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bilibili_data_75123309_BV1nL4y1N7TN_p32_BV1nL4y1N7TN_p32_m4-dialogue_0517927
[S1] I teach medical students and, and they, they're phenomenal, but they, yeah, they're under extremely challenged conditions. It's, uh- [S2] We shouldn't put them under those conditions. [S1] No, it's not, it's not optimizing performance. [S2] Yeah. [S1] Um, I have one- [S2] But sorry, I was, sorry. [S1] No, no, no, this, this is important, these, um, uh, it's an important digression. I have one question, which is you're saying that as, across the night, a greater percentage of these 90 minute cycles are going to be occupied by REM sleep as you progress through the night.
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[S1] I'm aware that they're based on work that you've done and, and, uh, and from your public education efforts and others, um, that we have so-called circadian forces and we have other forces that are driving when we sleep and when we wanna sleep, et cetera. Without going into the details of those, I have a simple question. The experiment is the following. Let's say, God forbid, you are prevented from going to sleep at your normal time. [S2] Yeah. [S1] And you stay up.
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[S1] for the four hours or five hours that normally you would be in predominantly slow wave sleep. [S2] Yeah. [S1] If, let's say you finally get to lie down at 3 a.m., a time when normally your sleep would be occupied mostly by rapid eye movement sleep. [S2] Yeah.
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[S1] Will you experience a greater percentage of rapid eye movement sleep because of these so-called circadian forces, meaning that's what's appropriate for that time, or will your system need to start at the beginning of the race that we're, that as a, as I'm referring to it- [S2] Yeah. [S1] ... that we're calling sleep?
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[S1] And who suffers more, those that lack the early phase or those that lack the later phase of the night sleep. In other words, if I have to sleep only four hours for whatever reason, am I better off getting the early part of the night sleep or the second half of the night sleep? [S2] Depends on what the outcome measure is. [S1] Um, so that gets right to the differences between slow wave sleep and REM. [S2] Right. [S1] Uh, I was, um, probably misinformed, but my understanding, a very crude understanding, I should, I should say before,
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[S1] I very much doubt it. [S2] Which is- [S1] No contra with someone like you. [S2] Yeah, which is that they're very nice of you. But the, the, the first part of the night, the slow wave sleep is restorative to the musculature, to motor learning, and that the dream content tends to be less emotional. The second half of the night being more emotional dreams and sort of the un-pairing of the emotional load of our previous day and other experiences.
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[S1] So in other words, if I were to deprem myself, deprive myself, excuse me, of REM, I would be hyper-emotional, not, maybe not as settled with the kind of experiences of my life. Whereas if I deprive myself of slow wave sleep, I would feel a, a more physical malaise. Is that correct or is that far too simple? And if it is too simple, please, uh, tell me where I'm wrong. [S2] No, I think much of that is correct and it's sort of that plus. [S1] Mm-hmm. [S2] So,
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[S1] ... regulated blood sugar perspective versus dysregulated pre-diabetic look of profile, that's where deep sleep seems to matter. If we selectively deprive you of that, we can see- [S2] Growth hormone. [S1] Growth hormone is different, actually. So that's a, that's a beautiful demonstration where growth hormone seems to be more REM sleep dependent, and that's why we can come on to the effects of alcohol. And there's, there's some really impressive frightening data on, on alcohol and its disruption of, um, of sleep.
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[S1] But then we also know testosterone. You know, peak levels of testosterone happen during REM sleep. [S2] So the second half of the night. [S1] It's just the second.
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[S1] ... really prefer to avoid. Uh, and that's the, that's the reason from an evolutionary standpoint that we've preserved those stages of sleep. I mean, sleep is just so idiotic, you know, from an evolutionary perspective. [S2] Or maybe waking is idiotic. [S1] Or waking is- [S2] [LAUGHS]
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[S1] ... you know, is so profoundly detrimental to us. If you were to take it at face value, you know, you're not finding a mate, you're not reproducing, you're not foraging for food, you're not caring for your young, and worst of all, you're vulnerable to predation. On any one of those grounds, sleep probably should have been selected against. But it wasn't. Sleep has fought its way through heroically. [S2] Mm-hmm. [S1] You know, every step along the evolutionary path. And
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[S1] Yeah, it's, it's incredible. I want to introduce a, another, um, Gedanken experiment, another thought experiment. So in this arc of the night, uh, slow-wave sleep predominates, uh, early in the night and then REM sleep. There's a scenario that many people, including myself, experience on a regular basis, which is they go to sleep, sleeping just fine, three, four hours into it, they wake up. [S2] Yeah. [S1] They wake up, for whatever reason. Maybe there was a noise, maybe the temperature isn't right. We will certainly talk about sleep hygiene, et cetera.
