Dr. Robert Sapolsky: Science of Stress, Testosterone & Free Will

- [Andrew Huberman] Welcome to the Huberman Lab Podcast

where we discuss science and science-based tools

for everyday life.

- I'm Andrew Huberman,

and I'm a Professor of Neurobiology

and Ophthalmology at Stanford School of Medicine.

Today I have the pleasure of introducing

Dr. Robert Sapolsky.

Dr. Sapolsky is a Professor of Biology

and Neurosurgery at Stanford University.

His laboratory has worked on a large variety of topics,

including stress, hormones,

including testosterone and estrogen,

and how the different members of a given species interact

according to factors like hormones,

hierarchy within primate troops,

and how things like stress, reproduction

and competition impact behavior.

One of the things that makes Dr. Sapolsky's work

so unique is that it combines elements from primatology,

including field studies with human behavior,

in essence trying to unveil how humans as old world primates

are controlled by different elements of our biology

as well as our psychology.

Dr. Sapolsky is also a prolific author of popular books,

such as "Why Zebras Don't Get Ulcers",

"The Trouble with Testosterone",

and "Behave: The Biology of Humans at Our Best and Worst".

During the course of our discussion today,

Robert also revealed to me

that he is close to completing a new book entitled,

"Determined: The Science of Life Without Freewill."

And indeed we discuss the science of life

without freewill during this episode.

We also discuss stress and how best to control stress

and how stress controls us at both,

conscious and subconscious levels.

We talk about testosterone and estrogen

and hormone replacement therapy

and how those impact our mind, our psychology

and our interactions with others.

As with any discussion with Dr. Sapolsky,

we learn about scientific mechanisms

that make us who we are.

And today we also discuss tools

and how we can leverage those scientific mechanisms

in order to be better versions of ourselves.

I should mention that unlike most guest interviews

on the Huberman Lab podcast,

this one had to be carried out remotely

due to various constraints,

so you may hear the occasional audio artifact,

please excuse that.

We felt that the value of a conversation with Dr. Sapolsky

was well-worth those minor, minor glitches.

And indeed the information that he delivers us

is tremendously valuable, interesting,

and in many cases actionable as well.

Before we begin, I'd like to emphasize

that this podcast is separate from my teaching

and research roles at Stanford.

It is, however, part of my desire

and effort to bring zero cost to consumer information

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And now without further ado,

my conversation with Dr. Robert Sapolsky.

Great, well, thank you so much,

Robert, for joining us today.

I've been looking forward to this for a very long time

and I appreciate it.

- Oh yes, glad to be here.

- There is an enormous range of topics

that we could drill into, but just to start off,

I want to return to a topic that is

near and dear to your heart, which is stress.

And one of the questions that I get most commonly is,

what is the difference between short and long-term stress

in terms of their benefits and their drawbacks?

And the reason I say benefits is that,

obviously stress and the stress response can keep us alive,

but stress, of course, can also sharpen our mental acuity

and things of that sort.

So how should we conceptualize stress

and how should we conceptualize stress

in the short-term and in the long-term?

- Well, basically sort of two graphs that one would draw.

The first one is just all sorts of beneficial effects

of stress short-term,

and then once we get into chronicity,

it's just downhill from there.

Short-term because it saves you from the predator,

short-term because you're giving a presentation

and you think more clearly or your focus is better,

all sorts of aspects of that.

And what then winds up being an argument is,

how long does it take to go from short-term to long-term?

And that's somewhat arbitrary,

but the sorts of chronic stressors

that most people deal with are just undeniably

in the chronic range, like having spent the last 20 years,

daily traffic jams or abusive boss or some such thing.

The other curve that's sort of perpendicular to this

is dealing with the fact

that sometimes stress is a great thing.

Like our goal is not to cure people of stress

because if it's a right kind, we love it.

We pay good money to be stressed that way

by a scary movie or a rollercoaster ride.

What you wind up seeing is

when it's the right amount of stress,

it's what we call stimulation.

And the basic curve there is,

here is an optimal level of stimulation and too little,

and function goes down with what we would call boredom,

and too much and function goes down

with what we would call stress.

And the optimum is what all of us aim for.

- In terms of the benefits of stress in the short-term,

one thing that's really striking to me is,

how physiologically the stress response

looks so much like the excitement response

to a positive event.

And we can speculate that the fundamental difference

between short-term stress and short-term excitement

is some neuromodulator like dopamine or something like that.

But is there anything else that we know

about the biology that reveals to us?

What really creates this thing we call valence

that an experience can be terrible or feel awful,

or it can feel wonderful, exhilarating depending on

this somewhat subjective feature we call valence?

