Leading Stanford Professor on Fatigue, Sleep Issues and Circadian Biology

Welcome to Self Pack. Brady, we're cutting-edge science. He's cutting-edge. Now, go hear from Self Hacked. I am here with Dr. Jamie Site. Sir, he is an expert on circadian biology and sleep. Got a BA in biology at Vassar College. He got a PhD in neurobiology at Harvard University. And he was a fellow, a postdoctoral fellow, at UCLA and Stanford. And currently, he is an assistant professor at Stanford.

The reason why I wanted to talk to him today is because he happens to be an expert. He's published a lot of research on a lot of topics that I'm interested in, such as sleep, circadian biology, and also the vagus nerve as well. And he happens to have researched a few snips that are of interest. So, I actually don't know if he's into health at all. I'm trying to get the science. What is the, the most recent science on these topics? So, I'm really excited to have him here today.

Now, a topic of interest is lighting at night. What amount of light at night will phase shift a circadian rhythm, you know, or affect people's melatonin production, or negatively impact their sleep? Can you, you know, discuss that?

Sure. So, it's, um, you know, sadly, it's not not as straightforward an answer as we'd like it to be because it's, there are kind of two aspects to it. One is how much light can affect you, and one is how much light does affect you. So, you know, if we bring someone into a laboratory and keep them under very dim lighting for most of the day, we can then show that really dim light at night can have an impact. So, we usually measure things in terms of the Lux unit. You know, just to orient you to that, kind of, you know, five to ten Lux would be really dim lighting. Like what? Like, you know, somebody's people are in cities and, you know, even if they have, they think that, well, I turned off my lights, but there's usually like lamps or light pollution coming from outside. Is that enough? Is that what is that like? Is that five to ten Lux? Usually, it is. If you can still see color, you're at least above a Lux. Oh, wow. So, yeah, if you're seeing color, you're getting, you're getting pretty good light.

Okay. So, what about things like, I have a charger that emits blue light, you know, various appliances are going to be emitting blue-green light. That's like what, ten, twenty Lux? Well, so those are going to be pretty dim. You know, so if you, if you like watching television at night and the lights are out in the room, yeah, and you're sitting, say, you know, five to ten feet from the TV, yeah, that's going to be around five Lux or so. Five, ten Lux? Okay. Who's much brighter because of the contrast, but it's not that bright, and it has, it has a nominal effect. It does have an effect, but it's a nominal effect. When you get up into the, the room lighting area, then you're seeing much more substantial effects.

The problem with this is that much of this is mitigated by daytime light exposure. So, you know, if you spend most of the day, you know, indoors in a dimly lit room, then these are going to have a much greater impact. So, for example, you know, if you're spending all day in a dimly lit room and then you're using an iPad at night, you know, that's going to have an impact. But if you get out and you're, you know, you, you walk to work, you're in a well-lit office, it's going to have a much, much lower impact on your system.

Let's say somebody is getting bright light in the day. What should they stay away from at night? So, if they're getting bright light during the daytime, you know, when, during the time that you want to be asleep, during that kind of time, you want to avoid anything brighter than normal room lights. So, if you've got, you know, say a 50-watt bulb, if people still use, you know, incandescent bulbs, you know, something like that would give adequate light to read by. You can watch television, you can use the computer. You know, that amount of lighting really isn't going to have a big impact.

One of the keys with the lighting is what are you doing with that light? So, the thing that keeps people up, I think, more than the light, and I mean, it's kind of shooting my own, my own work in the foot here, in the sense that, you know, I spent years describing how light impacts the system, but in terms of how it's affecting sleep, you also have to focus on, you know, what the person is doing with that light. So, you know, if you're up and you're checking on your email right before you're going to bed, and this is stressing you out, well, that's going to do a lot more harm than the light in terms of impacting your sleep.

Is that because stress hormones like CRH or an overactive nervous system in general is going to cause a phase shift for your circadian rhythm? Well, it's not going to cause a phase shift, but it will cause an acute increase in alertness and anxiety, and these things will make it more difficult to fall asleep. So, you know, in the sleep area, you know, it's a very interpersonal or a person-dependent kind of thing. So, for example, some people have difficulty falling asleep because they have a kind of difficult time with the next day, all the stresses of the next day. So, for some people, it's recommended that what you do is you kind of write down a list of all the things you have to do the next day.

Now, and some, that's great, it works very well because what happens is that instead of thinking, "Oh, I've got, you know, I've got this to do at work, and that to pick up, and this errand to run, and all these things to do," and you kind of keep on cycling through this in your brain, and you forget that you've already worried about that, and you start worrying about it again. You write it down, you're nice, it's a finite list, it's not so bad. So, in some people, this is really effective. In other people, it's terrible because it just reminds them of all the things they have to do the next day.

So, again, it really depends on who the person is and what their personalities like. Um, so, for example, I don't check email at home. You know, when I'm at home at night with my family, I don't check email because all it does is stress me out. You know, it's just things that I need to do the next day, and usually their emails are, "Here's this thing that you need to do," but of course, you can't do it because no one's at work. So, if I can't learn about it, I just wait until the morning.

So, what's your personal approach for lighting at night? Do you, and with you and your family, if you were to implement something for optimal health, what would you do, and what do you do? I mean, I, there are two different questions because your family might, you know, not be on board with certain things. Sure. No, so I, I'm a firm believer in, you know, getting the, you know, good amount of darkness, you know, at night. I think it's very helpful. You know, when you wake up in the middle of the night, you know, if you have to, you know, use the restroom or something like that, or something wakes you up, you know, having a good dark environment, I think, is very conducive for sleep. And so, personally, I mean, you know, in my kids' rooms, we installed blackout shades. Not so that's very dark in the room. My, my youngest, who's a three-year-old, is sleeping in a room that actually has no windows in it. I mean, totally dark.

Was that on purpose? Or well, it's a limitation of living in the area that I live in, which is we don't have a lot of space, but it has helped him sleep tremendously being in a very quiet, very dark. As he used to be easily aroused during the nighttime by random sounds around the house. And, you know, so when he was, you know, two years old and going to sleep earlier than everyone else, it was very difficult for him to do so because he'd hear things and he'd want to be up and, you know, join in the party. So, he's, uh, in a very quiet, dark place, you know, he sleeps much better. And, and I, for sleep, you know, for much of sleep, it's about establishing good patterns.

And so, you know, if part of the pattern is going to sleep in a, you know, in a quiet, dark room, that's, you know, that's a good thing. Okay. And when do we want to turn off the light? So, you know, there was just a recent study about what hunter in certain parts of places close to the equator were doing. I'm sure you read that. No. So, they did find that before they went to sleep, there was four hours of darkness before they went to sleep. And, and I find personally, and other people, this may be some anecdotal support, and we see that even a small amount of light, five Lux, which is less than just turning on a light, it's what you can get from even outside. So, we see, and a lot of people are doing better. Like, I've done a lot better when I cut out the more light, I cut out the, the better I'm able to go to sleep. So, what do you think that's about? Because your recommendation is that, you know, okay, it's fine as, you know, as long as you don't have it brighter than a room light or something, and right before you go to bed, it seems like that's what your recommendation is.

Well, again, you know, this is, it's a very, you know, inter-person dependent thing. So, it's basically, people have to find a balance. Okay. So, the light is going to be alerting. That's negative in terms of, you know, going to sleep. But the question is, is the light for what purpose? So, you know, for example, I like doing crossword puzzles before I go. All right. Now, it relaxes me. You know, it keeps my mind focused on basically on, you know, silly things. You know, it's a crossword puzzle. It has no intrinsic meaning or value. You know, there's no stress involved in it. And so, it helps me relax. Now, there's a certain amount of light that's required to do this, right? So, well, the light is going to be, you know, somewhat alerting, but I find that the, the relaxing nature of doing the crossword for me, you know, outweighs, you know, the small alerting effect that I get from the light.

And so, that, what I'm saying is, it's a real balance that people have to strike. And so, you know, if you get up and, you know, so, for example, for people with insomnia who might get up in the middle of the night, if they have kind of fragmented sleep, you know, they technically should avoid light because that's going to make them even more awake. However, if just sitting in darkness makes them more anxious and makes their sleep worse, well, then perhaps they should get up, turn on a, on a dim light, and read, and that can help them. So, again, it's one of these things where there's really no absolute. You know, it's not that it will prevent you 100% from sleeping, but it does contribute to not having as good sleep, and you have to balance that out with what the purpose of the lighting is.

