Tim FerrissAll Things Sleep (Weight Gain, Alzheimer’s Disease, Caffeine, and More) — Dr. Matthew Walker
EVERY SPOKEN WORD
150 min read · 30,170 words- 0:00 – 1:37
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- TFTim Ferriss
[upbeat music] My good Dr. Walker.
- MWDr. Matthew Walker
[laughs]
- TFTim Ferriss
Matthew. [laughs]
- MWDr. Matthew Walker
Tim, it is a splendid delight to be with you. Thanks very much for having me.
- TFTim Ferriss
Absolutely. And this is, for people listening, a very self-interested conversation. You and I connected, I think, not that long ago, maybe six months ago or so after I finished Why We Sleep, which is a spectacular book. It has as many highlights, I think, as words in the book in my Kindle notes. [laughs]
- MWDr. Matthew Walker
[laughs] Yeah.
- TFTim Ferriss
And not only did it change how I think about sleep, but it both gave me answers to outstanding questions, because I've battled with onset insomnia my entire life, or for as long as I can remember, certainly. It gave me better questions and it gave me better frameworks for thinking about-
- MWDr. Matthew Walker
Yeah
- TFTim Ferriss
... sleep. And this conversation, for folks who are wondering what the roadmap might look like, is intended to explore areas of personal interest to me, and also several or many areas that I don't think you have explored in, in depth in other places. So we're, we're in-
- MWDr. Matthew Walker
Yeah
- TFTim Ferriss
... we're intending to check
- 1:37 – 14:50
Sleep and Alzheimer’s disease.
- TFTim Ferriss
both of those boxes. And I thought we would start, if we can just, you know, skip the foreplay and jump right into the, the main event here, discuss the connection or connections, the interrelatedness between sleep and Alzheimer's disease. I wanted to just hop right into it. I have Alzheimer's disease on both sides of my family, and have-
- MWDr. Matthew Walker
Yeah
- TFTim Ferriss
... seen this up close and personal. What are the connections, if any, between those two?
- MWDr. Matthew Walker
Yeah, I think this is perhaps one of the most exciting areas to have emerged in sleep science over the past maybe five or six years or so. And, and just taking a step back, of course, everyone knows that Alzheimer's disease, it's a form of dementia typified by memory impairment and memory decline. And we've learned that there are at least two protein pathological culprits that contribute to Alzheimer's disease. One of those is called beta amyloid, which is a sticky toxic protein that builds up in the brain, and the second is called tau protein. So coming back to your question, how are those things related to sleep? Well, it, it's probably unfolded, gosh, maybe in a three-part or even four-part story. I'm, I'm very nervous to say four-part, and you'll see why in terms of that in just a second. But the three main parts were correlation, causation, and then mechanism. And so early on, what we started to discover is that individuals who reported sleeping six hours or less across their lifespan had a significantly higher risk of developing high amounts of this toxic beta amyloid and also tau protein in the brain. Then we discovered that two sleep disorders, both insomnia and sleep apnea, which is a condition of sort of heavy snoring, sometimes you stop breathing, and it's clinically diagnosed, both of those conditions were associated with a higher risk of both Alzheimer's pathology, but also the transition to early stages and ultimately the transition to full-blown Alzheimer's disease. In fact, I think there was a recent meta-analysis looking at maybe it was over 27 different studies, and what they found is that people who had sleep problems during their lifespan were about 3.78 times more likely to develop the early stages of Alzheimer's disease in a premature fashion. So those were these epidemiological studies. Those are simply correlational. They're associational. They don't prove, you know, causality. So correlation then went in search of causation, and what we've discovered, we and other individuals, some people working in animal studies, we work in humans, but across species, what we found is that if you deprive individuals of a night of sleep, or even if you deprive them selectively of just their deep non-REM sleep across a single night, then the next day we can see an immediate and significant increase in beta amyloid and tau protein circulating in the bloodstream, circulating in what we call the cerebrospinal fluid of the brain, which is this, a fluid that bathes the brain. And also using special PET scanning images, we've been able to see that same buildup of amyloid within the brain itself. And in fact, there was a recent study that looked at this, these signals of metabolic sort of detritus in the brain, and what they found is that after one night of sleep deprivation, even a full recovery night of sleep was not sufficient to downgrade those metabolic toxins that have been building up in the brain. So, so in that sense, it was a demonstration causally that you can remove this thing called sleep, or even selectively excise different types of sleep, and you can manipulate the amount of Alzheimer's protein in the brain the next day. So that was the causal evidence. Causation then wanted sort of, you know, a mechanism and Perhaps here in some ways you can reverse engineer it or you can flip it on its head. If that's the bad that happens if I take sleep away from you, then what is it about sleep when we get it that deescalates your Alzheimer's disease pathology risk? And this comes onto a series of discoveries. The principal person underlying this was a wonderful scientist at the University of Rochester called Maiken Nedergaard, and she was working in mice. And she made three stunning discoveries, in my mind at least. The first is that she discovered that the brain has a cleansing system. Now, [laughs] it sounds strange. You know, many people would think, "Well, it must have," 'cause the body has a cleansing system, and everyone's familiar with it. It's called the lymphatic system. But we didn't think that the brain had its own cleansing system. She discovered it, and it's called the glymphatic system. And it's, it's named, by the way, that way because of the cells that make it up. These, they're called glial cells. They're a different form of brain cell. We've got neurons and we've got glial cells, and it's the glial cells that make up this network of this cleansing system. So that was the first discovery that she made. If that wasn't amazing enough, she then found two more related discoveries. What she then found was that that cleansing mechanism in the brain is not always switched on in high flow volume across the 24-hour period, across the 24-hour clock face. Instead, it was particularly when those mice fell asleep and when they went into deep non-rapid eye movement sleep, or non-REM sleep, um, the other stage of sleep being rapid eye movement sleep. But it was during deep non-REM sleep when that pulsing cleansing system kicked into high gear. And so that was then her sort of shift to then say, "Well, what are those things that the brain is cleansing during deep sleep?" And this is what brings us onto or back to Alzheimer's disease. Two of the pieces of the metabolic byproducts that were being washed away by deep non-REM sleep at night were beta amyloid and tau protein, these two culprits associated with Alzheimer's disease. And scientists in Boston a couple of years ago, and we've now replicated this in humans as well, identified a similar cleansing mechanism in humans using special MRI scans. So that was evidence almost from a, a biochemical s- perspective, and this is probably slightly hyperbolic to say and I'm mindful of it, but biochemically perhaps it's true, which is we were starting to understand that wakefulness was low-level brain damage and sleep was your sanitary salvation. It was almost like a good night sleep clean that was a power cleanse for the brain that was happening during sleep. But this started to explain why you got maybe this trajectory of Alzheimer's disease. It went all the way back to the associational studies. So now we can understand why night after night if you're not getting the sleep that you need, you're not cleansing the brain of the pathology, and it's, it's not vast that builds up after one night of sleep. And I don't want to scare anyone here, and I've ... You know, I'm sure I'll probably get some concerned voices. I'm not trying to make anyone nervous about a bad night of sleep, and the next day you've guaranteed your Alzheimer's disease fate. That, that's not at all the, the situation. But it did help us understand that night after night if you're not cleansing the brain, it becomes like compounding interest on a loan, that it continues to escalate time and time again, night after night. And then [laughs] if that wasn't depressing enough, we then went on to make a further discovery that it's a vicious cycle, that Alzheimer's disease pathology, those proteins, do not build up in the brain homogeneously. They don't build up in all areas of the brain equally. And what we discovered is that the parts of the brain that start to get attacked by Alzheimer's disease early on are unfortunately the same regions of the brain that generate deep non-REM sleep.
- TFTim Ferriss
Oh.
- MWDr. Matthew Walker
The same stage of sleep that's associated-
- TFTim Ferriss
That's unfortunate
- MWDr. Matthew Walker
... with the cleansing. Isn't it just? And so now we'd found this vicious spiral that if you don't get enough sleep each night, you get more of that Alzheimer's buildup. The more that builds up, the less the brain is capable of generating deep sleep. The less deep sleep, the more that builds up.
- TFTim Ferriss
What are the structures involved with the production of that deep non-REM sleep?
- MWDr. Matthew Walker
It's essentially a, a network of brain regions.
- TFTim Ferriss
Constellation.
- MWDr. Matthew Walker
Exactly. But one of ... If you look at it with brain scans or electrical recordings, one of the main epicenters, in fact probably the principal epicenter that generates this deep sleep, is a part of the frontal lobe, particularly the middle part of your frontal lobe. So if you sort of put your finger just above your nose and slide it up about an inch and a half, that's the middle part of what we call the prefrontal cortex or the medial prefrontal cortex. That is a deep sleep generating center for the brain. You get principal dominance of your deep sleep in that part of the brain, and then these big brainwaves, they splash on the brain and they actually wave across the brain from the front of the brain to the back, from the front to the back. It's this beautiful mechanism that we can see, this, this sort of wave of these deep slow brainwaves. It's amazing. And so that was a part of the brain that showed these Alzheimer's attacks early on, and it's the same region that is generating the deep sleep in adults. So that was the demonstration of mechanism that helped us perhaps go back and explain the associations. Then perhaps the, the fourth ingredient that I'm really ... You know, I'm almost nervous to say it because it's the most dangerous of all things, which is the suggestion of hope, and I don't mean to make false sort of promises here. But what I find interesting is that unlike many of the other features that we know are associated with Alzheimer's disease For example, changes in the physical structure of the brain or even the, the blood flow dynamics of the brain. Those are very difficult to treat right now, and medicine doesn't have any good wholesale approaches. But if sleep is a missing piece in the explanatory puzzle of aging and Alzheimer's disease, then maybe we can do something about it. Sleep is a modifiable factor.
- TFTim Ferriss
Mm.
- MWDr. Matthew Walker
And we've been looking at this in the laboratory. We've been approaching this not by using sleeping pills, and, and we may come onto those things. They seem to be more blunt instruments that don't produce necessarily naturalistic sleep. But we've been developing some technology, it's called direct current brain stimulation, which [laughs] which sounds like the stuff of science fiction. It's actually science fact, where you apply these pads to your head and you in- insert a small amount of voltage into the brain. And it's so small, by the way, that you typically don't feel it, but it has a measurable impact. And early studies demonstrated that if you apply this stimulation during sleep, as if you're sort of singing in time with those deep sleep brain waves, not only can you amplify the size of those deep sleep brain waves, but in doing so, people were able to almost double the amount of memory benefit that you get from sleep. So, so the question then was, could we translate that same affordable, potentially portable technology into older adults? And could we restore back-
- TFTim Ferriss
Mm
- MWDr. Matthew Walker
... some deep sleep and sort of salvage aspects of learning and memory function? That's, that's one of our goals, and we've been developing this and have a startup company that's public now that's l- looking at this. To me, though, that is probably not really where I'll ultimately be excited about. Because thinking about late stage Alzheimer's disease, when the brain has been pathologized that much, it's very difficult to salvage. I am much more interested in shifting from a model in Alzheimer's of late stage treatment to midlife prevention.
- TFTim Ferriss
Mm-hmm.
- MWDr. Matthew Walker
Because to me, if I look at the sleep data, that's when you start to see the Great Depression of your deep sleep. [laughs] It's bloody depressing, I know. I'm, I'm an incredibly depressing person. But if you look, it's in your mid to late 30s that we start to see the decline in deep sleep. So could I intervene in midlife and start sort of pushing back against the decline of deep sleep? And in doing so, could we bend the arrow of Alzheimer's disease risk down on itself? So that's ... So sort of shifting from a model of late stage sick care to a model of midlife health care. I think that's probably a much more reasonable approach.
- TFTim Ferriss
Hmm.
- 14:50 – 19:38
What causes the decline of deep sleep as we age?
- TFTim Ferriss
Matt, what causes the decline in deep sleep, whether it's absolute hours or just percentage of sleep, when people get into their mid-30s, let's just say? How is that explained currently?
- MWDr. Matthew Walker
You can already start to see the brain atrophy [laughs] beginning.
- TFTim Ferriss
Okay, so it, it's just overall brain atrophy. [laughs]
- MWDr. Matthew Walker
Yeah. There is a, a development. And there are some sort of sex differences. It turns out, unfortunately, that men seem to decline in that deep sleep earlier than women. Women will hang in there.
- TFTim Ferriss
Hmm.
- MWDr. Matthew Walker
Females will hang in there for their deep sleep a little bit longer than men. But ultimately, by late stage, there's a more severe sort of decrease later in life in females. So net-net, they ultimately get there. So, but it's simply because we start to ... Just like the rest of us, I'm sure many people, once you get into your mid to sort of late 30s, you start to think, "Wow, I'm just not as robust as I used to be. I start to get more injuries."
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
You know, the body starts to deteriorate.
- TFTim Ferriss
That's a very generous way to put it, robust. I'm not as robust as I used to be. [laughs]
- MWDr. Matthew Walker
Well, I'm, I'm so sensitive now, 'cause, you know, I am ... I, I think I'm about the same age as you. You know, I'm, I'm now in the, solidly in the foothills of middle age. So I want to be tender and sensitive to myself and be politically correct.
- TFTim Ferriss
[laughs] You know what? I'll take the tender to yourself. With the politically correct we can skip, but ...
- MWDr. Matthew Walker
Yeah, I, I think it's political correctness is the language of cowards, in truth.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
So you're right.
- TFTim Ferriss
All right. Let's be ... So we can be the countervailing force. But before we get to that, gender differences. And, and I apologize in advance, I'm going to ask a lot of questions in the, in the line of three-year-olds and four-year-olds. I'm gonna ask why and why and why a lot.
- MWDr. Matthew Walker
Yeah, I love it.
- TFTim Ferriss
In part because I find it so simultaneously exciting and depressing, more so exciting, that we spend, let's call it, and I'm not using a precise number here, but a third of our lives asleep, and we, relative to so many other areas, know so little about it.
- MWDr. Matthew Walker
Yeah.
- TFTim Ferriss
It's just incredible. And I find it so full of promise as a result, meaning it could represent one of the most powerful levers that we can pull for different purposes. But coming back to the age-related decline, why do women hang in there longer? Is that due to estrogen, a lower level of other hormones, other factors? Do you have any, any explanation for why they seem to hang in longer than men?
- MWDr. Matthew Walker
It's a great question. Largely unclear at this stage.
- TFTim Ferriss
Mm-hmm.
- MWDr. Matthew Walker
That some of it may, again, come down to brain atrophy, that the speed of that atrophy in the brain in those sleep generating regions is more rapid and more accelerated in men than it is in women.
- TFTim Ferriss
Mm-hmm.
