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Tim Ferriss: My good Dr. Walker, Matthew.
Dr. Matt Walker: Tim, it is a splendid delight   to be with you. Thanks very much for having me.
Tim 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.

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 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 depth in other places.

So   we're intending to check both of those boxes.
And I thought we would start, if we can just   skip the foreplay and jump right into 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 seen this   up close and personal. What are the 
connections, if any, between those two?  Dr. Matt Walker: 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 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's probably unfolded, gosh,   maybe in a three-part or even four-part 
story. 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 high 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 heavy snoring, sometimes 
you stop breathing and it's clinically diagnosed,   both of those conditions were associated with 
a high 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, 
but those are simply correlational. They're   associational. They don't prove 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 cerebral   spinal fluid of the brain, which is this 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 the signals of metabolic 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 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 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 with 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, 
it sounds strange. Many people would think,   "Well, it must have," because 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 named by the way,   that way because of the cells that make it up. 
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 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, 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 shift to 
then say, "Well, what are those things that the   brain is cleansing during deep sleep?" And this 
is what brings us 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 biochemical 
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's 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 not vast that builds up after one night   of sleep.

And I don't want to scare anyone 
here. And 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 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 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, the same stage of sleep 
that's associated with the cleansing.  Tim Ferriss: That's unfortunate.
Dr. Matt Walker: Isn't it just? And so now,   we've found this vicious spiral that if 
you don't get enough sleep each night,   you get more of that Alzheimer's build up. 
The more that builds up, the less the brain   is capable of generating deep sleep.

The 
less deep sleep, the more that builds up.  Tim Ferriss: What are the structures involved 
with the production of that deep, non-REM sleep?  Dr. Matt Walker: They are a collection. 
It's essentially a network of brain regions.  Tim Ferriss: A constellation.
Dr. Matt Walker: Exactly. But one,   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 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 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 a 
mechanism that helped us perhaps go back and   explain the associations. Then perhaps 
the fourth ingredient that I'm really,   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 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 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. And we've been 
looking at this in the laboratory. We've   been approaching this not by using sleeping 
pills. 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 sounds like the   stuff of science fiction. It's actually science 
fact where you apply these pads to your head and   you 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 the stimulation during sleep, as if you are 
singing in time with those deep sleep brainwaves,   not only can you amplify the size of those 
deep sleep brainwaves, but in doing so,   people were able to almost double the amount 
of memory benefit that you get from sleep.  So the question then was, could we translate that 
same affordable, potentially portable technology   into older adults and could we restore back some 
deep sleep and salvage aspects of learning and   memory function? That's one of our goals.

And 
we've been developing this and have a startup   company that's public now that's 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.   Because to me, if I look at the sleep data, that's 
when you start to see the great depression of   your deep sleep. It's bloody depressing, I 
know. 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 
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 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.
Tim Ferriss: Matt, what causes the   decline in deep sleep, whether it's 
absolute hours or just a percentage   of sleep when people get into 
their mid 30s, let's just say?   How is that explained currently?
Dr. Matt Walker: You can already   start to see the brain atrophy beginning.
Tim Ferriss: Oh, that's it. Okay. So it   is just overall brain atrophy.
Dr. Matt Walker: Yeah. There is a   development. And there are some sex differences. 
It turns out, unfortunately, that men seem to   decline in that deep sleep earlier than women. 
Women will hang in there. Females will hang in   there for the deep sleep, a little bit longer than 
men, but ultimately, by late stage, there's a more   severe decrease later in life in females. So net 
net, they ultimately get there. 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 late 30s, you start to think, "Wow, I'm just 
not as robust as I used to be.

I start to get   more injuries. The body starts to deteriorate."
Tim Ferriss: That's a very generous way to put it,   robust, I'm not as robust as I used to be.
Dr. Matt Walker: Well, I'm so sensitive now,   because I think I'm about the same age as you. 
I'm now solidly in the foothills of middle age.   So I want to be tender and sensitive 
to myself than be politically correct.  Tim Ferriss: You know what? I'll 
take the tender to yourself.

With   the politically correct, we can skip, but —
Dr. Matt Walker: I think it's politically   correct. This is the language of 
cowards and truth. So you're right.  Tim Ferriss: All right. So we can be the 
countervailing force. But before we get to that,   gender differences — and I apologize 
in advance. I'm going to ask a lot of   questions in the line of three-year-olds 
and four-year-olds. I'm going to ask why   and why and why, in part because I find it 
so simultaneously exciting and depressing,   moreso 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. 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 explanation   for why they seem to hang in longer than men?
Dr.

Matt Walker: It's a great question. Largely   unclear at this stage, 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. 
Other aspects, you are absolutely right. Maybe   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 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 far less clear. And to come to your point, 
you're absolutely right in terms of sleep. And   we know so much about our waking lives, but we 
seem to know so little about our sleeping lives.  There's definitely been a remarkable amount of 
evidence, so much so that perhaps a dimwit like me   can try and write a book that's 130,000 words of 
facts.

But 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," which is, it is the ridiculous   equivalent of saying, "Well, I eat to cure 
hunger." That tells you nothing about the   biological and nutritional benefits of food. And 
the same was true for sleep. 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 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?" 
And, so far, the answer largely seems to be "No."  Tim Ferriss: Are there any species, I'm going 
to get way outside of 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 poorly worded question.

But 
is there anything notable that does not require   sleep? How far down can we go? Down to bacterium? 
I mean, how small can we go and still see a near   ubiquitous need for something resembling sleep?
Dr. Matt Walker: It's a lovely question. And 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 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.

Perhaps there's one   common theme 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.   An emerging controversy is perhaps there's 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 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. 
It literally looks like these worms go into this   state and cellular state, in fact, not just a 
motility state, but a cellular state 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 predecessor,   the precursor of these things that we call wake 
and sleep states. You can even do a nerd out.   And I kind of put this out. I'm thinking 
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, 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.  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 play with.
Tim Ferriss: Oh, I love that. Did you say   "G'Dunkin?" Is that what you just said?
Dr. Matt Walker: Yeah, gedanken,   it's a brain experiment. It's just one those 
[inaudible 00:23:49] philosophical experiment.  Tim Ferriss: Oh, I see what you did there, just 
that you pulled out some German. That's what   it was. Gedanken. I see what happened.
Dr. Matt Walker: I'm bilingual. I can   speak both British and a little 
bit of American and that's it.  Tim Ferriss: What I heard was "G'Dunkin," "Good 
day" from Australia, but like G apostrophe and   then Dunkin like Dunkin' Donuts, but yes, I hear 
you. And I should also say, I think Lethargicus is   my gladiator name.

But I'll put that to one side.
Dr. Matt Walker: It may actually have to be a   license plate on, 'cause our mutual friend, Peter 
Attia, we love to race cars. But based on my lap   times, I think I need Lethargicus as my number 
plate. Clearly, no one here is going to see it.  Tim Ferriss: Well, all the emptor license plates 
are taken, so you'll have to make due with   Lethargicus. Let's revisit this direct current 
brain stimulation for the amplification, let's   say, extension 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. But I would 
love to learn more of the direct current brain   stimulation and what that looks like in practice.
Dr. Matt 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 start to   temporally predict where the next brainwave will 
hit in its monumental peak of explosion.

And then   you time the stimulation, this is almost at the 
millisecond level, to strike at 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, that these deep 
sleep brainwaves, 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 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
Tim Ferriss: And people are wearing caps. Or   what is the format, the physical format?
Dr. Matt 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 stripped-down number of those   electrodes.

This makes it much more —
Tim 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 the 
stimulation pads. So those are effectively being   placed in over that cortical area?
Dr. Matt Walker: That's right.  Tim Ferriss: Or are they being —
Dr. Matt Walker: No, they're placed   over that cortical area. And this is why I can 
speak about the simulation and it sounds fairly   simplistic. It's actually an incredibly complex, 
high-dimensionality problem. 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 to create 
this profile? The next component is what   frequency do you stimulate? So coming 
back to the more complex version of this,   you are measuring the brainwaves and then 
you're stimulating in this predictive manner,   as I said, at that 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 the head and 
wishing to go to bed. And this is the reason that   I'm not necessarily the biggest fan of sleep 
trackers where you stick them on your head or   even wristwatches, et cetera, or chest straps, 
because 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 company is rather than stimulating —
Tim Ferriss: What is the name of the company?  Dr. Matt Walker: The company's name is 
StimScience. And we're just in the early stages   here. 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. My mother, for example, who's in her   elderly age is told that the 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. And this is a slightly   different approach. A good analogy would be a 
child on a swing, where 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.
So now, we've taken this approach where we're   stimulating as you're cleaning your teeth, you 
stick the headband on, you get the stimulation,   and you are essentially fertilizing and 
stimulating that territory of the brain   to then germinate more deep sleep naturalistically 
when you fall asleep. And what's nice about it is   when you do this stimulation for that duration 
of time, it has an efficacious, a dose   impact for about two to three hours afterwards. 
So you can stimulate and you can take it off.

It   has this lingering effect, as it were. And what's 
nice about that is that's the time when we have   most of our deep non-REM sleep. Deep non-REM 
sleep does not keep coming cycle after cycle,   90-minute cycle after 90-minute cycle across 
the night. You get most of your deep sleep in   the first half of the night, and most of 
it in the first two hours of the night.  So we can nicely fertilize that territory of the 
first couple of hours of deep sleep using the   pre-sleep stimulation. And therefore, you can 
remove the component of having to measure the   brainwaves and do all of this fancy acrobatic 
technology. But coming back to your question,   I keep digressing, so —
Tim Ferriss: Actually,   let me pause for one second. So just, I know 
I'm subverting my own question here. But   a few things. The first is, if we're looking at 
the option of pushing the swing set, so to speak,   while people are brushing their teeth and so 
on, so they're having that amplification for   10, 15 minutes and then they go to sleep, what 
types of clinical outcomes or measurable outcomes   would you hope to observe? I'm not asking you 
to paint a picture of something that's pie in   the sky, but just speculating a bit.

