performance vehicle. If you interfere with the choreography of those stages, you might be getting eight hours of shut eye, but your brain might still be essentially starving for the restorative processes that should have happened.
Daniel also asked about the next frontier. What comes after these heavy hitters? We have seen some massive movement in Orexin receptor antagonists and these newer calibrated treatments. Plus, since we are all here in Israel, he is curious about the local landscape. When does the latest stuff actually hit the pharmacies in West Jerusalem or Tel Aviv?
I have been diving into the latest clinical reviews from late twenty twenty four and the early twenty twenty five journals, and the landscape is shifting. But before we get to the future, we really need to look at what Daniel is taking right now, because Seroquel and Ambien are two very different beasts with very different impacts on the brain's architecture.
Let us start with Seroquel. For those who do not know, the generic name is quetiapine. Now, Herman, when people hear that it is an atypical antipsychotic, it usually raises some eyebrows. Why is a drug designed for schizophrenia being handed out for insomnia?
It is all about dosage and receptor affinity. This is a concept called the binding profile. At very high doses, like four hundred to eight hundred milligrams, quetiapine works on dopamine and serotonin receptors to manage psychosis. But the drug has a much higher affinity for histamine receptors than it does for dopamine receptors. This means that at the tiny doses used for sleep, usually between twelve point five and fifty milligrams, it acts primarily as a very potent antihistamine and an alpha one adrenergic blocker.
So it is basically like a super charged Benadryl at that level?
In a way, yes, but with a darker edge. It hits the H one histamine receptors in the brain, which are responsible for arousal and wakefulness. When you block those, you get very sleepy. But the problem, and this speaks to Daniel's mention of the sledgehammer effect, is that quetiapine has a relatively long half life and it is not very selective. It lingers. That is why you get that heavy, groggy feeling the next morning. It is not just that you slept deeply, it is that the drug is still physically sitting on those receptors, refusing to let the wakefulness system turn back on.
Daniel mentioned a nasty next day downer feeling, almost like a subtle depression. Is that a common side effect of quetiapine, even at those low doses?
Absolutely. A twenty twenty four meta analysis actually looked at this specifically. Even at low doses, quetiapine can affect the mood because it still has a slight touch on those serotonin receptors, specifically the five H T two A receptor. And because it is so sedating, it can lead to a sort of emotional blunting. You are not just tired, you are chemically dampened. Your brain's reward system is essentially being muffled.
Now, compare that to the Z drugs like Ambien, or zolpidem. That was the other one Daniel mentioned. Those are the ones people usually associate with weird sleepwalking stories and midnight kitchen raids, right?
Right. Ambien is a non benzodiazepine hypnotic. It targets the G A B A receptors, specifically the alpha one subunit. Think of G A B A as the brain's primary inhibitory neurotransmitter. It is the brakes of the nervous system. Ambien basically slams on the brakes. It is much more targeted than the older benzodiazepines like Valium, which hit all the subunits and caused massive muscle relaxation and memory loss. But Ambien is still a blunt instrument.
But is it better for the quality of sleep? If Seroquel is a sledgehammer that keeps you down too long, is Ambien a cleaner break?
This is where the restorative quality question comes in, and the news is not great for either drug. Natural sleep is a cycle. You have light sleep, stages one and two, then deep slow wave sleep, stage three, and then R E M sleep where you dream. You repeat this cycle about every ninety minutes. The problem with almost all sedative hypnotics, including Ambien and especially Seroquel, is that they tend to suppress R E M sleep and can significantly reduce the amount of deep slow wave sleep you get.
So even if the clock says you slept eight hours, your brain did not get to do its laundry?
That is a perfect analogy. We know now that during deep sleep, the glymphatic system opens up. It is like the brain's waste management system, flushing out metabolic debris like beta amyloid and tau proteins. These are the same proteins linked to Alzheimer's. If a drug keeps you in a state of light sedation but prevents you from reaching those deep, slow waves, the cleaning process is inefficient. You wake up with what I call a chemical debt. You are unconscious, but you are not being restored.