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[S1] they get up, they go to the restroom. They might flip on the lights, they might not. They'll get back in bed. Hopefully they're not picking up their phone and starting to browse and wake up the brain through various mechanisms, light and cognitive stimulation, et cetera. They go back to sleep. Let's say after about 10, 15 minutes, they're able to fall back asleep, and then they sleep till their more typical wake time. [S2] Yeah. [S1] How detrimental is that wake up episode or, or, um, event in terms of,
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[S1] ... longevity, learning, et cetera. I would love to sleep the entire night through every night. [S2] Yeah. [S1] But most nights I don't. And yet I feel pretty good throughout the day. [S2] Yeah. [S1] Some days better than others. [S2] Yeah. [S1] So if you were to kind of evaluate that waking episode and compare it to sleeping the whole night through, what are your, what are your thoughts on that?
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[S1] ... movement. We turn over because we've been paralyzed for so long and the body will also like to shift. It's- [S2] Do we ever look around? [S1] Wait. [S2] Do we ever open our eyes and look around? [S1] Position.
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[S1] You, sometimes people will open their eyes, but usually it's only for a brief period of time, and they usually never commit those awakenings to memory. [S2] Right. [S1] Your situation, and it's my situation as well, I usually now at this stage of life, I don't sleep through the night. I'll usually have a bathroom, uh, break, and then I'll come back. That's perfectly normal.
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[S1] But I'm going to be awake for upwards of 30 minutes, net some time. [S2] Mm-hmm. [S1] Sometimes that can be after a 10 minute, you know, dalliance after having gone to the bathroom and I'm just gradually drifting back off again. Other times it will just be for a couple of minutes and most of those you don't commit.
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[S1] So I think we need to stop. We don't need to get too worried about, you know, periods of time awake. Just because we're not sleeping throughout the night, I would love to do that too. And I remember when I, that used to happen. And it still happens occasionally. [S2] Everyone's like, "It feels great when it does happen." [S1] And it's, it's a lovely thing, but- [S2] It's a surprise, right? [S1] It is now a surprise. [S2] I slept through the whole night. [S1] Yeah. [S2] Yeah. [S1] It is a surprise. [S2] Yeah.
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[S1] Let's not get too worried about waking up and having some time awake. That's perfectly normal and natural. But if it's happening very frequently throughout the night, all those periods of time, all long stretches of time, upwards of 25 minutes, then let's look into it. [S2] Well, I can assure you, just, um, helped a lot of people, uh, feel better about this waking up episode that I and many other people experience. [S1] I, I hope so because
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[S1] You know, Sleep was still a neglected stepsister in the health conversation of today. And I could see all of the- [S2] That has certainly changed. [S1] And it's changing, you know, and not because of my efforts, but because of all of my colleagues. [S2] No, I would say, I would say-
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[S1] provided it's not too frequent, is, is great and will also help people who may have been overly concerned about that. I, I do want to use this as an opportunity to raise something about the so-called Uberman schedule. [S2] [LAUGHS] [S1] Not to be confused with the Huberman schedule. [S2] [LAUGHS] Yeah. [S1] Um, fortunately, no one, uh, has confused those yet. [S2] [LAUGHS] [S1] Um, the,
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[S1] Some years ago, there was a discussion about the so-called Uberman schedule, meaning the Superman schedule. So that's Uberman without an H, which I have nothing to do with. [S2] [LAUGHS] [S1] Um, if you read your Nietzsche, this will, this will have a subtext. But regardless, um, the Uberman schedule, as I understand, is one in which, um, the person
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[S1] ... elects to sleep in 90 minute bouts spread throughout the day and night- [S2] Right. [S1] ... in an attempt to get more productivity, um, and/or reduce their overall sleep need. There was a paper published recently that explored whether or not this is good or bad for us. Maybe you just give us the take home message on that.