But 
with the information that you have, what   would you hope to observe in terms of changes?
Dr. Matt Walker: We're actually measuring these   outcomes. So we're doing a whole bunch of validity 
trials within the company, essentially scientific   studies. So we have outcome measures along the 
following lines. The first is the speed with which   you fall asleep. And it's something that we call 
sleep onset latency. How long does it take you —  Tim Ferriss: My nemesis.
Dr. Matt Walker: Yeah. And that's a component   of what we call one of the flavors of insomnia.
Tim Ferriss: SOL.  Dr. Matt Walker: Yes, SOL.
Tim Ferriss: My good friend, SOL, sleep   onset latency.
Dr. Matt Walker:   It is. And that, that's a form of what we 
call onset insomnia or sleep onset insomnia.  Tim Ferriss: Shit out of luck, in my case.
Dr. Matt Walker: I know, I'm so sympathetic.   It's miserable, isn't it? And I've certainly 
had my bouts with insomnia across the lifespan.   It is no fun at all. So one of the things that 
we're trying to do is to see, will that pulsing,   and we're pulsing still at the slow brainwave 
frequency, I should note.

Can we increase   the drowsiness pre-sleep so that sleep 
arrives with you with greater alacrity,   as it were, and you reduce the nice sleep onset 
latency, as it were? That's the first thing.  The second is that we then, in our scientific, 
studies are measuring sleep electrically and   we're looking to see if the amount of 
deep sleep or the number of those deep   sleep brainwaves has increased during 
sleep. That's another outcome measure.  A third outcome measure is the number of 
awakenings that happen during the night.   So one form of sleep difficulties and 
insomnia is difficulty falling asleep,   which is, as you have described publicly before, 
something that has been a challenge for you. The   other component though is something 
called sleep maintenance insomnia,   which is, I can fall asleep fine, but then 
I wake up and I can't fall back asleep.   So that's something else that we're trying to 
target just because of the clinical efficacy.  The third component involves another actual flavor 
of insomnia, which is not just, "I have problems   falling asleep," or, "I have problems staying 
asleep," but you can also get a diagnosis of   insomnia if the next day you say, "Well, I fell 
asleep fine and I stayed asleep, but I don't feel   refreshed.

I don't feel restored and rejuvenated 
by my sleep." That's a different form of insomnia   and they're not mutually exclusive, those three 
things. Unfortunately, you can have all of them.   That's another outcome measure that we're 
looking at. When you wake up the next morning   and you subjectively ask people, "How refreshed 
and restored by your sleep do you feel?" is that   better as a consequence of nights when you've 
had stimulation versus nights when you haven't?  So those are some of the outcome measures that 
we're interested in. If we see some of those   outcome measures, then we're looking at function 
not just did you sleep better the night before   and do you wake up feeling more refreshed? 
But then the next day presumably, because   sleep is interwoven with so many incredible 
brain and body benefits, are there outcomes,   are you better able to learn and remember the next 
day because of that better sleep? Is your mood   improved? Is your metabolic regulation of your 
blood sugar better and do you not crave food as   much because your appetite hormones are controlled 
or your blood pressure is altered? That's my dream   set of things much later down the pipeline.
Tim Ferriss: All right, so 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 going   to talk for a second so I apologize in advance.
Dr.

Matt Walker: Please do.  Tim Ferriss: 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 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 in that.
Dr. Matt Walker: Brilliant point.  Tim Ferriss: 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 direct current brain stimulation along 
the lines that you're describing?” What   are some other things that people can do?
I'd like to pause here just to maybe front   load a bit for folks of personal 
context, if that's okay with you.  Dr. Matt Walker: Please do.
Tim Ferriss: 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 taking or 
ceasing anything, especially prescription   drugs. 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 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 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.  A number of things I'd say in the last year 
have been very helpful and I owe you thanks for   taking the time to have several 
conversations with me. 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 what 
we're 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 the SOL, and increasing the speed to   sleep. Pregabalin, which we might talk about 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   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 want to thank you for the book and then 
also 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 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 operating in top order?
Dr. Matt Walker: It's a great question and in   some ways you can break it down. I'm [inaudible 
00:40:52] going to pull a Peter Attia and think   about it as like a two by two, but I won't go 
there in terms of matrix.

I think there are some —  Tim Ferriss: Not going to go full McKinsey on us.
Dr. Matt Walker: I know. Yeah, maybe I can one   up him and do like a two by three. You can 
think about things that you should not do   that otherwise would be roadblocks to deep 
sleep, and things that you should do more   of that will facilitate and increase 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 will 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 
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. 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. 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 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 temperature.   Temperature makes a huge difference 
to the amount of deep sleep.   Temperature is not quite as simple as 
keep it cold, even though people like me   have probably been out there just saying, "Oh, 
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.

In fact, people 
with insomnia, interestingly, have problems with   thermo regulation 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, the 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,   the way that we drop our core body temperature is 
actually by 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 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 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 you would get rosy 
cheeks. And all of a sudden the blood comes to   the surface and it's almost as though 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,   you are core body temperature actually 
plummets, and that is what helps you   fall asleep and stay asleep more soundly.
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. You don't need to jump in the bath or 
the shower.

You can use a hot water bottle, for   example. We're thinking about a lo-fi version of 
technology rather than a fancy headband as well.   We haven't yet got funding for these studies, but 
can you selectively just warm 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. You can replicate that   in humans now too. So that's another 
way that you can think about doing it.  Other aspects that we know can 
increase deep sleep, exercise   is a really good one.

We found that both —
Tim Ferriss: Any particular types of exercise?  Dr. Matt Walker: 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 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 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, cardio versus lifting 
weights, cardio seems to give you a slightly   greater benefit. People have then tried to 
split down the cardio, running versus cycling,   and at that point, I think the analyses just get 
so fine-grained that you start to lose 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 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 p.m. or   from 8:00 a.m. to 10:00 a.m.?" 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. 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.
Tim Ferriss: Yeah, I would say pick the schedule   and the type of exercise you're actually going 
to fucking do consistently would probably beat   the perfect prescription. It's like, yeah, 
you're going to do wind sprints up that hill   with bowling balls taped your hands.

The 
literature shows that's ideal. It's like,   well, good luck with adherence.
Dr. Matt Walker: Exactly.  Tim Ferriss: So stick to what you're going to do.
Dr. Matt Walker: Yeah.  Tim Ferriss: I want to come back to caffeine. So 
I'm looking at prep notes for this conversation.   You've changed your mind, it seems, on 
coffee in so much as you now advocate for it,   or at least support the idea of a cup of 
coffee in the morning.

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, to make immediate sense.  So both of those. Why a cup of coffee in the 
morning, and then why is it associated with some   of the benefits of sleep? And maybe you could also 
get into some of the pharmacokinetics of caffeine.   I guess coffee could be its 
own thing just in terms of   half-life and stuff, so people have an idea.
Dr. Matt Walker: So I've certainly changed my   tune on caffeine and I think I 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 in public communication.

I   think I was probably a bit too absolutist in 
truth. And anyone who speaks in absolutes,   you should always be weary 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,   despite those things, I would still advocate for 
it? Caffeine is a chemical, as I'm sure you and   everyone else knows.

It's a stimulant, it's a 
psychoactive stimulant, one of the few that we   feel readily comfortable giving our children.
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.

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 by 
the way. It doesn't mean that at the end of the   day, your head is nearly going to explode on the 
basis of your adenosine. 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 you're   getting sleepier and sleepier. 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, 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.  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, 
of sleepiness. So it's what we call a competitive   receptor blocker, and it has very sharp elbows. It 
will come in, 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, 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. Sleepiness 
is still present, and it will continue to   build up the longer that you are awake. It's 
simply that your brain is no longer getting   the message of adenosine because caffeine is 
blocking the signal, 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 mentioned that too. The other aspect of   caffeine, though, is that it's what we call 
anxiogenic, that it increases your anxiety.   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.
So what happens is that psychologically the   caffeine is preventing you from falling asleep. 
Then you start to get anxious because 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 because   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 dead in the water for the next two hours,   as it were.

So that's one of the problems.
Tim Ferriss: Story of my life.  Dr. Matt Walker: Yeah, I'm so sorry. This can 
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's still in your system,   which means that caffeine has a quarter life of, 
for the average adult at least, 10 to 12 hours.   And it's probably, again, not really a very 
good analogy, but if you have a cup of coffee,   let's say at 1:00 p.m. or 2:00 p.m. 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 hope for a 
good night of sleep." That's probably not going to   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. 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. So now sleep maintenance, insomnia.  And then the final part of caffeine comes back 
to deep sleep. We've done these studies where   we can dose people at different times of the 
day and into the evening.

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 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 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 percent,   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. Or you could just do it   every night with an espresso if you wanted to.
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 brain wave activity, but 
yet you may still be suffering from that excising   of a significant amount of your deep sleep.
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 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 fall asleep.
Tim Ferriss: So let me hop in.

Let me hop   in. I'm going to stage an intervention. All 
right. So the stimulant depressant cycle is   a whole mess. I've been an active 
participant on that field before.   But if I could just return to some 
of the questions that kicked us off.   So why allow or endorse the idea of a cup of 
coffee in the morning, number one, if it is after   this litany 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?
Dr. Matt Walker: You're absolutely right.   I think at the time when I was writing 
the book a few years ago, the evidence   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. 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 number of   different polyphenols that it contains, but 
chlorogenic acids are probably the principal   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 the whole food dietary intake,   the humble coffee bean has been asked to carry 
the Herculean weight of all of our antioxidant   needs. And that's why drinking coffee has such a 
strong statistical health signal in the data when   you do epidemiological studies. So it's not the 
caffeine that's related to the health benefits,   it's the antioxidants. In case in point, 
if you look at de-caffeinated coffee,   you get many of the same health —
Tim Ferriss: I was just going to say,   I hate to spoil the party with a question.