That is a terrifying thought. So when Daniel asks if chemically induced sleep lacks restorative quality, the scientific answer is likely yes. It is better than zero sleep, because total sleep deprivation is a literal killer, but it is not a one to one replacement for natural sleep.
Exactly. It is a trade off. Doctors often view it as a harm reduction strategy. If a patient is so stressed or has such severe insomnia that they are non functional, the sedation of a Z drug or low dose quetiapine is better than the physiological stress of staying awake for forty eight hours. But it is a pale imitation of the real thing. In fact, recent studies from twenty twenty five have shown that long term use of these sedatives can actually lead to a permanent shift in sleep architecture, making it harder and harder for the brain to ever reach stage three sleep naturally again.
I want to dig deeper into that next day feeling Daniel described. He called it a subtle depression. Beyond just the lingering sedation, is there a risk that these drugs are actually messing with our neurotransmitter balance over the long term?
There is a real concern about receptor down regulation. If you are constantly flooding your G A B A receptors with a drug like Ambien, your brain might start to produce less G A B A naturally, or the receptors might become less sensitive. That is why people build a tolerance. Eventually, they need the drug just to feel normal, and without it, they get rebound insomnia that is worse than their original problem. With Seroquel, the metabolic side effects are the bigger worry over time, even at low doses. We are talking about weight gain, changes in blood sugar, and even a risk of tardive dyskinesia, which is a movement disorder, though that is much rarer at the sleep doses.
It feels like a bit of a trap. You need the sleep to function, but the medicine makes you feel like a zombie the next day. This leads perfectly into the second part of Daniel's prompt. He asked about the next frontier. He mentioned melatonin agonists. Herman, I know you have been reading up on the newer classes of drugs that are trying to be more surgical and less sledgehammer.
This is where it gets really exciting. For decades, we only really had two ways to handle sleep: hit the G A B A system to knock you out, or hit the histamine system to make you drowsy. But in the last few years, we have seen the rise of a completely different approach called Orexin Receptor Antagonists, or D O R A s.
Orexin. I have heard that name. Isn't that the chemical that keeps you awake?
Yes! It was actually discovered through research into narcolepsy. People with narcolepsy lack orexin, so they cannot stay awake. Scientists realized that if we could block orexin in people with insomnia, we could turn off the wakefulness signal instead of just trying to overpower it with a sedative. It is a fundamental shift in philosophy. Instead of adding a "downer," you are removing the "upper."
So instead of hitting someone over the head with a mallet, you are just gently turning off the lights?
Precisely. Drugs like Suvorexant, Lemborexant, and the newest one, Daridorexant, which has been making waves in twenty twenty five, are designed to do exactly that. The data suggests they have a much smaller impact on sleep architecture. They allow the brain to move through R E M and deep sleep more naturally because they are not forcing a specific state of sedation; they are just removing the chemical drive to stay awake.
That sounds like a massive step forward. What about the melatonin agonists Daniel mentioned? I know a lot of people take over the counter melatonin, but these prescription versions are different, right?
Right. Over the counter melatonin is often inconsistent in dosage, and your body processes it very quickly. Melatonin agonists like Ramelteon or the newer Tasimelteon work on the same receptors but they are much more potent and have a longer lasting effect on the circadian rhythm. They do not knock you out. They tell your brain that it is night time. They are particularly good for people with shifted schedules or those who have trouble falling asleep at the right time, though they are often less effective for people who struggle with staying asleep all night.
So if the Orexin blockers are the off switch, and the melatonin agonists are the sunset signal, are these available here in Israel? Daniel was specifically asking about the timeline for newer treatments reaching us.
That is the tricky part. Israel's Ministry of Health is generally very diligent, but the market here is small. Often, a drug will get F D A approval in the United States or E M A approval in Europe, and it can take two to four years before it is fully registered and covered by the health funds, the Kupat Cholim, here in Israel.
I did a bit of searching on the Ministry of Health database before we started. It looks like some of the Orexin antagonists, specifically Daridorexant, which is marketed as Quviviq in Europe and the U S, have finally started to appear in the Israeli private market as of late twenty twenty five. But they are often not the first line of treatment. You usually have to show that you have tried the older, cheaper stuff like Ambien or Bondormin first.
