Dr. Zeitzer is extremely knowledgeable in areas such as sleep, fatigue, and circadian rhythms.
Why You Need to Listen to This Interview
Dr. Zeitzer is a beast when it comes to publishing, especially about topics I’m interested in.
I found Dr. Zeitzer when I was searching for the top researchers at Stanford on circadian biology. After looking through what he’s published, I knew he’d be a wealth of knowledge.
This interview isn’t necessarily about health, as Dr. Zeitzer isn’t an alternative health guy. But it’s what drew me to him in the first place; he’s simply a good scientist (and also pretty skeptical).
In order to make the right health moves, we need the most recent science – and the best way to get that science is straight from the source.
Dr. Zeitzer is more true to skepticism, and frank about the great unknown. He doesn’t claim to know what he doesn’t know or to be scientific and skeptical (such as in science-based medicine) without the follow-through. Dr. Zeitzer stays true and hard to these ideas, and for that, he’s earned a great deal of my respect.
As is the case for most of my interviews (I recorded this about 4 months ago), I have found that some of his ideas had a significant impact on me.
However, during the interview, you’ll hear some significant pushback on some of his opinions.
Here’s a list of what he’s published. The following is what he’s published in 2014:
- Nocturia reported in nightly sleep diaries: common occurrence with significant implications? Health psychology
- Millisecond flashes of light phase delay the human circadian clock during sleep. Journal of biological rhythms
- Actigraphy-Measured Sleep Disruption as a Predictor of Survival among Women with Advanced Breast Cancer SLEEP
- Bedtime misalignment and progression of breast cancer CHRONOBIOLOGY INTERNATIONAL
- Randomized controlled trial of pharmacological replacement of melatonin for sleep disruption in individuals with tetraplegia JOURNAL OF SPINAL CORD MEDICINE
- Correspondence of Plasma and Salivary Cortisol Patterns in Women with Breast Cancer
- Longitudinal assessment of sleep-disordered breathing in Vietnam veterans with post-traumatic stress disorder. Nature and science of sleep
- Retinohypothalamic regulation of light-induced murine sleep. Frontiers in systems neuroscience
About Dr. Jamie Zeitzer
Dr. Jamie Zeitzer is an expert on circadian biology in sleep. He received his BA in biology at Vassar College, a Ph.D. in neurobiology at Harvard University, and was a postdoctoral fellow at UCLA and Stanford. Currently, he works as an Assistant Professor at Stanford.
The reason I wanted to talk to Jamie Zeitzer today is because of his strong research background and expertise in sleep medicine. He has published a lot of research on many topics that are of interest, including sleep, circadian biology, the vagus nerve, and several SNPs. I’m actually not sure if he’s into health at all. The purpose of this interview is to try to peek our heads into some of the most recent science on these subjects. So I’m really excited to have him.
What We Cover In This Interview:
In this interview we cover:
- how light affects our circadian rhythm and our sleep,
- what percentage of genes may be controlled by our circadian rhythms (his prediction may shock you),
- how to determine your individual requirement of necessary sleep,
- testing for ‘sleep quality’ (and what the definition of sleep quality is),
- sleep apnea,
- why you’re waking up tired,
- marijuana‘s effects on sleep,
- the problems in our medical establishment, which are preventing necessary testing and treatments needed for certain sleep disorders.
Lighting Effects on Sleep
A: It’s not as straight forward of an answer. There are two aspects. One is how much light can affect you, and the other is how much light does affect you. If we bring someone into a laboratory and keep them in dim lighting for most of the day, we can then show that really dim light at night can have an impact. We usually measure things in terms of the lux unit. 5-10 lux would be really dim lighting.
Q: Like what? People are in cities and they think, well, they’ve turned off their lights, but there are usually light bombs coming in from outside. Is that enough? What is that, 5-10 lux?
A: Usually it is. If you can still see color, you’re usually at least above a lux.
Q: What about things like my charger that emits blue light, or various appliances that emit blue/green light. What will that be, 10-20 lux?
A: Those are going to be pretty dim. If you’re watching television at night and the lights are out in the room, and you’re sitting 5-10 feet from the T.V, that’s going to be 5-10 lux or so. It seems bright because of the contrast, but it’s not that bright. It has a nominal effect. When you get into room lighting, you see much more substantial effects. The problem with this is much of it is mitigated by daytime light exposure. If you spend much of the day indoors in a dimly lit room, then these lights will have more of an impact. For example, if you’re spending much of the day in a dimly lit room and use an iPad at night, then that’s going to have a stronger impact. But if you get out, it’s going to have a much lower impact on your system.
Q: Let’s say someone is getting bright light in the day, what should they stay away from at night time?
A: If they’re getting bright light during the day, then during the time that you want to be asleep you want to avoid anything brighter than normal room light. If you have a 50W bulb, something like that would give adequate light to read, watch TV, use the computer. That amount of lighting won’t have that much of an impact. One of the keys with the lighting is, “what are you doing with the light?” The thing that keeps people up, I’m kind of shooting my own work in the foot here in the sense that I spent years describing how light impacts the system, but in terms of how it’s affecting sleep, you also have to focus on what the person is doing with that light. If you’re up and you’re checking your email before you’re going to bed, and it’s stressing you out, that’s going to do a lot more harm than the light is, in terms of affecting your sleep.
A: 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. In the sleeping area it’s a very person-dependent thing. For example, some people have difficulty falling asleep because they have a difficult time with all the stresses of the next day. So for some people, it’s helpful to write a list of all the things they have to do the next day. In some, it works very well so they aren’t cycling through the to-do list in their head. In other people, it’s terrible because it just reminds them of all the things they have to do the next day. It really depends on the person and their personality.
Q: So what’s your personal approach for lighting at night, with you and your family, if you were to implement something for optimal health? What would you do and what do you do? These are two different questions because your family may not be on board with some things.
A: I’m a firm believer in getting a good amount of darkness at night. When you wake up in the middle of the night, having a dark environment is conducive to sleep. In my kids’ rooms, they’ve installed blackout shades. The youngest is sleeping in a room with no windows. It’s a limitation because where we live we don’t have a lot of space, but now he isn’t aroused by certain sounds around the house. For much of sleep, it’s about establishing good patterns. If part of the pattern is going to sleep in a dark quiet room, then that’s a good thing.