That's really interesting because it seems like you're approaching it in terms of alertness versus non-alertness, or how much is going to turn on your, yeah, oh, just overall alertness and your overall nervous system. Whereas I kind of, I guess before we spoke, I kind of thought of it as in like, the light is activating your suprachiasmatic nucleus, and that's shifting your circadian rhythm, or it's changing it in some subtle ways that we may not even be able to fully appreciate at this point, just because it's such a complex system. Do you think there's anything to that, or it's mainly just, okay, how alert are you, and how much, how relaxed you feel?

Right. So, there's, you know, so light is going to have, you know, multiple effects. This, in addition to the obvious, you know, seeing images aspect of light, you know, light does lots of other things. It shifts circadian rhythms, it increases alertness acutely, it can change the hormonal release, it changes pupil dilation, and there's probably even other things that we're unaware of. It, you know, it probably, there's pretty good evidence that it's linked to changes in mood. Right. Now, you know, these are all things that light can do. In terms of its impact on when you sleep, the, the lighting that you're getting at night, I think, is going to have both an acute effect, which is going to be the increasing alertness, as well as the long-term effect, which is going to be, you know, establishing a different circadian time, and therefore, on subsequent days, making it easier to stay up later.

And so, there's kind of a combination. So, if you're, say, if you normally stay up until 11:00, and now you're staying up in, you know, in a well-lit room until 1:00 AM, well, that, to add that extra two hours, the light that you're getting there is going to, you stay up because of the direct effect of alertness, and it can also be shifting your rhythm, or at least, you know, contributing to a shift in the rhythm, so that it happens at a later time. So, that way, the next day, it'll be easier to stay up until 1:00 in the morning because you've been shifted part of the way there from the light exposure, and you're continuing to receive light.

Now, I'm curious what you have to, what your take is about this. There's a doctor who claims that just the amount of light, amount of, what's a blue light that we're getting is harmful. He claims that it causes photo-oxidation of DHA and it causes an increase in ubiquitination. Do you have anything to say about those two things?

Yeah, I mean, there's definitely evidence that, you know, this, that, you know, excess amount of blue light is not good for the retina. How much of that is, you know, applicable at a, kind of, a, you know, a real physiological level? Well, that's kind of the unknown. So, you know, it has the capacity to do that kind of damage. Now, whether the, you know, the standard amount of blue light that you're getting, you know, that's coming off of electronics, which tends to be a little blue light-rich, um, is that enough to do that kind of damage? That's really unknown. Because, you know, usually what happens in these studies is you're extrapolating from high-intensity, short-term exposures to low-intensity, long-term exposures. And that's not necessarily a proper equation. And now, again, it's not to say that there is no damage or that it's not damaging, it's just that we don't know.

Do you, um, personally, like, have a program like f.lux to reduce the amount of blue light that you're getting from screens? Um, I don't. I, I know a lot of people like it, and if, you know, and when it helps people, that's great. I, I don't use it because, again, I, I don't do a lot of screen time at night. You know, I, I try to avoid that, not, not because I'm worried about the light, but because actually I'm more worried about, you know, the cognitive activation that might occur from it.

What about something like bright light sensitivity? Now that we're just talking about, you mentioned that blue light has the capacity to damage the retina. It, some people are more sensitive to bright lights, and it's probably mainly from the blue spectrum. What is that from? That bright light sensitivity? We don't know. Um, we're, at least I don't know. I, the, I, you know, I know that definitely people have different kinds of sensitivities to that. Sometimes they're, it's more of a central process because they're hypersensitive to lots of different modalities. You know, so they're not only sensitive to light, but they're also more sensitive to, to sound, to touch, smell. And that's usually more central. But, yeah, we don't know. We don't know why some people, you know, have that. You know, can think of it as, you know, there are also people who are super tasters, you know, who, you know, more, more ability to taste. There are people who have actually, there are some people who have extra cones and have a, you know, greater ability to discriminate colors. So, you know, that there are various things that, there are various kind of biological explanations, but, you know, for that one, I don't think we have a direct explanation.

Now, what are the percentage of genes directly and indirectly controlled by the circadian rhythm? I know there's no firm answer, but what is the current research say, and what do you think as like, you know, just more of a liberal take on it?

Sure. Yeah. So, the, the current research is, you know, says, you know, like 15, 20 percent, something in there. I have a feeling that that number is drastically incorrect. I have a feeling that the number is closer to 90 percent.

My gosh. Wow. Well, and the reason is, is that, and I'm, well, the reason basically is that the circadian clock temporarily organizes everything. Right? It's a master clock. It controls clocks that are found in basically every tissue over the body, and it helps to anticipate changes. And so, the question is, is that, you know, it takes energy to transcribe genes and make them into proteins. Now, if you don't need that, or if there's no reasonable expectation that you were going to need a certain process, then there's no reason to be making that gene or to be transcribing that gene. And, you know, you can think of it in the most simple approach would be saying a plant. You know, a plant at night has no reason to have photosynthetic machinery up and running.

And so, why bother? And so, when you look, that, if you look at plants, you know, you look at how the genes are transcribed, well, you know, things that are involved in photosynthesis aren't being transcribed at night. Right? And, you know, you can think of this in very much the same way in humans. If you're going to optimize energy utilization, which I think much of, you know, many of our cells do, you don't need to have everything active at all times. In fact, the interesting genes are the ones that need to be, you know, actively transcribed at all times of the day because these are the ones that are totally necessary for the cell just to function. But anything that's going, you can think of, well, many of the events that are occurring during the day are different than the ones that are occurring at night. And so, it makes sense that there's going to be some sort of anticipatory regulation of that, the basis of the circadian clock.

So, that's really interesting. I mean, you know, I, so somebody like you realizes the importance of the circadian clock isn't just instrumental to everything the body does, or almost everything. And then we also know that a tiny amount of light at night can really disturb things. And we know that we're getting more light at night, even if we try to block it out, than we've ever gotten, really. I believe the moon is one Lux. That's what one researcher told me. Oh, yeah. Well, yeah, full moon is one Lux. Full moon on a cloudless night, you might get a lot. Okay. Well, so then that means that that's even rarer. A full moon. Yeah. So, we've been exposed to maximum one Lux. You know, and, and it seems like we're just getting way more. It seems like it's just such an important thing that I would, I try to take as many measures as I can. I do wear red glasses at night to try to block out as much because I do want to use the screen. And I do know that blue and green, mainly blue, but secondarily green, right, can disrupt the circadian clock and, you know, maybe play around with melatonin, the suprachiasmatic nucleus. It just seems like it's such a delicate system in some ways. You know, I'm, I try to take the most precautions, especially for someone like me who has had issues with insomnia in the past.

What's your commentary on that? Yeah, so the, when looking at kind of the, the spectral sensitivity, there's, as you mentioned, that there's a blue shift. So, we are more sensitive to blue than to other wavelengths of light in terms of the circadian system. When we look at visual perception or image formation, we are optimally perceptive to green light. And so, if you need to function and do things at night, then say, exposure to kind of an orange light is going to be optimal in the sense that you're still going to have good acuity, and you're going to minimize the effects on the circadian clock. Now, we don't know, again, what the long-term, you know, consequences of this, you know, behavior. As you mentioned, evolutionarily, you know, what we're doing now, you know, has never been done before. You know, the past couple hundred years of electric lighting, you know, we have exposed ourselves to far more light at night than, than humanity had ever in the, you know, the millions of years of evolution have preceded. Right? But we don't know. We don't know what the consequences are.

Right. So, I guess, I guess it's just a matter of, number one, is what your symptoms are. If you're having insomnia, I guess you want to try out blocking out more light, especially the blue spectrum. I guess it's how, I guess, how precautionary someone is as to the unknown.

Yeah. Well, and again, as you point out, you know, a lot of this is, you have to compare our kind of who you are as a person and your personality and your, your basic biology and your traits, you know, with the countermeasures. So, for example, if you sleep fine, then you don't need to do any of this stuff. You know, well, I mean, it's still possible that there are some effects or a variety of effects on the circadian clock and then your wholeness, this system is going to, you know, I mean, look, if you, if you have a night shift job, you might sleep fine, but the fact is, you're at risk for a whole host of diseases. Right? So, it's not, only the better you sleep, the less you're, you know, the better you sleep, the, I think, the, the lower your your risk is.