- MWDr. Matthew Walker
Other aspects, you're absolutely right, may be the sex hormones, that we think that aspects of estrogen, luteinizing hormone may be more either sleep protective or neuroprotective. It's a little bit-
- TFTim Ferriss
Hmm
- MWDr. Matthew Walker
... unclear right now. Certainly menopause, of course, is a huge issue, and once that begins, we know that the sleep issues are markedly higher in women than they are in men as well. So right now the evidence there is, is far less clear. And to come to your point, you're absolutely right in terms of sleep. And, you know, we know so much about our waking lives, but we seem to know so little about our sleeping lives. Th- there's definitely been a remarkable amount of evidence, so much so that perhaps a dimwit like me can write, try and write a book that's [laughs] 130,000 words of, of facts. But, you know, you're absolutely right. If you think about it, 20, 30, 40 years ago, we used to ask, what are the functions of sleep? And back then, the crass answer was that we sleep to cure sleepiness [laughs] which is-
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
... you know, just the ridiculous equivalent of saying, "Well, I eat to cure hunger." That tells you nothing about the biological nutritional benefits of, of food.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
And the same was, was true for sleep. In, in a way, though, now, 20 or 30 years later, we've had to upend that question based on the weight of the evidence. Now we have to ask, is there any major physiological system within your body or m- any major operational network of your brain that isn't wonderfully enhanced by sleep when you get it, or demonstrably impaired when you don't get enough?
- 19:38 – 24:21
Are there any known species that don’t require sleep?
- TFTim Ferriss
Are there any species in any ... I'm gonna get way outside of my, my area of expertise here. Phylum, kingdom. Are there any species that you're aware of, of anything, that do not require sleep? And maybe that's a, a poorly worded question, but is there-
- MWDr. Matthew Walker
No, it's a great question
- TFTim Ferriss
... anything notable that does not require sleep?
- MWDr. Matthew Walker
Yeah.
- TFTim Ferriss
How far down can we go, down to the level of-
- MWDr. Matthew Walker
[laughs]
- TFTim Ferriss
... bacterium? I mean, how, how small can we go and still see a near ubiquitous need for something resembling sleep?
- MWDr. Matthew Walker
You know, some people have said that nothing in biology makes sense unless you look at it through the lens of evolution, and we have certainly done that in the sleep field. I think it's fairly safe to say that at least in every species that's been carefully studied to date, sleep, or something that looks very much like it, seems to be present. And so what that means is that sleep perhaps emerged with life itself on it, on the planet, and has fought its way through heroically every step along the evolutionary path. Which, if that's the case, it must mean that sleep is absolutely fundamentally necessary across phylogeny. There perhaps is one common theme and, and function of sleep. How far back in our time capsule can we go through evolution? Certainly we see it there in all mammalian species. Then if we descend down, if we look at birds, reptiles, and fish, we can see sleep. We also see both types of sleep in mammals and in birds. We don't actually see REM sleep or dream sleep in most reptiles.
- TFTim Ferriss
Hmm.
- MWDr. Matthew Walker
And th- there is some evidence ... It's an emerging sort of controversy as to have ... Perhaps there's like a proto version of dream sleep that comes out, which is REM sleep you can think of it as, in reptiles, but we don't see it there. Can we go further back? Yes, we can see insects even sleep. So fruit flies will, will sleep. Go back even further and you can find that earthworms, which are ancient in terms of their evolutionary history, even earthworms will have a period that looks very much like sleep. It's called lethargicus, and they just become immobile.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
Literally looks like these worms sort of, you know, go into this state, and cellular state, in fact.
- TFTim Ferriss
Wow.
- MWDr. Matthew Walker
Not just a, a motility state, but a cellular state of, of sleep. And then some people have even suggested that for some forms of bacteria, as long as they live several days, some bacteria don't live longer than 24 hours, so you can't really ask this question. But if they live for several days, they will go through cycles of activity and inactivity from a cellular perspective, which is perhaps the, the predecessor, the precursor of these things that we call wake and sleep states. You can even do a nerd out, and I've, I kind of put this out. I think I'm desperately wrong on this one too, but most of us assume that sleep evolved. But why should we make that assumption? Why isn't it that sleep was the default state when life emerged?
- TFTim Ferriss
Right.
- MWDr. Matthew Walker
And it was wakefulness that evolved? That it was from the sleep state that wakefulness emerged, that we came out and we started to develop wakefulness. That's, you know, it's almost this assumption that sleep evolved and there was wakefulness before it, rather than the other way around. Now, I don't think we'll necessarily ever be able to prove that, but it's an interesting kind of gedanken to, to play with.
- TFTim Ferriss
Oh, I love that. Do you say gedanken? Is that what you just said? [laughs]
- MWDr. Matthew Walker
Yeah, gedanken. It's a, like a, a brain experiment. Like, it's just a, you know-
- TFTim Ferriss
Wow
- MWDr. Matthew Walker
... one of those philosophical experiments.
- TFTim Ferriss
Oh, I see what you did there. You pulled out some German, that's what it was.
- MWDr. Matthew Walker
[laughs]
- TFTim Ferriss
Gedanken.
- MWDr. Matthew Walker
I'm bilingual, you know.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
I can speak both British and a little bit of American.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
And that, that's it.
- TFTim Ferriss
What I heard was g'duncan, like g'day from Australia, but like G apostrophe and then Duncan like Dunkin' Donuts. But yes.
- MWDr. Matthew Walker
[laughs]
- 24:21 – 35:08
Brain stimulation for more deep sleep, less insomnia.
- TFTim Ferriss
Well, all the mTOR license plates are taken, so you'll have to [laughs] You'll have to make do with lethargicus. Let's revisit this direct current brain stimulation for the amplification, let's say, extension of-
- MWDr. Matthew Walker
Mm
- TFTim Ferriss
... of deep sleep. Could you describe in practice what this looks like over the course of an evening? You could also mention the company name, because I know people will be interested. And compare this to, TMS might be too much of a layup in terms of comparison, but let's just say TDCS. So other types of transcranial or brain stimulation that can be used for other purposes, which could relate to different types of therapy and treatment of depression, could relate to the enhancement of memory in some cases.
- MWDr. Matthew Walker
Yeah.
- TFTim Ferriss
But I would love to learn more of the direct current brain stimulation and what that looks like in practice.
- MWDr. Matthew Walker
So the complex version of it requires you to be in the sleep laboratory, or at least for us to be recording the electrical brainwaves of your natural sleep. And then essentially what we start to do is we'll develop an algorithm that understands the cycling cadence of your deep slow brainwaves, and then starts to temporally predict where the next brainwave will hit in its sort of monumental peak of explosion. And then you time the stimulation, this is almost at the millisecond level, to strike at the, the point of midnight, as it were, on that big, powerful, slow wave. And therefore, it's almost like acting as a choir to a flagging lead vocalist.
- TFTim Ferriss
Mm.
- MWDr. Matthew Walker
That these deep sleep brainwaves, sh- hundreds of thousands of cells in your cortex, what they're doing to create these deep sleep brainwaves, by the way, they all fire together, and then they all go silent together, and they all fire together and go silent. And what we're trying to do is estimate the point, the next wave, when they're all going to fire together, and then we stimulate to activate and sort of amplify that stimulation even more. So it requires this closed loop feedback where you're measuring the brain and you're stimulating, then you keep measuring, and then you stimulate.
- TFTim Ferriss
And people are wearing caps, or what is the, the format, the sort of physical format?
- MWDr. Matthew Walker
It's different. Sometimes we're just placing electrodes on the head, and then the stimulation pads are going in between those electrodes. And you can have a very simple number of, a very stripped down number of those electrodes.
- TFTim Ferriss
I see. Right.
- MWDr. Matthew Walker
And this is what makes it much more-
- TFTim Ferriss
And now you pointed, for people who are not watching, you pointed basically to that medial prefrontal area, if I'm not mistaken, when you mentioned-
- MWDr. Matthew Walker
That's right
- TFTim Ferriss
... the stimulation pads. So those are effectively being placed over that cortical area?
- MWDr. Matthew Walker
That's right.
- TFTim Ferriss
Yeah.
- MWDr. Matthew Walker
No, they're placed over that cortical area. And this is why, you know, I, I can speak about the, the stimulation, and it sounds fairly simplistic. It's actually an incredibly complex high dimensionality problem. And what I mean by that is you can ask, well, firstly, where do you put the pads to try to create this stimulation? Whereabouts on the frontal lobe? Or do you put another one somewhere at the back of the brain so you're exiting current from the front to the back? How do you do that? The next question is, how long do you stimulate for-
- TFTim Ferriss
Right
- MWDr. Matthew Walker
... to create this profile? The next component is, what frequency do you stimulate? So coming back to the more complex version of this, you're measuring the brainwaves, and then you're stimulating in this predictive manner, as I said, at that sort of stroke of midnight. What we're now starting to try and do is a very different approach with the stimulation company. I think it's unlikely that people are going to start strapping things on their head and wishing to go to bed. And this is the reason that I'm not necessarily the biggest fan of sort of sleep trackers where you stick them on your head, or even wristwatches, et cetera, or chest straps, because, you know, we take things off to go to sleep. We don't put things on. And so the shift that we made with the technology that we've been developing with the, the company is-
- TFTim Ferriss
What is the name of the company?
- MWDr. Matthew Walker
The company's name is StimScience, and we're just in the early stages here, and I think, you know, I, I am very happy to take a long time to develop something that is scientifically proven. I don't want to sell snake oil out there if it's a device. And, you know, if my mother, for example, who's in a elderly age, is told that a stimulation device is going to help her, then I don't want that to be scientific falsehood. So we're taking our time, but the company's called StimScience and people can have a look at it. What we're trying to do, though, is something slightly different. We're trying to stimulate before sleep for about five to 10 minutes.
- TFTim Ferriss
Mm.
- MWDr. Matthew Walker
And this is a slightly different approach. It's a little... A good analogy would be a child on a swing, where-
- TFTim Ferriss
Mm-hmm
- MWDr. Matthew Walker
... you know, to begin with you have to start pushing the child on the swing. And at some point they gain enough momentum that you can stop pushing, and they keep oscillating back and forth.
- TFTim Ferriss
Mm-hmm.
- MWDr. Matthew Walker
So now we've taken this approach where we're stimulating sort of, you know, as you're cleaning your teeth, you stick the headband on, you get the stimulation, and you're essentially fertilizing and stimulating that territory of the brain to then germinate-
- TFTim Ferriss
Mm
- MWDr. Matthew Walker
... more deep sleep naturalistically when you fall asleep.
- 35:08 – 46:18
Tips for better sleep without laboratory budget or access.
- TFTim Ferriss
I have a million follow-up questions, as you might imagine, and what I'd like to do is return to the concern and fear that people have related to neurodegenerative disease, specifically Alzheimer's. And I'm gonna talk for a second, so I f- I apologize in advance. First, I'm going to double down on my apology and say I did not mean to imply that the state of sleep research is dismal by my previous comment, only that-
- MWDr. Matthew Walker
[laughs] Not at all
- TFTim Ferriss
... all of those centimillionaires and billionaires who are spending their time trying to figure out how to live to 140 should take a substantial amount of their funds for research and allocate it to sleep related research, in my opinion. If they're looking at optimizing not just lifespan but healthspan. So I'll put a button on that. Then we were talking about the direct current brain stimulation, but an outstanding question for many people listening to this might be along the following lines: I agree, I now understand how important this deep sleep is for the, let's just call it brain maintenance, recovery, et cetera, vis-a-vis the glymphatic system and perhaps other pathways. How do I increase my deep sleep if I do not have access, which no one presumably does, to-
- MWDr. Matthew Walker
Right
- TFTim Ferriss
... direct current brain stimulation along the lines that you're describing? What are some other things that people can do? And I'd like to pause here just to maybe front load a bit for folks of personal context, if that's okay with you. And, and so I'll mention a few things, the first of which being a disclaimer that nothing we're discussing in this podcast is intended to be medical advice. It is for informational purposes only. Please consult your licensed healthcare professionals before [laughs] taking or ceasing anything, especially prescription drugs. And I mention that in part because we'll be talking about some of these compounds. So I have had onset insomnia for as long as I can remember, and I have theories for why that, that, that may be the case, some of them relating to premature birth and being in the NICU for a very, very long time. But who knows ultimately what the causes are. But, but symptomatically, I often, throughout my life, have required or seemingly required one to three to four hours to fall asleep, and that has had, I think, far-reaching consequences, including, or at least contributing to, depressive episodes and other types of cognitive challenges, short-term memory being the most obvious, I think. And a number of things, I'd say in the last year, have been very helpful, and I, I owe you thanks for taking the time to have several conversations with me, and of course, in conjunction with my conversations with doctors and people like Peter Attia and so on, have led me to experiment with a number of things that I've found very helpful. There are the environmental factors, and those are worth talking about, and the behavioral factors, avoiding screens past a certain point, et cetera. But I will just mention a few things that have been very helpful. Trazodone, particularly for decreasing that, the SOL. [laughs]
- MWDr. Matthew Walker
Yeah.
- TFTim Ferriss
And increasing the speed to sleep. Pregabalin, which we might talk about in just a little bit to explain what that is, due to lower back pain and some muscular issues that have been contributing to several species of sleep problems. Thirdly, and these are not taken at the same time typically in my case, but some type of THC and CBD combination. And for me, THC is a necessary-- appears to be a necessary component. If that is absent, CBD, at least at the dosages that I have most frequently experimented with, does not seem to address any of these primary issues. But I will say, in the last six months, paying attention to temperature, consistent timing, caffeine intake, both quantity and schedule, I actually had a pretty good run of good sleep. So I wanna thank you for the book and then also the, the input that you've provided over time. So folks who are listening to this podcast, we will talk about a number of the things that I just mentioned. It's not all going to be technology that is in the, in the lab and unavailable. So how might people think about increasing-- let's say they have a family history of Alzheimer's, and they want to get on the maintenance train. They want to do as much possible to ensure that their glymphatic system and so on is, is operating in top order.