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[S1] You know, 'cause that's the way that babies- [S2] Yeah, in 90 minute naps. [S1] ... will sleep, that they will have, you know, these brief naps, then they're awake, then they're asleep, then they're awake. And to the chagrin of parents, across the night, it's basically the same. They're awake, they're asleep, they're awake, they're asleep. And that's more the, the schedule that these types of protocols have, um, have suggested. And there was a really great comprehensive review that found not only that they weren't
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[S1] And it's not surprising. If you look at your, the way that your physiology is programmed, if you look at the way your circadian rhythm is programmed, none of that screams to us that we should be sleeping in that way. [S2] Well, I'm chuckling because, uh, we always hear sleep like a baby. This is how babies sleep. And, uh, I would say don't sleep like a baby, sleep like an adult. [S1] Yeah. [S2] Be an adult. [S1] I mean, it's Billy- [S2] Get, get your solid eight hours. [S1] It's Billy-
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[S1] No, I think that's exactly what we recommend right now, which is try to get at least 30 to 40 minutes of exposure to some kind of natural daylight. Now, there may be parts of the world where, you know, it's- [S2] Yeah, you're from, you're from a, a rather cloudy part of the world. [S1] I am-
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[S1] Despite you thinking sort of from a perception wise, maybe they're, they're much closer than I would think. [S2] Yeah, I've been, um, sorry to interrupt. I've been a- [S1] Oh, no. [S2] ... a big proponent of, there's a, an app called Light Meter, which will, it's a free app. Uh, I have nothing to do with it. They will allow you to, uh, get a pretty decent measurement of the amount of, of light energy coming toward you. And if you, um, hold it up to a cloudy morning,
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[S1] ... where you don't think it's very bright out, kind of a dismal day, you'll notice that they'll be a thousand, two thousand, even, you know, five thousand lux. Lux just being a measure of brightness, of course. And then you can point the same light meter toward an indoor light that seems very bright and very intense, and it'll say 500 lux. [S2] Yes, yeah. [S1] And you realize that the intensity as we gauge it perceptually is not really what the system is receiving. So outdoor light is key. How do you, what,
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[S1] ... to get this light stimulation. [S2] I am no poster child, but, um, usually I will, um, if I'm working, I usually work out most days. Um, and I shopped around and I found a gym that has huge amounts of window exposure facing to the east. This is sound, this is going to sound so, uh, ridiculous. You know, Matt Walker chooses a gym on the basis of- [S1] I love it. [S2] ... the solar input so he can, you know, correct his circadian- [S1] Well, there are a lot of criteria for selecting gyms. This one is actually grounded in physiology. [S2] [LAUGHS]
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[S1] So- [S2] And selfishness about my own sleep. [S1] No, it's great. So you, so you get your exercise and your light stimulation simultaneously. [S2] That's right. Yep, yep. [S1] And so you're stacking cues for wakefulness early in the day.
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[S1] That's great. And probably, um, folks might want to consider spending a little less time with sunglasses provided they can do that safely. [S2] Yeah. [S1] You know, driving, et cetera. You're not alone with your exercise behavior and facing east. So, um, the one and only Tim Ferriss told me recently that his morning routine nowadays consists of jumping rope,
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[S1] ... while facing east to get the sunlight stimulation of, of the eyes. And, um, as, uh, Matt and I both know, it has to be of the eyes, right? [S2] Yeah. [S1] I mean, th- these portals are the only way to, to, um, convey to the rest of the brain and body about the time of day and wakefulness. Um, it, along the lines of wakefulness, I have a number of questions about caffeine. [S2] Yeah. [S1] The dreaded and beloved caffeine. [S2] Yeah. [S1] I love caffeine, but I like it in relatively, um,
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[S1] ... restricted periods of time. So, um, I'm a big fan of waking up and even though I wake up very groggy, allowing my natural wakefulness signals to take hold. Meaning I wake up very slowly but I don't drink caffeine right away. [S2] Yeah. [S1] I sort of delay caffeine by a little, a little while, usually 90 minutes to two hours. [S2] Okay. [S1] And that,
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[S1] idea came to me on the basis of my understanding of how caffeine and the adenosine receptor interact. I have a feeling you're going to pronounce adenosine differently than I do. [S2] No, no, no. I will go with, I will go with adenosine. [S1] I
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[S1] I'll, I'll try to go with your skeletal instead of skeletal and synapse and synapse. [S2] Schedule and schedule. [S1] There we go. But, um, but to make it really simple for folks, how does caffeine work to make us feel more alert and does the timing in which we ingest caffeine
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play an important role in whether or not it works for us or against us. So maybe we just start with how does caffeine work? Why is it that when I drink mate or coffee, which are my preferred sources of caffeine, do I feel a mental and physical lift? [S1] Yeah. So I'm going to suggest counter to what most people would think, drink coffee. [S2] Or mate. Is mate okay also? [S1] Yeah, yeah, yeah. [S2] Or whatever form you enjoy. [S1] Well,
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[S1] ... you enjoy. [S2] Well, we'll, we'll come on to sort of why I suggest that, but when it comes to coffee, uh, I would say the dose and the timing makes the poison. [S1] Mm-hmm. [S2] So let's start with how caffeine works. Um, caffeine is in a class of drugs that we call a psychoactive stimulants.
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[S1] Yeah, so the adenosine here that we're talking about that is creating the sleep pressure is a central brain phenomenon, and it comes from the neurons themselves combusting energy. And as they're combusting energy, one of the offshoots of that is this chemical adenosine. [S2] Okay. [S1] And so as we're awake throughout the day, and our brain is metabolically very active, it's accumulating and building up this adenosine.
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[S1] May, may I just interrupt you again to just ask, uh, do we know what the circuit mechanism is for that? I mean, not to, um, go too far down the rabbit hole, but for the aficionados and for myself, uh, we have brain mechanisms like locus coeruleus that are release things that are brain areas, locus coeruleus just being a brain area, of course, that release things that create, that proactively create wakefulness. [S2] Yeah. [S1] So are those neurons shutting down as a consequence of having too much,
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[S1] Also increasing and dialing up the volume on sleep, activating sleep- [S2] Biology is so beautiful. [S1] Oh, fantastic. [S2] It's always a push pull. [S1] Yeah. [S2] I mean, we, and we could have a larger discussion at some point about that, um, everything, seeing dark edges, seeing light edges. [S1] Yeah. [S2] Uh, our ability to, to smell or to sense pressure on the... Everything's a push pull in biology. [S1] Oh, it's great. Yeah, yeah.