If 
I could jump in for a second, just a quick side   note. So the antioxidant and nutritional 
value of coffee bean in, let's just say,   less industrialized or lower income 
strata of various countries is true   also for cocoa in the Peruvian Andes 
and elsewhere. It's actually a source of   very important nutrition for a lot of 
these communities and indigenous groups.  So I just wanted to say that as an aside. Also, 
chlorogenic acid, I think, is contained in   quite a few other compounds and beverages, if 
I'm not mistaken. So I want to say that it's   present in yerba mate, which they drink all the 
time in Argentina. I may be getting that wrong,   so somebody can fact-check me. But is 
chlorogenic acid found in camellia sinensis   tea plants or other types of beverages? 
Or is it particularly prevalent in coffee?  Dr. Matt Walker: No, you can find it. It's 
certainly nowhere near exclusive to the coffee   bean itself. By the way, it doesn't contain any 
chloride. Please don't be worried about drinking   in bleach or something like that.

It's got nothing 
to do with that. But yep, the chlorogenic acids,   that's certainly one group. It's not to say 
it's the only group though. There are others.   Acrylamide is another one that we've been 
very interested in terms of the coffee bean,   which is another antioxidants. 
So it's a cluster of different   antioxidants that provide these benefits.
Tim Ferriss: Any brewing methods, roasts, grinds,   any combination of those variables that if one 
wanted to maximize for the good stuff and minimize   the potential damage to sleep and sleep 
architecture? Any thoughts on what that   Goldilocks combination might look like?
Dr.

Matt Walker: It is interesting,   and by the way, I think the Goldilocks combination 
comes onto the idea that when it comes to coffee,   it's the dose and the timing that make the 
poison here. Obviously, if you look at the   health benefits too, once you get past about 
two and a half, three cups of coffee a day,   the health benefits start to go down in the 
opposite direction. So it's not a linear   relationship. Don't start drinking like seven 
cups of coffee, and be mindful of the timing.  But to come to your question, I suppose, if we're 
talking about caffeine concentration and then   maybe antioxidant concentration, actually here I 
am going to do a Peter Attia.

I'm a two by three,   because you could think about the rows of this 
table being the caffeine and the antioxidants.   And then the columns, three columns would 
be the roast maybe of the coffee bean,   the grind of the coffee bean, the granularity, 
the coarseness, and then maybe the brewing method.  It's not quite as simple as this, but certainly 
what we found is that for the roast of the coffee   bean, and this comes onto the color of the coffee 
bean, a coffee bean is a coffee bean in terms of   when it comes out, what changes its color is 
how you roast it.

And what we found is that   gram for gram, light roast actually has about the 
same caffeine content as dark roast. But the issue   is that the dark roast, the longer that you roast 
it, the more degraded the coffee bean becomes and   hence the lighter its density. So net-net on 
average, a lighter roast will contain more   caffeine than a darker roast. So it's a little 
bit complex.

[inaudible 01:05:39] that's clear.  In terms of the grind, I think it's fairly 
clear that fine-grain coffee produces higher   degree of caffeine concentration than a 
coarse grain. Now of course, we're not   talking about brewing methods yet, but that's 
simply probably on the basis of surface area,   that the finer the grain, the greater the surface 
area, the greater the release of the caffeine.  Brewing method, it's really interesting 
if you look at some of the data. The   longer the brewing method, the greater the 
caffeine concentration relative to shorter.   Also, cold brews tend to produce a stronger 
caffeine content than hot brews. I think part   of that simply is down to the duration of the 
brew itself. Cold brews typically take longer,   and therefore you get a stronger pound for the 
punch in terms of caffeine. So that's caffeine.  Antioxidants. In terms of the chlorogenic acids, 
you're probably going to favor lighter rather than   darker roasts. Lighter roasts typically 
have higher amounts of chlorogenic acid   than darker roasts, although there is some 
evidence that darker roasts have higher amounts   of some of the other antioxidants like acrylamide, 
for example.

So I don't think you need to worry   too much in terms of the antioxidants. And also, 
by the way, thankfully, the decaffeinating process   still preserves the antioxidants, and 
that's why it's still related to the   health benefits. You don't lose out on the 
antioxidants when you switch to decaffeinated.  Finer grinds typically produce more antioxidants 
than coarser grind in terms of that. And then   brewing method, it's probably that cold brew seems 
to produce stronger antioxidant concentrations.   Then probably the next down would be espresso 
preparation. Then instant coffee seems to have   finally higher concentrations of antioxidants 
than drip or infusion bag versions. So I'm sure   that I'll stand corrected by the internet, 
but that's my reading of the literature.  Tim 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 a   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, 
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 five milligrams or 7.5 
milligrams, am I inhibiting my REM sleep?   Coming back to what you said earlier, sometimes 
you don't know what you don't know because you're   not 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? So   that's the context, but please, in any way that 
makes sense, tell us what you know about CBD,   THC and anything else related to this fine plant.
Dr. Matt Walker: 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.  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 effect. And 
by the way, if you go back, some of the first   writings of the first emergence of this story 
of THC for sleep, at least from what I found,   came from the writings of this brilliant British 
physician, Dr. Clendinning. He published his   first monographs in 1843, I think it was. And 
if you read it, I think you would love it,   Tim.

I should send you some of these articles.
Tim Ferriss: Before it was cool.  Dr. Matt Walker: Yeah, before it was cool.
Tim Ferriss: Yeah, he was   on it before it was cool.
Dr. Matt Walker: It was hemp   resin this that he was talking about. But just 
the writing itself you would love. 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 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. And this is just what you are describing 
too. It seems to have sedative benefit. And   we're starting to unpack and understand 
exactly why THC has that sedating effect.  The next issue, however, isn't quite such 
rosy news, that you seem to develop tolerance,   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.   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 obviously 
don't want to transit illicit drugs into other   countries 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 wish for people not to have necessarily.  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.
Tim Ferriss: Do we have any idea of the   dosage range that we're talking about, right? 
Because you could develop DT and tremors and so   on from alcohol withdrawal, but that's not going 
to 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 you know?
Dr. Matt Walker: Yeah, I wish I had an answer   and we currently just simply don't know. 
There are not enough systematics. Right now,   it's more simply survey studies where people —
Tim Ferriss: But it's observable,   like it can happen.
Dr.

Matt Walker: 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 psychiatry Bible. It   forms part of the criteria symptoms for cannabis 
withdrawal, this insomnia syndrome. That's how   consistent and reliable it is.
Tim Ferriss: Wow.  Dr. Matt Walker: It's part of the diagnostic 
criteria. And in fact, often it's the insomnia   that happens when you stop using it that 
is one of the prime reasons for remittance,   that people will then go back to using it because 
they just dislike the insomnia so much. And so —  Tim Ferriss: Go back to the wacky 
tobacco. They can't stay away.  Dr. Matt Walker: And so you get that —
And then the other aspect is that it seems   to quite significantly disrupt your REM sleep, 
and it does it in three ways.

The first is that   it will decrease the overall amount of REM sleep 
that you are getting. The second is that it delays   the arrival of the first episode of REM sleep 
in the cycling nature of sleep. And then the   third aspect of that is it seems to decrease the 
intensity of rapid eye movement sleep. And one   of the ways that we measure that is just how many 
of these eye movements — that's where it gets its   name by the way, rapid eye movement sleep because 
your eyes dart back and forth — and the more of   those rapid eye movements that you're having, the 
more intense the REM sleep and, in fact, the more   intense the dreaming and THC will decrease 
the intensity, that metric of REM sleep too.  I think perhaps the more powerful piece of 
evidence for me looking at the literature that it   is REM sleep disruptive is less about the amount 
or the quality of the REM sleep as you are using,   but what happens when you stop using, which is 
all of a sudden you get a rebound effect where   you start to get significantly more REM sleep when 
you stop using THC.

And that's a demonstration,   as a scientist, that we would say is a 
homeostatic response, which is that if   you deprive yourself of something, when you 
get the chance to get it, you get an increase   in the amount. There is a response. And that 
increase, that homeostatic rebound effect,   is usually a sign of a deficiency that's been 
happening before that. Does that make sense, Tim?  Tim Ferriss: It does make sense. And if you could 
allow me to indulge myself for a second here,   I would say that in my personal experiences, and 
this is an end of one anecdote and I understand   that, but I've also used sleep trackers.

So 
I've used various devices. I have observed   over and over again, with more or less a hundred 
percent predictability, the destructive effects of   alcohol. It's so obvious. You feel miserable the 
next day. You see it in the numbers. It's just   incontrovertible evidence 
that alcohol is not friends   with my sleep, at least the quality of my sleep.
Now on the other hand, and I say this as someone   who only began experimenting with cannabis 
a few years ago — so I am not a lifelong   pothead. This is not a religion to me. I have 
no identity wrapped up in cannabis whatsoever.   And for the most part, I had a very low opinion 
of cannabis because I saw so many people become   unproductive through overuse of cannabis over the 
decades. But I have seen incredible effects on   sleep, and I've not observed, at least at the 
dosing that I'm using — and as you mentioned,   Paracelsus' "The dose makes the poison." You need 
to be careful with the dosing on all these things,   including water, for instance. But it 
hasn't seemed to inhibit my REM sleep.  And I suppose there's also a question 
that comes to mind, which is, well,   let's say it inhibited your REM sleep or 
hypothetically, on average, it reduced REM sleep   10 percent.

If it took you from 90 minutes 
to fall asleep to 15 minutes to fall asleep,   could that end up in an absolute 
increase in your REM sleep, even if   theoretically it would decrease it percentage-wise 
10 percent, if that makes any sense at all.  Dr. Matt Walker: No, it does.
Tim Ferriss: So how would you suggest   we think about this? Because the dosing has always 
been a question for me. How much does it take? And   I could also just do an end of one experiment 
where I do some on/off, as you mentioned,   to try to observe what happens.

But do we have 
any literature to point us in any direction with   respect to what type of dosing starts to suppress?
Dr. Matt Walker: Yeah, it's a fantastic question.   We don't right now in terms of looking at a 
dose response curve. We probably have that   dose response curve when it comes to the 
benefit of reducing the time it takes you   to fall asleep. And there, going up starting at 
2.5 milligrams all the way up to 20 milligrams,   there is that sedating effect, and we start to 
understand why there is that. Do we have that   same data for REM sleep? We don't. Simply that 
if you look at acute studies where you bring   individuals into the lab, often they're cannabis 
naive individuals, you dose them with THC —  Tim Ferriss: You just bake the shit out of them.
Dr. Matt Walker: They are seeing visions of   biblical characters in the sleep 
laboratory before you put them   to sleep.