Q: Ok, and when do we want to turn off the lights? There was a recent study about what hunter-gathers in certain parts of places close to the equator were doing (I’m sure you read that), and they did find that before they went to sleep there were 4 hours of darkness. I find personally, and other people find, and there’s maybe some anecdotal support that even a small amount of light, 5 lux, which is less than just turning on a light (it’s even what you can get outside), and we see that a lot of people are doing better. I’ve done a lot better, the more light I cut out the better I’m able to fall asleep. So what do you think that’s about? So your recommendation is that ok it’s fine as long as you don’t have it brighter than a room light or something, and right before you go to bed, is that what you’re recommending?
A: So again, it’s a very interpersonal thing. Basically, people have to find a balance. The light is going to be alerting, and that’s negative in terms of falling asleep. But the light is for what purpose. So, for example, I like doing crossword puzzles before I fall asleep. It relaxes me. There’s a certain amount of light required to do them which will be somewhat alerting, but for me, the relaxing effect of the crossword puzzle outweighs the small alerting effect that I get from the light. It’s a real balance that people have to strike. For example, for people with insomnia, who get up in the night, they technically should avoid light, because that’s going to make them even more awake. However, if just sitting in darkness makes them anxious and their sleep worse, perhaps they should turn on a light and read that can help them. So there’s no real absolute.
Q: It seems like you’re approaching it in terms of alertness vs non-alertness and overall alert system, vs. before we spoke I thought of it more 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 is it mainly how alert are you and how relaxed you feel?
A: So light is going to have multiple effects. In addition to the obvious seeing images aspect of light, light does lots of other things, shifting circadian rhythms, increasing alertness acutely, change the hormonal release, purple dilation, and there are probably other things we aren’t even aware of, there’s pretty good evidence that it’s linked to changes in mood. these are all things light can do. In terms of its impact on when you sleep, the lighting that you’re getting at night I think is going to have an acute effect, increasing the alertness, as well as the long term effect, which is going to be establishing a different circadian time, therefore on subsequent days making it easier to stay up later. There’s kind of a combination there. So if you normally stay up until 11, and now you’re staying up in a well lit room until 1am, that extra 2 hours, the light that you’re getting there is going to help you stay up because of alertness, and it’s going to also shift your rhythm or at least contributing to a shift in your rhythm so that the next day it will be easier to stay up until 1 am.
Blue Light and DHA
Q: I’m curious what your take is about this. There’s a doctor that claims just the amount of blue light that we’re getting is harmful. He claims that it causes photooxidation of DHA and it causes an increase in ubiquitination. Do you have anything to say about those things?
A: There’s definitely evidence that excess of blue light is not good for the retina. How much of that is applicable at a real physiologic level is the unknown. So it has the capacity to do that kind of damage. Whether the standard amount of blue light that you’re getting off electronics is enough to do that kind of damage? That’s really unknown. Usually what happens in these studies is you extrapolate from high-intensity short term exposures to low-intensity long term exposures. That’s not necessarily a proper equation. That’s not to say that it is or isn’t damaging, it’s just that we don’t know.
Q: Do you personally have a program like F.lux to reduce the amount of blue light you’re getting through screens?
A: I don’t. I know a lot of people like it, and if/when it helps people it’s great. I don’t use it because I don’t use computers at night, not because I’m worried about the light, but because of the cognitive activation that might occur from that.
Bright Light Sensitivity
Q: What about something like bright light sensitivity, now that we’re talking about blue light having the capacity to damage the retina. Some people are more sensitive to bright light, and probably from the blue spectrum. What is the bright light sensitivity from?
A: We don’t know, or at least I don’t know. I know that people definitely have sensitivities to that. Sometimes it’s more of a central process because they’re hypersensitive to lots of different modalities. So they’re not only sensitive to light, but they’re also sensitive to sound, touch, smell, and that’s more central. But we don’t know why some people have that. There are also people who are supertasters. There are some people who have extra cones and have a greater ability to discriminate color. So there are various biological explanations, but for that one, I don’t think we have a direct explanation.
% of Genes Controlled by Circadian Rhythm?
Q: What are the percentage of genes, directly and indirectly, controlled by the circadian rhythm? I know there’s no firm answer, but what does the research say, and what do you think as more of a liberal take on it?
A: The current research says 15-20% or so, I have a feeling that number is drastically incorrect. I have a feeling that the number is closer to 90%. The reason basically is that the circadian clock temporally organizes everything. It’s a master clock that controls clocks found in basically every tissue of the body, and it helps to anticipate changes. The question is it takes energy to transcribe genes and make them into proteins. If you don’t need that or there’s no reasonable expectation that you are going to need a certain process, then there’s no reason to be transcribing that gene. You can think of it in the most simple approach in a plant. A plant at night has no reason to have photosynthetic machinery running at night, so why bother? If you look at plants you look at how the genes are transcribed, things involved in photosynthesis aren’t being transcribed at night. You can think of this in the very same way in humans. If you’re going to optimize energy utilization, which I think many of our cells do, you don’t need to have everything active at all times. In fact, the interesting genes are those that need to be actively transcribed all day because these are the ones that are necessary for the cell just to function. Many of the events that are going on in the day are different than the ones that are occurring at night. So it makes sense that there is going to be some sort of anticipatory regulation of that at the basis of the circadian clock.
Q: That’s really interesting. So somebody like you realizes the importance of the circadian clock, instrumental to almost everything in the body. We know that a tiny bit of blue light can really disturb things, and we know we’re getting more light at night even if we try to block it out than we’ve ever gotten. I believe the moon is 1 lux, what one researcher told me?
A: Yes, a full moon on a cloudless night you might get a lux.