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[S1] And I would love to look at, you know, people's sleep history. We've sort of seen that time and time again, but, um, and then it could be, you know, with, with folks like me, people just lose the will to live within about five minutes of speaking with me, so- [S2] Not true. [S1] That's- [S2] They hear that sleep is important. That's also- [S1] And that's flattery. That's great. But, so the way that, then, caffeine comes into this, um, equation, as I was saying, it's usually a, kind of a linear process, or maybe it's probably closer to an exponential in terms of your subjective feeling of sleepiness. Um,
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[S1] Your brain doesn't know that you've been awake for, you know, f- f- 10 hours, 16 hours at that point when you've downed a cup of coffee because all of that adenosine, that's still there, can't communicate to the brain that you've been awake for 16 hours because- [S2] But it's, but the adenosine is still in brain- [S1] Correct. [S2] ... circulation. [S1] So- [S2] So, so the real question is what happens when caffeine is dislodged from the adenosine receptor?
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[S1] Delved into the data, which was pretty recently, there are two gene variants that will dictate the enzymatic speed with which the liver breaks down caffeine. And that's why you can have some people who are very sensitive to caffeine and other people who say, you know, I'm just, it doesn't affect me really that much at all. [S2] These are the people that have a double espresso after a 9:00 PM dinner and can sleep just fine. [S1] Yeah.
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[S1] Well, I'm, we'll come on to- [S2] Well, at least subjectively, they think they're sleeping. [S1] Subjectively, yeah. [S2] That's fine. [S1] And we, we should speak about that, that assumptive danger too. So, then the caffeine is in the system, um, and after some time period, it will be-
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[S1] All of the adenosine that's been building up during the time that the caffeine has been in my system. [S2] So sort of a, an avalanche of- [S1] It is a- [S2] ... adenosine. [S1] ... a tsunami wave, yeah. [S2] Well, and I've- [S1] And that's the caffeine crash.
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[S1] I have ideas about what the ideal world looks like for sleep, but I also realize that none of us live in this thing called the ideal world. [S2] We certainly don't. [S1] So, you know, I want to be really mindful of that, and I think I've done a really bad job of being sort of too forthright, particularly for people who struggle with sleep. You know, early on when I would offer these sort of messages about sleep, I want to be, you know,
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deviate from these, uh, these ideal circumstances. Along these lines, I, I do want to talk about alcohol. [S1] Yeah. [S2] Because I think caffeine and alcohol represent the, uh, the kind of two opposite ends of the spectrum. Clearly, there are other stimulants, um, they're your Adderalls and your, uh, high energy drinks that people use, but alcohol and caffeine are, are the most commonly consumed. [S1] Yeah. [S2] A stimulant and, and sedatives, depressants, as they're sometimes called. So, um,
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[S1] What happens when somebody has a glass, we always hear, a glass or two of wine in the evening or a, or a, uh, a cocktail after dinner. [S2] Yeah. [S1] Or before dinner. How does that impact their sleep? And then we'll be sure to circle back in terms of what is reasonable ranges of behavior when it comes to, uh, avoiding alcohol or if it's age appropriate, et cetera, enjoying alcohol.
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[S1] Sort of, and this process of, this event, I, that we call falling asleep, I have to imagine is a process. [S2] It is a process. [S1] Like everything in biology. [S2] Yeah. [S1] And that, that process involves in some way, as we talked about, push-pull before, turning off thinking, planning. [S2] Yep. [S1] Et cetera, and turning on some sort of relaxation mechanism. I have to imagine that these two things are knobs turning in opposite directions- [S2] That's right. [S1] ... that gives us this outcome we call falling asleep. Alcohol, it seems, is helpful for some people to,
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[S1] The, the third part of alcohol in terms of an equation is that it's quite potent at blocking your REM sleep, your rapid eye movement sleep. And REM sleep is critical for a variety of cognitive functions, um, some aspects of learning and memory. It seems to be critical for aspects of emotional and mental health. [S2] You've described it before as a sort of self-generated therapy that occurs while we sleep. [S1] Yeah, it's overnight therapy. You know, it's emotional first aid, uh, is REM sleep. [S2] Well, certainly people that don't
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[S1] Well, certainly people that don't get enough sleep, um, are very easy to derail emotionally. [S2] Yeah. [S1] Um, not that one would want to do that to people, but we all sort of fall apart emotionally. Our, I, I, I always think of it as almost like our skin sensitivity can be heightened. [S2] Yes. [S1] When we are sleep deprived, um, our emotional sensitivity, um, is such that when we're sleep deprived, uh, such that it takes a, um, much finer grain of sandpaper to create that kind of friction. [S2] Yeah. [S1] Things bother us.