Do we know what valence is or where it resides?

- On a really mechanical level,

if you're in a circumstance that is requiring

that your heart races and you're breathing as fast

and you're using your muscles and some such thing,

you're going to to be having roughly the same

brain activation profile,

whether this is for something wonderful

or something terrible with the one exception being

that if the amygdala is part of the activation,

this is something that's going to be counting as adverse.

Whether that's the circumstance,

an adverse circumstance recruiting the amygdala into it,

and how much it's the amygdala being involved,

biases you towards interpreting it as even more awful.

The amygdala in some ways is kind of the checkpoint

as to whether we're talking about excitement or terror.

- Let's use the amygdala as a transition point

to another topic that you've spent many years working on

and thinking about, which is testosterone

and other sex steroid hormones.

I heard you say once before that

among all the brain areas that bind testosterone,

that where testosterone can park and create effects

that the amygdala is among

the most chockablock full of these parking spots,

these receptors.

I realize there's a lot here,

but how should we think

about the role of testosterone in the amygdala

given that the engagement of the amygdala is fundamental

in this transition point between a exhilarating,

positive response and a negative stressful response?

Or maybe just broadly,

how should we think about testosterone

and its effects on the brain?

- And pertinent to the transition from

whether this is a stressor that's evoking fear

or revoking aggression in terms of that continuum,

also because the amygdala is in the center of all

four points on those axes.

Basically, almost everybody out there

has a completely wrong idea as to what testosterone does,

which is testosterone makes you aggressive

because males, virtually every species out there

have more testosterone and a more aggressive

and seasonal measures have testosterone surging

at the time of year, they're punching it out over territory.

And you take testosterone out of the picture,

you castrate any mammal out there, including us,

and levels of aggression will go down.

And the easy thing then tends to conclude

that testosterone causes aggression.

And the reality is testosterone does no such thing,

it doesn't cause aggression.

And you can see this both behaviorally and in the amygdala.

What does testosterone do?

It lowers the threshold for the sort of things

that would normally provoke you into being [mumbles]

so that it happens more easily.

It makes systems that are already turned on, turn on louder

rather than turning on aggressive music or some such thing.

What does that look like behaviorally?

You take five male monkeys, put them together,

they form a dominance hierarchy.

Number one is great, number five is miserable,

number three is right in between.

Now take number three

and shoot the guy up with tons of testosterone

and he's going to be involved in more fights.

Aha, testosterone uniformly causes aggression,

but you look closely and there's a pattern to it,

is number three now challenging numbers two and one

for their place in the hierarchy.

Absolutely not, he is brown-nosing them

exactly as much as he used to.

What's going on is he's just a miserable terror

to poor number four and five.

And in that case, what testosterone is doing

is amplifying the preexisting patterns of aggression.

Amplifying the social learning,

that's where it'd gone into there.

Now on sort of the more reductive level,

so how does that translate into the amygdala?

Does testosterone make amygdaloid neurons

have action potentials?

Does it cause those neurons to suddenly speak

about fear and aggression spontaneously?

Absolutely not.

What they do is,

if the amygdala is already being stimulated,

it increases the rate of neuronal firing.

What its worth?

It shortens after-hyperpolarizations.

So the theme there exactly is,

it's not creating your aggression,

it's just upping the volume of

whatever aggression is already there.

And once you factor that in,

it's impossible to say anything about what testosterone does

outside the context of what testosterone related behaviors,

how they get treated [laughs] in your social settings.

- Mm-hmm, yeah.

And in terms of status and the relationship

between individuals, either nonhuman primates or humans,

can we say that testosterone and levels of testosterone?

Or I should say, can we say

that relative levels of testosterone between individuals

is correlated to status within the hierarchy?

- Yes, but in a way that winds up

being totally uninteresting.

Like you go back on whatever number of decades,

the endocrinology texts,

and there were two totally reliable findings in there.

Let's see, I have a dog in here that's-

- Oh, good, we like dogs at the Huberman Lab podcast.

- Oh, okay, it is jingling with that.

- They are welcome, they are absolutely welcome, yeah.

- And there'd be two truisms,

which is higher levels of testosterone

predict higher levels of aggression

in humans and other animals.

Higher levels of testosterone

predict higher levels of sexual activity.

Whoa, testosterone causing both,

and the correlation is there.

And when you look closely, we've got cause and effect stuff,

sexual behavior raises testosterone levels,

aggression raises testosterone levels.

Your levels before had were barely predictive

of what's going to happen,

so it's a response rather than a cause.

When you look at that though

in terms of making sense of individual differences,

they don't matter a whole lot.