- MWDr. Matthew Walker
Great question, and in some ways you can break it down. [laughs] I'm all of a sudden gonna do a pull a Peter Attia and think about it as like a two by two, but I, I won't go there into the matrix.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
But I think there are certain-
- TFTim Ferriss
Not gonna go full McKinsey on us. [laughs]
- MWDr. Matthew Walker
Yeah, I know, yeah. Well, maybe I can one-up him and do like a two by three. But-
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
... you can think about things that you should not do that otherwise would be roadblocks to deep sleep, and things that you should-
- TFTim Ferriss
Mm-hmm
- MWDr. Matthew Walker
... do more of that will facilitate and increase-
- TFTim Ferriss
Perfect
- MWDr. Matthew Walker
... the amount of deep sleep. At least that's one of the ways, the frameworks with which I think about it. So you've already mentioned some of the things to be mindful of that will decrease the amount of deep sleep. The first of those being, unfortunately, caffeine. Caffeine, and we can, we'll probably go into detail here, is certainly something that not only disrupts your sleep and makes it harder for you to fall asleep, it does seem to selectively deprive that deep sleep, and particularly the quality of those deep sleep brainwaves, especially in the first couple of hours of the night. So that's one thing to be mindful of. The second is probably light exposure. Light exposure in the evening. In fact, there was a recent study published by Phyllis Zee from Northwestern demonstrating that even light exposure in the bedroom at night while you're sleeping, despite your eyelids being closed, can still penetrate and provide a signal into the brain that will decrease the amount of deep sleep. So trying to aim for darkness, not just in the last couple of hours before bed, but also darkness when you're in bed. Blackout curtains, eye masks, all of those good things. Feel free to do those things too. So be mindful of caffeine. Be mindful of also light, I think. The other big issue, and it's really hard to manage, is stress and anxiety. One of the ways, and we've been doing a lot of work in sleep and mental health, one of the ways that you can decimate your deep sleep is to increase your state of anxiety. And this has been demonstrated in animal studies, and we've demonstrated it in humans too. If you induce a state of anxiety, not only is sleep disrupted, but the type of sleep that is excised most powerfully from your sort of finger buffet menu of different stages of sleep is deep sleep. So that's another way that there will be a prevention of deep sleep. Coming onto the things that you can do for yourself to enable more deep sleep that are not necessarily technologically advanced One of the most interesting I find is, is temperature. Uh, temperature makes a huge difference to the amount of deep sleep. And temperature is not quite as simple as keep it cold, even though people like me have probably been out there just saying, "Oh, you know, keep your bedroom cold. It's the best thing." It's actually a three-part equation that you need to warm up to cool down to fall asleep, and then you need to stay cool to stay asleep, and then you need to warm up to wake up. But coming back to the first two parts of that ingredient and why temperature is important and what people can do, what we've discovered is that you need to drop your core body temperature to initiate sleep. And in fact, people with insomnia, interestingly, have problems with thermoregulation, and they don't seem to be able to thermoregulate as well. So you can do these studies where you place people's hands or feet into a hot bath, and you can look at how well the hands and their feet vasodilate, which is in other words, their vessels open up, and that's how we release heat. That's how we regulate our body temperature. But insomnia patients don't seem to be able to regulate their body temperature as well. They don't vasodilate as well. What this means is that for most people who are healthy sleepers, we can sort of ... The way that we drop our core body temperature is actually by having pushing the blood out to the surface of the skin. And as we fall asleep, if you move the blood out to the hands and the feet and the face, which is particularly where you get the highest amount of vasculature sort of surface area, at that point, you can emit the heat from the core of the body and your core body temperature plummets. The way that people can manipulate this is by using hot baths or showers before bed. I think many people sometimes will say, "Well, I know that if I have a hot, hot bath or a shower before bed, I get into bed and I typically fall asleep faster." And you think that it's because you're nice and warm and toasty. It's the opposite. It's that the warm water on the skin actually dilates the blood vessels. That's why I would get rosy cheeks, and all of a sudden the blood comes to the surface, and it's almost as though the ... You're charming like a snake charmer. You're charming the heat out of the core of the body, bringing it to the surface. And when you get out of the bath, your core body temperature actually plummets, and that is what helps you fall asleep and stay asleep more soundly. If we... It's so reliable, by the way. We call it the warm bath effect in sleep science, and that will consistently increase the amount of deep sleep that you get as well. There's also been some studies where you can warm the hands and the feet, right? You don't need to jump in the, the bath or the shower. You can use a hot water bottle, for example, and we're thinking about a lo-fi version of technology rather than a fancy headband as well. We, we haven't yet got funding for these studies, but can you selectively just warm, you know, parts of the bed or parts of the feet, and can you instigate sleep? And they did it actually in rats, these studies way back. They started to warm the paws of rats and bring the blood to the surface of the paws, and those rats started to fall asleep more quickly. And y- you can replicate that in humans now too. So that's another way that you can think about doing it.
- 46:18 – 48:31
Ideal types of exercise for promoting deep sleep.
- MWDr. Matthew Walker
Other aspects that we know can increase deep sleep, exercise is a really good one.
- TFTim Ferriss
Any particular types of exercise?
- MWDr. Matthew Walker
[laughs] There have been a series of reviews that have looked at this, and it seems to be that when it comes to deep sleep, it may be that more aerobic forms of exercise, so basically sort of more cardio-based forms of exercise, may get you greater bang for your buck in terms of deep sleep enhancement relative to, let's say, just heavy resistance training and lifting weights in the gym. Of course, that can also be aerobic depending on sort of how intense you go. But also any form of exercise seems to be beneficial for deep sleep. But if you want to then split it apart, sort of cardio versus lifting weights, cardio seems to give you a slightly greater benefit. People have then tried to split down the cardio, you know, running versus cycling. And at that point, I think the analyses just get so fine-grained that you start to lose-
- TFTim Ferriss
Yeah
- MWDr. Matthew Walker
... some of the signal in the noise. But exercise is another great way that you can enhance that deep sleep. There are not so many studies, but there are a few studies demonstrating that it doesn't seem to be strongly time of day dependent. So some people may then ask, "Well, when should I be doing that exercise to best optimize my deep sleep? Should I just be doing it from 7:00 to 9:00 PM or from, you know, 8:00 AM to 10:00 AM?" We don't really see that much of a difference. There's a few studies that can argue differences there, but I wouldn't worry about that. And though the overall message is that exercise versus non-exercise, exercise always wins out in terms of generating that more and greater and more powerful deep sleep.
- TFTim Ferriss
Yeah, I would say pick the schedule and the type of exercise you're actually gonna fucking do consistently [laughs] would probably beat the perfect prescription. It's like, yeah, okay, you're gonna do wind sprints up that hill with bowling balls taped to your hands. This ... The literature shows that's ideal. It's like, well, good luck with ad- adherence, right? So stick to-
- MWDr. Matthew Walker
Exactly
- TFTim Ferriss
... st- stick to what you're gonna do.
- 48:31 – 1:06:52
Matt’s updated thoughts on caffeine and sleep.
- MWDr. Matthew Walker
Yep.
- TFTim Ferriss
I want to come back to caffeine. So I'm looking at notes, prep notes for this conversation. You've changed your mind, it seems, on coffee insomuch as you now advocate for it, or at least support the idea of a cup of coffee in the morning. And an outstanding question, because we were going back and forth on what we should talk about in this conversation- that I really don't know the answer to, and that is why is coffee associated with so many of the same health benefits as sleep? It doesn't seem, at least at face value-
- MWDr. Matthew Walker
Mm
- TFTim Ferriss
... to, to make immediate sense. So, so both of those. Why a cup of coffee in the morning, and why is it associated with, uh, some of the benefits of sleep? And maybe you could also get into some of the pharmacokinetics of, of caffeine or, I mean, I guess coffee could be its own thing, just in terms of half-life and stuff so people have an idea.
- MWDr. Matthew Walker
Yeah, so I've certainly changed my, my tune on caffeine, and I think just tried to change my tune in general. I think when I first came out with the book and was just getting my training wheels underneath me [chuckles] in public communication, I think I was probably a bit too absolutist i- in truth, and anyone who speaks in absolutes you should always be wary of, and I was very much guilty of that. And I think this, that was true for caffeine and sleep in general. But let me just come back to the first part of the question, which is caffeine, what is it? How does it work in terms of waking you up? How does it work in terms of preventing you from sleeping? But also why I [chuckles] despite those things, I would still advocate for it.
- TFTim Ferriss
All right.
- MWDr. Matthew Walker
Caffeine is a chemical, as I'm sure you and everyone else knows. It's a stimulant. It's a psychoactive stimulant, one of [chuckles] one of the few that we feel readily comfortable giving our children.
- TFTim Ferriss
[chuckles]
- MWDr. Matthew Walker
But caffeine works in a very interesting way within the brain, which brings us back to another chemical that sounds very similar called adenosine. Caffeine, adenosine. From the moment that you and I and everyone listening, I suppose, woke up this morning, a chemical built up in your brain, and that chemical is called adenosine. And the more of it that builds up, the sleepier that you feel. And so we think of adenosine as a signal of sleep pressure. It's not a mechanical pressure, [chuckles] by the way. It doesn't mean that the end, the end of the day your head is nearly gonna explode on the basis of your adenosine. It's just, it's a chemical pressure. Caffeine works to keep us awake by way of competing with adenosine. So the longer that we're awake, the more adenosine is building up, and that adenosine is telling your brain, "Okay, you're getting sleepier and sleepier," and after about 16 hours of being awake, you should feel heavily weighed down by that adenosine signal that you can fall asleep easily, and then you can stay asleep. Caffeine works by way of racing into the system, and it latches onto those adenosine receptors. But what it doesn't do is activate them, because you would think, well, if it's binding on and latching onto those welcome sites of adenosine in the brain, then wouldn't that make you more sleepy? Well, the reason it doesn't is because it has the opposite effect. Well, not quite the opposite effect. It races in, and it just latches itself onto those receptors and inactivates those receptors. So it doesn't inhibit the receptors. It just blocks them. And so it's almost as though caffeine is like the mute button on your remote TV controller. It just comes in, and it mutes the signal of adenosine-
- TFTim Ferriss
Mm-hmm
- MWDr. Matthew Walker
... of, of sleepiness.
- TFTim Ferriss
Mm.
- MWDr. Matthew Walker
So it's what we call a competitive receptor blocker, and it has very sharp elbows. It will come in and it will nudge adenosine out the way, latch on and hijack those receptors, and block the signal of sleepiness. And that's why all of a sudden you think, "Well, gosh, I was feeling pretty sleepy. I've been awake for 14 hours. I have an espresso. I don't feel sleepy anymore." It's not as though you've removed the adenosine. The adenosine is still present. The sleepiness is still present, and it will continue to build up the longer that you're awake. It's simply that your brain is no longer getting the message of adenosine because caffeine is blocking the signal.
- TFTim Ferriss
Mm.
- MWDr. Matthew Walker
If that makes some sense. So that's the reason that caffeine will then start to disrupt your sleep, and it will disrupt your sleep in probably several different ways. The first is that it will, because it's a stimulant, prolong the time it takes you to fall asleep, and you, you mentioned that, too. The other aspect of caffeine, though, is that it's what we call anxiogenic, that it increases your anxiety. And anxiety, including what we think of as physiological anxiety, biological anxiety, which is essentially having your fight or flight branch of the nervous system switched on into higher gear, and aspects of your stress chemistry and things like cortisol, those things will be ramped up by way of caffeine, and that is the exact opposite of what you need to be able to fall asleep. You need to disengage the fight or flight branch of the nervous system and shift over to the more restful branch of the nervous system that we call the parasympathetic nervous system. And you can't do that because of the caffeine. And so what happens is that psychologically, the caffeine is preventing you from falling asleep. Then you start to get anxious, 'cause it's anxiogenic. It increases anxiety. At that point, you start to ruminate. This Rolodex of anxiety begins to whirl, and you start to then ruminate. And when you ruminate, you catastrophize, 'cause everything seems so much worse in the darkness of night than it does in the light of day. And at that point of catastrophizing and ruminating, you're sort of dead in the water for the next two hours, as it were.
- TFTim Ferriss
Story of my life. [chuckles]
- MWDr. Matthew Walker
Yeah. I'm so sorry.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
It's gonna sound painfully familiar to many people out there. So that's one of the issues with caffeine. The other is its duration of action. You mentioned its pharmacokinetics. It has a half-life of what we call five to six hours, which is just a fancy way of saying that after about five to six hours, half of the caffeine is still in your system, which means that caffeine has a quarter life of, for the average adult at least, 10 to 12 hours. And I, it, it's probably, again, not really a very good analogy, but, you know, if you have a cup of coffee, let's say, at 1:00 PM or 2:00 PM in the afternoon Is it similar to then saying, well, that's the equivalent of tucking myself into bed at midnight before I switch the light out? I swig a quarter of a cup of coffee, and I, I hope for a good night of sleep. That's probably not gonna happen, because a quarter of the caffeine is still in the brain swilling around at midnight. So its duration of action is something that people may want to be mindful of, and that will impact sleep. The other component is that caffeine will destabilize your sleep, so it makes your sleep more fragile. And as a consequence, if you are prone to waking up, and we all will wake up across the night, even healthy, good sleepers will wake up. Because caffeine will destabilize and make your sleep more fragile, it's more likely that you'll wake up, and when you do wake up, your sleep is less robust, and it's harder for you to fall back asleep, and so now sleep maintenance insomnia. And then the final part of caffeine comes back to deep sleep. If we, and we've done these studies where we can dose people at different times of the day and into the evening, and if you give people a standardized dose of caffeine, maybe 150, 180, or 200 milligrams, which would be, I suppose, the equivalent of probably a, a very strongly dripped, brewed cup of coffee, or probably one and a half cups of coffee, what we can see is a decrease in the amount of deep non-REM sleep. Particularly in the first two hours of the night, it can decimate that, that deep sleep. In fact, there was a reduction, if you look at that, and we've done some of these studies, by a single cup of coffee in the evening, it will drop the amount of deep sleep by about 30%, 3-0, which to put that in context, I would probably have to age you by about 12 to 14 years to get that type of reduction in your deep sleep [laughs] or you could just do it every night with an espresso if you wanted to. And I do think that that's relevant, by the way. Some people will say, "Look, I can have a cup of coffee with dinner, or even two, and I can fall asleep fine, and I stay asleep, so no harm, no foul." The problem there is that it discounts the idea that you have no sense of how much deep sleep that you get at night. Yes, you probably remember, did you struggle to fall asleep, or did you wake up? But none of us has a recollection of the quality of our deep, slow brainwave activity. But yet you may still be suffering from that excising of a significant amount of your deep sleep. And so the next morning, you don't feel refreshed or restored by your sleep, but you don't remember struggling to fall asleep or having a hard time staying asleep, and so you discount the idea that it was the coffee the next night. But now you start reaching for three cups of coffee the next morning, and then so on and so forth. The sort of vicious cycle begins. The harder it is the next night to fall asleep, the less deep sleep, the more coffee you get, and then people start falling into the trap of alcohol or sleeping aids to help them.
- TFTim Ferriss
So, so let me hop in. Let me hop in. [laughs] I'm gonna stage an intervention. All right, so [laughs] so the cycle, the stimulant depressant cycle is, is a whole mess.
- MWDr. Matthew Walker
Yeah, the business as.