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[S1] Well, I should, here, here I am. [S2] Maybe, maybe everyone of them. [S1] Here I will editorialize because the notion of not looking at comments is, um, is unreasonable for, to ask of any academic because academics, we are all trained to look at our teaching evaluations. [S2] Yeah. [S1] And just like with online comments, to ignore 20% of them. No, I'm kidding. [S2] [LAUGHS] [S1] We look at them all, um, in any event. So,
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[S1] ... is yes. Um, I think one study just looked at a single glass of wine in the evening with dinner, and I would be untruthful if I didn't just simply say, "It has an effect," and we can measure that, uh, in terms of- [S2] Less REM sleep. [S1] ... less REM sleep. [S2] Mm-hmm. [S1] And one of the fascinating studies, I can't remember what dose, I think they got them close to a standard
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[S1] ... their growth hormone release during alcohol-laced sleep at night. [S2] Wow. [S1] You know. [S2] And growth hormone is so vital for metabolism and repair of tissues and, um, keeping body fat low and- [S1] Yeah. Yeah. It's not just for kids. It, it, it is essentially- [S2] Oh, it's essential. [S1] ... adults, yeah. [S2] Essential.
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[S1] Well, it is released in, in, across both of those, but across the different stages. But what we also know is that when you disrupt REM sleep, there are those growth hormone consequences. [S2] I see. [S1] So it's not an exclusive, uh, system. Just like with testosterone, we can see changes throughout non-REM sleep, but if you ask when are the peak release rates of testosterone, it's right before we go into REM sleep and then during REM sleep.
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[S1] And of course, testosterone being important both for, for males and for females, right? [S2] Yeah. [S1] For libido and tissue repair and well-being. [S2] Yeah. [S1] Nobody, regardless of chromosomal, hormonal, or any other background, wants to have their normal levels of testosterone reduced acutely. [S2] No. [S1] That's just a bad, it, it, it equates to a terrible set of psychological and physical symptoms. [S2] Yeah, and the mortality risk that's associated with low testosterone is non-trivial. [S1] Prostate cancer. [S2] Right, exactly. You know, so,
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[S1] ... of your longevity. And it was a linear relationship. It wasn't sort of one of these U-shaped or J-shaped curves that we often see with total sleep and mortality risk. It really was linear, that the less and less REM sleep that you were getting, the higher and higher your probability of death. And then they did- [S2] Was that death due to, um, natural causes or accident? 'Cause I could imagine if you're not getting enough REM sleep, you're more likely to drive off the freeway, step off a cliff. [S1] Yeah, I think it was all- [S2] You just make bad-
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[S1] ... they did this great machine learning analysis, and I may get these numbers backwards, but I think for every 5% reduction in REM sleep, there was a 13% associated increased risk of mortality. [S2] Wow. [S1] Uh, and I could have, I'll have to go back and, and check, but
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[S1] ... to me, the, and in the machine learning algorithm, what they ultimately spat out was that of all of the sleep stages, REM sleep is the most predictive of your longevity, of your lifespan. So we often, I hear people saying, "How can I get more deep sleep?" Uh, or they sometimes say, "How can I get more dream sleep?" And my answer is a question. Why do you want to get more of that? And they'll say, "Well, isn't that the good stuff?" And I'll say, "Well, actually, all stages of- [S2] It's all the good stuff. [S1] ... of sleep are, yeah.
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[S1] Well, it's like the exercise question. And it took decades for people to understand that moving around at, uh, for about 150, probably 180 minutes a week at doing endurance-type work, zone two cardio type work, it is correlated with living longer, feeling better, less diabetes, et cetera. There's really no way around it. [S2] Yeah. [S1] I mean, you can,
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[S1] Um, you can ingest Metformin until the cows come home. [S2] [LAUGHS] [S1] You can take NMN, all of which I think have, have their place in, um, certain contexts. I'm a big fan of the work surrounding all, all those protocols. [S2] Yeah, likewise. [S1] But without getting proper amounts of movement, meaning sufficient numbers of, doesn't matter how many 12 minute exercise regimes you follow per week, you need that
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[S1] ... threshold level. And it sounds like the same is true of REM sleep and to- and total amount of sleep. There's just- [S2] Yeah. [S1] You, you, um, you pay the piper somehow. You know? [S2] Yeah, the return on investment, I mean, to, to flip the coin, the return on investment is, is astronomical. [S1] Mm-hmm. [S2] You know, I think of sleep. It, it is the tide that moves, you know, that raises all of those health boats. [S1] Mm-hmm.