No. So you can give them these —
I would say cut that part out. Leave it in,   please do. Absolutely. Leave it in.
But what we have are these acute studies   where when you dose acutely, you also certainly 
get that reduction, that decrease in the amount   of REM sleep. That's fairly reliable, fairly 
consistent. But we don't have other studies where   we will then, say, do a longitudinal study where 
we keep dosing people across a month and we track   the evolution of these REM sleep impairments.
Could it be that there is also some homeostatic   pushback where gradually the brain starts to 
fight back against the deprivation of REM and   turn up the volume on REM sleep generation, and 
therefore, you don't see the effects long term?   The only reason I would predict that that's not 
the case is when you speak to lots of people   who are chronic cannabis users and they 
say that they stopped after one year,   two years, they will say, "I just started 
to have all of these crazy intense dreams   as soon as I stopped smoking."
Tim Ferriss: Yeah, very common.  Dr.

Matt Walker: It's so common. And so I 
think at that point, it still tells me that   the brain was bereft of REM sleep throughout that 
period. It was undernourished. And by way of that   nutrient deprivation of REM sleep, it had built 
up this increasing hunger and desire for REM,   where as soon as you stopped the blocking 
agent, which is the THC, it comes back with   a vengeance.

That, I think, is the only evidence 
that I know of right now that still tells me it   probably is having a suppressing REM sleep effect.
Tim Ferriss: Yeah. And I will say that I have met   a number of chronic users who have told me some 
version of, I haven't remembered a dream in 10   years, and then they stop and begin having these 
extremely vivid dreams. And to your point, it does   seem to have that effect. I have not personally 
observed it. I think that may also be partially   due to the fact that I try, or historically I 
have tried, to cycle on and off very deliberately   to avoid the development of tolerance, and I 
have to imagine that that helps on some level.  How does CBD fit into things, if at all?
Dr.

Matt Walker: It is an interesting   emerging story. So CBD, which is the 
non-psychoactive component of that,   firstly emerged on the sleep map probably in the 
1970s, much later than THC in the literature.   It's actually really interesting. They were 
dosing pigeons, Tim, would you believe it,   with all of these different compounds. And they 
were looking at the learning ability of pigeons.   Turns out pigeons are actually very smart. 
You can teach them things like the alphabet.   And they were dosing them in the '70s with 
different compounds. One of them was with   CBD, and they were using —
Tim Ferriss: Sorry, can I just pause?  Dr. Matt Walker: Yeah.
Tim Ferriss: I'm imagining this experimenter,   like the PI, going to the IRB and they're like, 
"Can we do this in humans?" They're like, "No."   "Okay.

Can we do this in monkeys?" "No." "Cats?" 
"No." "Rats?" "No." "What the hell can we do this   in?" "All right, we'll give you pigeons." And 
they're like, "Ah, fine. We'll do it in pigeons."  Dr. Matt Walker: Yeah, I know. People seem 
to think of pigeons as rats with wings. "Oh,   sure, you can work on them."
So they were looking at pigeons — I   would love to be able to say that I'm a sleep 
scientist and my specialty is in pigeon sleep.   But they were studying pigeons. And what 
they found was that with CBD exclusively,   at higher doses I should say, the waking life 
of those pigeons became a lot less wakeful.   They started to demonstrate the expression 
of slowed motoric movements. Their learning   started to become worse. They demonstrated signs 
of drowsiness. Now, by the way, they weren't high.   They weren't getting these pigeons baked because 
there was no THC. It was just CBD components. So   that was the first evidence that we had.
If you look at the human stuff,   I don't think there's anywhere near enough data to 
go on record to suggest that CBD is the Shangri-La   of good sleep at night.

It's mixed right now. 
But I think the story is that in higher doses,   CBD does seem to be able to potentially increase 
the amount of deep non-REM sleep that one gets,   if you look at some of the studies.
The concern, though, is that CBD seems   to have a bimodal distribution. And what I 
mean by that is in lower doses — and again,   I don't think there's good enough signs 
to tell you exactly what those doses are,   but perhaps if you squint your eyes 
and you look at it slightly sideways,   maybe it's about 25 milligrams or less of CBD. 
And again, this is not me being medical in terms   of my advice or anything like that, as you said. 
This is simply me being descriptive on the basis   of the scientific data, not prescriptive in 
terms of medical.

But less than 25 milligrams,   you actually get a wake-promoting effect 
where CBD will actually make you more alert.  Tim Ferriss: Oops.
Dr. Matt Walker: Yeah, exactly. Whereas   in higher doses, maybe perhaps 50 milligrams or 
above, it may have some sleep-inducing effects.  Part of the reason that I think there's a lot of 
variability out there is that, at least here in   the United States, it's not FDA-regulated and 
there's a lot of variability from one batch.  Tim Ferriss: Right.
Dr. Matt Walker: And if it   really is so dose sensitive dependent that there's 
this U-shape function, then you could be thinking,   well, the bottle is telling me I take 50 
milligrams every night and some nights I   struggle with sleep and other nights I get knocked 
out.

And I don't understand. It's not consistent.  So that's the reason I think there is 
some emerging evidence that gets me   more excited about CBD. And for myself, 
I think, and perhaps other scientists,   for a long time we were a little bit puritanical 
about THC and CBD. Well, it's an illicit drug and   you don't want to do it. But I think in truth, 
you can't just as a scientist sit it out and say,   "Well, it's illicit and therefore I'm going 
to discount it." I think you need to put your   feet in the trenches and get your hands dirty.
And so I've actually decided to start working   with a proper clinical outfit based from 
a group, Imperial College in London,   and we're really trying to actually dig in and 
create a proper clinical-based CBD compound and   do the studies to see if it's —
Tim Ferriss: Amazing.  Dr. Matt Walker: — really real or not.
Tim Ferriss: Great.  Dr. Matt Walker: And it's a particular CBD 
analog. Obviously, they've got a patent on   it.

But we really want to look at this. So 
we're going to do proper studies, phase one,   phase two, phase three studies and try 
and pull out all of the nonsense there.  But if you were to then say, "Well, what is it 
about CBD?" If it does have a sleep benefit,   that would be helpful. Because we know some of 
the ways in which THC is "helpful" for sleep,   and we also know how it's harmful 
to your REM sleep. What about CBD?  For CBD, I think there's probably at least 
two mechanisms that I become thoughtful   about. One is indirect. The other is direct.
The first is that CBD is quite a significant   anxiolytic, that it seems to reduce down 
anxiety. And there's great science using   brain scanning technology. This has got nothing 
to do with sleep. But where you dose people with   CBD and inside the brain scanning, you can 
see a reduction in the emotional centers,   regions like the amygdala that light up, CBD will 
decrease those.

So I think as we mentioned before,   anxiety is a roadblock to good sleep, and if 
you remove that anxiety, sleep arrives to you   on that royal road in a slightly more kindly 
fashion. So that's one way. It's anxiolytic.  The second is a direct pathway that if you 
dose rats with CBD, it drops their core body   temperature. So CBD seems to be hypothermic. 
And as I said, we need to drop our core body   temperature to get colder. And so I think 
that's the other plausible route, if it   does benefit sleep, that I would hang my hat on.
Tim Ferriss: So on 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 — 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 THC by itself — 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, one 
of the counter arguments would be that   cannabis can sometimes have an amnesic effect 
on people. And if you are 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 methylenedioxy methamphetamine, 
which by the way, one could say would improve   recall in some people, then maybe you just 
end up net zero at baseline, 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 — handle on Twitter?   What is your username on Twitter?
Dr. Matt Walker: On Twitter,   you can find me @SleepDiplomat. I chose not 
to use my own name because I'm quite shy and   I'm typically a little bit private, and also 
it's not about me. It's about sleep. And so   I wanted to remove my name and just be —
Tim Ferriss: Sleep Diplomat. All right.   So @SleepDiplomat and I, @tferriss, 
T-F-E-R-R-I-S-S — actually, I don't want   to speak for you, Matt, but I'll speak for myself.
Dr. Matt Walker: No, speak for me, please. You'd   be much better with eloquence than I would.
Tim Ferriss: I'm @SleepLoudmouth and he's   @SleepDiplomat.

No, @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 to at least read studies well,   to see what's out there 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 anyone is willing to share that,   specifically dosage, dosage range, 
and whether or not they have observed   it to interfere with REM sleep.
Dr. Matt Walker: Yeah, I would   love see that. Please loop me in 
on that. Because I think we can   probably crowdsource a good amount of that 
data. Will it be scientific? Of course,   it's not going to necessarily be scientific, 
but it's a little bit like Amazon reviews. If   there's a product that has 30,000 reviews and its 
4.9 stars, you probably don't need the science to   suggest that it's going to be a fairly decent 
product. And so thank you for suggesting that.  Tim Ferriss: For sure.
Dr. Matt Walker: I would love   to be included in that.
Tim Ferriss: Yep. 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 don't want to make too strong a case, but   I have seen — I'm not going to name names, but 
when I was much younger, I volunteered as a   subject in scientific studies all over the place, 
including at some very well-known universities   because I wanted to see how it was done.


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 when the output is very precise and it's 
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   experiment design and execution.
On the other hand, if you have,   let's just say, an N of a thousand people who 
claim to be using THC at a certain dosage range,   it's unlikely that all of them are lying. So even 
if you account for some degree 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. And it's still very, very fertile ground.
Let me 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   this is something that came to me in 
a fever dream and it's not even in the   book. 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 is the case? Am I making this up? 
Is this just a figment of my imagination?  Dr. Matt Walker: There's nothing wrong with your 
memory.

It's wonderfully exquisite. That's what   we found. 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 and I didn't come up with the idea.

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 chains, which starts to sound very 
S and M, and please stick with me. It's not   quite going there.
Tim Ferriss: Oh,   I'm on the same page. I'm ready for it.
Dr. Matt Walker: Yeah, maybe that's the   conversation we have after we stop recording. 
So yeah, there's no candle wax on the nipples,   nothing like that that's involved in this study.
Tim Ferriss: Never say   never. There's funding for it.
Dr. Matt Walker: Oh, Tim, you're a great guy.   So they got the bed and they suspended it from 
the ceiling, and then they put this device,   this oscillating device that would 
essentially rock the bed in a lateral   fashion left and right. And what they —
Tim Ferriss: Just so I'm envisioning this   properly, laterally would mean if I'm laying 
on the bed, I would be moving side to side —  Dr.