Oh, I see. Huh. And so, again, you know, it's, look, that we have, there are a lot of stories, you know, basically, our older people come in and they have a sleep, they're not asleep. And so, you talk to them and you find out, well, you know, they slept fine until recently. You know, so, for the previous 75 years, they liked, they did have sleep problems. Now they have sleep. I say, you talk, right? You know, what do you do? Tell me about your sleep. The right, well, you find out, you know, basically every night after dinner, they have a cup of coffee. Right? Well, perhaps that's doing something. You know, perhaps it's not so good to have, you know, you know, 300 milligrams of caffeine, you know, right before you're trying to initiate sleep. Right? And then they say, well, that's never been a problem before. And it's true, it never was a problem before because their sleep was good enough that they could have a big dose of caffeine right before falling asleep and didn't affect their sleep. It didn't really impact.

That's the problem though. How does somebody know if it's affecting their sleep? Sleep is what, you know, you only know by taking it away. Well, no, but you still don't know. You, you haven't put yourself in an EEG machine. I mean, you're not putting yourself through all the testing, the modern technological testing. I mean, oh, subjectively, I think I got a decent sleep. I'm not sure.

Well, you know, and it's kind of funny. So, we actually, we have just submitted a paper. So, you can't find it. Yeah. Okay. Hopefully soon. Um, we're, what we did is we took a look at the gold standard of sleep recording, which is polysomnography. Okay? You know, where you hook up electrodes to someone's head and you monitor all of this electrical activity in their brain during sleep. And this is the gold standard for clinical sleep studies. And so, we looked at this in 1,500 older men and women. And in the morning, after they had one of these sleep studies, they were asked a series of questions, basically looking at their sleep quality. How good was your sleep? And so, that was kind of the, you know, the questions they were asking. So, you know, be like, if I said, "Joe, how'd you sleep last night?" And you give an answer. Well, we did all sorts of fancy statistical modeling techniques with this, the latest and greatest, and basically found that the polysomnography has very little to do with how you answer that question. About 15 percent of the variability was explained. Which basically means is that what we're recording in our gold standard method of recording sleep, and the current things that we can derive from that, actually explained very little about the answer to the question of how to sleep last night. And so, there is a split, you know, which is, you know, this, this question of sleep quality. How good is your sleep? It is a very, it is very dependent on the actual, more precise question that you're asking. So, is it sleep quality from a subjective perspective, which is one thing, and you can get eight hours? Or sleep quality from the perspective of the functions of sleep? For example, you know, was there, you know, good consolidation of memory that occurred during sleep? You know, did you have proper, you know, reorganization of various metabolites in the brain during sleep? And these are the questions that we're only starting to address in the field. So, these are basically, that we just don't know. So, for example, if you sleep for three hours, is that sufficient for memory processes?

We don't see. You seem to be agreeing with me that when, well, well, in that study that you did, something's up. Either the EEG is wrong, or the people, or the people's subjective, you know, their subjective evaluation of this sleep is wrong. It seems like you're saying that probably the EEG is not. Well, I'm saying what I'm saying is that what the EEG is picking up is not subjective sleep quality. So, the phenomenon of sleep that we can each describe as an individual is not being encoded in the EEG signal that we are recording. But is that, at least as word? I mean, it's possible that we're just not looking at it correctly, which I think is a distinct possibility. But at least, you know, when you go to a sleep lab and have a sleep study done, it really doesn't, that doesn't really reflect on kind of this individual sleep quality.

So, if we seem to be agreeing that, I, I think we both agree that, you know, EEG is not, there's a lot missing from that. Okay, that's one thing. But we also agree that probably someone's subjective evaluation of their sleep is not completely accurate either. You know, they can't tell how much their brain is clearing out plaque or whatever it is, or how much autophagy they're having during the night. So, that's my problem is that when we try to evaluate, okay, how much light at night is affecting someone, we do know that light is, a small amount of light is having effects, but we just don't know all the effects. And, and even if someone has good sleep, and even if that, you know, they have good sleep after caffeine, it's still probably a good idea not to do it, in my mind.

We, yeah, yeah. No, it's, it's definitely a possibility. And it's, this is again, it's just getting into the great unknown. Right? I mean, ideally, you know, you're going to want to sleep eight hours at night, or, you know, however long it takes. And, you know, honestly, the, so I say eight hours, and there have been all sorts of, you know, questions about how long. And honestly, the best advice I've ever received about that is from Dr. William DeMint, who kind of invented the field of sleep medicine. And his advice to answer that question is, because, you know, people ask, "How much sleep do I need?" Right? Well, in terms of, you know, sleep, if you are sleeping in on the weekends or when you have an opportunity to sleep in, if you do, then you're not getting enough sleep. You look, some people sleep for six hours and, you know, and then they'll say, "Well, I'm not tired." And this is usually after the third or fourth night. Because frankly, you know, the main thing that people are using as a metric for sleep is daytime sleepiness. Right? You know, how tired am I during the day? Well, you know, that is, in terms of, you know, relating that to nocturnal sleep, it's a little fuzzy because people can kind of inure themselves to sensations that the body will produce to indicate that it's tired. Right? So, if you look at people who are, who have a job, routinely work overnight, they have two choices. Right? They're working overnight. We don't currently have the ability to fully shift them because they want to, you know, when they're working overnight, they want to be alert at night. When they're off, they want to be alert during the day. We currently don't have the capacity to do that. But, you know, when they're working the overnight shift, they have two choices. One is they can feel tired and be miserable, or they can just kind of learn to ignore that feeling of fatigue. Now, if you test them, they're still performing poorly. Right? The brain still isn't working right. They're still performing as if they were up in the middle of the night, which they are. Right? But they don't feel tired. Right? Don't feel. And, and so again, because you can kind of get used to that feeling, well, you know, that means that that kind of that subjective feeling of sleepiness isn't a great marker for, you know, how well you're sleeping.

What about, let's say, my, my advice. Let's say myself and other people, it is just sleep out over much you need. So, you know, I guess if you're keeping to the proper sleep hygiene and you're, let's say, go on and sleep at a reasonable time, well, what time do you wake up? And whatever, you know, basically don't use an alarm clock. Right? And, and that seems to me the most sensible, because then you're going to be getting the amount of sleep that you need. What do you think about that?

Sure. I mean, ideally, people, you know, should get up without an alarm clock, you know, getting the amount of sleep that, you know, they feel refreshed after. Unfortunately, and this has been a conundrum for me, and I think for the field, is how to convince people that sleep is actually more important than some other thing. So, you know, most people aren't, you know, shortchanging their sleep just because, you know, it's for a reason. Well, they, you know, they're going to sleep too late, getting up too early because, well, they've got a two-hour commute because that's the closest job they can find, or they're staying up late because that's when they get to see their family, right? Or they're sitting up late because they've got work to do, or because they want to socialize. So, I mean, there are a variety of things that interfere with getting an optimal amount of sleep. And, you know, there's some, you know, basically a line in the sand where you have to make a decision as to what's more important. Because frankly, when you're doing that, again, you can kind of get away with with cheating sleep for quite a while, but in the end, it's going to affect your health. And this, I think, is what we struggle with as a field is, you know, we have to be able to define what that health consequence is. And, you know, so some of it, I think that's been coming out, there's been a lot of nice studies looking at how it impacts your, you know, your feeding behavior and your weight and weight gain and things like that. And so, I think that you're accumulating enough evidence there that people are starting to believe that. And I think that's true that when you're not getting enough sleep, this can affect your weight. Um, and so, you know, again, that's, that's a, that's a step, that's a positive step in the right direction. And I think there are lots of other things that, you know, I do think that, you know, when you're shortchanging sleep, you are affecting things like cancer risk. And again, what we need to do, you know, in in science, really, is to be able to give people the information so that they can make informed decisions. So, for example, if I say, if you get, you know, six instead of eight hours of sleep per night, and that's going to increase your cancer risk by one percent. Right? Okay. Well, what is the, you know, what do I get in return for, you know, doing the, having six hours of sleep instead of eight? Obviously, you know, if that's the consequence, what am I getting in return? And then you have to ask, well, is it worth it? Um, you know, and I, look, I think this is what people have done with smoking. And, you know, if you talk to people about smoking as well, what is the trade-off? Well, what is the risk of, you know, say, you know, getting cancer and likely dying of cancer versus what, you know, whatever you're getting out of smoking? Right? Um, and again, it's, but at least there's a trade-off that I think people are much more educated about now. And that's the problem with sleep is we don't have that, we don't have that information.