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[S1] And the most fundamental layer of mental and physical health. Whenever people ask me, uh, even though I'm not a physician, they'll ask me, "What, what should I, what should I take or what should I do?" [S2] Right. [S1] The first question is always, "How's your sleep?" [S2] Great. [S1] Meaning, how well do you sleep every night and, and how, how long are you asleep? I always recommend your book, I always recommend your podca- I, you, you know, the podcast you've been a, a, a guest on, et cetera. Um,
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[S1] they can be revised, but it's more or less a one and done kind of thing until the next book comes out. [S2] Yeah. [S1] One thing that I like about the podcast format is that updates can be provided regularly, corrections and updates as new data come out. And so that's a, a wonderful aspect to, to this format and, and uh, hopefully the format that you'll be, uh, embracing. [S2] Yeah, I think, I, uh- [S1] I think the world needs to hear
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[S1] More from you more often about sleep and its various contours, um, not less. And, um, so I do have a question about, uh, drinking, alcohol. [S2] Yeah. [S1] Not that we want to promote day drinking, but let's say that the one,
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[S1] ... or two glasses of wine or a cocktail is consumed with lunch, something that isn't traditionally done nowadays, or- [S2] Yeah. [S1] ... in a late afternoon happy hour type cocktail, and then one is going to sleep seven or eight hours later. Do you think that that will improve or somehow mitigate the effects of alcohol? Or if you have a drink, are you, are you basically screwed for the next 24 hours?
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[S1] And not the ketones that people are all excited about. [S2] No, no, no. [S1] The other, the other ketones. [S2] Yes. [S1] The chemists, the chemists know what we're referring to, but- [S2] Yeah, this is not about ketogenesis. [S1] This is not about ketogenesis. [S2] Please don't worry. [S1] There are ketone bodies and, uh, that are released, uh, after ingesting alcohol that are not of the positive sort- [S2] Correct. [S1] ... that, uh, a ketogenic diet might promote.
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[S1] Right. [S2] Yeah. [S1] So I think in terms of that alcohol, um, profile, we certainly know that, you know, as you're heading into the evening hours, once again, timing and dose make the poison.
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[S1] I also want to say that life is to be lived to a certain degree. It's all about checks and balances. So, you know, if I go out and, you know, I have an ice cream sundae, I'm not big on those either, but, you know, sure, I know that my, you know, blood glucose is not going to be ideal for another 12 hours maybe. That's just the price you pay for having some kind of relaxed, fun life. [S2] Sure. [S1] I don't want to look back on life
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[S1] and think, "Gosh, you know, I lived until I was, you know, 111 and it was utterly miserable." [S2] [LAUGHS] [S1] You know. [S2] Right. So, but it's all about some kind of a balance. And, and my, my job is not to, to tell people, um, a prescription for life. It's just to offer some scientific information.
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[S1] key ingredients. We've got THC, tetrahydrocannabinol, and we've got CBD. And CBD is sort of the, the less psycho- well, it's what we think of as the non-psychoactive component. In other words, when you take CBD, you don't get high. If you take THC, you can get high. That's the psychoactive part of the equation. [S2] Are both considered sedatives in the technical sense? [S1] Uh,
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[S1] Um, when alcohol blocks your REM sleep. And your brain is smart. It understands how much REM sleep you should have had, how much REM sleep you have not, because the alcohol's been in the system. And finally, in those early morning hours when you're getting through to sort of, you know, 6, 7, 8 a.m. [S2] REM like crazy. [S1] ...
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[S1] That thought scares many of them. And many of them will experience intense anxiety without marijuana, which speaks to a, perhaps not addiction, but a certain kind of dependency. [S2] Right. [S1] Um, and again, I, I, you know, I know many pot smokers, um, some of whom, uh, have jobs that are, that are quite high performing and they, and they manage. [S2] Here in Berkeley, I don't know any of those. [S1] Yeah, no, none of those, right. [S2] [LAUGHS]
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[S1] ... becomes, and now again, you just don't know about, you know, purity. It's, it's very difficult. Although I think, and again, I'm, I'm not a user, not necessarily because I, you know, have anything against it. It's just that's not, you know, necessarily my cup of tea. There are some firms that are now doing third-party independent laboratory tests. [S2] Yeah. [S1] I don't know how game that is, so I've got no sense of it. [S2] No, I think some, some-
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[S1] ... sense of it. [S2] No, I think some supplement companies are quite, um, honest and accurate about the amounts of various substances that are in other, uh, products and some are not. [S1] Yeah. [S2] And I think there's just a huge range. I think the FDA is starting to explore CBD. There are, I,
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[S1] Certainly, I saw some grant announcements to explore- [S2] Yeah. [S1] ... the function of CBD. Most of the work on CBD is being done by the general public, ingesting it and seeing how they feel. [S2] Yeah. [S1] I gave it to my dog who was, had some, uh, dementia-related sleep disturbances, and it actually get, created a heightened wakefulness. It completely screwed up his sleep. [S2] Okay. It sounds as though he just wasn't- [S1] He's a bulldog, so if he's gonna get access to sleep, he's gonna take it. [S2] Okay. [S1] Um, really messed him up, took, took it away. He did better. Um, but, you know, that's, that's a canine, so- [S2] Right. And it could
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[S1] Right. And it could have been, you know, sort of dose related too, but- [S2] Or binders or other things that are in there. Sure. [S1] Correct. Yeah. And we, but, but right now if we were to, and I'm not making this statement, I don't think anyone can make this statement now, but if it ends up being that CBD is potentially beneficial for sleep, how can we reconcile that mechanistically? And I think there are, to me at least, there are at least three candidate mechanisms that I've,
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[S1] ... Amygdala deep within the brain is quiet and down with CBD. So I think that's at least a second non-mutually- [S2] That's great. That's interesting. [S1] ... exclusive, you know, possibility. I think the third, um, is some recent data that's come out that was suggesting that CBD can alter the signaling of adenosine.