Matt Walker: That's right.
Tim Ferriss: — my left to right?  Dr. Matt Walker: Yep. So you'd be shifting towards 
your left side and then your right side. It's as   if you're on a boat and it's shifting.
Tim Ferriss: Sure.  Dr. Matt Walker: Yeah.
Tim Ferriss: Or in a hammock.  Dr. Matt 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 brain waves. So those deep, slow brain 
waves, the reason they're called slow brain   waves is because they go up and down maybe once or 
twice every second, which for brainwave activity   is actually very slow. Now, when you and I are 
both awake, it's going up and down maybe 30, 40,   50 times a second. So it's very, very, very slow.
They were trying to match that frequency of   brainwave with the rotating rock of the bed back 
and forth, the oscillation back and forth.

And   what they found was that lo and behold, they 
were able to increase the amount of those deep,   slow brainwaves by rocking the bed back and forth. 
They also increased another brain oscillation   that's associated with deep sleep and with non-REM 
sleep, which is called a sleep spindle, which are   these incredible bursts of electrical activity 
that ride like surfers on the top of these slow   brain waves. They increased those as well and they 
also demonstrated that they're learning and memory   function the next day was improved. And we may 
speak about learning and memory with sleep. So   in other words, it wasn't just an epiphenomenon. 
That it wasn't simply just epiphenomenologically   that you increase deep sleep and it doesn't 
really mean anything. You increased it,   and it has a functional outcome, which was better 
memory as a consequence. So I believe there is a   company that has — I saw them a couple of years 
ago. I don't know where they're at. That develops   these little feet that you then place underneath 
the frame of your bed.

They're mechanical feet,   and they will start to try and sort of rock 
the bed back-and-forth on the basis of this   scientific literature. Now, whether 
or not that's making any difference,   I don't know. I haven't seen any evidence, 
but you're right. There's that paper, and   it's a great paper. Haven't seen it replicated.
Tim Ferriss: Yeah. As soon as I came across that,   I was thinking, "Why have I not seen more 
companies looking at this?" Because you could   try to — I'm going to use a word that's going to 
get people to laugh at me.

So taking, say, the   bed that we have and putting it on these feet or 
the rockers, I could see working. I would actually   be very interested in testing that. But it's also 
skeumorphic in the sense that we're trying to take   something we know, and slightly modify it with a 
new technology to make it work. But we could take   something that most of the world is very familiar 
with, but Americans are perhaps less accustomed to   using, and those are hammocks. Right? I mean, all 
throughout the tropics, hammocks everywhere. And   you could have a very lightweight system that you 
could set up in the home. I can think of a number   of different configurations.

And you would just 
need a mechanism by which you could perpetuate the   rocking and establish a cadence. Right?
Dr. Matt Walker: Right.  Tim Ferriss: But, I mean, you could ostensibly 
have a system that you could put in a suitcase and   travel with, in that case. I mean, it got me very 
excited, because I have had, and I'm not saying   this is the same thing, but some of the best sleep 
of my life in hammocks in the tropics. And there   are a million other factors. I get it. This isn't 
a controlled experiment. But you can also take   a hammock and fold it up into something that you 
could, I mean, stick inside a large jacket pocket.   I mean, there are such hammocks.

They're so easy 
to set up and so easy to move around. So anyway,   that was just scratching my own itch.
Dr. Matt Walker: No, I think it's a   very interesting idea. It's one that I've also 
had too myself, so I sort of — you throw out   or you develop these patents with this sort of 
sci-fi knowledge, but 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 machinery within the eardrum itself.  Tim Ferriss: Right. The vestibular system.
Dr. Matt Walker: Correct. So it   would be vestibular stimulation.
Tim Ferriss: Whoa. That's wild. Okay.  Dr. Matt Walker: [inaudible 01:42:10] 
patents that I wrote because I sort of   had this idea. It's sort of like —
Tim Ferriss: That is sci-fi.  Dr. Matt Walker: It's like I'm trying be an 
academic beer podcaster, help some startup   companies teach and research, and then also 
do some of these other things. And by the way,   make sure you get your eight-plus hours of sleep. 
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, perhaps if people are in 
couples, that they don't necessarily want to   get into a bed and some people like rocking, 
other people don't. But I'm talking about the   physical — I'm getting myself into trouble. 
You get what I'm trying to say, which is —  Tim Ferriss: Yeah, I get it.

I get it.
Dr. Matt Walker: — there's some point there   that you may not wish to do the physical movement 
and the rocking. 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, fool your brain 
into thinking that it's rocking. 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 brain waves,   not by 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,   and then I can match the vestibular stimulation 
to your individual unique slow oscillation.   So I've got all the crazy ideas.
Tim Ferriss: No.

I'm just imagining   you on late-night television selling The Da Vinci 
Code magic sleep device. You may run into some   trademark issues. But you know what?
Dr. Matt Walker: Oh, please.  Tim Ferriss: Let him chase it. Let him chase it.
Dr. Matt Walker: If you ever see me doing that,   please just come over and extinguish my life with 
rapidity that I would be most grateful for. Never   do I want to become the George Foreman grill of 
sleep. Oh, my goodness. No offense, George. You   are brilliant and [inaudible 01:44:17].
Tim Ferriss: Yeah. No offense, George.   So how far in would this need to go in your ear, 
and is it something you could easily remove,   or is it an implant? I guess I'm 
wondering, is it some type of — I'm   thinking of the beetle.

It's not really 
a beetle. It's like this strange, alien,   creepy-crawly millipede-type thing in The Wrath 
of Khan, I think it was, the Star Trek II movie,   that crawls in your ear. But is this 
something that you could put in and take out,   or is it something that's implanted that 
you turn on and off? What does it look like?  Dr.

Matt Walker: No, I think it would be put-in 
and take-out. In fact, I was at a conference some   years ago, and I'd already sort of put together 
the patent. But I think maybe the military,   maybe it was DARPA, the advanced component of 
the American Military Technology Agency, they had   already developed something that was quite like 
this. And the reason that they were using it was   as a silent method for directing soldiers in terms 
of their direction of progression at a particular   special-ops location. So where you don't want 
any communication, you don't want to put out   there any signals. They were just using this 
inner-ear to say, "Go left, go right, go front,   go back." So that technology is, I think, is out 
there, and they've developed some of that. Can't   we just turn it for sleep? Anyway, crazy idea.
Tim Ferriss: So, side note on DARPA.

If people   want to see an incredible, I mean, just 
mind-boggling, many, many multi-decade-long   track record of innovation, study DARPA. 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.
I'd like to come back to the glymphatic   system for a moment. 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. I phrase   that carefully, because 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 want to make is that in 
conversation, I want to say they described how   some of these psychedelics, and I want to 
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 the 
administration, hypothetically, on let's just say   the longevity of some of the cortical structures 
we were talking about earlier.

Would there be the   potential of staving off or slowing the onset 
of some of these neurodegenerative conditions?  I happen to be very — look, I'm talking 
out-of-turn here. 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 
self-repair and cellular-cleaning in the brain,   are there any other levers people can 
pull? Any other things that people can do,   or not do, that you're aware of?
Dr. Matt Walker: I think right now,   sleep seems to be the more —
Tim Ferriss: The big one.  Dr. Matt Walker: — [inaudible 01:48:11] of 
those. But I think there's also some emerging   evidence that physical activity, i.e. exercise, 
can increase 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 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, sorry, less than 50 percent of the   normal antibody response, rendering that flu 
shot significantly less effective. 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 are 
seeding the brain with sufficient sleep before,   does it predict certain outcomes? Second, 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 narrowly there, I 
don't think we've got good data on sleep.

There   were some age 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 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 re-establish, re-stabilize, re-energize 
sleep. Does it impact and harm sleep? That,   to me, would be even more interesting.

That you 
can get an emotional therapeutic benefit despite   disruptions in sleep. Wonderful to learn that too.
Tim Ferriss: So let's talk about this. We'll   do — I'm not sure I'm using this correctly. 
Maybe the Germans can come in and say yay or nay,   or ja or nein, as the case might be. Gedanken. 
Let's do a gedanken or two. Good Duncan,   as I like to say. No, no. 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 reasonably long time now. I 
mean, publicly, probably since 2014 or '15. Maybe   a bit earlier, and then 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 effectively a methamphetamine,   people generally don't sleep at all 
afterwards. Sleep is terrible. It's awful.   Which would be, just as a 
side note, another possible   pro argument for a combination therapy 
using THC. So I won't go into too much   of the personal details on that, but that would 
be, I think, 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 want to 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. This is like   '96, '97. I put this paper online somewhere, and 
I don't think it's defensible. There's a lot of   undergrad hand-waving going 
on. But 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 pressing space bars a lot,   looking at tons of screens, which was 
actually really instructive.

But I wrote   an either sophomore or junior paper on 
what appeared to be similarities between   REM sleep and LSD administration or consumption. 
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,   because I realized 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 really ruin your day. So 
lots of legal risk, and also psychoemotional,   and in some cases physical risk.

But 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 a 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 3 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 want to say,   25 to 30 milligrams, which would simulate a 
roughly five-gram experience. So now we're talking   about 1/10 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 waking state.   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?
Dr. Matt Walker: I think it's fascinating. Some   of these components actually work neurochemically 
very differently to dream sleep.

So if you're   getting some of the similar benefits — and 
the reason I say similar benefits is because   dream sleep and REM sleep, and we try to do as 
much work as we can in this area, does provide a   form of mental health benefit. It provides a form 
of overnight therapy. That is during dream sleep,   when we strip away emotion from memory. 
So we can detox those emotional memories,   almost like a nocturnal soothing bomb that sort 
of takes the sharp 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 these 
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.   In fact, if you look at REM sleep dreaming, 
it's the exact opposite.