- TFTim Ferriss
I've been a active participant on that field before.
- MWDr. Matthew Walker
Mm-hmm.
- TFTim Ferriss
But if I could just return to some of the questions that kicked us off. So why, why allow or endorse the idea of a cup of coffee in the morning, number one, right? If, if it is-
- MWDr. Matthew Walker
Yeah
- TFTim Ferriss
... after this litany of, of sins, and then how could coffee be associated with any of the health benefits of sleep? And if so, how is that the case?
- MWDr. Matthew Walker
You're absolutely right. I think, you know, at the time when I was writing the book a few years ago, the evidence was, was starting to emerge there that drinking coffee had health benefits, and there's been some great meta-analyses quite recently. And it is striking, and you just can't really deny it on the strength of the evidence, that drinking coffee is associated with numerous health benefits and the reduction in risk for numerous health conditions. And what's striking, as you mentioned elegantly, is that many of the same health related conditions that drinking coffee is associated with reducing are the very same diseases that sleep will also reduce in terms of your risk. So how on earth does this work? They seem completely paradoxical. The answer is antioxidants.
- TFTim Ferriss
Mm.
- MWDr. Matthew Walker
Because it turns out that the coffee bean itself contains much more than just caffeine. It contains a very healthy dose of antioxidants, a family called the polyphenols. Perhaps the principal one is ... Well, there's a, a number of different polyphenols that it contains, but chlorogenic acids are probably the, the principal kind that we think carry, it's an ester that carries some of these health benefits. So what we realized is that the coffee bean, because most people in developed nations are still deficient in their whole food dietary intake, the humble coffee bean has been asked to carry the Herculean weight of all of our antioxidant needs.
- TFTim Ferriss
Yep.
- 1:06:52 – 1:26:58
Cannabis (CBD, THC, CBN) and sleep.
- TFTim Ferriss
Perfect. So let's go from one socially acceptable psychoactive to one that is certainly becoming more and more socially acceptable that I'd like to ask about next, and that is cannabis, broadly speaking, but specifically in this case- CBD, THC, and then potentially CBN, if you have any thoughts on it, because it is commonly sold as for sleep, but I don't know how much that is supported in any way. So let's talk about the CBD, THC, and this is of personal interest to me, because I find that THC specifically helps me tremendously with turning down the volume on the rumination that tends to be associated with really horrible sleep onset insomnia. It tones down the chatter tremendously for me, and I find that, at least subjectively, to be one of the primary reasons it helps me to sleep. However, I've often wondered if I'm taking, say, smaller... what I would consider smaller doses in the forms of edibles, which are then converted through first pass metabolism into other things. But at 2.5 milligrams, or 5 milligrams, or 7.5 milligrams, am I inhibiting my REM sleep? Coming back to what you said earlier, like sometimes you don't know what you don't know because you're not straight immediately aware of how much REM sleep you're getting unless you're tracking it using some type of biometric device. Am I screwing myself in the long term by using this aid in the short term, right? So that's the context, but please, please, in any way that makes sense, tell us what you know about CBD, THC, and anything else related to this fine plant.
- MWDr. Matthew Walker
[laughs] So there's probably more research that we have right now on THC, which is the psychoactive component of cannabis, but there is some fairly interesting data on CBD too, and a little significantly less data on CBN. The THC, so it... we have a set of cannabinoid receptors in the brain, both what's called the CB1 receptor and the CB2 receptor. The CB1 receptor is the primary one that's expressed in the brain. That's where we think THC is having its sleep effects. And so what we've found... And by the way, if you go back, some of the first writings, the, the first emergence of the story of, of THC for sleep, uh, at least from what I've found, came from the writings of this brilliant British physician, Dr. Clendening, and he published his first monographs in 1843, I think it was. And if you read it, oh, T- I think you would love it too, actually. I should send you some of these articles.
- TFTim Ferriss
Before it was cool. Wow, he was on it.
- MWDr. Matthew Walker
Yeah, before it was cool, and it-
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
... this is like this hemp resin that he was talking about. But just the writing itself, you would love.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
It's this wonderful... Oh, gosh, I wish I could write that way. But his writing is lovely and delicious, and I could read it all weekend. But he des- he was the first to describe some soporific and sedating benefits of hemp resin, and then another doctor the same year, O'Shaughnessy, published some evidence too. What we probably know are four things related to THC with a possible caveat. The first is that you get a fairly reliable, very nice reduction in the time it takes you to fall asleep. This is just what you're describing too. It seems to have sedative benefit, and we're starting to unpack and understand exactly why THC has that sort of sedating effect. The next issue, however, isn't quite such rosy news, that-
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
... you seem to develop tolerance.
- TFTim Ferriss
Mm-hmm.
- MWDr. Matthew Walker
Which is that the same dose, if you're using it chronically, consistently every single night, can, in some individuals, lead to a tolerance that means that you have to increase the dose, and therefore you develop a dependency.
- TFTim Ferriss
Mm-hmm.
- MWDr. Matthew Walker
And I think the way, if people want to test dependency, would be to say, "Look, if I have to, let's say, travel internationally, and I'm... I obviously don't want to, you know, transit illicit drugs into other countries if, if they're not legal there, then would I start to just get very anxious?" I would think, "Well, my goodness, I've lost my crutch of THC." And at that point, it probably demonstrates that there is a dependency that you have on it, which I'd prefer or, or wish for people not to have necessarily. The, the third feature of THC is that it has quite a significant withdrawal rebound effect. So when people stop using THC, they typically don't just go back to the bad sleep that they were having before. It's often even worse.
- TFTim Ferriss
Do we have any idea of the dosage range that we're talking about, right? Because you could develop DT and [laughs] tremors and so on from alcohol withdrawal, but that's not gonna happen if you're having one glass of wine per night. So in this particular case with THC, how much does one need to be taking, or do we know, on a consistent, let's just say, nightly basis to experience that type of rebound that would be so harmful to sleep? Do we know?
- MWDr. Matthew Walker
I wish I had an answer, and we currently just simply don't know.
- TFTim Ferriss
Yeah. Okay. Got it.
- MWDr. Matthew Walker
There are not enough systematics to this. Right now it's more simply surveys where people are-
- TFTim Ferriss
But it's observable, like it ca- it can happen. Yeah.
- MWDr. Matthew Walker
But it's very... I mean, it's so observable, it's so reliable, this rebound insomnia withdrawal, that it forms part of the DSM, the Diagnostic and Statistical Manual of Mental Disorders, the sort of psychiatry bible. It forms part of the criteria symptoms for cannabis withdrawal, this insomnia syndrome.
- TFTim Ferriss
Huh.
- MWDr. Matthew Walker
That's how consistent-
- TFTim Ferriss
Wow
- MWDr. Matthew Walker
... and reliable it is. It's part of the diagnostic criteria. And in fact, often it's the insomnia that happens when you stop using That is one of the prime reasons for remittance that people will-
- TFTim Ferriss
Mm
- MWDr. Matthew Walker
... then go back to using it because they just-
- TFTim Ferriss
Yeah
- MWDr. Matthew Walker
... dislike the insomnia so much. And so-
- TFTim Ferriss
Go back to the wacky tobaccy. They can't stay away.
- MWDr. Matthew Walker
Yep. Ah.
- 1:26:58 – 1:33:10
A crowdsourcing request from listeners.
- TFTim Ferriss
So on the, the hypothermic side, one study I would love to see someone do, and studies cost money, and they cost a lot of money, and they take a long time, often, as you know. And but the potential combination therapy of MDMA and some type of cannabis derivative, probably not whole plant, but whether it's THC, CBD, or CBD by itself, or, or THC by itself, because ... And people will take issue with this, I'm sure, but one of the risks if you go to any uncontrolled environment where MDMA is consumed, at a festival or otherwise, and you go to the medical triage teams, you will find people who are overheating. That is one of the primary risks of excessive MDMA intake. So could you not just mitigate some of the physiological risk, but also improve clinical outcomes by combining the two? I haven't seen anything on this, but I did about a year ago a bunch of reading on both, looking at if that could not only stem some of the risk factors, but also enhance clinical outcomes. Now, I will say that on the con side, the ... one of the counterarguments would be that cannabis [laughs] can sometimes have an amnesic effect on people, and if you were doing it in a clinical setting where you want to have recall, that could be an issue. If you're with a therapist, they should also be doing a lot of the recording and so on. So you might end up at neutral if you're taking, you know, methylenedioxymethamphetamine, which by the way, one, one could say would improve recall in some people. Then maybe you just end up kind of net zero at baseline, but depending on the dosing. I just haven't seen much research done with it, so I'd be curious at some point. Side note, what is your, just for everyone listening and for myself, your handle on Twitter? What is your username on Twitter?
- MWDr. Matthew Walker
On Twitter you can find me @sleepdiplomat.
- TFTim Ferriss
[laughs] That's right.
- MWDr. Matthew Walker
I chose not to use my own name because, you know, I'm quite shy, and I typically a little bit private, but ... And also it's not about me, it's about sleep. And so I wanted to remove my name and just be animal.
- TFTim Ferriss
[laughs] Sleep Diplomat. All right. So @sleepdiplomat and I, @tferriss, T-H-E-R-I-S-S ... Actually, I don't wanna speak for you, Matt, but I'll s- I'll speak for myself, which is if-
- MWDr. Matthew Walker
No, speak for me, please. You, you'd be much better-
- TFTim Ferriss
Okay. All right
- MWDr. Matthew Walker
... at doing that with eloquence than I would.
- TFTim Ferriss
[laughs] I'm @sleeploudmouth, and he's @sleep-
- MWDr. Matthew Walker
[laughs]
- TFTim Ferriss
... diplomat. No.
- MWDr. Matthew Walker
[laughs]
- TFTim Ferriss
I'm @tferriss. So @tferriss, with two Rs, two Ss. I would like to hear from people out there who fall into a few camps. One would be researchers who have looked very closely at this literature, scientists or even amateur scientists who have the technical ability, uh, to at least read studies well to see what's out there, or, or what people would like to do from a research perspective. And the second group I would love to hear from are self-trackers, people in the quantified self movement or who are using devices like the Oura Ring or others who may have data from their own measurements related to, say, THC and/or CBD consumption, and how that has affected REM sleep as an example. I would be so interested to know, if, if, if anyone is willing to share that, specifically dosage, dosage range, and whether or not they have observed it to interfere with REM sleep. Would be super interested. So-
- MWDr. Matthew Walker
Yeah, I would love to do that. Please loop me in on that, because I think we can probably crowdsource a good amount of that, you know, data. Will it be scientific? Of course it, it's not gonna necessarily be scientific. But it's a little bit like Amazon reviews.
- TFTim Ferriss
Yeah.
- MWDr. Matthew Walker
You know, if this product that has 30,000 reviews and it's 4.9 stars, you probably don't need the science to suggest that it's gonna be a fairly decent product.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
And so thank you for, for sort of suggesting that. I would love to be included in that.
- TFTim Ferriss
Yeah, and people can just tag both of us on Twitter with what they have found. And I would say furthermore that some of the self-tracking can go a long way. I, I, I, I don't want to make too strong a case, but- I have seen, I'm not gonna name names, but I've, uh, when I was much younger, I volunteered as a subject in scientific studies all over the place in, it- including at some very well-known universities, because I wanted to see how it was done. I wanted to see how various studies were conducted. And I will say that there is high variability in how tightly experiments are run, and some of them with very small subject sizes can be run quite sloppily. And the, uh, when the output is very precise and it's, like, a P value out to four decimal points, and this, that, and the other thing, it can create the illusion of being much more compelling, or at least more accurate, than it might be. And that's not to malign all of science. There are great scientists out there. I fund a lot of them. But there's also the good, the bad, and the ugly in the realm of, of experiment design and execution. On the other hand, if you have, let's just say, an N of 1,000 people who claim to be using THC at a certain dosage range, it's unlikely that all of them are lying, right? So even if you account for some degree of, of fudge factor, it can at the very least be very useful in formulating more precise hypotheses that you can then test. I've felt this way for a long time. Since predating The 4-Hour Body, I went to the first Quantified Self meetup ever. I think it was 12 people at Kevin Kelly's house in Pacifica in 2008.
- MWDr. Matthew Walker
[laughs]
- TFTim Ferriss
And it's still very, very fertile ground. Let me
- 1:33:10 – 1:39:25
If the bed’s a-rocking…
- TFTim Ferriss
take a hard left turn, if I could for a second, and ask you a question that has been on my mind since I first read your book. There was passing mention of this, and I'm not looking at my highlight. This is from memory, so I apologize if, if this is something that came to me in a fever dream and it's not even in the book.
- MWDr. Matthew Walker
[laughs]
- TFTim Ferriss
But I feel like I read a passage that said something along the lines of rocking, having a bed that rocks, or having a rocking motion, has been experimentally, or at least observationally, determined to improve some facet of sleep quality or duration. And it prompted me to think, why are more people not spending time on this, if that's, if that is the case? Am I making this up? Is this just a figment of my imagination?
- MWDr. Matthew Walker
There's nothing wrong with your memory. It's, it's wonderfully exquisite. That's-
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
... what we found. You know, you think of, it comes from the early inception of parents, that they would take their child and they would rock them back and forth, and it seemed to have a sleep inducing benefit. And then you'd get cradles, where you would rock the cradle. So there seemed to be something about the rocking motion. And so then there were a group of scientists from the University of Geneva who conducted a brilliant study. It was one of those studies that I was just so envious that I didn't do the study [laughs] and I didn't come up with the idea.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
And what they did was they essentially took a bed frame and a mattress, and they suspended it from the ceiling rather than planting it on the floor, on these sort of chains, which [laughs] starts to sound very S&M, and please stick with me.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
It's not, I'm not quite going there. But-
- TFTim Ferriss
Oh, I'm on the same page. I'm ready for it.
- MWDr. Matthew Walker
[laughs] Yeah. Maybe that's the conversation we have after we stop recording. But-
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
So yeah, there's no candle wax on the nipples, nothing like that that's involved in this study.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
So there's-
- TFTim Ferriss
Never say never. [laughs]
- MWDr. Matthew Walker
[laughs]
- TFTim Ferriss
There's funding for it. All right. [laughs]
- MWDr. Matthew Walker
Tim, you're a great guy.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
So they, they got the bed and they suspended it from the, the ceiling, and then they put this device, this oscillating device, that would essentially s- sort of rock the bed in a lateral fashion, left and right.
- TFTim Ferriss
So just so I'm envisioning this properly, laterally would mean if I'm laying on the bed, I would be moving s- m- side to side. My left to right?
- MWDr. Matthew Walker
That's right. Yeah.
- TFTim Ferriss
Mm-hmm.