You know, I get a lot of people, or some people say they wake up tired. And especially some people, it's common that some people will say they'll take a nap and they'll be even more tired after than that. What's the cause of that? The biological cause? My take would be that they're having maybe some of that, it could be from chronic inflammation or oxidative stress. And sometimes it could be from a circadian amplitude problem, that, you know, the amplitude of their circadian rhythm is, you know, or maybe the, the phase or whatever it is, or they're not sleeping enough. I mean, there's a few reasons. But what would you, what would your take be?

George? So, I mean, to me, there's kind of the two, I think, largest answers. Again, this is not for everyone, but I think this encompasses quite a few people. One is that you have a lot of people who have undiagnosed sleep apnea. Right? So, these are, you know, pauses during, basically, you stop breathing during sleep. You then slowly choke yourself into consciousness, and then you go right back to sleep. And because of a phenomenon called retrograde amnesia, where you don't have memories made right around the time of sleep onset, you don't remember this. And then someone would say, moderate, so not even severe sleep apnea, with someone with moderate sleep apnea, is going to say, "Wake up 200 times a night." It is very disruptive to sleep, and most of them are on, most of the individuals who have this aren't aware that they have this. In fact, many of them will come into a sleep clinic, not because they have a problem sleeping. In fact, you ask them how their sleep is, they say, "They sleep great. They're heading to the pillow, they go right to sleep. Eight hours later, they wake up." They come in because they're exhausted during the day.

Uh, well, and then you find out, well, yeah, it's because, you know, you're waking up, you know, hundreds of times per night, you're never getting into deep sleep, and you're likely causing lots of, you know, again, oxidative stress, you know, to your system, which is probably causing lots of long-term damage to your brain and to your cardiovascular system. So, that, that's one of the things where people are waking up unrefreshed. But a second is that there's this phenomenon again, where we don't understand the physiologic cause of it, but it's called sleep. Well, people, some people call it sleep drunkenness, other people call it sleep inertia, which is basically, sometimes when people wake up, it takes a little while for their brains to get going. Now, in some individuals, this is because they're waking up at the wrong time in their circadian cycle. So, basically, one of the things that happens with your circadian clock is that it anticipates when you are going to be waking up. And as part of this anticipatory process, it's basically moving lots of the energy in the system from kind of stored energy to available energy. And this means that when you get up in the morning, if you're getting up at the right circadian time, you have lots of available energy to actually get your brain is active, it's alert, you have the energy to get up and move about, and you feel refreshed. Now, if you're getting up at the wrong circadian time, you're not going to have that. And what's going to happen is, instead of the energy being available in kind of a proactive manner, the energy is going to have to become available in a reactive manner. So, basically, your body's going to respond to you waking up by all of a sudden having to convert all of the stored energy into freely available energy. And that lag time there, again, is in many individuals, this kind of waking up unrefreshed because you just don't, you woke up the wrong time.

So, you think it's a phase problem in some individuals? Yes. They're waking up at the wrong phase. And then, still, they wake up at the right phase and they still don't feel, you know, that refreshed. And, you know, this is the great unknown. Is there something wrong with their sleep? Or is this kind of expectation? You know, one of the things that in sleep that's always kind of a weird thing is that many problems in people's sleep that, you know, may or may not have a biological basis, and some they do, and some they don't, but man, it's a, you know, they have problems with sleep. Much of it is perspective. And so, there, there's a whole field in sleep medicine which deals with kind of changing, changing people's perception towards their own sleep. And so, what they try to do is kind of, you know, rejigger how you think about your own sleep so that whatever you get, then becomes okay. So, in essence, so, for example, let's just say it takes you 20, that for whatever reason, psychological, biological, whatever, it takes you 20 minutes to fall asleep. If this doesn't bother you, taking 20 minutes to fall asleep, then it's not a sleep problem. Right? Right. You would never go to a sleep clinic about it. You'd never get anything done about it. So, it doesn't bother you. Now, if it does bother you, well, now, the exact same behavior, the taking 20 minutes to fall asleep, if that bothers you, then all of a sudden, that becomes a sleep problem. So, much of the sleep field, in that part of the field, is kind of allocated to figuring out how to kind of change, you know, people's opinions about their their own sleep so they don't worry about it so much. Because frankly, when they worry about it, usually it gets better. When they don't, I'm sorry, when they don't worry about it. So, for, you know, for example, I have a colleague whose husband gets up every night in the middle of the night, and, you know, three o'clock in the morning, and he reads a book for 45 minutes and goes back to sleep. Doing this for 30 years. Right? Now, if someone else did that, if they get up, you know, in the middle of the night for 45 minutes, and they got anxious about it, and they worried about it, and they were in emotional distress about it, right? Well, that's a problem. And so, the thing is that the behavior is the same, basically, which is, you know, being awake for 45 minutes in the middle of the night, but the response to that is very different. And so, again, a lot of it is kind of just changing the response to the the same behavioral event.

Right. Now, what about diagnosing sleep apnea? I've had some, some people I deal with that, you know, they had sleep problems, different kinds of sleep problems, and most of the time, they, they would wake up feeling under refreshed. They would get a sleep study, and it would come back normal. And then, some of those times, you would look at the results and you'd see that the percentage of slow-wave sleep and REM sleep is lower than a healthy population, yet they wouldn't be diagnosed with sleep apnea. And then, you know, there's variability with like sleeping in this foreign place, people will have different levels of anxiety. I mean, you know, where you're sleeping and who your doctor is, it seems like there's a lot of variability in diagnosing sleep apnea. What is the criteria exactly? What, like, what percentage of slow-wave sleep should people be getting, REM sleep, and then obviously, is the oxygen saturation what it dips to at night? What's your take? How do you diagnose sleep? How would a clinic diagnose sleep apnea?

It's actually one of the more straightforward of diagnoses. Because it's just very dependent on something called the apnea-hypopnea index, which basically just counts how many apneas and how many hypopneas. And hypopneas are when you stop breathing, and hypopneas are basically where your oxygen level kind of drops over a specific amount of time. And right, these are kind of codified and can be counted. And then, you know, the decision has to be made if you have, you know, if you've got lots of these. So, for example, if you've got, you know, 15 or 20 of these per hour, you know, then they're going to recommend treatment. All right. If you're down around five, and you're an adult, yes, technically that's apnea, but, you know, the cure or the fix for it is not the most comfortable thing. It's basically having kind of a tube over your nose and maybe your mouth during sleep, and it kind of forces air in your throat to keep your throat open during sleep. Again, you know, for something down at that level, a lot of clinicians aren't going to recommend treatment.

But a lot of these studies do show, let's say, that people are having a sleep problem, maybe they don't have sleep apnea, but they're having a lower percentage of slow-wave sleep, a lower percentage of REM, and they're not going to even mention anything. Sure. So, what would you say to those people?

Yes. So, basically, we don't, we have no idea what it means. You know, so if you have, you know, less slow-wave sleep, you know, what does that mean? We have no idea what that means. You know, we think we know what slow-wave sleep does, but for example, you can have, if you look in a lot of older individuals, you know, many older individuals have no deep sleep. You know, they don't have these big slow waves that are happening. Now, does that mean that whatever the function of the slow wave isn't happening in these individuals? I don't think so. And so, we don't know what these things mean. And that's kind of one of the problems. So, you know, if you're not getting enough REM sleep, well, I don't know what enough REM sleep is. Now, if you weren't getting any REM sleep, that would be something to worry about. Wrong. But there's quite a bit of REM sleep, what, you know, kind of normal amount of REM sleep would constitute that would look like. I guess, you know, it is, I guess you read research, or I read research sometimes on the benefits of slow-wave sleep. And, you know, so if it contributes to X, Y, and Z, or they think so, at least in animals, and same with REM. And there's a whole bunch of hypotheses, nothing is 100%, of course, but we have ideas about what slow-wave sleep is doing and REM sleep. Generally, they're associated with positive health outcomes. So, yeah, you're right, it's, it's lower slow-wave sleep when you get older, but then, you know, that also coincides with a whole bunch of issues. Now, you know, what's the cause and effect? Nobody knows exactly. But we do know that there's general consensus that the more slow-wave sleep, and then maybe the more REM sleep, generally, it's better. And we also know that they're maybe not waking up or as refreshed. I guess what would you do for those people? They may not have sleep apnea, but in my mind, they're having some kind of sleep problem.