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,   but if they do produce both very similar emotional 
health and mental health benefits — which I think   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 5-HT. The other is noradrenaline,   which everyone knows downstairs in the body 
its sister chemical's name, called adrenaline.   But upstairs in the brain, noradrenaline.
So I think mechanistically, I'm fascinated by   these two questions that you pose, because they 
probably come through two different routes. But   yet you arrive 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? 
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? That would be a stunning finding too.  Tim Ferriss: Yeah. Let me throw out another 
wild aspect, which I probably should have   mentioned up front. That is, when people have 
experimented with these, let's just call it,   two to 500 — usually on the lower range, 
two to 300 milligram pre-bed experiments,   very often the report goes 
something like this.

"Holy shit,   that was intense. That was like 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." Which relates to the first question,   which is a valid question. That is, well, 
if these are operating very differently,   is it not reducing the need for sleep, but 
rather inhibiting your ability to sleep? 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.  I should say also, I want to give credit where 
credit is due, that the person who initially   galvanized a lot of my interest in the 
scientific study of psychedelics was a professor,   might still be there, named Barry Jacobs 
at Princeton.

Very impressive researcher   and professor who also spent a lot of his time 
studying cats, because cats sleep all the time,   and was certainly studying a lot more than 
psychedelics. But I want to give him a nod,   since looking at a lot of his work and what he was 
doing — which was really pushing some incredible   boundaries at the time. I had 
a lot of respect for that.  These are some outstanding questions that I 
wish, I really wish, people would take a look   at. I do know there's some people, some 
groups who have tracked their sleep post   experiences with, say, psilocybin. And I would 
be curious to see any reports from folks who   have tracked over time, on-off, on-off, that type 
of data. So once again, please, please send me   a note on Twitter if you have that. Not just a 
trip report, please. As much as I want to hear   about the neon diamond-encrusted crocodiles 
that you rode across the waters to Australia,   where you learned the secrets of the universe. 
What I'm most interested in right now is just —  Dr.

Matt Walker: Oh, you too? 
Yeah, that's [inaudible 02:01:31].  Tim Ferriss: Yeah. You too. Yeah. Graphs 
and numbers. Graphs and numbers. And once   you're lucky twice, you're good. I know I'm 
misusing that, but I don't want to see one   example. Ideally, someone who's looked at 
it multiple times. What I will say is that,   and I don't know what effect this can have on 
sleep or what relationship it has to sleep, but   I have seen some evidence to suggest that certain 
psychedelics can increase heart-rate variability.   So that's another piece of the puzzle 
that I haven't seen people examine too,   too closely.

There may be a few 
studies that have tracked it,   but I'm not really aware of anyone that's 
done it en mass. All right. So that's my   musings with Tim. Gedanken on the psychedelics.
Let's talk for a second about sleep, food intake,   weight gain, all that kind of good stuff. 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?  Dr. Matt Walker: Yeah. Yeah.
Tim Ferriss: Cannabinoids?  Dr. Matt Walker: Yeah.
Tim Ferriss: And how do you say this?   What's the proper pronunciation of this?
Dr. Matt Walker: Endocannabinoids.  Tim 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, or for 
that matter, who have had enough edibles, will be   familiar with the munchies. Very consistent. Very 
consistent for a lot of folks 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 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 waking gain. So it   makes me wonder, why would that be the case?
Dr. Matt Walker: Yeah. It is very interesting.  Tim Ferriss: 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.  Dr. Matt Walker: It's striking, and I've certainly 
noticed that too when I travel. If I'm 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. The evidence is 
really very strong now that when sleep gets short,   unfortunately it will lead to a waistline that 
can expand. The early evidence came on to —  Tim Ferriss: @ObesityDiplomat.
Dr. Matt Walker: Yeah. Exactly.  Tim Ferriss: Very nice way to put it.
Dr. Matt Walker: Yeah. My Twitter handle   is changing by the minute here. And then 
at some point, there will just simply be   #cancelculturesleepdiplomat, which is kind 
of [inaudible 02:04:46]. But anyway, so   the evidence looked at two appetite-regulating —
Tim Ferriss: It takes a village, internet. Let's   make his dreams come true. Sorry. Go ahead.
Dr. Matt Walker: The world will be a better   place without me, I'm sure.
Tim Ferriss: Oh, stop it.  Dr.

Matt Walker: So there are two 
appetite-regulating hormones. One   was called leptin, one was called ghrelin. 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 appetite. What researchers found —
Tim Ferriss: Ghrelin. G stands   for "Go eat the cookies."
Dr. Matt Walker: Yeah. Exactly. G for,   "My stomach is growling and I desperately want 
to eat more." 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 I'm-satisfied-with-my-meal 
satiety signal, that dropped by about 18 percent.   If that wasn't bad enough, levels of ghrelin, 
which is the hunger hormone, that increased by   28 percent. 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 percent, depending on the study.
So that was the emerging evidence on the   appetite-regulating hormones.

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 — 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, sweets, 
et cetera. Also, they found an increase in your   preference for eating salty snacks, which can 
put you towards a path of greater hypertension.  So that was the evidence at the basic 
appetite-regulating hormone level.   But then the more recent data came out. You're 
right. That all of us, even if we're not smoking   the wacky tobacco, as you described, 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 TCH,   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 increase   the amount of these cannabinoids within the brain 
and within individuals. So all of the sudden you   start to see, perhaps it's not just these leptin 
and ghrelin that are changing to conspire to   increase your hunger and your waistline, but it's 
also that these endocannabinoids are increasing.  You can then start to ask, "Well, why? Why 
would that be the case? How can we explain   those things?" Currently, we don't quite know. 
One hypothesis is that the only time when you   see other species deprive themselves of sleep 
— because human beings, in truth, are probably   the only species that will deliberately deprive 
themselves of sleep for no apparent good reason.   But animals will do it occasionally, and the 
most common occurrence is when they're under   conditions of starvation.

So here, under those 
conditions, the brain releases a wake-promoting   chemical called orexin. The reason is because 
the brain has figured out, "I'm under conditions   of starvation. It must mean that my ability 
to forage for food in my standard perimeter   during the time that I'm awake is not yielding 
enough food. So I need to push myself to be   awake longer to forage in a wider perimeter, and 
therefore to find and solve this caloric deficit."  So one possibility is that because you are 
deprived of sleep, you're getting this signal of,   "Let me ramp up my hunger even more. 
Let me drive up my motivation to go   and search for food.

Because otherwise, 
I'm going to be an omission-critical,   break-glass-in-case-of-emergency situation." 
But we don't truly understand why these hormonal   patterns go awry. We certainly know that you will 
increase your intake of food. We then went on to   discover that it's not just about what changes 
in your endocannabinoids or in your hormones,   because in fact the choices that you make for your 
foods are controlled by your brain. That's the   central dominating decision pivot point for here.
So we took a group of individuals, and we deprived   them of sleep, and then we gave them a full night 
of sleep. And it was a counterbalance study, where   they go through both full sleep and without sleep. 
The next day we placed them inside an MRI scanner,   and we started to show them different images 
of food that range from really unhealthy foods,   pizza, and donuts, and ice cream, all the 
way up to really healthy different types   of foods.

And they had to rate the desire 
that they had for those individual foods.   We also did something a little bit dastardly to 
make it more ecologically valid. We told them,   and we did do this, that one of those items 
that they said that they found desirable,   we would then serve them when they came out of the 
MRI scanner. And they had to, politely please, eat   that food. So it sort of just forced them to make 
sure that they're making the choices correctly.  What we found is that the brain — you started 
to rate these obesogenic foods as much more   desirable. And the reason was that the 
control regions of the brain, once again,   in the prefrontal cortex, were shut down.

Whereas 
more hedonic drive centers within the brain,   dopaminergic centers and also the amygdala, 
which is also controlling hedonic food desires,   those ramped up in terms of their activity. 
That's a profile that we typically see in   patients who are suffering from obesity. It's 
this profile of what we would call a brain state   of hedonic eating. That you shift over into 
just going after desirous foods, unhealthy   foods. So it was a two-part equation, changes 
downstairs in the body and then changes upstairs   within the brain. There have been since some 
studies looking at dieting without sleep,   which I think is probably some really fascinating 
data, but let me just pause there for a second   because I keep just talking. I get so excited.
Tim Ferriss: So, orexin. Is that O, R, E, X, I, N?  Dr. Matt Walker: Yes.
Tim Ferriss: How do you spell   that? I was hoping you would say E, R, E, X, I, N, 
because then I was going to suggest that you could   actually cross-sell the orexin for male vitality 
after The Da Vinci Code magic sleep device.   [inaudible 02:12:48].

I'll take my customary five.
Dr. Matt Walker: [inaudible 02:12:49], is   assured after this conversation.
Tim Ferriss: Yeah, I'll take my customary   15 percent. That's fine. So orexin, I was asking 
about that and also just contextualizing my own   mind, everything you just said because I'd 
love to get your read on just a amateurs   play hypothesis, and this came about after, 
unfortunately, my personal experience of many   sleepless nights, lots of sleep deficit over 
many decades, and have observed this eating,   increased volume of intake, even if it's 
healthier foods. 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.
Let's say this is an adaptive and not a   pathological behavior, 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 going to 
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?
Dr. Matt Walker: I think it's certainly   one alternative hypothesis that 
what you're trying to do is   eat yourself in an overcoming way and to overcome 
the sleep deprivation and see if you can placate   some of what you are 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 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 has   been largely dismissed. That's a myth, which is 
that when you are awake, surely you are burning   many more calories than when you are 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 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 three to 600 calories 
when you are sleep deprived. So it's not simply   that you are trying to eat back.
Tim Ferriss: Amateurs. Oh, my God,   these guys should see my diet log. 300 calories.
Dr.

Matt Walker: Yeah, maybe it's not twofold.   Maybe it's a 10x situation. So I think 
that's the, 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 and increased weight gain.
Tim Ferriss: Again, just looking at this as   a layperson who's had a lot of sleep problems, 
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 achieve repair that wasn't permitted by 
insufficient sleep is because when I think about,   and thank you for putting up with me because 
I know that I'm coming at this as a layperson   who should know better, but so I've done a 
lot of fasting, done tons of fasting up to   10 days. I've done a lot of fasting, and that's 
water fasting. And so 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 under starvation conditions 
or 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 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 experience as 
fasting, 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, 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.