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[S1] ... the kind of grand, the original, I should say, the, not the granddaddy, but the OG of sleep supplementation, which is melatonin. [S2] Yeah. [S1] The so-called hormone of darkness, uh, that's inhibited by light, et cetera. Frame for us melatonin in the context of its naturally occurring form. [S2] Yeah. [S1] And then I'd like to talk about melatonin, the supplement, because as, in my experience, anytime I say the word melatonin, people think about,
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[S1] Even though we'd, without necessarily getting into precise nanograms per deciliter values, what are the typical amounts of melatonin that we release each night? And then I'd like to compare that to what is contained in, say, a three milligram or six milligram tablet that one might buy at the pharmacy. [S2] Right, yeah. [S1] So I go to sleep at night. Has melatonin already kicked in before I shut my eyes and lay down my head?
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[S1] Usually, yes. [S2] Uh-huh. [S1] If your system is working in the correct way, as dusk is starting to happen, so let's say that you look at hunter-gatherer tribes who aren't touched by electricity, and so they're sort of the puritanical state par excellence when it comes to electric, uh, light influence. Um, and usually it's as dusk is approaching, that's when melatonin will start to rise, and so when you lose the
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[S1] Any human brain I've ever dissected, or I confess I've dissected a lot 'cause I teach neuroanatomy and have for years, um, I, I love looking at the pineal. It's the one structure in the brain that's not on both sides. It's usually pretty easy to find. [S2] Yeah. [S1] And it's pretty good size. It, it looks like a, it looks like a pea. [S2] Yeah. [S1] And it, it's sitting right there and it's remarkable that it releases this hormone, is that probably our entire lifespan? [S2] Yeah. [S1] And is inhibited by light. The, um,
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[S1] Correct. So, yeah, essentially your brain has a central master 24 hour clock called the suprachiasmatic nucleus that keeps internal time. Now, it's not a precise clock if left to its own devices, nothing that a Swiss clockmaker would be proud of. It runs a little bit long and laggy. [S2] It's like an American clock. [S1] So- [S2] There are a couple of good American
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[S1] There are a couple of good American watches, by the way. Hamilton's are very nice, but- [S2] It's very much like a Berkley. [S1] But we're not famous for our timekeeping or our punctuality for that matter, but the Swiss are. [S2] It's very, it, it's, it's not quite Swiss-like, it's more Berkley-like, which is very relaxed. Oh, you know, whatever. Um, so in most adults, the average adult, I should say, your biological clock normally runs a little bit long. It's about, um, about 24 hours and 13 minutes, I think was the last calculation. But,
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[S1] So it tells the rest of my brain and body, it's time to go to sleep. It, it perhaps even aids with the transition to sleep, but it's not going to, for instance, ensure the overall structure of sleep or, um, it's not the conductor that's guiding the sleep orchestra, so to speak, throughout the entire night. [S2] Yeah, it's, yeah- [S1] It's more like the, um, the, the people that essentially take you to your seat and sit you down and give you your program. [S2] Right. Exactly. Yeah. So the, the,
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[S1] ... analogy. [S2] It call, calls all of the, the sleep races to the line and it begins the great sleep race. [S1] Yeah, better analogy, by the way. [S2] It doesn't participate. No, no, no, no. [S1] Coming from the sleep researcher of all people. [S2] No, no, uh, the, uh, but it doesn't participate in the race itself. That's a whole different set of brain chemicals and brain, and brain regions. Which then brings us on to perhaps the question of supplementation, which is
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[S1] ... the individual studies, and we put them in a big bucket, and we kind of do this kind of statistical fancy sleight of hand, and we tried to come up with a big picture of what all of those individual studies tell us. And what that meta-analysis told us is that melatonin will only increase total amount of sleep by 3.9 minutes on average. [S2] Minutes? [S1] Minutes. [S2] Not even percent. [S1] Not, and it will only increase your sleep efficiency by 2.2%. So it really- [S2] Wow. This is-
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[S1] It is as, as, uh, they say in, um, certain parts of California, that's weak sauce. [S2] [LAUGHS] [S1] That's a weak sauce effect. [S2] It, the, the sauce is not strong. The force is not strong in, in, in this one. When it comes to a, a tool that in healthy people who are not of older age, it doesn't seem to be especially beneficial. Now, you know, results can vary. Everyone is different, of course. So we're talking about the average, the so-called average human adult here.