- MWDr. Matthew Walker
So you'd be sort of shifting towards your left side, and then your right side. And it's as if you're on a boat and it sort of, you know-
- TFTim Ferriss
Sure
- MWDr. Matthew Walker
... shifting you.
- TFTim Ferriss
Or in a hammock.
- MWDr. Matthew Walker
Exactly, in a hammock. Much better visual. So they started to rock the bed, and they were rocking it at a frequency that was trying to match those deep, slow brainwaves. So those deep, slow brainwaves, they go-
- 1:39:25 – 1:43:21
The Da Vinci Code magic sleep device.
- TFTim Ferriss
my own itch.
- MWDr. Matthew Walker
No, I think it's a very interesting idea, and it's one that I've also had too myself, so I sort of [laughs] y- you throw out these pat- or you develop these patents with this sort of, you know, sci-fi knowledge. But I, I did this anyway because another way you could stimulate the sensation of rocking is not by physically rocking, but by having a small inner ear device that will actually stimulate the, the, the machinery within the eardrum itself.
- TFTim Ferriss
Like the vestibular system.
- MWDr. Matthew Walker
Correct. So it would be vestibular stimulation.
- TFTim Ferriss
Whoa.
- MWDr. Matthew Walker
And so-
- TFTim Ferriss
That's wild. Okay
- MWDr. Matthew Walker
... I grabbed this patent that I sort of wrote because I sort of had this idea, you know?
- TFTim Ferriss
That is sci-fi.
- MWDr. Matthew Walker
It's another, okay, try and be an academic, be a podcaster, you know, help some startup companies, uh, teach and research, and then also, you know, do some of these other things. And, and by the way, make sure you get your eight plus hours of sleep.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
So I put this together because I think that that's another interesting way that you could do it. I don't have to physically rock you, because you could imagine that, you know, perhaps if people are in couples, that they don't necessarily want to get into a bed.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
And some people like rocking, other people don't.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
But I'm talking about the physical ph-
- TFTim Ferriss
Yeah
- MWDr. Matthew Walker
... I'm getting myself into trouble. You get the i- what I'm trying to say.
- TFTim Ferriss
Yeah.
- MWDr. Matthew Walker
Which is that-
- TFTim Ferriss
I get it. I get it
- MWDr. Matthew Walker
... there's some point there that you may not wish to do the physical movement and the rocking.
- TFTim Ferriss
Yeah.
- MWDr. Matthew Walker
So why don't you just get these little devices, you could put them in the ear, and you could travel with them too, and it will just stimulate the vestibular system.
- TFTim Ferriss
Mm.
- MWDr. Matthew Walker
Fool your brain into thinking that it's rocking.
- TFTim Ferriss
Yeah.
- MWDr. Matthew Walker
And could I do that? Also then, could I do it even more carefully where that device that I put into the ear also has a sensor? Because it turns out that you can pick up electrical brainwave activity that is bleed over, and it comes down into the ear. So I could actually measure your brainwaves, not by-
- TFTim Ferriss
Wow
- MWDr. Matthew Walker
... sticking electrodes on your head, but just simply with the inner ear device alone. Then I can measure the sweet spot of your own sort of Da Vinci Code frequency of slow wave sleep.
- 1:43:21 – 1:43:51
DARPA innovation.
- TFTim Ferriss
So side note on DARPA, if people want to see a, an incredible, I mean, just mind-boggling, many, many multi-decade long track record of innovation, study DARPA. It's-
- MWDr. Matthew Walker
Yeah
- TFTim Ferriss
... it is unbelievable. I mean, if you invent the internet, you get free license to do a lot of stuff, but take a look at DARPA. And if anybody can recommend a really good book or long form article that describes innovation at DARPA- Please let me know also on Twitter.
- 1:43:51 – 1:48:19
Ensuring proper function in the glymphatic system.
- TFTim Ferriss
I'd like to come back to the glymphatic system for a moment. And I, I, I don't want to attribute this to anyone, but I've spoken to a number of very credible researchers who are now heavily engaged with psychedelic compounds. And I phrase that carefully because it's ... They're not exclusively psychedelic researchers. These are world-class researchers who are now directing their attention to certain psychedelic compounds. Not that there's anything wrong with people who focus exclusively. I am very fond of a number of excellent scientists who do incredible work who might fit that description. However, the point I wanna make is that in conversation, I want to say they described how some of these psychedelics, and I wanna say we're talking about the serotonergic classical psychedelics, or at least psychedelics that affect the type 2A receptor, and how they impact microglia in the glymphatic system, which then raises questions about what long-term impact that might have with a certain frequency of administration, hypothetically, on, let's just say, the longevity of some of the cortical structures we were talking about earlier. And would there be the potential of staving off or slowing the onset of some of these neurodegenerative conditions? I happen to be very... And look, I'm talking out of turn here. I, I couldn't prove this, but I happen to be very bullish on this. I think it's worth exploring at least. Are there other means by which people can ensure the proper functioning of their glymphatic system if they want to ensure they are facilitating this, this self-repair and cellular cleaning in the brain? Are there any other, any other levers people can pull, any other things that people can do or not do that you're aware of?
- MWDr. Matthew Walker
I think right now sleep seems to be the, the more-
- TFTim Ferriss
The big one
- MWDr. Matthew Walker
... potent of those. But I think there's also some emerging evidence that physical activity and, i.e. exercise, can increase the, the efficiency of that system. But to come back to your question about psychedelics, I think I would love to examine what's going on with sleep during the treatment phases. Well, actually, I would like to look at it both pre, post, and during. Because one could imagine, is there something about the integrity of your sleep as you go into those therapeutic experiences that sets you up for and is deterministic of the efficacy success of that? In other words, it's, uh, it's a little bit like the evidence for sleep and the immune system and vaccination, that if you're not getting sufficient sleep in the week before you get your flu shot, you'll produce less than 50% of the normal antibody response-
- TFTim Ferriss
Huh
- MWDr. Matthew Walker
... rendering that flu shot significantly less effective. And by the way, we've found similar evidence most recently with the COVID shot as well. So is there something similar like that, but upstairs in the brain when it comes to the therapeutic effects of MDMA, that if you're seeding the brain with sufficient sleep before, does it predict certain outcomes? Second-
- TFTim Ferriss
Mm
- MWDr. Matthew Walker
... I don't think we really understand in detail, at least not in this kind of Web 0.2 or sort of the second coming of these psychedelic compounds with the hard science that's now really there. I don't think we've got good data on sleep. There are some-
- TFTim Ferriss
Yeah
- MWDr. Matthew Walker
... age-old studies back in the '60s and the '70s looking at different psychoactive components and how they would impact your sleep, but I would love to see science and be involved in that. If there's people doing these types of studies, I sh- I should probably have more conversations with them and see if we can just get some even lite, L-I-T-E, versions of sleep tracking in those to see what's going on. And then also, what happens afterwards? What happens to your sleep as a consequence of that treatment? Is part of the long-term trajectory because it helps reestablish, restabilize, reenergize sleep? Does it impact and harm sleep? And that, to me, would be even more interesting that you can get an emotional therapeutic benefit despite disruptions in sleep.
- TFTim Ferriss
Yeah.
- MWDr. Matthew Walker
Be wonderful to learn that too.
- 1:48:19 – 1:59:35
Psychedelics and sleep.
- TFTim Ferriss
So let's talk about this. We'll do ... I'm not sure I'm using this correctly. Maybe, maybe the Germans can come in and, and say yay or nay, or ja or nein, as the case might be. Gedanken. Let's do a gedanken or two.
- MWDr. Matthew Walker
[laughs]
- TFTim Ferriss
A gedunken, as I like to say.
- MWDr. Matthew Walker
Sorry, yeah. [laughs]
- TFTim Ferriss
We'll approach it by me sharing a number of observations, patterns that I've recognized just having been involved in the discourse around psychedelics for a, a reasonably long time now. I mean, since publicly probably since 2014 or '15, maybe a bit earlier, and then have, have been immersed in it for quite a bit longer. The first is that ... Well, let me say a few things. So with MDMA, given that it is, you know, effectively a methamphetamine, people generally don't sleep at all afterwards. Like, sleep is terrible. It's awful. Which would be, just as a side note, another possible pro argument for a combination therapy using THC. And I won't go into too much of the personal details on that, but th- that, that would be, I think, a, a compelling reason to do research looking at that as a combination therapy. With the classical psychedelics ... So flashback, let me give a flashback. My sophomore year, I wanna say it was my sophomore. It might've been my junior year. Sophomore or junior year in college. So this is a long time ago. So it's like '90- 697. And I put this paper online somewhere, and I don't think it's defensible. There's a lot of, like, undergrad hand-waving going on. But I was, I was at Princeton focused on becoming a psychology major with a focus on neuroscience, and I actually was able to be a subject for some of Daniel Kahneman's studies while I was there. So, you know, pressing space bars a lot, looking at tons of screens, which was, was, was actually really instructive. But I wrote a junior, uh, an either sophomore or junior paper on what appeared to be similarities between REM sleep and LSD administration or consumption. And what I have now, many decades later, seen over and over again is that people need less sleep after psychedelic experiences. And I would be curious to know how you might explain that. If we take that as true, they have this experience, and then they seem to require less sleep. To me, that implies there may be similarities between the two. But I would be curious to hear your thoughts. I'll give you another, I don't want to say data point, 'cause I- I realize this is all anecdotal, but I've seen this now replicated a whole bunch of times. If some people, and I'm not advising this, folks. These are illegal in most places still, and Schedule 1 can, can really ruin your day. [laughs]
- MWDr. Matthew Walker
[laughs]
- TFTim Ferriss
So lots of legal risk, and also, you know, psychoemotional and, in some cases, physical risk. But if, if someone takes, let's just call it 250 to 500 milligrams of dried psilocybe mushrooms, which would be considered not a microdose. So a microdose might be in the range of 50 to, say, 100 milligrams. And there's high degree of variability. So let's just assume that it's been finely ground and mixed, so it's been homogenized somewhat in terms of actual psilocybin content. A solid session, let's just say, for someone who is maybe an intermediate would generally be in the three to 4.5 gram range. The Terence McKenna heroic dose is five grams, although some people go significantly higher. The clinical studies of psilocybin are generally using, I wanna say, 25 to 30 milligrams, which would simulate a roughly five gram experience. So now we're talking about one-tenth of that as the top end, 500 milligrams, and you could actually go significantly lower, like 200, 300 milligrams. If someone takes that immediately prior to sleep, what I have heard reported multiple times now is in their dreams, they have what they would consider a almost mirror experience of taking five grams outside of sleep, in a, in a waking state. And this isn't 100 people, but it's enough now where there might actually be something there. What would you make of any of this?
- MWDr. Matthew Walker
I think it's fascinating. Some of these components actually work neurochemically very different to dream sleep.
- TFTim Ferriss
Mm-hmm.
- MWDr. Matthew Walker
So if you're getting, you know, some of the similar benefits, and I... The reason I say similar benefits is because dream sleep and REM sleep, and we've tried to do as much work as we can in this area, does provide a form of mental health benefit.
- TFTim Ferriss
Mm.
- MWDr. Matthew Walker
Provides a form of overnight therapy. That is during dream sleep when we strip away-
- TFTim Ferriss
Mm
- MWDr. Matthew Walker
... emotion from memory, and so we can detox those emotional memories almost like a nocturnal soothing balm that sort of takes the sharp-
- TFTim Ferriss
Mm
- MWDr. Matthew Walker
... edges off those memories, and you come back the next day feeling better about those things. So in that sense, when it comes to dream sleep, it's not time that heals all wounds, but it's time during sleep and particularly during REM sleep dreaming that provides that form of emotional convalescence. So how does that then fit with some of the psychedelic stories? I think it fits because both of them provide mental assistance benefits, but through, I suspect, very different mechanisms. Many of those psychedelic drugs will act on serotonergic mechanisms within the brain.
- TFTim Ferriss
Mm-hmm.
- MWDr. Matthew Walker
And in fact, if you look at REM sleep dreaming, it's the exact opposite.
- TFTim Ferriss
Yeah.
- MWDr. Matthew Walker
And in fact, you mentioned the point where people were sort of needing less sleep. I wonder if it's that they need less sleep or that the brain is prevented from generating sufficient sleep. And I don't know if we have the scalpel to sort of systematically separate one from the other there right now.
- TFTim Ferriss
Yeah.
- MWDr. Matthew Walker
But if it does, if they do produce both very similar emotional health and mental health benefits, which I think is, that's what the evidence is suggesting, they both seem to do it. I think mechanistically they do it through two different routes, because during REM sleep dreaming, your brain shuts down levels of two monoamines. One is called serotonin or 5HT, the other is noradrenaline, which everyone knows downstairs in the body its sister chemical. It's named called adrenaline, but upstairs in the brain, noradrenaline. And so I think mechanistically I'm fascinated by these two questions that you posed because they probably come through two different routes, but yet you arrive-
- TFTim Ferriss
Mm
- MWDr. Matthew Walker
... at the same destination by way of two different trajectories neurochemically and mechanistically. But then also, what does that mean in terms of sleep need? Are we impairing the generation of sleep by way of these compounds?
- TFTim Ferriss
Yeah.
- MWDr. Matthew Walker
Or are we simply because we're making up for what sleep ... produces naturally, you relieve the burden on sleep, and so the homeostatic drive for sleep is reduced and therefore you don't need to sleep as much.
- TFTim Ferriss
Yeah.
- MWDr. Matthew Walker
That would be a stunning finding too.
- TFTim Ferriss
Yeah. Let me throw out another wild aspect, which I probably should've mentioned up front, and that is when people have experimented with these, let's just call it 2 to 500, usually on the lower range, 2 to 300 milligram pre-bed experiments, very often the report goes something like this. "Holy shit, that was intense. That was like I took five grams. I feel like I didn't sleep at all, but I'm not tired at all. I actually feel fully rested." And which relates to the first question, which is a valid question, and that is, well, if, if these are operating very differently, is it not reducing the need for sleep, but just, but rather inhibiting your ability to sleep? And I think that's a very interesting question that also can be entertained side by side with the fact that when you do both at the same time, you have this very bizarre set of outcomes. [laughs]
- MWDr. Matthew Walker
Yeah.
- 1:59:35 – 2:09:23
How sleep affects food intake and weight fluctuation.
- TFTim Ferriss
Let's talk for a second about sleep, food intake, weight gain, all that good stuff. And part of the reason I wanted to ask about this is because it seems, this is based on a comment that you had sent to me a few days ago about, and maybe you can tell me how to pronounce this, endocannabinoids. Am I saying that correctly?
- MWDr. Matthew Walker
Yeah.
- TFTim Ferriss
Cannabinoids?