Q: Wow so that’s even rarer. So we’ve been exposed to a maximum of 1 lux and it seems like we’re getting way more. It seems like such an important thing. I try to take as many measures as I can. I wear red glasses at night to try to block out as much light. Because I do use computers at night. Mainly blue but secondarily green can disrupt the circadian clock and play with melatonin and the suprachiasmatic nucleus. It seems like such a delicate system. I try to take the most precautions, especially for someone like me who’s had issues with insomnia in the past. What’s your commentary on that?
A: When looking at the spectral sensitivity, as you mention there’s a blue, we are more sensitive to blue than other spectrums of light, in terms of the circadian system. When we look at visual perception or image perception, we’re optimally perceptive to green light. So if you need to function and do things at night, with say exposure to an orange light, it’s going to be optimal in a sense that you’re still going to have good acuity, and going to minimize the effects on the circadian clock. Now we don’t know again what the long-term consequences of this behavior are. As you mention evolutionarily what we’re doing now has never been done before. In the past couple hundred years of electric lighting, we’ve exposed ourselves to far more light at night than humanity had ever, in the millions of evolution proceeded. But we don’t know what the consequences are.
ME: So I guess it’s just a matter of, for one thing, if you’re having insomnia, you want to try blocking out more light, especially the blue spectrum. I guess how precautionary someone is to the unknown.
A: As you point out, a lot of this is you have to compare who you are as a person, personality, basic biology and traits with the countermeasures. for example, if you sleep fine, you don’t need to do any of this stuff.
Q: It’s still possible there’s some effects or a variety of effects on the circadian clock. 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?
A: Correct. But the better you sleep I think the lower your risk is.
ME: Oh I see.
Define Quality of Sleep?
A: Again, there are a lot of stories, basically a lot of older people come in. They’re not sleeping. So you talk to them and you find out well they slept fine for the previous 75 years of their life, now they don’t. You talk to them and find out every night after dinner they have a cup of coffee. Well, perhaps that’s doing something. Perhaps it’s not good to have 300 ml of caffeine right before they are trying to go to sleep. And they say it’s never been a problem before. And that’s true. Because their sleep was good enough that they could have a big dose of caffeine before sleep and it didn’t impact their sleep.
Q: That’s the problem, though. How do you know what’s affecting their sleep? You’re not putting yourself through an EEG machine, through the modern technology testing. Subjectively you can say, ‘yes I think I got a good night’s sleep,’ but I’m not sure.
A: It’s kind of funny we actually just submitted a paper, you can’t find it yet but hopefully soon, where what we did was we took a look at the gold standard sleep recording which is polysomnography where you hook 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. We looked at this in 1,500 older men and women. In the morning after they had one of these sleep studies, we asked questions about their sleep quality, like “how was your quality of sleep?” So those were the types of questions we were asking. 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% of the variability was explained, which basically means that what we’re recording in the gold standard 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 did you sleep last night.’ And so there is a split in this question of how is your sleep, it is very dependent on the actual more precise question that you’re asking. So it is sleep quality from a subjective perspective, which is one thing, and you can get 8 hours of sleep quality. There’s also the sleep quality from the functions of sleep. So, for example, was there a good consolidation of memory during sleep? Did you have proper reorganization of various metabolites in the brain during sleep? And these are the questions we are only starting to address in the field. So, for example, if you sleep for 3 hours, is that sufficient for memory processes? We don’t know.
Q: So you seem to be agreeing with me, in that study you did, that something’s up. Either the EEG is wrong, or the people’s subjective evaluation of their sleep is wrong. So it seems you’re saying probably the EEG is insufficient.
A: What I’m saying is that what the EEG is picking up is not subjective sleep quality. It’s possible we’re just not looking at it correctly, which I think is a distinct possibility. But when you go to a sleep lab and have a sleep study done, that really doesn’t reflect on this individual sleep quality.
Q: So we seem to be agreeing that there’s a lot missing from EEG. But we also agree that probably someone’s subjective quality of their sleep is not completely accurate either. 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. That’s my problem. When we’re trying to evaluate how much light at night is affecting someone, we do know that a small amount of light is having effects, but we just don’t know all the effects. Even if someone is having good sleep after caffeine, it’s still probably a good idea not to do it, in my mind.
Amount of Necessary Sleep
A: It’s definitely a possibility. This is again, it’s just getting into the great unknowns. Ideally you’re going to want to sleep 8 hours at night or however long it takes. I say 8 hours and there are all sorts of questions about how long, and honestly the best advice I’ve ever received about that is from a doctor William Demeth, who kind of invented the field of sleep medicine. His advice, to answer that question is, in terms of sleep, if you are sleeping in when you have an opportunity, on the weekends, for instance, then you aren’t getting enough sleep. Some people sleep for 6 hours, and then they say I’m not tired. This is usually after the 3rd or 4th latte. Because frankly, the main thing that people are using as a metric for sleep is sleepiness, how tired am I during the day? Well, that is, in terms of relating that to nocturnal sleep is a little fuzzy. If you look at people at a job who work overnight. We don’t currently have the ability to fully shift them, because when they’re working overnight they want to be alert, and when they’re off they want to be alert during the day. We currently don’t have the capacity to do that. When they’re working overnight they have 2 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. Their brain still isn’t working right. They’re still performing as if they’re up in the middle of the night, which they are. But they don’t feel tired. Again, this is because you can kind of get used to that feeling. That subjective feeling of sleepiness isn’t a good marker for how well you’re sleeping.
Q: My advice to myself and other people is sleep however you need. So if you’re keeping to the proper sleep hygiene and going to sleep at a reasonable time, and don’t use an alarm clock, then that seems most sensible because you’re getting the sleep that you need, what do you think about that?
A: Sure, ideally people should get up without an alarm clock, getting the amount of sleep 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 things. Most people aren’t short-changing their sleep just because. It’s for a reason. Well, they’re going to sleep too late or getting up too early because they have a 2-hour commute because that’s the closest job they can find. Or they’re staying up late because that’s when they can see their family, or they have work to do, or that’s when they can socialize. There are a variety of things that interfere with getting optimal sleep, and there’s some imaginary line in the sand where you have to make a decision of what’s more important, because frankly when you’re doing that you can kind of get away with cheating sleep for a while, but in the end it’s going to affect your health. This I think is what we struggle with, in the field we have to be able to define what that health consequence is. Some studies have come out that say how sleep has an impact on feeding behavior and weight and weight gain and things like that. So I think we’re accumulating enough evidence there that people are starting to believe that, and I think it’s true, that when you’re not getting enough sleep this can affect your weight. So again that’s a positive step in the right direction. I think there are lots of other things. When you are short-changing sleep you are affecting things like cancers. Again what we need to do in science really is to be able to give people the information so that they can make informed decisions.