That is the standard protocol. It is a cost thing. The newer drugs like Daridorexant are much more expensive than a generic pill of quetiapine or zolpidem. However, for the twenty twenty six health basket, the Sal HaBriut, there has been a significant push to include these newer sleep medications for patients who have failed traditional therapy. For someone like Daniel who is experiencing those heavy side effects and mood changes, it might be worth talking to a sleep specialist specifically about these newer classes. Sometimes you can get them through private prescriptions even if they are not yet fully subsidized.
It is interesting that you mentioned sleep specialists. I think a lot of people in Israel just get these prescriptions from their family doctor, their Rofeh Mishpacha. Is that part of the problem? That we are using these powerful psychiatric drugs like Seroquel for sleep without a full sleep study?
I think so. In Jerusalem, we have some great sleep clinics, like the one at Hadassah or the sleep lab at Shaare Zedek, but the wait times can be long. If you go to a general practitioner and say you cannot sleep, they want to help you today. Seroquel is cheap, it is effective at causing drowsiness, and it is not a controlled substance in the same way that benzodiazepines are, so it feels safer to prescribe. But as Daniel is finding out, just because it is not addictive in the traditional sense does not mean it is without consequences.
You know, we have talked about this in previous episodes, especially when we looked at how different medications are regulated globally. It feels like we are in this transition period where we are moving away from broad spectrum sedatives toward what Daniel called calibrated treatments. Herman, what does a calibrated treatment look like in twenty twenty six?
I think we are looking at two things. First, the drugs themselves are becoming more specific to certain receptors, as we discussed with the Orexin blockers. But the second part is personalized timing. We are starting to see treatments that are timed to a person's specific genetic chronotype. Some people are natural night owls, and trying to force them into a nine to five sleep schedule with a pill is always going to cause issues. Calibrated treatment might involve using light therapy and low dose melatonin agonists at very specific intervals to nudge the internal clock rather than crushing it.
That sounds a lot more sustainable than taking a sledgehammer to your brain every night at eleven P M.
Much more. And we should also mention that there is a lot of research right now into the role of the gut microbiome in sleep. There are trials looking at specific probiotics that might influence G A B A production in the gut, which communicates with the brain via the vagus nerve. It is a much more holistic way of looking at it.
Wait, so you are saying in the future, Daniel might be taking a specific yogurt instead of a Seroquel?
Maybe not just a yogurt, but a highly engineered synbiotic. It sounds like science fiction, but the gut brain axis is one of the hottest areas in neurology right now. If we can fix the internal chemistry that creates the natural drive for sleep, we will not need the heavy sedatives.
That is an incredible thought. But back to the present for Daniel. If he is feeling this depression and grogginess from the Seroquel, and he is worried about the quality of his sleep, what are the practical steps? Obviously, we are not doctors, but based on the research you have seen, what is the path forward for someone in his position?
The first thing is a slow taper, always under a doctor's supervision. You cannot just jump off these meds, especially if your brain has adapted to them. Second, I would really encourage anyone in this spot to push for a referral to a dedicated sleep specialist, especially here in Israel where the newer drugs are just starting to trickle in. Mention the Orexin antagonists by name. Ask about Daridorexant. It has a very short half life, meaning it is out of your system by morning, which solves that grogginess issue Daniel mentioned.
And what about the non drug stuff? I know we always hear about sleep hygiene, but does it actually make a difference when you are already on heavy meds?
It makes more of a difference than people think, but not in the way most people do it. It is not just about turning off your phone. It is about morning light. If you are taking a drug that makes you groggy, you need to hit your eyes with bright, natural sunlight as soon as you wake up. That helps suppress the lingering melatonin and resets the circadian trigger for fourteen hours later. In Jerusalem, we are lucky, we have plenty of sun even in February. Using that as a tool is vital.
That is a great point. I think we often view sleep as a nighttime problem, but it is really a twenty four hour cycle. If you do not get the right signals in the morning, your night is already compromised before it begins.