- MWDr. Matthew Walker
Yeah. You are.
- TFTim Ferriss
How do you say this? What's the proper pronunciation on this?
- MWDr. Matthew Walker
Endocannabinoids.
- TFTim Ferriss
There we go. On endocannabinoids. Because I'm wondering if this somehow ties into the earlier conversation we were having about THC. Maybe not, maybe it does. But certainly people who have smoked a lot of weed, which is not me, but will be fa- or for that matter, who have had enough edibles, will be familiar with the munchies. [laughs]
- MWDr. Matthew Walker
[laughs]
- TFTim Ferriss
Very consistent. Very consistent for a lot of folks who, who might dance with the wacky tobaccy on occasion. So could you introduce this in any way that makes sense to you, just in terms of, of how sleep relates to food intake, relates to weight gain, sleep and food timing, all of that jazz? Because the endocannabinoids, or changes in endocannabinoids caused by sleep loss seem to increase hunger, food intake, and thus weight gain. It makes me wonder, like, why would that be the case? [laughs] Why is that? I have observed, as someone who's had a lot of sleep trouble, that I become ravenous or at least much more compelled to overeat when I don't sleep.
- MWDr. Matthew Walker
It's striking, and I've certainly noticed that too when I sort of travel, if I'm, you know, going back home to the UK, to England, and my sleep is usually always rough with that. I definitely notice the change in my appetite, and the evidence is really very strong now that when sleep gets short, unfortunately it will lead to a waistline that can expand.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
And the, the early evidence came on to-
- TFTim Ferriss
@obesitydiplomat. It's a very nice way to put it. [laughs]
- MWDr. Matthew Walker
Yeah, exactly. Yeah, my Twitter handle is changing by the minute here.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
And then at some point it'll just simply be #cancelculture, #sleepdiplomat.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
Which is kind of... Yeah. But anyway, so the, the early evidence looked at appetite regulating-
- TFTim Ferriss
It takes a village, internet. [laughs]
- MWDr. Matthew Walker
[laughs]
- TFTim Ferriss
Let's make his dreams come true. All right. [laughs] Sorry, go ahead.
- MWDr. Matthew Walker
The world will be a better place without me, I'm sure, so.
- TFTim Ferriss
Oh, stop it. [laughs]
- MWDr. Matthew Walker
So there were two appetite regulating hormones. One was called leptin, one was called ghrelin, and- Leptin, by the way, is a hormone that says to your brain, "Okay, don't eat it." We think of it almost like the satiety signal that makes you ... When you've had food, it makes you feel satisfied by your food, and so you don't want to eat more. And then ghrelin, on the other hand, it does the opposite. It is the, "I want to eat more," hormone. It increases your-
- TFTim Ferriss
Yeah
- MWDr. Matthew Walker
... appetite.
- TFTim Ferriss
Ghrelin. G stands for go eat the cookies.
- MWDr. Matthew Walker
Yeah, exactly. [laughs] Sort of G for my stomach is growling and I desperately [laughs] want to eat more. And what they found was that when you limit people to, let's say, just four to five hours of sleep a night for several nights, you see a dastardly change in those two appetite hormones. Firstly, what they found was that leptin, the don't eat, the I'm sort of satisfied with my meal satiety signal, that dropped by about 18%. If that wasn't bad enough, levels of ghrelin, which is the hunger hormone, that increased by 28%. So in some ways it's almost like physiological double jeopardy, that you're getting punished twice for the same crime of not sleeping. Once by a loss of the signal that says, "Don't eat. You're full with your food." You lose that signal. And then, if that wasn't bad enough, you ramp up your ghrelin signal, which is I'm hungry. Hunger levels would increase by around about 24% to 25%, depending on the study. So that was sort of the emerging evidence on the appetite regulating hormones. And by the way, that doesn't necessarily lead to a consistent change in eating more of every type of food. The unfortunate thing is that the class of food that you start to increase your greatest d- desire for, it's not just that you want to eat more, it's the things that you want to eat more of are the things that are more obesogenic. So these are more carbohydrate rich foods, simple sugary foods, ice cream, sort of sweets, et cetera. And also they found an increase in your preference for eating salty snacks, which can put you towards a path of greater hypertension. So, so that was the evidence at the basic appetite regulating hormone level. But then the more recent data came out, and you're right, that all of us, even if we're not smoking the, the wacky tobacco as you described-
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
... all of us have our own cannabinoids that we release inside of our brain and our bodies. We have naturally occurring cannabinoids in our brain, and they're called the endocannabinoids, meaning that they come from inside of us, endo. And you're absolutely right that when you give people exogenous cannabinoids like THC, it makes them hungry. You get the munchies. But what they found was that when you sleep deprived individuals, this has got nothing to do with THC or cannabis or smoking weed, you increased the amount of these cannabinoids within the, the brain and within individuals.
- 2:09:23 – 2:21:18
Orexin, I reckon.
- TFTim Ferriss
So orexin, is that O-R-E-X-I-N? How do you spell?
- MWDr. Matthew Walker
Yes. Yes, orexin. Yep.
- TFTim Ferriss
I was hoping you would say E-R-E-X-I-N, because then I was gonna suggest that you could actually cross-sell the Orexin for male vitality after the Da Vinci Code [laughs] magic sleep device. You know? I'll take my customary fi-
- MWDr. Matthew Walker
Oh, my spot on late night television is assured after this conversation.
- TFTim Ferriss
[laughs] Yeah, I'll take my customary 15%, it's fine.
- MWDr. Matthew Walker
[laughs]
- TFTim Ferriss
[laughs] So, so orexin, I was asking about that and also just contextualizing in my own mind everything you just said, because I, I'd love to get your read on just a amateur's play hypothesis. And this is based ... This came about after, unfortunately, my personal experience of many sleepless nights, lots of sleep deficit over many, many decades, and have observed this eating, this increased volume of intake, even if it's healthier foods, right? If I'm trying to exert control, I'm still just eating a lot more, and the drive is so strong that I started to wonder what the evolutionary explanation for that might be, right? If the ... Let's say this is an adaptive and not a pathological behavior. Like, what would ... W- how would this be adaptive? And I was thinking, and this may not hold any water, but I was thinking, if you rob the body of its ability to repair itself during sleep, could this not be a compensatory mechanism by which you try to fix things by, say, driving up anabolism? It's like, "Okay, you're not gonna give us the sleep that we need. Fine. We're going to try to turn on all the anabolic machinery we can by throwing insulin into hyperdrive, by increasing caloric intake, which might have some effect on testosterone or who knows what." Do you think there might be anything there, or is that just me yelling nonsense into the wind as usual?
- MWDr. Matthew Walker
[laughs] I think it's certainly one alternative hypothesis, that what you're trying to do is eat yourself in an overcoming way and sort of to overcome the sleep deprivation and see if you can placate some of what you're not getting by way of sleep. I think that's one hypothesis. Right now, I think the evidence is entertained in the other direction, which is sort of flipping the causal inference, which is that-
- TFTim Ferriss
Mm-hmm
- MWDr. Matthew Walker
... it's the lack of sleep that your brain is receiving the signal of, which then suggests, "Oh my goodness, I must be under conditions of starvation." Because from an evolutionary standpoint, the only time that Mother Nature ingrained in its biology has experienced insufficient sleep is under conditions of starvation, and that's why you increase the drive to eat. Other people have suggested it's because of energy expenditure, but that m- has been largely dismissed. That's a myth.
- TFTim Ferriss
Mm-hmm.
- MWDr. Matthew Walker
Which is that when you are awake, surely you are burning many more calories than when you're asleep. And so the increase in food intake is simply trying to offset the increased metabolic caloric expenditure. The problem is twofold. First, that sleep itself metabolically is an incredibly active process. We think of it as a passive process, but metabolically, it's hugely demanding. And in fact, the difference between you lying on a couch doing nothing versus you sleeping is a very small amount, meaning that sleep is a highly metabolic process. Second, if you look at it across a full eight-hour period of sleep, if you keep people awake, in particular chambers where we can measure very concretely the amount of caloric and metabolic activity that's going on and how much, how many calories you're burning, what you find is that you will probably burn only around about an extra 140 calories by being sleep deprived all night than you would be if you slept. However, the amount of increased calories that you take on board is usually at least double or triple that. You will overeat by somewhere in the region of 300 to 600 calories when you are sleep deprived. So it's not simply that you are trying to eat back the calories.
- TFTim Ferriss
Amateurs. Amateurs. Oh my God.
- MWDr. Matthew Walker
Yeah.
- TFTim Ferriss
These guys should see my diet log. 300 calories.
- MWDr. Matthew Walker
[laughs] Yeah, maybe it's not twofold, maybe it's 10 f- it's a 10X, uh, situation.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
And so right now, that's the sort of the model that we have, which is it, it's not you trying to overcome necessarily your caloric expenditure, because you do that plus a lot more, and that's why it sets you on a path towards obesity-
- TFTim Ferriss
Yeah
- MWDr. Matthew Walker
... and increased weight gain.
- TFTim Ferriss
A- again, just Looking at this as a layperson who's had a lot of sleep problems, I, I would totally agree with the caloric deficit, if any, being ... I don't know, it just seems trivial enough that it wouldn't drive that type of overeating. The reason I wonder about the plausibility of turning on the anabolic machinery to try to, try to achieve repair that wasn't permitted by insufficient sleep is because when I think about, and, uh, thank you for putting up with me, because I know that I'm coming at this as a layperson who, who should know better.
- MWDr. Matthew Walker
Not at all.
- TFTim Ferriss
But I've done a lot of fasting, done tons of fasting, up to 10 days, right? I've done a lot of fasting, and that's water fasting. And so when I h- when I hear the example, which I believe, which is the only time you see animals depriving themselves of sleep is when they are in s- under starvation conditions or in, under conditions of food scarcity, it would seem to me that maybe another way to put that would be the only time that animals sleep very little is when they're under those conditions, because they're not actively ... I, I would imagine they're not actively trying to deprive themselves of sleep. And the only reason I say that is that it would seem to me, based on my experiences fasting, if, if I were to extend that to then other mammals at least, or some other mammals, when you fast, it gets really hard to sleep.
- MWDr. Matthew Walker
It does.
- TFTim Ferriss
Very often, at least. I mean, you can experience tachycardia, you can have all sorts of ... I don't know if it's a cholinergic response. You could probably tell me, but it is very hard for a lot of folks to sleep when they fast. And you take, say, humans as an example, right? So if you were to really fast, you would have trouble after, after a handful of days, of course, and some people would get kidney pain or pain associated with muscle loss because of the catabolism. Now, there are a couple ways that you can attenuate that, right? One is, and it doesn't solve it completely, but it helps a lot, is to consume supplemental electrolytes. And so one is to consume supplemental electrolytes. Another is to consume stuff that monkeys like so much, and that is fruit, right? So fructose will help you to maintain blood pressure where it might otherwise plummet, and you could get, what's it called, orthostatic hypotension, where you stand up and you think you're gonna pass out and, which, which can happen if you're-
- MWDr. Matthew Walker
Yeah, orthostatic intolerance.
- TFTim Ferriss
Orthostatic intolerance. There we go. So, so I just wonder if the lack of sleep is basically directly caused by the caloric insufficiency. I think that was-
- MWDr. Matthew Walker
Yeah
- TFTim Ferriss
... a bit of a word salad that I just tossed all over the place.
- MWDr. Matthew Walker
No, let me sort of mix it further. I think it's a, it's a, it's a-
- 2:21:18 – 2:24:48
Fainting goats and narcolepsy.
- TFTim Ferriss
So let me make a few comments, and then I'll ask a thousand more questions. So the first, I would say, not to make light of narcolepsy, but if anyone listening has not seen video of the fainting goats, which have been bred [laughs] to have narcolepsy ...
- MWDr. Matthew Walker
That's actually not narcolepsy.
- TFTim Ferriss
Oh, they're not?
- MWDr. Matthew Walker
The fainting goats-
- TFTim Ferriss
What is that?
- MWDr. Matthew Walker
No. It looks very much like narcolepsy, but it's a condition-
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
... where in patients with who have narcolepsy, one of the other features is not just that you're unstable in terms of your sleep-wake and you fall asleep during the day. There's something called cataplexy.
- TFTim Ferriss
Ah.
- MWDr. Matthew Walker
And cataplexy happens where all of a sudden if you get strong emotion or you frighten a patient with narcolepsy or an animal with narcolepsy, and there are dogs that have been bred with the narcoleptic gene, then all of a sudden they lose all muscle tone. And part of the reason is when we go into-
- TFTim Ferriss
Uh-huh
- MWDr. Matthew Walker
... REM sleep, we actually become paralyzed. Our brain paralyzes our body so the mind can dream safely. But that same-
- TFTim Ferriss
Mm-hmm
- MWDr. Matthew Walker
... mechanism of paralysis seems to go awry in narcolepsy, and these patients will go into this just cataplectic attack, where they will lose all muscle tone and they'll collapse down on the floor, and it looks like they've gone into REM sleep. They haven't. They're awake. They're just locked into the unusual paralysis that would normally-
- TFTim Ferriss
Wow
- MWDr. Matthew Walker
... happen during REM sleep. Whereas with the fainting goats, it's actually a different mechanism, where when they get frightened, all of a sudden their muscles become incredibly rigid, and then they topple over.
- TFTim Ferriss
Yeah, they look like some type of statue you would see in a menagerie for a Christmas display in front of a church or something. I mean, they totally just stiffen and then fall right over.
- MWDr. Matthew Walker
Straight-legged out. That's right, yeah.
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
And they will sometimes just hop on their straight legs to try and get away, or they just keel over. But that's actually-
- TFTim Ferriss
Oh, poor things
- MWDr. Matthew Walker
... quite different. But-
- TFTim Ferriss
Poor things [laughs]
- MWDr. Matthew Walker
... but you can go online and look at, sort of search for dogs and narcolepsy, and you'll see many of these things. It's, it's a stunning condition, and very tragic, of course, for the narcoleptic-
- TFTim Ferriss
Yeah
- MWDr. Matthew Walker
... patients. Cataplexy is a major daytime disruptive feature.
- TFTim Ferriss
All right. So I'm glad I brought up fainting goats, just so I can stand corrected. [laughs]
- MWDr. Matthew Walker
[laughs]
- TFTim Ferriss
So would it be fair to say that these are cataplectic, cataplexic goats? Or what would you call them?
- MWDr. Matthew Walker
No, not on the basis of the way that we term cataplexy within narcolepsy.
- 2:24:48 – 2:29:58
Modafinil.