Waking up Tired & Sleep Apnea
Q: Now I get some people who say they wake up tired. Especially some people who say they take a nap and will be even more tired after a nap. What’s the biological cause of that? My take would be that some of that could be from chronic inflammation and oxidative stress, and sometimes it could be a circadian amplitude problem, or the phase or whatever it is, what would your take be?
A: To me, I think the two largest answers, again, not for everyone, but I think this encompasses a lot of people. One is I think you have a lot of people who have undiagnosed sleep apnea. So these are pauses during sleep where you stop breathing, then you slowly choke yourself into consciousness, and fall back asleep. 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 if someone with moderate sleep apnea, not even severe, is going to say wake up 200 times a night like that. It is very disruptive to sleep and most of the individuals who have this aren’t aware. In fact, many of them will come into a sleep clinic, not because they have a problem sleeping, often they say they sleep great, their head hits the pillow and 8 hours later they wake up. They come in because they are exhausted during the daytime. Well and then you find out yea that’s because you’re waking up hundreds of times per night. You’re never getting into a deep sleep, and likely causing oxidative stress to your system which is probably causing lots of long term damage to your brain and cardiovascular system. So that’s one of the things where people are waking up unrefreshed.
The second is the phenomenon, again we don’t understand the physiological cause of it, some people call it sleep drunkenness, some people call it sleep inertia. This is basically when some people wake up it takes a little while for their brains to get going. In some individuals, it’s because they’re waking up at the wrong time in their cycle. Basically one of the things that happens with your circadian clock is that it anticipates when you are going to be waking up. As part of this anticipatory process, it’s basically moving lots of the energy in the system from stored energy to available energy. This means that when you get up in the morning if you’re getting up at the right time, you have lots of available energy to actually get you up. Your brain is active and you feel refreshed. Now if you’re getting up at the wrong circadian time, you’re not going to have that. What’s going to happen is instead of the energy being available, the energy is going to have to become available in a reactive manner. Basically, your body is going to respond to your body waking up by all of a sudden having to convert all of this stored energy into freely available energy. That lag time is in many individuals this kind of waking up unrefreshed because you woke up at the wrong time.
Q: So you’re saying it’s a phase problem?
A: In some individuals yes, waking up at the wrong phase. Then in others still they wake up at the right phase and they don’t feel refreshed. Is there something wrong with their sleep, or is this kind of expectation? So one of the things in sleep that’s always kind of a weird thing is that many problems in people’s sleep, that may or may not have a biological basis, much of it is perspective. So there’s a whole field in sleep medicine which deals with kind of changing people’s perception towards sleep. So what they try to do is kind of register how you feel about your own sleep so that whatever you get then becomes ok. So, in essence, let’s just say that for whatever reason, psychological, biological, whatever, it takes you 20 minutes to fall asleep. If this doesn’t bother you, then it’s not a sleep problem. You would never go to a sleep clinic about it because it doesn’t bother you. Now if it does bother you, the exact same behavior, then all of a sudden it becomes a sleep problem. So much of the sleep field is to kind of figure out how to change people’s opinions about their sleep, because frankly when they don’t worry about it, it usually gets better. So, for example, he has a colleague who’s husband gets up every night in the middle of the night at 3 am and reads a book for 30 minutes and goes back to sleep. And has been doing this for 30 years. If someone else did this and got anxious about it, then that’s a problem. The behavior is the same, but the response is very different. Again, a lot of it is changing the response to the same behavioral events.
Q: What about diagnosing sleep apnea? I’ve had people I deal with who had different kinds of sleep problems, most of them would wake up feeling unrefreshed. They would get a sleep study and it would come back normal. Then some of those times you would look at their results and you would see the percentage of slow wave sleep and REM sleep is lower than healthy people, yet they wouldn’t be diagnosed with sleep apnea. And then, you know, there’s variability to sleeping in a foreign place, people will have different levels of anxiety, and who your doctor is. It seems like there’s a lot of variability in diagnosing sleep apnea. What are the criteria exactly? What percentage of slow wave sleep should people be getting, REM sleep, and oxygen saturation what should it dip to at night? What’s your take how a clinician would diagnose sleep apnea?
A: Sleep apnea is one of the more straight forward diagnosis because it’s just very dependent on something called the apnea hypoxia index which basically just counts how many apneas and how many hypopneas and apneas are when you stop breathing, and hypopneas are basically when your oxygen drops for a specific amount of time. And these are codified and can be counted, then the decision has to be made if you have lots of these, say 15-20 of these per hour, they’re going to recommend treatment. If you’re down around 5 and you’re an adult, yes that’s technically apnea, but the fix for it isn’t that comfortable, it’s basically having a tube down your throat and maybe your mouth and it kind of forces air down in your throat to keep your throat open during sleep.
Q: 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 even going to mention anything. So what would you say to these people?
A: So basically we have no idea what it means. If you have less slow-wave sleep, what does that mean? We have no idea. We think we know what slow wave sleep does, but for example, if you look at a lot of older individuals, many of them have no deep sleep. They don’t have these big slow waves that are happening. Now does that mean whatever the function of the slow waves isn’t happening in the individuals? I don’t think so. If you’re not getting enough REM sleep, now I don’t know what REM sleep is. Now if you aren’t getting any REM sleep, that would be something to worry about. But there’s quite a bit of range what normal amount of REM sleep would constitute and what that would look like.