Well, again, you know, if they're going into a sleep clinic, that means...

They have a sleep problem, bro. You know, okay, that's, you know, that's usually one of the giveaways. And so, you know, the problem is, is that what can you do about it? Well, you know, that we don't know. And so, you know, is it that, you know, you've slept eight hours and you're not refreshed, and you look, and there's no apnea, and you know, you wake up in the morning, and you wake up the same time every morning, and you know that there's not quite as much, you know, stage 2, it's not as much REM, you know, we don't know. We don't know what that means. We don't know how to fix that.

Mom, there are, you know, there are a limited number of pharmacologic techniques that can kind of improve sleep. And, you know, it's, it's a problem. So, I mean, one of the things that I, I think has been an interesting development in the field, which is, there's a new medication that has been approved by the FDA for sleep. And what it does is, instead of, so most sleep medications act by kind of increasing inhibition in the brain. So if you look at, you know, the things like benzodiazepines or drugs like Sonata or Lunesta or Ambien, which act on the benzodiazepine receptor, these are all things that are just increasing inhibition and basically shutting the brain down, right? Now, they are very good for the most part at making someone not awake. Mmm. It's not the same as being asleep, but they're not awake, at least. And in many cases, this is what people want. You know, so someone's had a traumatic experience, they need to just not be awake for eight hours, all right? And this is an effective kind of thing for that. But then you've got a lot of people who have chronic insomnia, and this is not necessarily the best kind of treatment for that. Mmm-hmm.

And so, what this new drug that's out is doing is, it's, instead of increasing inhibition of the brain, what it's doing is that it's blocking awake-promoting signals. Mmm-hmm. And so, this, this wake-promoting stimuli, it comes from orexin or histamine. Yes. Yeah, it's, it's orexin. It's not Roxanne. Hypocretin. These are, these are two names for the same molecule. Histamine, and basically blocks that system. And that system seems to be a much more limited system in terms of what it's doing, because it does seem to be important for organizing things that are occurring during wakefulness. So the idea here is that what you're doing is you're blocking this wake-promoting system, and then you are allowing natural sleep-promoting systems to act. You know, it's creating a permissive environment for sleep, as opposed to forcing the brain into a state of sleep. And so, you know, I think a lot of people are very interested to see how this plays out and see if this is actually helpful for people, especially people who have difficulty initiating sleep because of stress or anxiety or basically too much wakefulness when they're trying to initiate sleep. You know, does this, you know, kind of pharmacotherapy, you know, how interesting.

Now, I'm curious about a few things and sleep. Let's say, so one of the things I've been trying out for a few months is, I'm naturally a, you know, relatively thin guy, so I don't have to worry about my weight so much. But I historically have eaten less. I wanted to see what the effect of maybe increasing my caloric intake and I would assume, let's say, improving, let's say, my mitochondria in some ways, whatever. But anyway, basically, when you do that, you increase adenosine, and adenosine is the main driver for sleep pressure or sleep onset. Is that true? I mean, it's kind of like more of a hypothetical thing with me. I'm thinking, well, if you increase metabolism, you're gonna increase adenosine, increase in adenosine, more that's gonna build up, and then you're gonna be able to fall asleep better, right?

So, the, yeah, so with adenosine, it's definitely true. As cells become more metabolically active, they convert more ATP, and that eventually then becomes adenosine, right? That, that's, this is factorable, right? Um, however, the process of adenosine release by cells and its impact on sleep appears to be a very regionally specific thing in terms of its impact on sleep. Mmm-hmm. So it appears to be very specific parts of the brain can do this, where the increase in adenosine release is contributing towards the increase in sleep. And one of the ways you can think about this is that the main, well, wake-promoting drug that people use worldwide is caffeine, right? Right. The main effect of caffeine is to block adenosine receptors, right? Right. It has other effects, but not at concentrations that you would ever reach in the brain. You're talking about the PD inhibition? Well, yeah, it can, it can do that, and it can also work through receptors called ryanodine receptors. Mmm. Our cell, calcium storage? Okay. It doesn't work that. Its prime, you can localize it most to adenosine. Okay. Now, when do most people have coffee? You know, morning. In the morning, right? When, in theory, their adenosine should be at its lowest point, right? So there's a disconnect somewhere in this theory, because, you know, if you're having caffeine to block the effects of adenosine, and you're having it in the morning when you have the least amount of adenosine, how is that working?

No, we're still trying to figure that out because it doesn't work. I mean, that part of the theory does not work. And, you know, we've done studies looking at actually adenosine in human brains and, you know, basically found that it doesn't seem to increase in, well, in the areas of the brain we looked at, which were not at all the areas, and definitely not some of the areas that you can look at in animals or non-human mammals. Yeah, we didn't see this kind of ubiquitous increase in adenosine. Mmm-hmm. Though something's missing in the theory. Mmm-hmm. And I'm not sure what it is, but something is missing. But I find interesting is, I actually get tired from caffeine first, initially, and then I get more awake. Have you ever seen something like that? And if yes, do you know what that's from?

I used to have more fatigue in the day, a lot more fatigue in the day. But when I had more of those issues, if I would take caffeine, I would crash from it. Yeah. So, and that is a common effect from people, especially people with an overactive nervous system, more of a stressful phenotype, they're crashing from caffeine. What is that from? That, you know, I don't know. It's a good question. You know, there are lots of systems in the body that kind of have this paradoxical response. And so, for example, you know, in, there are lots of, especially in kids, Mmm-hmm, where if you give them sedating agents, they become hyperactive. Mmm-hmm. And so, that, and so you refer to these as these paradoxical responses. And then there's various theories as to why they might happen, but at this point, it's mainly phenomenological. Mmm-hmm. It does happen. We just don't know why. And I think that's, you know, that's the case in the caffeine. Oh, I see. Say that, you know, we did study caffeine and college students, and not during particularly stressful times or anything. And what we did find is that the caffeine pretty much had no effect on their sleep because they were just so sleep-deprived that they could have a Red Bull and then go right to bed. Uh-huh. It just didn't matter. Wow. Just so they were under so much sleep pressure, then it didn't have much of an effect. Now, the only two things to remember with caffeine is that caffeine takes about a couple of things with caffeine. One of them takes about 45 minutes for it to peak in your blood. And so there's going to be this, you know, that this right after you drink something with caffeine in it, you know, the immediate time after, you're not going to have much of an effect. It's really around 45 minutes later we're gonna start feeling the effects much stronger. And second is that the, the inter-person variability in caffeine metabolism. So, so how rapidly you get rid of caffeine is huge. Not, I mean, a normal range is between say, two hours and 12 hours. And so that means, you know, one person who had a cup of coffee in the morning, if they have a 12-hour half-life, and they had it at 7 a.m., that means at 7 p.m. And so if they had say, 200 milligrams at 7 a.m., at 7 p.m., they still have 100 milligrams of caffeine running around their system. Mmm-hmm. And this can have a negative impact on sleep. Other people who are on the two-hour range, after, you know, they have it at 7 a.m., and by the time it's, you know, one, you know, one o'clock in the afternoon, and there's zero caffeine left in their system. Mmm-hmm. So, you know, again, lots of variability. And and it's affected by things like oral contraceptives and smoking. Both radically change the half-life of caffeine. So there are lots of things that kind of impact that.

What do you think of something like, I find it's normally if you, if you're eating the research, you see that if you have sleep deprivation, the sleep debt builds up, and then you do have more slow-wave sleep the next night, easier to go to sleep, things like that. Um, for me, I actually find that it's opposite. When I have a sleep debt, I don't function as well on the day, but then I'm like pushing through, pushing through, pushing through, and then at nighttime, I'm just more awake. To me, that seems like a circadian problem, something's off with that. What do you think is like going on there?