So if you were to really fast,   you would have trouble 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. 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. So fructose will help you to maintain 
blood sugar or not, I'm sorry.

It will help you to   maintain blood pressure where it might otherwise 
plummet, and you could get, what's it called,   orthostatic hypertension, where you stand up 
and you think you're going to pass out and.  Dr. Matt Walker: Orthostatic intolerance. Yep.
Tim Ferriss: Orthostatic intolerance. There we go.   So I just wonder if the lack of sleep is basically 
directly caused by the caloric insufficiency.   I think that was a bit of a word salad 
that I just tossed all over the place.  Dr. Matt Walker: No. Let me sort of mix 
it further. I think it's a delicious salad   because that evidence is fairly reliable. When you 
speak to people who are fasting very consistently,   they'll say one of the things that's perhaps 
hardest about the fast is not necessarily the   struggle with hunger, it's also that my sleep just 
takes a nose dive like a dart into the ground.   And if you look at the studies, there is some 
conflicting studies, but some studies are found   firstly, if you put people on either daytime 
fasting or reduced calories.

And what we're   talking about here is as little as sort of 300 
calories or less when you measure changes in sleep   regulating components, things like melatonin. 
Melatonin is a hormone that helps time your sleep,   when you do a reduced caloric diet, there is 
about a 20 percent I impairment in melatonin,   which is then associated with 
a difficulty in falling asleep.  Although there are some studies, I should note 
by the way, that with fasting, even though you   struggle to fall asleep once you fall asleep, 
there may be less time spent awake when you do   finally get to initiate sleep. And so I think 
there's nuance there that I want to respect if   probably the other evidence, and there's just not 
good enough evidence yet to really look at this,   but I think the strongest, most robust evidence is 
probably in areas of religious-based fasting such   as Ramadan, where people will fast from sunrise 
to sunset for about a month.

And there, what   we've noticed is probably at least five specific 
changes. First, once again, coming back to orexin   rather than erexin, orexin, the wake-promoting 
chemical, by the way, we discovered orexin by way   of studies in narcolepsy, where patients who have 
narcolepsy who have an unstable wake sleep switch,   where they just can't maintain wakefulness 
during the day, they keep flip-flopping back   and forth between unstable wake and sleep.
What we discovered is that narcolepsy is   principally a condition of a deficiency in orexin. 
In other words, orexin is this wake-promoting   chemical and the amount of orexin that they 
release in narcoleptic patients and the cells that   release it are markedly deficient and the number 
of orexin receptors in the brain are deficient,   which we think explains the reason why they lose 
the wake-promoting on switch during the day and   why they are so susceptible to sleep attacks.

But 
anyway, I digress. Coming back to Ramadan, you see   individuals, the levels of orexin 
in increase, they have a decreased   level of peak melatonin as I sort of just 
mentioned with reduced caloric diets. Also,   the arrival of when that peak in melatonin occurs 
is much later into the night. In other words, you   are not getting the signal of it's darkness, it's 
nighttime at the same time of your normal bedtime.  You get it several hours later, which may in part 
explain why it's harder for you to fall asleep.   Related, their bedtimes drift forward, 
which is really interesting. And we think   it's related to that delay in melatonin 
release. Total sleep time decreases by   probably about an hour if you look at those 
studies. And we also see an interesting   dissociation sleep stages in Ramadan. The 
thing that takes the greatest hit seems to be   rapid eye movement sleep, whereas non-REM sleep 
seems to be largely unaffected.

So right now,   that's probably some of the best evidence that we 
have as to what's going on to explain why people   suffer such problematic sleep when they're going 
through fasting. But again, I think most of these   looking at real true fasting are required 
because those aren't necessarily reflective   of the fasting that you are talking about.
Tim 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 to have narcolepsy.
Dr. Matt Walker: Well, that's actually not   narcolepsy, the fainting goats. No.
Tim Ferriss: What is that?  Dr. Matt Walker: Very much like narcolepsy, but 
it's a condition where when you frighten, so in   patients who have narcolepsy, one of the 
other features is not just that you are   unstable in terms of your sleep wake and you 
fall asleep during the day. There's something   called cataplexy, 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 at the narcoleptic gene, 
then all of a sudden they lose all muscle tone.  And part of the reason is 
when we go into REM sleep,   we actually become paralyzed.

Our brain 
paralyzes our body, so the mind can dream safely,   but that same mechanism of paralysis seems to go 
awry in narcolepsy. And these patients will go   into this just cataplectic attack where they all 
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 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.  Tim Ferriss: 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've   totally just stiffen in the fall right over.
Dr. Matt Walker: That's right. And they will   sometimes just hop on their straight legs 
to try and get away, or they just keel over,   but that's actually quite difficult.
Tim Ferriss: Poor things.  Dr. Matt 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 a 
stunning condition. Very tragic, of course,   for the narcoleptic patients. Cataplexy is a 
major sleep, sorry, daytime disruptive feature.  Tim Ferriss: So glad I brought up fainting goats 
just so I can stand corrected. So would it be   fair to say that these are cataplexic 
goats, or what would you call them?  Dr.

Matt Walker: No, not on the basis of the 
way that we term cataplexy within narcolepsy.  Tim Ferriss: All right, because that 
would be the loss of muscle tone.  Dr. Matt Walker: Correct. Exactly.
Tim Ferriss: What would even call them   if you wanted to use a fancy scientific term?
Dr. Matt Walker: My typical term is just muscle   rigidity, that they go into a muscle spasm 
rigidity, and that all of a sudden it's that   they, and there's sort of, it's bred, there's 
gene, and I think there's some evidence that,   because it's bred, there was this whole 
group of, I think it was cattle actually,   that had this genetic abnormality.

And what was 
interesting is that cattle were housed next to a   train track, right at the point where the train 
was on its points and it would always have to   honk its horn. And so reliably you could video a 
whole herd. And you knew it because you knew the   timing of the train. It would come through. 
You knew that the train would honk its horn,   it would startle the cattle, and the whole 
field of cattle would just collapse down.  Tim Ferriss: Oh, man.
Dr. Matt Walker: But anyway, so I'm   sorry, I'm taking us on a non-scientific tangent.
Tim Ferriss: Poor cattle. Oh, no, I mean I love   science, babe. We don't have to do it all the 
time. All right, well, let's get to story time   with Tim related to the Olympics for a second, 
and then we're going to get to a question about   modafinil. So I'm going to seed that. So there was 
a time, I want to say this was maybe two or three   Olympics ago, 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 narcoleptic. It's amazing.  Dr. Matt Walker: What a coincidence.
Tim 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. At least in 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's 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 just know   that they do X.

Is modafinil understood well?
Dr. Matt Walker: No, it's not. It certainly   doesn't work by the classic. So we used to 
prescribe, we collectively as the science   community and clinical, we used to prescribe 
patients with narcolepsy amphetamines to try   brute force them awake. So they didn't have 
that excessive daytime sleepiness that is so   prohibitive of a normal functioning life. And 
now 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 wake-promoting chemical, histamine, which 
we may come onto right about [inaudible 02:31:31].  Tim Ferriss: Just quick side note, for people who 
have ever felt drowsy after taking a Benadryl,   it would be experiencing an antihistamine.
Dr. Matt Walker: That's how we discovered   part of the role of histamine as a wake and 
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. 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.  Tim Ferriss: Yeah, and I'm asking 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 it strikes me as a bad idea when 
the mechanisms are poorly understood. But who am   I? Who am I to say, 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 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. I mean 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 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.


just didn't find it to be the tool for me.   So part of the reason I was asking about modafinil 
is just in case people are thinking of using it.  Dr. Matt Walker: 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 biology, you normally lose. And the way 
you've lost is long-term disease and sickness.  Tim Ferriss: I did find that my immune system 
felt funny also when I was using the modafinil   after a while. It didn't sit super well with 
me. But that's not to malign it as a tool in   the toolkit, especially for people who need it.
So 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?
Dr. Matt Walker: 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 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 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 are awake at night, you're not. 
But to argue that you are 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 bills, 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 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,   please speak to your doctor, don't do 
anything on the basis 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 
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 the, 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 are 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's a great 
study done by a colleague of mine, Marcos 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 been increased even 
more.

And this is part of the reason why sleep   is so beneficial for learning and memory.
What he then did was dosed 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 in 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 percent reduction, a weakening in the 
strength of the memory trace as a consequence.  So I think there's a, as I said, there's a time 
and a place that clinical medicine believes there   is 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.
Tim Ferriss: Let's get after it.

Why   don't we keep the momentum? So which would you 
like to put on the platter first? Trazodone?  Dr. Matt Walker: I think probably 
trazodone. Yeah. Right now, trazodone   is probably the most off label prescribed sleep 
medication. It's doesn't receive the current   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 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.  By the way, trazodone, I know sounds quite scary. 
It sounds like a tranquilizer. And it's not like   that at all. It's actually very nuanced.

And 
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 — 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 sleeves,   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.

You don't get a consequence to   REM sleep. And 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.  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 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 onto   aspects of tolerance and withdrawal. There didn't 
necessarily seem to be a significant tolerance   buildup, where 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 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.
Tim Ferriss: So 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 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?
Dr. Matt Walker: I think right now, if I wanted to   steelman 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,   other studies that look at things 
like learning, memory, plasticity —  Tim Ferriss: For sure.
Dr. Matt Walker: — in the brain, because   things like classic sleeping pills, like Ambien, 
have been found to produce non-naturalistic   sleep. There was obvious studies have them 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.
Tim Ferriss: Agreed. Totally   agreed. Yeah. Certainly for a   learning fanatic, 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 cycle, right, with medical supervision, 
but to try to not always hit the same nail with   the same hammer each night.