Q: I guess you know, I read research sometimes on the benefits of slow wave sleep, and it contributes to XYZ, or they think so, at least in animals. Same with REM and there’s a whole bunch of hypothesis, nothing’s 100% of course, but we have ideas about what slow wave sleep is doing and REM sleep, and generally they’re associated with positive health outcomes. So yes you’re right, it’s lower slow wave sleep when you get older, but then that also coincides with a whole bunch of issues. Now, what’s the cause and effect? No one knows exactly, but we do know there’s a general consensus the more slow wave sleep and maybe REM sleep, generally, is better. We also know these people aren’t waking up as refreshed. 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.
A: Well if they’re going into a sleep clinic, that means they have a sleep problem. The problem is what can you do about it. Well, that, we don’t know. Is it that you slept 8 hours and you’re not refreshed and you look and there’s no apnea, and you wake up in the morning at the same time, and there’s not quite as much stage two and REM? We don’t know what that means and we don’t know how to fix that. There are a limited number of pharmacologic techniques that can improve sleep, and it’s a problem. One of the things that I think has been an interesting development in the field, which is a new medication that has been approved by the FDA for sleep. Most sleep medications act by increasing inhibition in the brain. If you look at benzodiazepines, Sonata, Lunesta, or Ambien, which act on the benzodiazepine receptor, these are all things that are increasing inhibition and basically shutting the brain down. Now they are very good for the most part at making someone not awake. It’s not the same as being asleep, but they’re not awake at least. In many cases, this is what people want. So someone’s had a traumatic experience and they need to just not be awake for 8 hours. This is an effective thing for that. But then you’ve got a lot of people who have chronic insomnia and this isn’t necessarily the best kind of treatment for that. So what this new drug that’s out is doing, instead of increasing inhibition of the brain, what it’s doing is blocking a wake-promoting signal.
A: Yes it’s orexin, hypocretin, these are two names for the same molecule. It basically blocks this 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 in organizing things that are occurring during wakefulness. So the idea here is what you’re doing is blocking this wake-promoting system and allowing natural sleep-promoting systems to act. So it’s creating a permissive environment to sleep as opposed to forcing the brain into sleep. I think a lot of people are interested in seeing how this plays out and see if this is actually helpful for people, especially for people that have problems initiating sleep especially because of stress, anxiety, or wakefulness when they are trying to initiate sleep.
Q: Interesting. Now I’m curious about a few things in sleep. So here’s one of the things I’ve been trying out for a few months. I’m naturally a relatively thin guy so I don’t have to worry about my weight so much, but historically I’ve eaten less. I wanted to see what the effect of increasing caloric intake, improving my mitochondria in some way, basically when you do that you increase adenosine, and adenosine is the main driver for sleep pressure, or sleep onset. Is that true? It’s kind of like a hypothetical thing with me. If you increase metabolism, you increase adenosine, more of that’s going to build up and you’re going be able to fall asleep better.
A: So, with adenosine, it’s definitely true, as cells become more metabolically active, they convert more ATP, and that eventually becomes adenosine. This is factual. However, the process of adenosine released by cells and its impact on sleep appears to be a very regional thing, in terms of its impact on sleep. So it appears to be very specific parts of the brain that can do this, where the increase in adenosine release contributes to the increase in sleep. One of the ways you can think about this is the main wake-promoting drug that people use is caffeine. The main effect of caffeine is to block adenosine receptors. It has other effects but not at concentrations you would ever reach in the brain.
Coffee vs. Adenosine
Q: You’re talking about the PDE inhibition?
A: It can do that and can also work through receptors called ryanodine receptors, which are cellular calcium storage. But you can localize it most to adenosine. Now when do most people have coffee? In the morning, when in theory their adenosine should be at its lowest point. So there’s a disconnect somewhere in this theory, because if you’re having caffeine to block the effects adenosine, and you’re having it in the morning when you’re having the least amount of adenosine, how is that working? This is something we’re still trying to figure out because that part of the theory doesn’t work. We’ve done studies looking at adenosine in human brains and basically found that it doesn’t seem to increase in the areas of the brain we looked at, which are not all the areas, or definitely the areas that you can look at in animals. Again we didn’t see this ubiquitous increase in adenosine. So something’s missing in the theory, and I’m not sure what it is but something’s missing.
Q: What I find interesting is I actually feel tired after caffeine, then I feel more awake, have you ever seen something like that? And if yes, do you know what that’s from? I used to have a lot more fatigue in the day, when I had more of those issues, I would crash from it. And that is a common effect from people, especially with people with an overactive nervous system, more of a stressful phenotype. They’re crashing from caffeine. What is that from?
A: I don’t know it’s a good question. There are lots of systems in the body that has a paradoxical response. Especially in some kids, where if you give them sedating agents, they become hyperactive. There are various theories why it might happen but at this point, it’s mainly phenomenological. It does happen we just don’t know why. I think that’s the case in caffeine. We did study caffeine in college students, not during particularly stressful times, but what we did find was that caffeine had no real effect on their sleep because they were just so sleep deprived that they could have a red bull and go right to bed. They were under so much sleep pressure that it didn’t have that much of an effect. Two things to remember about caffeine: It takes about 45 minutes for caffeine to peak in your blood, right after you drink something with caffeine in it, you’re not going to have much of an effect until later. The interpersonal variability in caffeine metabolism, or how rapidly you get rid of caffeine, is huge. A normal range is between 2 hours and 12 hours. This can have a negative impact on sleep for the 12-hour cycle. Other people on the 2-hour range, after they have caffeine at 7 am, by afternoon there’s no caffeine in their system. So there are lots of variabilities, and it’s affected by things like oral contraceptives and smoking that both radically change the half-life of caffeine. So there are lots of things that impact that.
Q: I find normally if you read in the research if you have sleep deprivation, the sleep debt builds up and then you have more slow-wave sleep the next night, it’s easier to go to sleep, things like that. For me it’s the opposite, when I have a sleep debt, I don’t function well in the day, but then I’m pushing through during the day, and at night time I’m just more awake. To me, that seems like a circadian problem.