Yeah, so there's two things. One is the, the issue of the circadian timing, which is that your feeling of alertness is going to be regulated by both how long you've been awake and your circadian clock. So your circadian clock actually has a peak drive for wakefulness right before the time you normally go to bed, which means that's actually it's very difficult to initiate sleep early. Mmm. Then you normally. So if you normally go to sleep at midnight every night, and then also and you want to get some extra sleep, so you try to go to sleep at 9:00, it's really difficult to do that. Mmm-hmm. I'm not sure unless you again, you're sleep-deprived, in which case it becomes easier. But in normal circumstances, it's very difficult because again, your circadian clock at that point, what it's doing is it's saying you've been up for 16 hours and you've accumulated 16 hours of sleep debt. Mmm-hmm. And now you're tired, right? This is trying to keep you up. At the end of that 16 hours, it's trying to offset that accumulation. Mmm-hmm. And it basically, we think it's enabling you to spend 16 hours awake. And and frankly, this is a, in amongst mammals, a fairly unique kind of thing. So when you look at mammals besides, there's humans and then a few new world monkeys that have truly consolidated wakefulness, which basically means you can spend, you know, 16 hours awake, eight hours of sleep. All other mammalian species pretty much don't do that. They nap. So sleep at night and they nap during the day. Um, now we can nap during the day, but we don't have to. And so, getting to your question about, you know, the sleep at night is that if you're trying to, you know, initiate sleep when your circadian, again, a little early because you've been up so long and now you're really tired and wanna go to sleep, well, it's gonna be very difficult to initiate sleep at that earlier hour. Mmm. And, you know, so it's one of these odd phenomena where the flipside is that in the morning, say, you know, two hours before you normally wake up, that's when your circadian drive for sleep is at its peak. Mmm-hmm. And you experience this if you ever stay up all night and you have this feeling of a second wind. Right? This feeling of second wind is basically that you stayed up the whole night. So say you've now been awake for 24 hours, and at that point, the circadian drive for sleep starts to abate. So now you've, and now you have the homeostatic drive for, you've been up for 24 hours, but you no longer have this extra circadian drive for some. Mmm-hmm. So you actually feel more alert after say, 30 hours awake than after 22 hours awake, just because of the circadian rhythm. Right? You don't have the extra circadian drive. And then, so if you look at someone's, you know, kind of average, you know, sleepiness, again, it's pretty stable during the day, it drops off at night, and then the next day it'll go back up, not be as much as the first day, but it'll be better than that night. And so actually, when you look at some sleep debt, after 40 hours of being awake, they are less tired than they were after being 20 hours awake, right? And then of course, this kind of cycles through like that. So again, yes, that kind of feeling is very much a cycling thing. Huh. And you can also have an issue where you have, you seem to have these kinds of windows of opportunity for sleep. Right? Now, some of this window is created by the circadian system, where you basically, you've gotten to a point where the circadian system is now no longer signaling for wake, and now you have an opportunity to initiate sleep. Now, this window, though, seems to be modulated by how you respond to feeling tired. So basically, some people, you know, at when they're getting tired, their brain starts to fight that. And again, this is the kind of the, the kind of this, this paradoxical reactivity. And so you start to kind of, your brain starts to do things that are going to wake you up more. And the more that happens, then to look, the harder it will be to initiate sleep. I say, yeah. So it gets into this, you know, at night, you have this nice, you know, neat window where you can fall asleep. But if you stay awake too late, it can be, in some people, more difficult to initiate sleep because that, because that your brain starts to do things that are going to basically enable you to stay awake.

That's interesting. I definitely feel that where I kind of, I have this, I go through bursts where I'll feel really tired from this period. If I push through it, then I won't be able to go to sleep for another two, three hours or whatnot. Yeah. Yeah, that's, that's again, we, you know, we have, you know, various guesses as to what's going on at a biological level, but we do observe that kind of thing phenomenologically.

Is there any problem going to sleep at different times in the night? I know, you know, it's part of sleep hygiene, you go to bed at the same time. It just doesn't seem something like that's suited for me. It just seems like sometimes I want to go to bed at 9:00 and sometimes I want to go to bed at 12. What does that indicate to you? Is that a problem, or is your recommendation that you should go to bed at about the same time?

Well, my recommendation is, if it works, go to bed at the same time, right? Now, because again, that'll, you know, that does lots of things. That that helps stabilize the circadian system, right? That also helps to build good kind of cognitive patterns associated with bedtime. So if you have difficulty falling asleep, you know, the, the more kind of patterned your nighttime routine is, the more that your brain can kind of anticipate, right? But if somebody doesn't have a problem with sleep onset, then you would say it's mainly involved in sleep onset, is that what it is? Yeah. Okay. Yeah. Yeah. Well, and also, you know, again, if, if you have erratic sleep timing, you know, even on, even if it's not difficult falling asleep, and you can do that and going to sleep in a wide range of times, you may have difficulty staying asleep because again, the circadian system is going to turn off its drive at some point, and that point may not be where you want to sleep until. You know, so if you know you're normally going to sleep at 9:00, and then also and you want to go to sleep at 12, and you can do that, that's great. But then your circadian system is going to be expecting you to, you know, kind of wake up at, you know, 5:00, and it's gonna be difficult to stay asleep longer than that. I see. So, yeah, I mean, I guess I don't really have that many problems with that, especially now. I don't really have any problems with that now, so that's fine. If somebody were having those problems, then they should definitely pay more attention to that. Definitely.

What about something like marijuana for sleep? Um, in the states that it's legal, of course, you know, and just, just from, you know, research perspective here, right? You know, it hasn't been studied well. There's obviously lots of anecdotal evidence, and, you know, it has a definite biological effect. I mean, there are endocannabinoid receptors, and, you know, it's, it's likely to do something. But that being said, it has not been well. It's a micron with marijuana is that we know it really interacts with the suprachiasmatic nucleus in a strong way, and, you know, that causes the time-shifting. Even people who are high, you know, and then it also increases adenosine and slow-wave sleep. Or those mixed research on that, but it seems like that's what it, it does. I mean, so it seems like it has some positive, some negatives. When you have to be able to, like, I know there's not a lot of research on it, but what's your, like, guess? If it helps somebody, then, and they are in a state that it's illegal, then?

Yeah, I mean, I have to say that my guess is that it's going to have similar properties to alcohol. Oh, wow. Well, in terms of, I think that one of the main benefits of marijuana is its anxiolytic effects in terms of how it's affecting sleep. Mmm-hmm. And so I think it's enabled because it, it acts as an anxiolytic, I think that this definitely helps people kind of initiate. Now, the question is, is that, and this is where the research is mixed, does it help people maintain sleep? And that's a quite a bit fuzzier data. So that's the issue with alcohol is alcohol, again, as an anxiolytic, it helps people initiate sleep, but the dehydration effects of it often disrupt sleep later. Mmm-hmm. And also, the sleep isn't exactly normal sleep either. Again, you can have some instances where you have increased slow-wave activity, other instances where you've increased fragmentation. So, I mean, there's, there's lots of, you know, things associated with that, which probably have to do with, you know, dosing and timing and things. It's an individual biology, yo. And very, right.

This is when I try to read the research on sleep apnea, it goes like a headache and stuff because you don't know the cause and effect. Like, are these cytokines high because of sleep apnea, or is the cytokines causing sleep apnea? That's why it's such a hard condition to read up on because you don't know what's causing effect. What are the fundamental biological causes of sleep apnea? Is it cytokines? Is it a structural problem? Or B, someone being overweight and it's just so many pressure they're putting on?

Yeah, so I think for sleep apnea, you know, the two major groups of in sleep apnea, one is related somehow to obesity. The thought is that there is an excessive amount of tissue in the throat, which is then causing obstructions to occur, right? Now, we also know, though, this, this thin people have sleep apnea. So, yeah, so that's the other category. So you have a lot of individuals who, it's not just thin, it's actually odd of individuals who have, many of whom are of Southeast Asian descent, where the jaw is set back, like, and Mmm-hmm, when it's set back slightly, basically there's just a little less space in the throat. Mmm-hmm. And so that's another common group that you have. So these are two of the common areas.

Has there been like a, it seems like there's been a big increase in sleep apnea, and that may be wrong, you can correct me if that's wrong. And so it must be something in the modern environment that that's increasing that. Is that a great at all?