- TFTim Ferriss
Well, let's, let's get to story time with Tim related to the Olympics for a second, and then we're gonna get to a question about modafinil. So I'm gonna seed that. [laughs] There, there was a time, I want to say this was maybe two or three Olympics ago, it could have been further back, where lo and behold something amazing was observed, and that was almost all of the sprinters who made it to the final rounds of the Olympics were prescribed modafinil because they had been diagnosed as narcoleptics by their doctors. So who knew all of these world-class sprinters would happen to be narcoleptics? It's amazing.
- MWDr. Matthew Walker
What a coincidence.
- TFTim Ferriss
What a coincidence. So the subtext here is that modafinil can be used as a performance-enhancing drug. Now, modafinil, as I understand it, I think that is Provigil and not Nuvigil. Maybe it's both.
- MWDr. Matthew Walker
Provigil, yeah.
- TFTim Ferriss
Provigil. Do we know how modafinil works? Do we understand how it works, or was that a discovery in search of a mechanism, in a sense? Because there are so many drugs that are used, including some very common drugs, where we don't really know exactly how they do what they do. We, we just know that they do X. Is modafinil understood well?
- MWDr. Matthew Walker
No, it's not.
- TFTim Ferriss
Okay.
- MWDr. Matthew Walker
It certainly doesn't work by the classic ... So we used to prescribe, we, the science community and clinical, we used to prescribe patients with narcolepsy amphetamines-
- TFTim Ferriss
Mm-hmm
- MWDr. Matthew Walker
... to try and brute force them awake so they didn't have that daytime, that excessive daytime sleepiness that is so prohibitive of a normal functioning life. And now w- that clinical practice has shifted towards prescribing modafinil. Modafinil, like amphetamine, is a wake-promoting chemical, of course, but it doesn't seem to work by way of that classic- amphetamine-based route. Exactly how it works, it's a little bit unclear. It may be working by way of stimulating levels of noradrenaline, serotonin, and perhaps also levels of another chemical called histamine, which is a very strong-
- TFTim Ferriss
Huh
- MWDr. Matthew Walker
... wake-promoting chemical. Histamine, which we may come onto-
- TFTim Ferriss
Right
- MWDr. Matthew Walker
... when we speak about-
- TFTim Ferriss
Just quick side note. For people who have ever felt drowsy after taking a Benadryl-
- MWDr. Matthew Walker
That's right
- TFTim Ferriss
... would be experiencing an antihistamine.
- MWDr. Matthew Walker
Yeah, that's how we discovered part of the, the role of, of histamine as a wake and a sleep regulating chemical, was that the older forms of anti-allergy medications, that they would cross the blood-brain barrier. And the anti-allergy medications were principally blocking this thing called histamine, because in the body it controls the allergic response. But if it gets into the brain, then it also decreases levels of histamine in the brain, and histamine is a wake promoting chemical. So when you decrease it, you result in a level of sleepiness and it starts to knock you out.
- TFTim Ferriss
Mm.
- MWDr. Matthew Walker
So those are some of the different current chemical systems that we think modafinil may be working on, but it's still very unclear right now.
- TFTim Ferriss
Yeah. And I'm asking you this partially as a public service, because I know of a lot of folks out there who are self-described biohackers who use modafinil long-term without cycling off, and I just ... It strikes me as a bad idea when the mechanisms are poorly understood. But who am I? Who am I to say? I will, I will say from personal experience, because I've experimented with modafinil, I have never in my life experienced the development of tolerance as quickly with anything than with modafinil. I mean, it is, it is remarkable. I will say if I use it once at the sort of therapeutic dosing range, amazing day. Super productive. Oh, my God, I just got a week's worth of productivity crammed into one day. The next day, same dose doesn't work. The tolerance that I develop and the necessity to increase the dose is so violently rapid that I decided very quickly I didn't want to use this stuff, because I also experienced, and this should not ... This will not be a surprise to you, that if I used it for a few days and I'd already developed a tolerance by that point and I stopped, my productivity was absolutely annihilated for multiple days. I just didn't, didn't find it to be the tool for me. So that's, that's part of the reason I was asking about modafinil, is just in case people out there are using it.
- MWDr. Matthew Walker
Yeah, I think I would be concerned about its long-term use, in part because of its disruptive impact on sleep, and also the fact that in biology it's very rare that you get a free lunch. And when you fight-
- TFTim Ferriss
Yes
- MWDr. Matthew Walker
... biology, you normally lose, and the way you know you've lost-
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
... is long-term disease and sickness.
- TFTim Ferriss
Yeah. I did find that my, my immune system felt funny also when I was, when I was using modafinil after a while. Yeah, I ... It didn't, it didn't sit super well with me. But that's not to malign it as a tool in the toolkit, right? For especially for people who need it.
- 2:29:58 – 2:35:58
How sleep medications affect sleep quality.
- TFTim Ferriss
Let's talk about the name that has been invoked several times, and we may do it by speaking more broadly about sleep drugs, the good, the bad, and the ugly. But let's have it also include trazodone, since it's come up now at least twice. How would you suggest people think about sleep medications and sleep architecture? Where should we begin?
- MWDr. Matthew Walker
Yeah. You know, it's, it's really difficult. Again, just to state for the record, I'm not a medical doctor, and so this isn't anything sort of medical. And I've always been reticent to sort of go on record, I suppose because of that, because, uh, it's not clinical advice. But I can at least try to offer some of the scientific evidence regarding classic sleeping pills, and then maybe more about the more novel compounds that you and I have discussed. Right now, I'm probably not a big advocate of the classic sleeping pills, or even the newer classic sleeping pills. And I don't necessarily need to name any names. Everyone can name them, but they're in a class of drugs that we call the sedative hypnotics. And the problem is that sedation is not sleep. And so the way that those drugs work, those classic sleeping pills, is that they go after a chemical system in the brain that's an inhibitory system. It's called the GABA system, which stands for gamma-aminobutyric acid, which is the major kind of red light stop signal in the brain. So when you take those sleeping pills, I'm certainly not going to argue that you're awake [laughs] at night. You're not. But to argue that you're in naturalistic sleep, I think is perhaps an equal fallacy, because if I were to show you the electrical signature of your sleep with and without those classic sleeping pills, they're not the same thing. And one of the potential concerns is that if you map out the electrical brainwave sort of signature of sleep, the, the spectrum of electrical brainwave activity ... You and I were discussing deep sleep, and it's particularly the deepest of the deep slow brainwaves, and we can come onto some of the functions of those for learning and memory and immune function. But where those classic sleeping pills will leave the most significant dent in the quality of your sleep is particularly in the deepest of that deep sleep brainwave activity. So it's taking a bite out of that. So that would perhaps be scientific cause for being mindful about them. Now, by the way, current medical practice suggests that there is a time and a place for those sleeping pills, but they are typically not advocated long term. And again, we- Please speak to your doctor. Don't do anything on the basis of, of my advice. I would say, though, that one of the other aspects of those sleeping medications is first that you typically develop tolerance. You also get some pretty unfortunate side effects, things like next-day drowsiness, drowsy driving-related accidents, an increased risk of dementia. There's also been evidence that it increases your risk for falls, uh, leading to hip fracture and skull fracture. There was an FDA warning about these sleep medications recently that was published for those concerns. And due to that, I think back in 2016, the American College of Physicians offered the recommendation that sleeping pills should not be the first-line treatment for insomnia. It should be something called cognitive behavioral therapy for insomnia. So I think they've fallen somewhat out of favor. If you were to come back to what I was telling you, that they don't leave you with the very best quality of electrical sleep, they certainly will increase classically the amount of sleep that you have. And even in fact, they can look like they increase the amount of deep sleep that you get on the basis of classical sleep scoring. But if we separate the brainwave activity, then you start to see that the news is not all good. But if you're sleeping longer, shouldn't you get at least some benefit of that? And the reason I became less bullish, too, on those medications was because there was a great study done by a colleague of mine, Markus Frank, and he was dosing animals with different sleep medications. And firstly, he was using a learning paradigm, and as the animals would learn, they would create this memory trace in the brain that he would map, and he could measure the strength of the synaptic connections within the brain. Then what would happen is that if you let those animals sleep naturally, the next day they would come back, and the strength of that memory trace, the strength of those synaptic connections had be- increased even more. And this is part of the reason why sleep is so beneficial for learning and memory. What he then did was dose those animals with classic sleeping pills, one of which was zolpidem or Ambien. And firstly, those animals certainly they did sleep longer, which you would think on the basis of then sleep's role in learning and memory and plasticity would mean that the memory trace was even stronger the next day. However, what he found was that not only was the memory trace, the memory circuit not strengthened by way of that sleeping pill-induced sleep, it was actually reduced. In fact, he found almost a 50% reduction, a weakening in the strength of the memory trace as a consequence. So I think, as I said, there's a time and a place that clinical medicine believes there is a, a significant use case for these sleeping medications. But I think in the long term, the evidence is favoring against them and going towards psychological treatments or other types of non-traditional sleep medications, things like, as you mentioned, trazodone. We can also speak about pregabalin and gabapentin.
- 2:35:58 – 2:43:31
Trazodone.
- TFTim Ferriss
Let's get after it. Why don't we keep the momentum?
- MWDr. Matthew Walker
[laughs]
- TFTim Ferriss
So which would you like to put on the platter first? Trazodone?
- MWDr. Matthew Walker
I think probably trazodone, yeah. Right now, trazodone is probably the most off-label prescribed sleep medication. It's not currently-- It doesn't receive the current sort of labeling for a sleep medication, but it is used by many doctors off label. Trazodone I find fascinating for a number of reasons. It's originally designed as an anti-anxiety or antidepressant medication in, in higher doses. But what we've discovered is that in lower doses, and lower doses being anywhere between 25 milligrams all the way up to maybe 300 milligrams, it's quite sleep inducing. And the reason I find it interesting is firstly, it does not work like classic sleeping pills, which, as I said, just knock out the cortex, sedate the cortex by stimulating the inhibitory transmitter GABA. Instead, trazodone actually works on the three neurochemical systems that we've mentioned before, which are the wake promoting systems within the brain. Specifically, trazodone will target the noradrenaline system within the brain, and it's what we call an alpha-1 adrenergic antagonist, which simply means that it dials down the volume on noradrenaline. It is a 5-HT2A antagonist, meaning it reduces serotonin activity, and finally, it reduces down histamine by targeting the H1 receptor, which again, we spoke about histamine being wake promoting. If you block it with anti-allergy medications, you get sleepy. So trazodone has ... By the way, trazodone I know sounds quite scary. It sounds like a tranquilizer-
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
... and it's not like that at all. It's actually very nuanced. What I like about its profile perhaps is that, from a scientific perspective, is that it tries to do something more naturalistic. It tries to switch off the volume of the wake promoting regions, and therefore allows sleep, the passage of sleep to be produced and arrive with you in a more naturalistic way. Also, one of the other interesting features is that not only does it ... A- and by the way, it seems to be quite effective. There was a meta-analysis that was done recently on 11 different really well-controlled, randomized placebo-controlled trials or RCTs across probably almost around 500 different patients. And what they found probably was three things of interest. The first is dose, then age, and then duration of use or efficacy. They found that regardless of the dose, whether it be below 50 milligrams or above 50 milligrams- It provided benefits for reducing the time it takes to fall asleep, which is what you were describing with trazodone use. It reduces the amount of time you then are spending awake for the rest of the night. It increased deep non-REM sleep. But here was the fascinating part for me, it didn't come at the cost of REM sleep, which in some ways is a little bit surprising. They're not utterly antagonistic in their role, REM and non-REM, but I mentioned earlier on in the conversation that you can increase deep non-REM sleep by way of exercise. But if you look at some of those studies, when you increase deep non-REM, you can have an exercise induced reduction in REM sleep. But yet what's interesting about trazodone is that it seems to increase the amount of deep non-REM sleep, but leaves REM sleep untouched. REM, you don't get a consequence to REM sleep. We don't quite understand why that is, but that's one of the nice things is that whether it be below 50 milligrams or above 50 milligrams, you get these benefits.
- TFTim Ferriss
Hmm.
- MWDr. Matthew Walker
The age dependency is quite nice because if you look at people who are younger than 60 years old, you get these sleep benefits. But even you see many, not all of them, but many of the sleep, same sleep benefits for people who are 60 years or older. And we know that as we get older, as you and I discussed earlier, the harder that sleep becomes. And so that could arguably be a more challenging use case where that medication would fail, yet you seem to get quite a lot of the distance and the benefit even as you get older. So I think that's a potential upside. And then the other aspect of it was the duration of action. They did look at this, which comes on to aspects of tolerance and withdrawal. There didn't necessarily seem to be a significant tolerance buildup where you, if you look at acute dosing for one week, you get these nice benefits. But then if you keep assessing people week after week up to one month, at least in the meta-analysis, the benefits were still there for the most part, which suggests that there isn't necessarily tolerance to the drug, that those benefits persist even when you continue to take the drug. So right now that's why I think it's a, it's an interesting drug in terms of its profile and how it works. So I'm not anti-medication. Please don't think that. It's just that if those medications aren't producing naturalistic sleep, I prefer to say so. But here it seems to be a very different mechanism.
- TFTim Ferriss
Now, to those listening, they might say, "Well, wait a minute. Dr. Walker, you have said there is no biological free lunch. This sounds like a free lunch." So if you were to take the other podium, right? So you're on the debate team and you, you want to make the counter case, what is the downside risk or what is the be careful when you use trazodone argument to be made?
- MWDr. Matthew Walker
I think right now, if I wanted to steel man the argument on the other side, I would say it's unclear what the long-term necessarily health associated risks are. Certainly trazodone is being used for decades, as I said, for antidepressant purposes and anti-anxiety purposes, and it seems to have a largely safe profile. So maybe I'm less concerned about that, but what I would still like to see are the studies that look at things like learning memory plasticity-
- TFTim Ferriss
For sure
- MWDr. Matthew Walker
... in the brain. Because things like classic sleeping pills like Ambien have been found to produce non-naturalistic sleep, those obvious studies have then been done and found that the functional benefits of sleep are not emergent when you are taking those drugs, and that raised the red flag even more so. I don't think we have those studies yet for things like trazodone, not at least in a very strict, specific way. So for me, I think I would still want to warrant caution and look at those outcome measures long term.
- TFTim Ferriss
Agreed. Totally agreed. Yeah. I mean, certainly for a learning fanatic, [laughs] learning obsessive person like myself, those are highly important questions that lead me, at least for the time being, to, I'm not a doctor, I don't play one on the internet, folks, but to, to cycle, right? With medical supervision, but to try to not always hit the same nail with the same hammer each, each night, and I'm not giving medical advice. That's just my personal approach.
- 2:43:31 – 2:46:37
Serotonin type 2A antagonism.