A: So there are two things, one is 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. Your circadian clock actually has a peak drive for wakefulness right before the time you go to bed, which is why it’s very difficult to initiate sleep early, or earlier than you normally do unless you’re sleep deprived which is a little different, but in normal circumstances, it’s very difficult. Your circadian clock at this point is saying you’ve been up for 16 hours and have accumulated 16 hours of sleep debt. Now you’re tired. This is trying to keep you up at the end of 16 hours, it’s trying to offset that accumulation. We think it’s enabling you to spend 16 hours awake. Frankly, this is, amongst mammals, a fairly unique kind of thing. When you look at mammals, there are humans and a few new world monkeys that have truly consolidated wakefulness which basically means you can spend 16 hours awake 8 hours asleep. All other mammalian species don’t do that, they nap. We can nap during the day but we don’t have to. So getting to your question about sleep at night, if you’re trying to initiate sleep early since you’ve been up so long, it’s going to be very difficult to initiate sleep at that earlier hour. It’s one of these odd phenomena where the flip side is that in the morning, say 2 hours before you wake up, is when your circadian drive is at its peak. You experience this if you ever stay up all night and you have this sudden feeling of a second wind. This feeling of second wind is the feeling you’ve stayed up all night, so say 24 hours, and at that point, the sudden drive for sleep starts to abate. So you actually feel more alert after say 30 hours of being awake, than after 22 hours of being awake. You can also have an issue where you have these windows of opportunity for sleep. Some of this window is created by the circadian system where you’ve gotten to a point where the circadian system is no longer signaling for wakefulness, and now you have an opportunity to initiate sleep. Now, this window though seems to be modulated to how you respond to feeling tired. Basically, some people when they’re getting tired, their brain starts to fight that. Again this is kind of the paradoxical activity.
ME: I definitely feel that where I’ll be very tired for a certain period, and if I push through it I won’t be able to fall asleep for another 2, 3 hours.
A: We have various guesses for what’s going on, but we do see that phenomenologically.
Q: Is there any problem with going to sleep at different times? It just doesn’t seem like something that’s suited for me. Sometimes I want to go to bed at 9 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?
A: My recommendation is that if it works, go to bed at the same time. Because again, that does lots of things, it helps stabilize the circadian system and build good cognitive patterns around bedtime to help your brain anticipate sleep.
Q: Right, but you’re saying it’s mainly involved with sleep onset, is that what it is?
A: Also, again, if you have erratic sleep timing, even if onset isn’t difficult, you may have difficulty staying asleep because the circadian system is going to turn off its sleep drive at some point. That point may not be when you want to sleep until. If you’re going to sleep at 9, and you want to go to sleep at 12, that’s great, but then your circadian schedule is going to be ready to get up at say 5, and it’s going to be difficult to stay asleep longer than that.
Q: So yea, I guess I don’t have any real problems with that. If someone is having problems with that, they should definitely pay attention to it. What about something like Marijuana for sleep, in the states, it’s legal of course?
A: Of course. It hasn’t been studied well. There’s obviously lots of anecdotal evidence that it has a definite biological effect. There are endocannabinoid receptors and it’s likely to do something. That being said, it hasn’t been well examined.
Q: My problem with marijuana is that we know that it really interacts with the suprachiasmatic nucleus in a strong way. That causes the time shifting in people who are high. And it also increases adenosine, and slow wave sleep, or there’s mixed research on that, but it seems like that’s what it does. It seems like it has some positives and negatives. What’s your guess? If it helps somebody, and they’re in a state that it’s legal, then?
A: I have to say that my guess is that it’s going to have similar properties to alcohol. 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. So because it acts as an anxiolytic, I think this helps people initiate sleep. Now, the question is that this is where the research is mixed, does it help people maintain sleep? So that’s the issue with alcohol, it helps initiate sleep, but the dehydration effects often disrupts the sleep later. Also, the sleep isn’t exactly normal sleep either. You can have some instances where you have increase slow wave activity, other instances where you have increase fragmentation. So there are lots of things associated with that, which probably have to do with dosing and timing.
Causes of Sleep Apnea
Q: And individual biology. When I try to read the research on sleep apnea, it causes a headache sometimes because you don’t know the cause and effect. Are these cytokines high because of sleep apnea, or are these cytokines causing sleep apnea? That’s why it’s such a hard condition to read up on because you don’t know what’s cause and effect. What are the fundamental, biological causes of sleep apnea? Is it cytokines, a structural problem, or someone being overweight and some kind of pressure they’re putting on?
A: I think for sleep apnea the two major groups in sleep apnea are that one is related somehow to obesity. The thought is there is an excessive amount of tissue in the throat which is causing obstructions to occur.
Q: We also know there’re thin people with sleep apnea.
A: So yeah that’s the other category. You have a lot of individuals, actually, it’s not just thin, many individuals with Southeast Asian dissent where the jaw is set back slightly. When it’s set back slightly basically there’s just a little less space in the throat, so that’s another common group that you have. These are two of the common areas.
Q: It seems like there has been a big increase in sleep apnea, you can correct me if I’m wrong. And so, it must be something in the modern environment that’s increasing that. Is that accurate at all?
A: So there’s increased recognition. The increase in apnea has increased with obesity. One of the problems with the theory is that because you see sleep apnea so much in people who are overweight, that it has something to do with the amount of tissue in their throat. There are surgeries where these people have the tissue removed, and I have to say many of these surgeries are very unsuccessful. In some people, it’s true that the surgeries help and it fixes it. In others, it doesn’t. So there are other things going on that we just don’t know what they are yet.
Q: So the answer is the research is just not there yet. What do you think of the elevated cytokines, cause, effect, or bidirectional?
A: I’m thinking that’s more of an effect.
Q: Ok, I did read a study that claimed on mice that they had evidence it was a cause of sleep apnea as well.
A: Again, it can contribute to it, whether it can be a stand-alone cause that I’m not so sure. It’s a much trickier thing to study in humans than in mice.
Q: So now, let’s say somebody comes to you and says they’re fatigued during the day. Anybody that comes to you and says they have fatigue you’re going to recommend they do a sleep study, right?
A: Maybe, it depends on. That’s often a way to exclude other causes.