Or we've all gotten angry? There's, there's increased recognition. Okay. Think back, you know, thirty years ago, there was, you know, very little sleep medicine. So, you know, most people weren't getting treated or even aware of this as a disease. Um, so that's one thing. Second thing is that, yeah, there's, in, there's been a, the increase in apnea has followed quite nicely the increase in obesity. And obesity, right? So, you know, that's gonna be enough. Now, say that one of the problems that the theory is that because you see sleep apnea so much in people who are overweight, that's assigned to do with the amount of tissue in their throat. There are surgeries where people have this tissue removed, and I have to say is that many of these surgeries are very unsuccessful. How well? So again, there's, there's in some people, this is true, the surgeries help them, fixes it. In other people, not so. So there's other things that are going on, then we just don't know what they are yet. So the answer is, right, the research is just not there yet.

And what do you think about the elevated cytokines cause a factor? That's more of an in effect rather? Okay. All right. I did read a study that claimed on mice that it, you know, it was they had evidence that it was in a cause of sleep apnea as well. But again, I don't, okay, contribute to it. Whether or not it's, you know, it can be a standalone cause, that I'm not so sure. Right. Right. You know, it's again, a much trickier thing to study in people than it is in mice.

So now, let's say somebody comes to you and says, I've got fatigue in the day. They do a sleep study. Obviously, anybody with fatigue, I'm assuming you're gonna recommend, do a sleep study? Right? Yeah. Yes. If it's, yeah, you know, that's often a way to exclude other causes, right? So, okay. So let's say they do a sleep study, and then, you know, they just say they're tired the other day, and then you have, they improve their sleep hygiene, and they still have some problems. What are, like, you know, an esteemed researcher like yourself, what would you say? Like, what do we know about? We know that the orexin system is massive in the wakefulness, as a wakefulness promoter. It's, you know, controls the histamine neurons. Well, my opinion is, obviously something going on with that system. Now, what is the problem? We know that cytokines suppress that system. We know that, you know, there's different things that suppress it. And what, what would you say to somebody who has fatigue in the day?

Well, you know, being that I'm a researcher, I don't have to tell them anything, right? But, you know, see your doctor. Yeah, it's tough. I mean, if there's, you know, if there are no obvious problems with their sleep, you know, this is where you start to look to other issues. I have to say that, you know, in some individuals, you're gonna have to look and to see, you know, is there a psychiatric component to it? And in some individuals, there will be. When you see psychiatric component, mean by that exactly? Well, I mean, you know, in some individuals, they're gonna be depressed. Oh, I see. How that depression is going to kind of, you know, instantiate itself is going to be in, you know, in daytime fatigue. Or the other way, if it's, what is, you know, if I say, "Oh, I'm tired during the day." You know, this is, you know, the classic problem in philosophy, you know, it's theory of mind. Is I don't know what you mean. I mean, I know what I mean, but I don't know you mean. I'm just guessing. Okay. So again, you know, this is why, you know, is something like that, which is, you know, frankly, not a measurable thing. I mean, we can't measure someone's, you know, empirically measure actual fatigue in someone, right? So, you know, because of that, well, you know, what we're stuck with what they're saying, which again, I'm not denying that they have fatigue. I have to believe they do. And I believe they do. So the just the question is, well, you know, what is the cause? So if it's depression, then that's a two-to-one tree. If they keep biological, that's what you want. True. Here's just interesting things though. So let's say we do know that depression and fatigue correlate. That's something that's pretty, yeah, it's pretty known. Now, my my understanding is, you know, depression can cause fatigue, fatigue can cause depression. That's one way of thinking about it. Or another way is that something else is causing both of them, right? And so the way the medical establishment works is, well, they treat them by the symptoms. Are you diagnosed with depression or not? And depression is also a vague thing. Yeah. How do you, you know, they don't take brain scans of your brain, okay, you've got depression. And yeah, it's, it's a subjective thing. So it's kind of like, well, oh, what's the cause of fatigue? Well, I'd like to see if they have another subjective symptom. Yes. Um, so what I like to see is, well, even if they're depressed, what's causing their depression? Like, and if they have depression and fatigue, what would cause both? Depression? It's a teeth.

A hundred percent agree. It's actually, I think a big problem in the area of psychiatry is that things are defined as symptom clusters, right? So, you know, they're not defined based on, oh, there's an error in this very specific molecule, this part of the brain. Exactly. Are your symptoms? And because of that, things are treated symptomatically. Doesn't that strike you as?

Okay, so it strikes me as really strange because, well, it's inadequate. The question is, is that, you know, until we start to understand, which I hope that we are slowly doing, what the actual causes are, you know, what are the choices? Right. I see you saying. So you're saying it kind of evolved from more of like the medical establishment evolved from much earlier time where we did not understand anything about the body, whereas now we're understanding a lot more. Do you think there should be some kind of evolution where instead of, well, this person is depression, and we know depression is helped by SSRIs, it's kind of like two steps removed. And in some ways, like, what is this kind of like correlations? While this studies showed that there was a slight, you know, slightly more people where help is ours, instead we should try to figure out, are they having a serotonin problem? Are they having a dopamine problem? Are they having a norepinephrine problem? Are they just having an orexin problem, which we know increases motivation and wakefulness? And you're right, we don't know exactly. We have a bunch of theories and mouse studies and maybe some human studies, all the different possible causes, cytokines and this and that. But and they're just a hodgepodge of like, well, we don't know what this person has or that person, or we don't know what has the most effect, the least effect. But the point is, we do have a lot of theories that are somewhat supported that it seems like it would be a better system than to just say, well, you have depression, take an SSRI. Well, do you have a serotonin problem specifically? You know, what do you think?

Is something that I wholeheartedly agree with. I'm not even sure if things will be, in the end, a serotonin problem or something which is further upstream from that. Yeah, of course. You can even think about serotonin. You know, serotonin comes from the world. There are many different neurons that produce serotonin. So it's even likely to be even more limited than that. So it's going to be a serotonin problem in a specific area of the brain, right? So we have, I think, a decent handle on what is happening in the body for various diseases. And I think we have, you know, for the most part, no handle on what is happening to the brain. Mmm-hmm. For anything that's happening to the brain, I mean, so one of the very, very few disorders where we understand what is causing it is the sleep disorder narcolepsy. Right? Right. It's one of the very few disorders that we have, well, we actually know what the problem is. You know, is that you're not making hypocretin. Well, so that's very, very rare in, in anything having to do with brain function to have something which is that isolated. Right? And it's a brand. I agree. I think it's a very big problem. I think that the, the one-size-fits-all approach, it doesn't work and has lots of negative side effects and many problems. Unfortunately, think it's what we have now. Yeah. And, you know, so that being said, you know, that's what we've got. But yes, I do hope that in the future, I'm not sure if I'll be alive for that future, but that that's where we're heading to, is understanding being the causal etiology of these problems, which will then lead to a direct treatment of that cause, as opposed to the, the downstream us symptom. Right. It seems like that would be a while away. Yes.

What about, like, let's say, see, you have studied the HPA axis and studied? Yep. We know that the HPA axis is elevated in depression. Yep. So what do you think is going on there? Is there something? My opinion is probably bidirectional. The HPA axis is causing depression, maybe? Or then there's things that increase the HPA axis, like cytokines, inflammation. Mmm-hmm. Yes. Yeah. No, it's, I do think it's a bi-directional process. What's unknown is if basically if people have kind of a predisposition to this. And so I like to think of this as kind of a, you know, a depressive phenotype and a phenotype. And, you know, I think of the same way with insomnia. So, you know, if you have insomnia, you could sleep well for 10 years, and you still have insomnia, right? In the sense that I might get it at any moment. And I think it's the same way with depression. This is just, I think that this wave that, you know, certain brains work, right, to have a proclivity towards certain disruptions. This seems like there's like a variety, a whole spectrum of root causes, and based on people's genetics, how one receptor works or another, they manifest itself in different symptoms. So this is a variety of conditions, insomnia, depression, anxiety disorders, that have an elevated HPA axis or just an overactive nervous system in general, which is what, you know, an HPA axis is an indirect measure of. So it seems like it's better, it seems like a better approach to medicine would be, does a person have an overactive HPA axis? And we don't know if that is directly causing every condition that it's associated with, but wouldn't it be smarter to say, instead of like, okay, you've got depression, and necessary, let's try to decrease your overactive nervous system? And so you go back to a more first principles approach. Well, what is causing an overactive nervous system? Bad sleep will cause an overactive nervous system. Cytokines will. It seems like it's, it's a smarter way to approach dealing with with the human body. Is that something that you, what do you have to say about that?