- TFTim Ferriss
Question on the serotonin type 2A antagonism, how strong is that effect? And part of the reason that I ask is I know there are other drugs, well-known drugs, ketanserin, if I'm saying that correctly, which is classified as a antihypertensive by the WHO and the NIH, is being investigated by some as a potential, and I have a lot of strong opinions about this that I'll save for another time, but for a potential trip canceling intervention. So if someone is having a psychedelic experience that has become unmanageable or unpleasant, and I, I would actually generally take the position that I, I think it is premature to just hit the escape chute in a lot of those, in, in those cases, unless we're looking at actual physical risk, which, you know, the, the, the lead up is very important. But let's just say there are companies, for-profit companies, who are looking at ketanserin as a potential trip stopper, and I'm wondering if trazodone would be strong enough to exert that kind of effect. I just don't know at what type of dose it would even be plausible. Not to say that I'm going to use it for that purpose, but I'm wondering if it could go sort of toe-to-toe with some of these other type 2A antagonists.
- MWDr. Matthew Walker
I think it's a good question. I don't think we really know what percentage strength of pushback on each one of those three neuroche- chemical systems trazodone exerts its principal effect. Is it more so a histamine ... So if you rank order how it's impacting noradrenaline-
- TFTim Ferriss
Yeah
- MWDr. Matthew Walker
... serotonin, and histamine, is it that it's principally histamine where you get the greatest, let's say, you know, 70% of the impact is on histamine, then 20% is on noradrenaline, and then 10% is on serotonin? Or is it reversed in that order? We don't know. I think once you know that, you would then be able to understand exactly how the utility value of it for pulling the rip cord, as you described, to exit the trip. One way you could do that is in animal studies, where you were to dose animals with trazodone, and then you could selectively block each one of those things. So I could give trazodone. I could selectively block noradrenaline receptors and leave serotonin and histamine unchanged and ask, what's the impact? And then I can go through those. I can leave noradrenaline and histamine unchanged and block serotonin, and then leave noradrenaline and serotonin unchanged and block histamine, and that way I could create this rank ordering effect of the impact of trazodone on each of those three systems. I at least don't know of evidence that has systematically done that to disentangle-
- TFTim Ferriss
Mm-hmm
- MWDr. Matthew Walker
... the priority rating of those three things.
- 2:46:37 – 2:49:22
Perilous polypharmacy.
- TFTim Ferriss
Got it, and I should issue a warning here, which is work with professionals before you start combining drugs or taking any drugs for that matter because if you don't read the fine print on what I'm saying, you could get yourself into trouble. So to give an example, there are some cases where SSRIs will decrease the hallucinogenic effects, psychedelic effects of given compounds. There are other cases, most, maybe not most notably, but notably in the case of ayahuasca, where if you combine psychiatric medications with ayahuasca, you could actually suffer from potentially highly dangerous serotonin syndrome. And so instead of reducing the effect, you would be compounding the effects of the experience. So you gotta be very, very, very careful with this stuff. You can get yourself into deep water very quickly and get yourself into trouble, so.
- MWDr. Matthew Walker
I think that's actually a really important point, which is the interactive, what we call polypharmacy.
- TFTim Ferriss
Yeah.
- MWDr. Matthew Walker
A more benign version of that, or perhaps a less malignant is a better way of describing it, version of that actually comes onto ... Back, back to our discussion of caffeine. There is some emerging evidence that using SSRIs increases your sensitivity to caffeine and-
- TFTim Ferriss
Huh
- MWDr. Matthew Walker
... it decreases the clearance of caffeine. And so you can think, "Well, I'm this type of a person with my caffeine use."
- TFTim Ferriss
Interesting.
- MWDr. Matthew Walker
And then you can start taking these SSRIs, which then all of a sudden you realize, I'm not sleeping as well as I used to, and I don't think it's because of the caffeine intake. It's because my caffeine intake has remained stable. I haven't changed that. But what's changed is the interaction between those SSRIs ramping up the duration and the severity of action of caffeine. So you have to be really thoughtful, and that's where it gets very complex. That's where us-
- TFTim Ferriss
Yeah
- MWDr. Matthew Walker
... human beings are desperately messy things.
- TFTim Ferriss
So messy. Wow, what the, what a tangled web we weave. What a sad situation it would be if someone were using [laughs] trazodone for sleep and yet [laughs] experienced this [laughs] dramatic magnification of their experience with caffeine and [laughs] netted out in the red. That would be a real bummer.
- MWDr. Matthew Walker
Yeah, we don't yet know if it's trazodone in particular. These were the sort of the more classic SSRIs. So right now, jury is out.
- TFTim Ferriss
Yeah, trazodone's pretty weak.
- MWDr. Matthew Walker
Yeah.
- TFTim Ferriss
I don't wanna call it a failed antidepressant, but it's like [laughs] by the time it's gotten to-
- MWDr. Matthew Walker
No, it's certainly not a first-line, yeah, treatment, and that's why-
- TFTim Ferriss
Yeah
- MWDr. Matthew Walker
... it's become ... Its most popular use right now is not for-
- TFTim Ferriss
People just fall asleep
- MWDr. Matthew Walker
... as an antidepressant. It's because it's, yeah, sleep inducing. Yep.
- TFTim Ferriss
[laughs]
- 2:49:22 – 2:55:17
Pregabalin and gabapentin.
- TFTim Ferriss
All right. So let's, let's leapfrog to pregabalin and gabapentin. You can, you can take either. Gabapentin people may recognize because veterinarians love to hand it out like Pez candy-
- MWDr. Matthew Walker
Mm
- TFTim Ferriss
... when, when you take [laughs] your dog in or your cat in. But-
- MWDr. Matthew Walker
Yeah
- TFTim Ferriss
... which of those would you like to talk about first?
- MWDr. Matthew Walker
I mean, we can talk about both of them because in some ways they have-
- TFTim Ferriss
Yeah, great
- MWDr. Matthew Walker
... uh, the, the part of the same class of sort of drugs-
- TFTim Ferriss
Perfect
- MWDr. Matthew Walker
... pregabalin and gabapentin. You're right that they're used in, for multiple different reasons, one of which is pain medication, muscle relaxant.
- TFTim Ferriss
Yeah.
- MWDr. Matthew Walker
Neurologically they're often used in seizure disorders because they will reduce down the seizure tendency. And you would think by the names pregabalin and gabapentin that they're going to act by way of targeting, once again, the GABA system, that inhibitory system, and so they're sedatives, and so you are, don't seem to be a big fan of those, Matt. But it turns out that's not the case. You shouldn't be fooled. They actually impact the functioning of calcium channels on neurons and the, those calcium channels will dictate the firing of those neurons. And so you can reduce down the firing propensity of those neurons. That's why they're given in seizure disorders in epilepsy to try to suppress the excessive, this hyperpolarization, this hyperactivity of the brain that creates the epicenter of the seizure. If you look at the evidence, it's interesting when you dose both naive individuals, and meaning naive patients who have never received either of these drugs or don't have seizure disorders or sleep disorders. It does, they both do seem to increase the amount of deep non-REM sleep, and they do seem to reduce the amount of light stage one non-REM sleep. So I think it, they are interesting. I think there's probably indirect mechanisms, too. They certainly have a relaxing property. They can be a muscle relaxant. They can reduce some degree of anxiety. We kn- also know that those drugs will decrease down both the fight or flight branch of the nervous system and what's called the HPA axis, the stress-related cortisol axis. So I think part of it is because they reduce down anxiety, which as we've described before, is not great for sleep. So it's an indirect-
- TFTim Ferriss
[laughs]
- MWDr. Matthew Walker
... mechanism. And then the other component is that it may actually have some unknown to us right now neuronal impacts by way of calcium channel alteration that increases deep sleep. But right now, I don't know of anyone who's pulled apart that mechanism within the brain itself.
- TFTim Ferriss
Question on Pregabalin. So when I first used Pregabalin, so I had been using Trazodone as a monotherapy and then introduced Pregabalin. I experienced, and it was, it was very noticeable, could just be placebo effect, but I wasn't anticipating it, which is why, unless I'm just seeing things, it wasn't sort of expectancy effect. I, I, because I wasn't looking for it, but I seemed to notice a carryover effect of lowered anxiety, so an anxiolytic effect all the way through maybe the first five, six hours of my waking subsequent day after using Pregabalin pre-bed. Is that a mirage or i- is there a plausible explanation for that?
- MWDr. Matthew Walker
No, I think it, there is a plausible explanation. I mean, it actually has quite a, well, not a quite short, but a somewhat short half-life of about five to six hours. So when you come back then to the quarter life, we're talking about somewhere around 12 hours. So it would make sense that it's in the first part of the day where you still get that sort of floaty, reduced, jittery feeling in the morning, where things just feel a little bit more relaxed because that still is present in your system. It depends on the dose. By the way, Pregabalin and Gabapentin in the sleep field are principally used not for insomnia, but actually to treat a sleep disorder called restless leg syndrome-
- TFTim Ferriss
Mm-hmm
- MWDr. Matthew Walker
... uh, which is a horrific disorder where you get these, uh, in America, I think you call them Charley horses, but in England, we'll sort of just get these creepy-crawly feelings in your muscles, and you have to move, you have to stretch them. It disrupts sleep terribly. It's a, it's a pretty tough sleep disorder, and it's used there to try to treat some of the aspects of the muscle cramps and the muscle problems. There you can go up to doses, I think people can use up to 225 milligrams of Pregabalin. Gabapentin may be up to 600 milligrams. So there you can get lingering after effects that are not only a reduced level of anxiety, but also an increase in sleepiness that people kind of don't like it, that they have, you know, next morning grogginess and hangover effect. So one has to be a little bit thoughtful for dose, I think. But it makes complete sense based on the half-life of what you're describing, that you would still get some of that benefit.
- TFTim Ferriss
[laughs] So I do know someone, uh, I don't wanna name names here, I'll protect, protect the guilty, but [laughs] who is a, let's call this person a pharmacological champion. They have high tolerance for everything, and Pregabalin forced them to tap out. They [laughs] they-
- MWDr. Matthew Walker
Wow. Wow
- TFTim Ferriss
... in the sense that they were so laid out, not laid out, but altered the next day. They were like, "Okay."
- MWDr. Matthew Walker
Mm.
- TFTim Ferriss
"That was too much. That was too much."
- MWDr. Matthew Walker
Yeah.
- 2:55:17 – 2:59:09
The psychological value of emergency sleep medicine for insomniacs.
- TFTim Ferriss
I do not have that experience personally, but I do find it to be a fascinating drug. It really is a fascinating drug, and I don't wanna become too dependent on it. I should take a step back and also say, lest people think that I am just swallowing pills all day to wake up and then feel X, not feel Y, and then go to sleep. What I find is that if I simply have these drugs available, and I put them on my nightstand and say, "If I'm not asleep in 20 minutes or 30 minutes, I'm gonna give myself permission to take some of these sleep aids," that's enough a lot of the time. Just knowing it's there-
- MWDr. Matthew Walker
Yeah
- TFTim Ferriss
... having a rule in place often allows me to get to sleep without anything.
- MWDr. Matthew Walker
I think this is such a powerful message, thanks for bringing it up, which is, you know, it's almost this strange placebo effect of knowing security is there because when you suffer from insomnia, and I've been there too, one of the miserable parts is that you lose all faith in your ability to sleep. In other words-
- TFTim Ferriss
100%
- MWDr. Matthew Walker
... your sleep controls you, you do not control your sleep. And by way of these types of medications, that's why I'm not completely anti-medication, I think there's enormous value in you regaining your confidence that every time I go into this thing called my bedroom, because when you're in insomnia, if you'd never suffered from insomnia, you would never think this, but when you walk into the bedroom, it's already a trigger. You already start to get negative emotions. You look at the bed and you think, "I know what's going to happen. I am going to have a miserable night of sleep." And just to have a pharmacologically assured It's not guaranteed, but certainly higher probability of being able to get into bed and fall asleep. At that point, you've turned the tables. Now you control your sleep rather than your sleep controls you. That freedom, that release from the incarceration of the, I think, vicious condition of insomnia is incredibly powerful, and I'm so glad that that's what you experience.
- TFTim Ferriss
Yeah.
- MWDr. Matthew Walker
It's, it's a miserable place to be.
- TFTim Ferriss
It's a huge boon just to know that you have something reliable that can brute force the problem towards a solution if needed.
- MWDr. Matthew Walker
Yeah.
- TFTim Ferriss
Is not to suggest that I always want to brute force the solution, and you and I have also spoken about this, where there are tools out there like CBTI, right? Cognitive behavioral therapy for insomnia that are extremely valuable. But if your mind has suddenly become, on some level, or is, I don't wanna say the enemy, but if the mental self-talk is such that you walk into the bedroom, you try to sleep, you're failing to sleep, you start berating yourself, you get angry, then you start to worry about what the next day is gonna look like. So now your heart rate is 30% faster, your cortisol is being released, and on and on it goes in this vicious cycle that further ensures you are not going to sleep.
- MWDr. Matthew Walker
Yeah.
- TFTim Ferriss
Knowing that you have the emergency option which will put you to sleep is a tremendous stress reliever, and I have found that just having it there, just having the break glass in case of emergency pills on the nightstand allow me oftentimes to sleep without taking anything.
- MWDr. Matthew Walker
Ah.
- TFTim Ferriss
And it's just the security of
- 2:59:09 – 3:00:46
CBTI and the balancing role of pharmacology.
- TFTim Ferriss
knowing it's there.
- MWDr. Matthew Walker
I'm so glad that's the case for you. You know, and I am also a big advocate of CBTI, cognitive behavioral therapy for insomnia, which is just as ef- efficacious as classic things like Ambien, but I would also note that it's not uncommon that people combine both cognitive behavioral therapy, which is the psychological treatment that people can look up, CBTI, together with these types of sleep medications to produce the very best benefits. And then at some point, maybe you start to taper down the pharmacology, maintain the cognitive behavioral therapy components, and lead people out into that pathway of confidence with their sleep. But it's just having that reassurance can make the world of difference. And the other aspect, you know, with pharmacology, and I know it maybe goes against the idea of no free lunches, sometimes in medicine and science, we think of taking medicines as putting us out of balance, and that's the mentality that people have, I think rightly so, as to their resistance against pharmacology. Sometimes, though, a way that I think about it is that whatever condition that you're in that has led you to think about pharmacology probably means that you are biologically and physiologically out of balance, and what those medications are doing is actually putting you back into a more natural biological balance, rather than the inverse view that perhaps some people rightly have, which is, "When I take these drugs, I'm putting myself into an artificial, unnatural imbalance." That may not necessarily be the case.
Episode duration: 3:06:12
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Transcript of episode Y-bfodmHsP8