Problems in the Medical Establishment
Q: So let’s say they do a sleep study, and say they’re tired during the day. They do a sleep study, it comes back normal and they still have problems. What would an esteemed researcher like yourself say? We know the orexin system is massive as a wakefulness promoter, it controls the histamine neurons as well. My opinion is that there’s obviously something going on with that system. Now, what is the problem? We know that cytokines suppress that system, there are different things that suppress it. What would you say to someone who has fatigue during the day?
A: Well, being as I’m a researcher I don’t have to tell them anything.
Q: Right. “See your doctor.” That’s what you’d tell them.
A: It’s tough. If there are no obvious problems with their sleep, that’s when you start looking for other issues. I have to say in some individuals you have to see if there is a psychiatric component to it, and in some people there will be.
Q: When you say psychiatric component what do you mean by that exactly.
A: Well in some individuals they’re going to be depressed, and that depression may express itself as daytime fatigue. If I say I’m tired during the day, this is the classic problem in philosophy. It’s a theory of mind. I don’t know what you mean, I know what I mean, but I don’t know what you mean. So I’m just guessing, and so again this is why something like that which is frankly not a measurable thing..to empirically measure actual fatigue in someone. Because of that, we’re stuck with what they’re saying. I’m not denying that they don’t have fatigue. I have to believe that they do and I believe that they do. The question is, well, what is the cause? If it’s depression that’s what you’d want to treat. If it’s biological, then that’s what you’d want to treat.
Q: Here’s what’s interesting though. Let’s say that we do know that depression and fatigue correlate. That’s something that’s pretty well known. My understanding is that depression can cause fatigue, and fatigue can cause depression. That’s one way of thinking about it, or another way to think about it is that something is causing both of them. The way the medical establishment works is that they treat them by the symptoms in a,” Are you diagnosed with depression or not?” Depression is also a vague thing. They don’t take brain scans of your brain. It’s kind of like, let’s look at the cause of fatigue as another subjective symptom. So what I like to see is that even if they’re depressed, what’s causing their depression? And if they have depression and fatigue, what would cause depression and fatigue?
A: Yes, I 100% agree. Actually, I think a big problem in the area of psychiatry is that things are defined as symptom clusters. So they’re not defined based on there’s an error in this very specific molecule in the brain. It’s rather like here are your symptoms, and because of that things are treated symptomatically.
Q: Doesn’t that strike you as really strange?
A: Well, it’s inadequate. The question is that until we start to understand, which I hope that we are slowly doing, what the actual causes are, what are the other choices?
Q: Right, I see what you’re saying. So you’re saying the medical establishment evolved from a much earlier time when we didn’t understand anything about the body, whereas now we’re understanding a lot more. Do you think there should be some kind of evolution where we’re not saying, “Well, this person has depression and depression is helped by SSRIs… there are studies that show slightly more people were helped by SSRIs?” And that instead we should try to figure out are they having a serotonin problem, a dopamine problem… it’s kind of like two steps removed in some ways problem? Or ask if maybe they are just having a norepinephrine 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 possible causes, cytokines and this and that, but they’re just a hodgepodge of we don’t know that this person or that person has or what has the most or least effect. The point is we do have a lot of theories that are somewhat supported. It seems like it would be a much better system than to just say, “Well you have depression just take an SSRI.”
A: This is something that I wholeheartedly agree with. I’m not even sure if things will be, in the end, a serotonin problem or something that is further upstream from that. If you think about serotonin you know there are many different neurons that produce serotonin. So It’s even likely to become more limited than that, so it’s going to be a serotonin problem in a specific area of the brain. So we have I think a decent handle on what is happening in the body for various diseases. And I think we have, for the most part, no handle on what is happening to the brain, for anything that’s happening to the brain. So one of the very very few disorders where we understand what is causing it is the sleep disorder Narcolepsy. It’s one of the very few disorders we have where we actually know what the problem is. It’s that you’re not making hypocretin. That’s very very rare in anything having to do with brain function to have something that is that isolated. I agree. I think it is a very big problem, the one size fits all approach doesn’t work and has lots of side effects, and many problems. Unfortunately, I think it’s what we have now, and so that being said that’s what we’ve got. But I do hope in the future, I’m not sure I’ll be alive in that future, that that’s where we’re headed: understanding the causal etiology of these problems, which will then lead to direct treatment of the cause, as opposed to the downstream symptom.
Q: Right. It seems like that would be a while away. But what about, and I know you’ve studied the HPA axis. We know that the HPA axis is elevated in depression. So what do you think is going on there? My opinion is it’s probably bidirectional: the HPA axis causing depression maybe, but then there are things that increase the HPA axis like cytokines, inflammation.
A: I do think it’s a bidirectional process. What’s unknown is if people have kind of a predisposition to this. So I like to think of this as kind of a depressive endophenotype. I think the same way with insomnia. If you have insomnia you could sleep well for 10 years and you still have insomnia in the sense that you might get it at any moment. I think it’s the same way with depression. This is just, I think the way that certain brains work, having a proclivity towards certain disruptions.
Q: There seems like there’s a variety of root causes, and based on people’s genetics, how one receptor works or another, they manifest themselves in different symptoms. So there’s 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 the HPA axis is an indirect measure of. So 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 saying, “Ok you’ve got depression, here’s an SSRI,” instead trying to figure out how to decrease your overactive nervous system, in this way going to a more first principles system. Then asking, “Well, what’s causing an overactive nervous system?” Bad sleep will, cytokines will. It seems like it’s a smarter way to approach dealing with the human body. Is that something, I mean what do you have to say about that?
A: I do think it is. I think 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. Because of that, you don’t know how to asses it, and if that then how to treat it.
Q: You’re saying that researchers are, but clinicians aren’t studying the underlying causes of depression?
A: You know frankly the problem is there’s no blood test. For example, if you want to know if you’re diabetic you go in and get a blood test. There are various kinds of provocative tests you can do as well, but it’s pretty straight forward. If you’ve got depression, there’s no blood test, brain scan, there’s nothing that tells you A) you’ve got depression and B) What that depression’s caused by. Even testing that you can test the HPA axis and cortisol, and there have definitely been studies looking at that, which has been the most extensively studied. But for any of the neurotransmitter systems, there’s no provocative testing of these. And so 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 think I and many other people, this is what we are trying to do, basically apply principles of neurobiology to these clinical disorders.