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[S1] Well, melatonin, um, in defense of what you're saying, and also I should mention, I have a colleague at Stanford, uh, Jamie Zeitzer, who you know- [S2] Oh, wonderful. [S1] ... Chuck Zeitzer's lab at Harvard Med, where- [S2] Brilliant. [S1] ... where he also trained a terrific sleep researcher, and I asked him about melatonin, and he essentially said the same thing that you just said, which is, very little, if any, evidence that it can improve sleep, and yet it's probably the most, um, commonly consumed so-called sleep aid. [S2] Hundreds of million dollars industry. [S1] Yeah.
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[S1] counter measure on when you're undergoing insufficient sleep, um, there are two, uh, two different routes there. The first reason that I think it could have a sleep benefit for some people is not because it helps in the generation of sleep. We know that it doesn't. It's because it too seems to drop core body temperature. [S2] Mm. There it is. [S1] And so- [S2] Temperature again. I'm, I'm fascinated these days more and more by temperature as, um,
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[S1] Maybe not just a ref, a reflection of brain state and wakefulness and in sleep, but actually a lever that, uh, is quite powerful. [S2] I think it's both. [S1] And, and with all the interest in ice baths and hot showers and saunas and stuff, something that we, we'll definitely touch on. Um, temperature variation is so key. So if, if melatonin is dropping body temperature by a degree or so, something that you've said before can help induce a sleepy state, uh, maybe that's what's allowing people to get into- [S2] I think that's one-
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[S1] The only population where we typically see some benefit, and it often is prescribed, is in older adults. Because as we- [S2] Older meaning, um, 60 and older? [S1] No.
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[S1] Well, along those lines, um, if we were to compare dosages, uh, I don't, or do we know how much melatonin is typically released into the bloodstream per night? Um, and can we use that as a, kind of a rule of thumb by which to compare the typical amount that someone would supplement? [S2] Yeah. [S1] I mean, typically the supplements for melatonin that I see, uh, in the pharmacy and elsewhere and online range anywhere from one milligram to 12 or even 20 milligrams. [S2] Yep.
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[S1] My guess is that a normal night's release of melatonin, typical for somebody in their 20s, 30s, 40s, would be far lower than that. [S2] It's- [S1] Am I correct or wrong? [S2] Mm-hmm.
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[S1] ... super-gulp size. You know, nobody wants to lower price. They just want you to, you know, we'll just give you more for the same price and that's how we'll compete. So it's been this escalating arms race of melatonin concentration. [S2] Mm-hmm. [S1] And it really does not look meaningful for, you know, for sleep in any way. What we've actually found is that the optimal doses for where you do get sleep benefits in
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[S1] 20 times as much food today. [S2] I thought you were going to use testosterone as example. [S1] Uh, well, let's- [S2] You know, you're going to take 300 times the normal amount of testosterone. We know that would have, um, t- tons of deleterious effects. [S1] Right. [S2] It'd be terrible. [S1] Yeah. [S2] And yet you can do this. Well, one thing that I'm concerned about, about these super physiological levels of melatonin is that, uh, many years ago, actually here at Berkeley, when I was a graduate student, we would inject
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many hundred, hundred fold or more. Um, in other words, they would go from having, um, nice healthy sized hamster t-testicles, what a hamster would consider healthy size, um, for a hamster, and they would shrink to the size of a grain of rice. So from like an almonds to a grain, size of a grain of rice. I had to see that only once for me to be very concerned about- [S1] [laughs] [S2] ... super physiological levels of melatonin. And I realized that- [S1] Yeah. [S2] ... melatonin does different things in different species. We are not hamsters. We are not- [S1] Right. [S2] ... seasonal breeders.
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[S1] ... seasonally restricted breeders. There might be more breeding during certain seasons. I don't know those data. But nonetheless, hormones are powerful. [S2] Yeah. [S1] And, and sure, there is an optimal, and sometimes, uh, we see that going slightly above endogenous levels for certain hormones, not always, can have beneficial effects.
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[S1] ... supplementation, taking 110, 500, sometimes even 10,000 times the amount that we would normally release. That's, that's my concern, although it's not nested in any one specific human study. [S2] Right. [S1] I just, I just don't like to see, I certainly don't want to see other people and I don't want to, uh, personally take a hormone that's known to be androgen suppressive at high levels. Why would I, why would I take that? I, that's the question I ask myself. [S2] I, I, I,
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[S1] That's the question I ask myself. [S2] I think it's a very, you know, good point. And if you look at some of the evidence around, you know, melatonin's lethality, if you want to go to that extreme, for the most part, you know, it, it's pretty safe that, that it's- [S1] You mean, you can take a lot of it before you die. [S2] Right, exactly.
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