Exactly. And to Daniel's point about the restorative quality, one way to track this is through wearable tech. Now, these are not as accurate as a clinical polysomnography, but they have improved a lot by twenty twenty six. If you see that your deep sleep or R E M sleep is consistently below ten percent of your total sleep time while on a medication, that is a data point you can take to your doctor. It proves that while you are unconscious, you are not actually resting.
It is amazing how far that technology has come. I remember when those trackers were basically just glorified pedometers. Now they are actually measuring heart rate variability and blood oxygen.
They are, and heart rate variability, or H R V, is a huge indicator of whether your nervous system is actually recovering. If your H R V stays low all night while you are on Seroquel, it means your body is still in a state of stress even though you are passed out. Your sympathetic nervous system is still firing.
That is a really important distinction. Sedation is not the same as recovery. I think that is the big takeaway for me today. We have been conditioned to think that if we are not awake, we are sleeping. But science is showing us that there is a massive world of difference between being chemically silenced and being naturally restored.
It is the difference between a computer being turned off by pulling the plug and a computer running its background maintenance and updates. You want the updates. You want the maintenance. Pulling the plug just stops the noise, but the system stays messy.
That is a perfect Herman Poppleberry analogy. I love it. I think we should also touch briefly on the cultural aspect here in Israel. We live in a high stress environment. Between the news, the security situation, and the general intensity of life here, insomnia is almost a national pastime. Do you think that contributes to why these drugs are so widely prescribed?
Oh, absolutely. We are a nation in a state of hyper arousal. Our sympathetic nervous systems are constantly dialed up to eleven. When you are in that fight or flight mode, your brain is not going to let you sleep because it thinks it needs to stay alert for danger. That is why drugs like Seroquel, which also have that alpha blocking, anti adrenaline effect, feel so good to people here. They finally feel the physical tension leave their body.
So it is almost like the medication is doing the job that our environment makes impossible.
Exactly. But that is why we need those calibrated treatments Daniel mentioned. We need ways to dial down the arousal without turning off the whole brain. There is some interesting research into vagus nerve stimulation and even certain types of targeted sound therapy that can nudge the brain into those deep sleep frequencies.
I have seen some of those devices. They look like little headbands you wear at night. Are they actually effective?
The clinical data from twenty twenty five is starting to look very promising. It is called acoustic stimulation. By playing brief pulses of pink noise that are synced to your brain waves, they can actually amplify the height of those slow waves in deep sleep. It is like giving your brain a little push while it is on a swing, helping it go higher and stay in that restorative zone longer.
That feels like the ultimate calibrated treatment. It is not even a chemical; it is just physics.
It is! And for someone like Daniel, who is sensitive to the next day side effects of pharmaceuticals, these non pharmacological interventions might be the real next frontier.
This has been such a deep dive, Herman. I feel like we have covered the gamut from the heavy hitting antipsychotics to the future of sound based sleep. To wrap up the first part of Daniel's question, it seems the data is pretty clear: drugs like Seroquel and Ambien do interfere with sleep architecture, and that groggy, downer feeling is a direct result of that interference.
Yes, and the good news is that the next generation of drugs, the Orexin antagonists, are specifically designed to solve that exact problem. They are becoming more available in Israel, and while the regulatory process can be slow, the path is there.
It is a hopeful message, really. We are moving away from the era of the sledgehammer and into the era of the light switch.
I like that. The era of the light switch. It has a nice ring to it.
Well, I think we have given Daniel a lot to think about. Before we go, I want to remind everyone that if you are enjoying these deep dives into the weird prompts our housemate sends us, please leave us a review on your favorite podcast app. Whether it is Spotify or Apple Podcasts, those ratings really help other curious minds find the show.
It really does. And if you have your own weird prompt, or you just want to see the show notes for this episode with all the drug names and research we mentioned, head over to myweirdprompts dot com. We have the full archive there, including some of our older episodes on pharmacology and the brain.
We are so glad you joined us today. It is a complex world, and sleep is one of the most mysterious parts of it. But with a little bit of science and a lot of curiosity, we are starting to turn the lights on, or off, as the case may be.
Until next time, I hope you all get some truly restorative, non chemically induced rest.
Thanks for listening to My Weird Prompts. We will see you in the next one. Goodbye!
Goodbye everyone!