Yeah, I mean, I, I do think it is. I think that, you know, in theory, it is a much better way to approach these things. The problem is, I think from a clinical perspective, is they have no idea what causes these things. So because of that, you don't know how to assess it, and then even if that, then how to treat it. You're saying doctors don't know what they're not studying the underlying causes of depression? Researchers are, but no, I meant a clinician. Sorry. You know, frankly, the problem is, like, there's no blood test. It would be very nice if you could, like, for example, if you want to know if you're diabetic, you go in and you get a blood test, right? And if they want to, and they can do some, you know, there are various kinds of provocative testing that they can do as well, but I mean, it's pretty straight. If you've got depression, there's no blood test, there's no brain scan, there's nothing that tells you that A, you have depression, and B, what that depression is caused by. Even, you know, testing, you know, you can test the HPA axis and cortisol, and and they're definitely been studies looking at that, and that's been the most extensively studied. But any of the neurotransmitter systems, there is no provocative testing of those systems. And so, you know, until we get to that point, it's going to be exceedingly difficult to do this. Now, not to say that we shouldn't aim for that, and I do think that I, among, you know, many, many other people, you know, this is what we're trying to do, is basically apply principles of neurobiology to these clinical disorders. But you, you could test for some things. You could test for systemic levels of cytokines, which we're not doing. You can test for cortisol, which most doctors will not check for.

Well, again, because it comes a, so for example, if you want to look at cortisol, that would be not a single blood sample. You know, this is something where you're gonna have to take serial blood samples under a very specific set of, you know, conditions.

What about, let's say, saliva? That's becoming, that, you know, the alternative, quote-unquote, alternative health sphere, they do saliva tests. Do you think that saliva is accurate for a measure of cortisol?

Um, it can be, um, but it isn't necessarily so. We just actually published a paper looking at that exact question. Okay. Found that that in this is in a specific patient group, these, this is this is in women with cancer, that what was happening in the blood was not what was happening in the saliva. So there was a disconnect between the saliva and the blood.

I find the same thing in the people that I get. So I have read research that says that it is correlated, but in my, when I look at people and they give me their blood and they give me their saliva, I'm like, this is just two different people. It seems like.

Yeah, it's, um, again, you can't, it's that there is a correlation there, but it can be limited.

What, why is saliva not accurate? Why is the cortisol, what, what controls the cortisol in your saliva?

So what happens is basically is that you have cortisol when it's released, then basically some of it is free in the blood, and other is bound to specific proteins that are circulating in the blood. Cortisol binding protein? Yeah, okay. And so what goes into saliva is basically, you know, a pretty fixed ratio of what is free. Mmm-hmm. Right? Now, what you have available in the body is going to be a combination of the free and what is bound, because you can unbind what's bound and then use that. Um, what you're picking up in saliva is just the unbound fraction. So if there's something that's interfering with the binding at all, then that's going to disrupt how the salivary concentrations are perceived.

So, it seems like in some ways that would be a better measure because that's the free cortisol. And if you, if you want to check, it's not a measure of your HPA axis per se, but it's a measure of, if you want to see what cortisol is the biological activities of cortisol in the body, what, what level of that is free?

Um, it is, it can be a reasonable measure of that, yes. Okay. It's, it's a reasonable measure of, again, the amount of free cortisol. For the most part, again, that there is always, there are always situations where it's a little less true, but yes. Okay.

So, sorry, I interrupted you before. Oh, no, you were saying that you have to check your cortisol multiple times through.

Yeah, so if you wanted to actually know if this is working, you would, you would check it. You go into a laboratory, you spend several hours and have provocative testing with specific drugs to see if it can drive your cortisol and where the problem is. So, you know, when you look at cortisol, you've got, you know, the pathway is basically CRH being released in the hypothalamus, which buzzes ACTH being released pituitary, which causes then cortisol to be released from the adrenal gland. Mmm-hmm. And, you know, you want to see where is there a disruption, right? And how responsive is this to various kinds of specific kinds of medications. So it's, it's a, it would be something that it's saying that we do in research when we're looking for specific questions, but until it gets established as a real cause, doctors can't get reimbursed for it, and most of them don't have the capacity to prescribe even some a test like that, right? At this point, it's still a very, you know, experimental kind of test.

But it seems like even though it's experimental, it has value. You're measuring it, the studies on it, but it just hasn't transferred over.

Oh, it hasn't translated yet, but yeah. But you're looking at it and you see it has value. You're measuring it, the studies on it, but it just hasn't transferred over. Well, because the problem is, is that, okay, we say there's a problem in the HPA axis. We say that, you know, you have, you are for whatever reason, you're just not as responsive to CRH, okay? What are we gonna do about that? Well, that's where the story is, because so, you know, here's you saying this, it's a treatment problem.

It seems like a, now I'm a bit of a cynic, that, yep, the reason why it's not being translated is because there is no drug for it. That's correct.

Okay. Tibs. Well, there's no, well, not just a drug, basically, there's no way at this point. Is there a treatment for that problem? Well, is there a drug or a treat? Yep. Or, yeah. And well, yeah. And it doesn't have to be a drug, you know, I mean, dietary. But then even if it is dietary, who's gonna fund it? The only, that's right. The only, the only way the different thing is going to get the level of evidence that insurance companies will reimburse something. Yeah. And that it won't take a hundred years to study. Yep. Meaning you need billions of dollars. And then that's the own, and who can fund that? Or either the government or the insurance companies. But the government doesn't put that kind of money out for studying individual treatments generally. So generally, it's going to be a drug. Right? And so that's why basically when you, you know, when you think about it, you first have to establish what is the problem, right? Right. And and then you have to sell, and how many people is this a problem? Now, if you can establish that, that, okay, here's the problem, and here's the number of people that that we think this is the problem, and then you've established a market. And once you've established a market, there will be a drug company developing a drug for that market. Right? But again, it's, it's the first step is establishing that is the problem. Mmm. Uh, and I think that there's, it's, unless you have an easy way, a quick and easy way to diagnose in an office or with a blood test, you know, with a simple blood test, there's going to be very difficult to convince doctors to do any sort of prescribing for it, or insurance companies for paying for, you know, the tests.

So it seems like what you're saying is, well, there is value to it, but we have to ask, you know, the reason why it's not being adopted is because, you know, number one, is no drug for it. Number two, is we don't know the exact cause, the exact percentage of how much of either I'm sure that this is causing the problem, or how, you know, or is this the underlying cause? And number two, is the tests are tedious, they're hard to do. You're talking about what sounds like a CRH stimulation and dexamethasone suppression test. Yeah. So, you know, it's it's expensive. You're gonna have to test the cortisol. And the question is, well, if we don't have anything to do about it, there's no drug out there, and the research isn't conclusive 100%, then, and, and the test is tedious, then, you know, it's just you have to ask yourself, and it's expensive to do, you know, insurance companies are not going to get on board with it so quickly. And in patients and doctors are not gonna get on board with it. So who's gonna get on board with it? It's just not gonna be.

But what I would say is, if somebody did have a lot of money, or enough money to to to wanted to test for it, and they saw that this was, you know, a reasonable underlying cause for a problem of theirs, it seems like it could be, in my opinion, I'm more of a forward thinker. I would personally test it out if money wasn't a serious issue. Now, the problem that I guess I would come up to is that who's going to do it for you? A doctor is not gonna do it because they can't even order it, right? You'd have to go to a specialized research place, and they're not gonna do it for you unless this is in the context of some study. Yes. Yeah. Yeah. And so, yeah, this is, you know, these are the limitations that, you know, that we face in this.

That's okay. That is really interesting. Now, I've taken up a lot of your time today, and I do have a lot more questions, but I think you've been really helpful so far, right? And I really appreciate you taking the time. These are questions that really, I think this disconnect between what's happening in the research and what general people who are having these problems know, because they're not, unfortunately, getting the quality of information that you get given from their doctors, simply maybe because of the lack of time. But yes, so I really appreciate this and thank you very much and have a wonderful day.

Thank you. You too. All right. Thank you so much.