Cortisol, & Limited Testing
Q: But you could test for some things, you could test for systemic levels of cytokines which we’re not doing, for cortisol, which most doctors are not testing.
A: Well, again because, for example, if you wanted to look at cortisol, that would be not a single blood sample, this is something where you’re going to have to take serial blood samples under a very specific set of conditions.
Q: What about saliva, that’s become popular in the alternative health sphere, saliva tests. Do you think that the test is accurate for the level of cortisol?
A: It can be. But it isn’t necessarily. We just actually published a paper looking at that exact question and found that in, this is in a specific patient group…in women with cancer, that what was happening in the blood was not what was happening in the saliva. So there was a disconnect in the saliva and the blood.
Q: I find the same thing in the people that I get. I have found research that says it is correlated, but when I look at people and they give me their blood and their saliva, I’m like this is just two different people it seems.
A: Again, there is a correlation there, but it can be limited.
Q: Why is saliva not good? What controls the cortisol in your saliva?
A: So what happens is basically that cortisol when it’s released, basically some of it is free in the blood, and other is bound to specific proteins that are circulating in the blood.
Q: Cortisol-binding protein?
A: Yes. And so what goes into saliva is basically a pretty fixed ratio of what is free. 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 is bound and then use that. What you’re picking up in saliva is just the unbound portion. 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.
Q: So it seems like in some ways that would be a better measure because that’s the free cortisol and it’s not a measure of your HPA axis preset, but it’s a measure of, if you want to see what biological activities of cortisol in the body, which level of that is free.
A: It can be a reasonable measure of that, yes. It’s a reasonable measure again of the amount of free cortisol, for the most part.
Q: Sorry I interrupted, you were saying you have to check your cortisol multiple times throughout the day?
A: Oh so yea, so if you actually wanted to know if this was working, you would go into a laboratory, spend several hours, and have provocative testing with specific drugs to see if it can drive your cortisol and where the problem is. So when you look at cortisol you’ve got the pathways basically CRH being released in the hypothalamus, which causes ACTH being released in the pituitary which then causes cortisol to be released in from the adrenal gland. You want to see where there is a disruption and how responsive this is to specific kinds of medications. Until it gets established as a real cause, doctors can’t get reimbursed for it, and most don’t even have the capacity to prescribe a test like that. At this point, it’s still a very experimental kind of test.
Q: But it seems like even though it’s experimental, it has value, it just hasn’t transferred over to clinical medicine. It hasn’t translated yet. But you’re looking at it and you see it has value, you’re measuring it, there are studies on it, but it just hasn’t transferred over.
A: Well because the problem is, ok we say there’s a problem in the HPA axis, we say that you are for whatever reason just not as responsive to CRH. What are we going to do about that? Well, that’s where the story ends.
Q: So you’re saying it’s a treatment problem. It seems like, and I’m a bit of a cynic, that the reason why it’s not being translated because there’s no drug for it.
A: That’s correct. Well, not just a drug, there’s basically no treatment for that problem. And it doesn’t have to be a drug, it could be dietary…
Q: But even if it is dietary, who’s going to fund it? It needs to get the level of evidence that the insurance company will reimburse, and that can take 100 years to study, meaning you need billions of dollars..but who can fund that? It’s going to be either from the government or from the insurance companies. But the government doesn’t put that kind of money out for studying dietary treatments, generally. So generally it’s going to be a drug.
A: Right. So that’s why basically when you think about it, you first have to establish what the problem is. And then you have to establish how many people have this problem. If you can establish that: ok here’s the problem and here’s the amount of people that we think the problem is in, then we’ve established a market. Once you’ve established a market there will be a drug company developing a drug for that market. Again, the first step is establishing that this is a problem. And I think that unless you have a quick and easy way to diagnose it in an office or with a simple blood test, it’s going to be very difficult to convince doctors to do any kind of prescribing for it, and insurance companies for paying for the test.
Q: So it seems like what you’re saying is, well there is value to it, but we have to ask the reason why it’s not being adopted is number one there’s no drug for it, number two is we don’t know the exact cause, the exact percentage of how much this is causing the problem, or if this is 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 a dexamethasone suppression test. So it’s expensive, you’re going to 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% and the test is tedious and it’s expensive to do, insurance companies aren’t going to get on board with it so quickly, and doctors aren’t going to get on board with it. But what I would say is if someone has enough money to want to test for it and they saw it was a reasonable underlying cause for a problem of theirs, it seems like it could be, in my opinion as a forward thinker, I would personally test it out if money wasn’t a serious issue. Now the problem I would come up to is who is going to do it for you? A doctor isn’t going to do it for you because they can’t even order it. You’d have to go to a specialized research place and they’re not going to do it for you unless it’s in the context of some study.
A: Yes, and so yea these are the limitations that we face.
Q: Ok 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, and I really appreciate your taking the time. I think there’s a disconnect between what’s happening in the research and what general people who are having these problems know, because they are not, unfortunately, getting the quality of information that you’ve given from their doctors, simply maybe because of lack of time. So I really appreciate this. Thank you very much and have a wonderful day.
A: Thank you, you too. Thank you so much.
Learn more about Dr. Zeitzer
Jamie Zeitzer: https://med.stanford.edu/profiles/jamie-zeitzer
- Cortisol Rhythm (4 salivary samples). Will help determine how much you need to focus on your circadian rhythm… People with primary insomnia have an awakening cortisol of 3.6 ng/ml (9nmol/l). Healthy controls have 4.8 ng/ml (12 nmol/l) ….Cortisol (a 24-hour urine) – urine is a reliable indicator (as is hair) , but isn’t necessary if you take the saliva and blood tests….
- Circadian Rhythm of Hormones – Estradiol, Testosterone, Progesterone, Cortisol, DHEA, Melatonin Profile (All are salivary)
- Cytokines: Th1/Th2/Th17
Our book on normalizing the circadian rhythm and improving sleep, Biohacking Insomnia.