And I'm not giving 
medical advice. That's just my personal approach.  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 anti-hypertensive 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 would actually   generally take the position that I think it 
is premature to just hit the escape chute   in those cases, unless we're 
looking at actual physical risk,   which 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 toe-to-toe   with some of these other type 2A antagonists.
Dr. Matt 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   neurochemical systems, trazodone exerts 
its principle effect. Is it more so a   histamine? So if you rank order how it's impacting 
noradrenaline, serotonin, and histamine, is it   that it's principally histamine where you get the 
greatest, let's say 70 percent of the impact is on   histamine, then 20 percent is on noradrenaline, 
and then 10 percent 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 
the priority rating of those three things.  Tim 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 can 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,   maybe not most notably, but notably in the case 
of ayahuasca, where if you combine psychiatric   medications with ayahuasca, you could actually 
suffer from a potentially highly dangerous   serotonin syndrome. And so instead of reducing the 
effect, you would be compounding the effects of   the experience. So you've got to be very, very, 
very careful with this stuff.

You can get yourself   into deep water very quickly and get yourself 
into trouble. So work with [inaudible 02:58:48].  Dr. Matt Walker: I think that's actually a 
really important point, which is the interactive,   what we call polypharmacy.
Tim Ferriss: Yeah.  Dr. Matt Walker: And a more benign version of 
that, or perhaps a less malignant is a better   way of describing it, version of that actually 
comes back to our discussion of caffeine.   There is some emerging evidence that using 
SSRIs increases your sensitivity to caffeine   and it decreases the clearance of caffeine. 
And so you can think, "Well, I'm this type of   person with my caffeine use."
Tim Ferriss: Interesting.  Dr.

Matt Walker: And then you 
can start taking these SSRIs,   which then all of a sudden you realize, "I'm not 
sleeping. I'm not sleeping as well as I used to.   And I don't think it's because of the caffeine 
intake, 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.
Tim Ferriss: Yeah.  Dr. Matt Walker: That's where us human 
beings are desperately messy things.  Tim Ferriss: So messy. Wow. What a tangled web 
we weave. What a sad situation it would be if   someone were using trazodone for sleep and 
yet experienced this dramatic magnification   of their experience with caffeine and netted 
out in the red. That would be a real bummer.  Dr. Matt Walker: Well, yeah. We don't 
yet know if it's trazodone in particular.  Tim Ferriss: Yeah. Yeah.
Dr. Matt Walker: These were   the more classic SSRIs.
Tim Ferriss: Yeah. Trazodone   is pretty weak. Pretty weak.
Dr. Matt Walker: So right now,   jury is out.
Tim Ferriss: Yeah, pretty —  Dr. Matt Walker: Yeah.
Tim Ferriss: Well, yeah. It's sort of a —  Dr. Matt Walker: Exactly.
Tim Ferriss: — a failed — I don't   want to call it a failed antidepressant, 
but it's like by the time it starts to —  Dr. Matt Walker: No. It's certainly 
not a first line, yeah, treatment.  Tim Ferriss: Yeah.
Dr. Matt Walker: And that's why it's   become — its most popular use right now —
Tim Ferriss: People just fall asleep.  Dr.

Matt Walker: — would be 
not as an antidepressant.  Tim Ferriss: Exactly.
Dr. Matt Walker: It's   because it's, yeah, sleep-inducing. Yep.
Tim Ferriss: All right. So let's leapfrog   to pregabalin and gabapentin. You can take either.   Gabapentin, people may recognize because 
veterinarians love to hand it out like Pez candy   when you take your dog in or your cat in.
Dr. Matt Walker: Yeah.  Tim Ferriss: But which of those 
would you like to talk about first?  Dr. Matt Walker: We can talk about 
both of them, because in some ways —  Tim Ferriss: Yeah.

Great.
Dr. Matt Walker: — they're   part of the same class of —
Tim Ferriss: Perfect.  Dr. Matt Walker: — drugs, pregabalin and 
gabapentin. You're right that they're used   for multiple different reasons, one of which is 
pain medication, muscle relaxant. 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 don't seem to be a big fan of those, Matt.
But it turns out that that's not the case. You   shouldn't be fooled. They're actually calcium 
channel — they alter the functioning of calcium   channels, which in part — I'll start that 
again.

They actually impact the functioning   of calcium channels on neurons, and 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, meaning   naive patients who've never received either of 
these drugs or don't have seizure disorders or   sleep disorders, 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 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 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 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.  Tim 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   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 expectancy effect, 
because I wasn't looking for it.

But I seem 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 is there a plausible explanation for that?
Dr. Matt Walker: No. I think there is a plausible   explanation. 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 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,   which is a horrific disorder where you get these, 
in America, I think you call them Charliehorses,   but in England, we'll 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 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, 
maybe 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 don't like it that they have 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 there. You   would still get some of that benefit.
Tim Ferriss: So I do know someone,   I don't want to name names here, I'll 
protect the guilty, but who is a —   let's call this person a pharmacological champion. 
They have high tolerance for everything. And   pregabalin forced them to tap out.
Dr. Matt Walker: Wow. Wow.  Tim Ferriss: In the sense that they 
were so laid out — not laid out,   but altered the next day. They were like, 
"Okay. That was too much. That was too much."  Dr. Matt Walker: Yeah.
Tim 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   want to 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 going to give myself permission to take   some of these sleep aids," that's enough a 
lot of the time. Just knowing it's there,   having a rule in place often allows 
me to get to sleep without anything.  Dr.

Matt Walker: I think this is such a powerful 
message, thanks for bringing it up, which is   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.
Tim Ferriss: One hundred percent.  Dr. Matt Walker: In other words, 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 never suffer 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.
Tim Ferriss: Yeah.  Dr. Matt Walker: It's a miserable place to be.
Tim 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.   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 want to 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 going to look like, and   so now your heart rate is 30 percent 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, 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. And   it's just the security of knowing it's there.
Dr. Matt Walker: Yeah.  Tim Ferriss: And —
Dr. Matt Walker: I'm so   glad that that's, yeah, that's the case for you. 
And I am also a big advocate of CBTI, cognitive   behavioral therapy for insomnia, which is just 
as 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 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 are 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.
Tim Ferriss: That's a great observation.   And I think this is also a pretty good place 
to start landing the plane.

And I don't know   if you'd be open to this, so you can listen to 
my ramblings for another two and a half hours   and put up with my questions, but would you 
be open to doing a round two at some point?  Dr. Matt Walker: Oh, just sign me up —
Tim Ferriss: All right. All right. Beautiful.  Dr. Matt Walker: — next time. Yeah.
Tim Ferriss: So let me —  Dr. Matt Walker: Any time, I would love to.
Tim Ferriss: So let me give people — if   it's okay with you, I'm going to give 
people a teaser of what we might cover.   This is a non-exhaustive list, but 
there are a number of things that we   brainstormed beforehand. I do not know the answers 
to these things and I would really love to explore   them.

So we have sleep, learning, memory, and 
creativity, and there are many bullets to explore   there. We have sleep and sex, intercourse, orgasm, 
masturbation, libido, all my favorite things. So   we can talk about that next time around in round 
two. And then also dreaming and lucid dreaming. So   I have a long standing, multi-decade long 
interest in lucid dreaming and I really   want to dig into dreaming and lucid dreaming.
So those are just a few of the things that we can   and should explore in round two.

Matt, is there 
anything you would like to mention in closing that   we haven't brought up? Anything you would like 
to point people to? Certainly, people will want   to follow you @DastardlyDiplomat on Twitter. I'm 
kidding. It's @SleepDiplomat on Twitter. But are   there any resources, websites you'd like to point 
people to, closing comments, recommendations,   anything at all that you'd like to bring up?
Dr. Matt Walker: No.

Firstly, I would just say I   think I love those topics. I think there's so much 
to discuss. And maybe when people are threading   you and I in on Twitter, they can chime in as to 
whether those topics sound great. And anything   else that we can discuss, I would love to do that.
I think people have heard enough of my dulcet   British tones. I won't say too much more. 
If you want to find out more about sleep,   I would probably say the best place to learn more 
about what I'm doing with sleep is probably my own   podcast, which it took us months and months 
to come up with the creative naming of it,   and it's called The Matt Walker Podcast.

And so 
you can just find that on all places where you   get your podcasts. So The Matt Walker Podcast is 
probably the best place to get more info on me.  But no, I will keep my mouth shut. I've said 
enough. I've spilled enough of my diatribe   to not bore people with anything more.
Tim Ferriss: So British. So British. I   love it. Those dulcet tones. Oh, the —
Dr. Matt Walker: I think, yeah, some   people have suggested that my personality may 
be the best prophylaxis known to man. And so —  Tim Ferriss: Oh, boy.
Dr. Matt Walker: I'm sure   some people have probably lost the 
will to live listening to me during   this conversation.
Tim Ferriss: Well,   all the better to bring your mellifluous, 
dulcet tones back for the conversation   around orgasms and masturbation next time around.
Dr.

Matt Walker: Yeah. Maybe finally I will sort   of redeem myself with all of this bad news about 
different alcohol and caffeine. All of a sudden,   I can give you some good news about sex, 
masturbation, and why you have your own   sleep fate in your hands, literally, 
when it comes to masturbation. So —  Tim Ferriss: Oh, my God. What a cliffhanger. 
So folks, stick around. We have a lot of   exciting things coming. And this has been a 
fantastic conversation. Thank you so much,   Matt, for taking the time and also for doing the 
work and the research and designing these studies   and not only executing on the research, 
but conveying it then in a way that makes   it understandable and useful to a broader 
audience. A lot of science can stay in the   distinguished hallways of universities and be read 
by peers in journals, but it takes a very separate   and valuable set of skills to be able to translate 
that without dumbing it down or sacrificing   integrity to communicate to a broader audience. 
And I think you do a tremendous job of that.

So   thank you very much. Really appreciate it.
Dr. Matt Walker: Thank you so much for that,   Tim. I really appreciate those words. Thank you.
Tim Ferriss: Absolutely. And to everybody   listening, we will have links to everything in the 
show notes, as per usual, at tim.blog/podcast. So   until next time, be a little kinder than 
is necessary to others and to yourself.   Have faith that if you have sleep issues, and 
I've had sleep issues, some very, very crippling   sleep issues for decades, that there is hope, 
there are tools. And we will be and have been   discussing some of the options that are worth 
investigating and discussing with your licensed   professionals. And thank you so much for tuning 
in. So until next time, take care, everybody..

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