You can spend an entire career on the social circumstances

that produce 3.5% more testosterone in the circulation,

and expect to see all sorts of interesting implications.

And that's not really the case,

it's somewhat of a yes or no modulator

of the much more subtle social stuff that's already there.

- Very interesting.

I think that there are a lot of misconceptions

about human biology, but testosterone seems to be one area

where at least from what I can find on the internet,

it's sort of at the peak of misunderstanding.

Maybe we could just ask a few more questions

about testosterone and sexual behavior

because there's an interesting story there

about castration versus non-castration

and the causality, again.

But before you address that,

I just want to highlight something that you said

that I think is so vital, which is that behaviors,

such as aggressive behaviors and sexual behaviors

can actually increase testosterone.

Did I hear that correctly? - Yeah.

- And the reverse is sort of true, but not in a causal way.

Is that right?

- The opposite direction of the causality, yeah.

- Yeah, yeah, so if I were to increase

somebody's testosterone by 30%,

male or female doesn't matter,

their sexual behavior may or may not change.

- Essentially zero effect at all.

Your brain is not that sensitive

to fluctuations in testosterone levels.

In terms of things like aggression,

raising testosterone, this is a great footnote.

If you have the right type of

willing to die on the trenches devotion sort of thing,

watching your favorite team play a sport

will raise your testosterone levels

as you sit there with the potato chips in your armchair.

So it's not the physicality of aggression,

it's the psychological framing of it.

So, yeah, testosterone is not causing that.

And a great way to appreciate that is,

okay, so you had all these testosterone

sexual behavior correlations,

and you do the definitive endocrine intervention,

which is you do a subtraction study,

you've removed the testes.

And as I said before, levels of sexual behavior goes down.

Good, we've just shown

that testosterone is somehow have caused it.

Critically they go down, but not down to zero,

whether you are a rat or a monkey or a human, whatever.

And what predicts how much residual

sexual behavior is there,

how much sexual behavior there was before castration?

What that's telling you is by then

that's behavior that's being carried by social learning

and context rather than by the hormone,

exact same thing with aggression.

Drops after castration, doesn't go to zero,

the more prior history of it,

the more it just keeps coasting along on its own

even without testosterone.

- Very interesting.

Can we say that there is an exception

in terms of the early organizing effects of hormones?

Like, for instance, if a developing animal is deprived of

a testosterone or estrogen

or aromatized testosterone into estrogen,

there's a whole story there is, you know.

But then I could imagine that the circuits of the brain

that are responsible for initiating sexual behavior

in the first place might not emerge,

and therefore not be sensitive

to the testosterone later in life.

Is that right?

Okay. - Yeah, exactly.

And a great way of seeing that

is this totally nutty biological factoid,

which is the second to fourth digit ratio enhanced.

- Oh yeah.

- Totally obscure thing, the ratio of one to the other

in some way reflects levels of testosterone,

androgen exposure during fetal life.

And I can't remember which way it goes and it's minuscule

and you need a thousand people in your sample size

to be able to see anything,

but you see it in other primates,

it's already there in fetal sonograms, all of that.

So that's a readout of subtle differences

in prenatal exposure,

and that winds up being a predictor of a whole range of

sort of stuff in adult behavior.

So, yeah, at the fetal end,

when you're still building everything,

testosterone and the amount of that

is making a huge difference.

By the time you're an adult,

it's just somewhat of an old and a non-signal.

- Yeah, I have a confession,

which is that I was a master's student at Berkeley

in Marc Breedlove's arena, so I'm an author on that paper,

although I'm deep within the author line,

and you got the description of it exactly right

that it's the D2, the index finger to the ring finger ratio

is more similar in females than it is in males.

In males, the index finger tends to be shorter.

And for people out there who are listening to this

who are now freaking out or measuring,

that there is a proper way to measure this, which is,

eyeballing it doesn't work all the time

unless at the extremes.

And there's some very interesting stories there.

It actually has been replicated no fewer than five times,

Marc Breedlove tells me.

But yes, in terms of these early organizing effects,

those seem very robust in most studies.

These later effects are sort of activation of

neural circuits by hormones.

I'm absolutely fascinated by this.

And I do have a couple other questions,

which is, we normally associate testosterone with males,

but of course, females make testosterone as well

from the adrenals and presumably elsewhere too.

I'm guessing if we looked hard enough,

we'd probably find that there were other sources

of androgens in females.

Can we say

that these general contours of effects on aggression

also pertain to females?

And I suppose I should ask in particular

about female-female aggression,

which does exist in many species,

female-male agregression as well as maternal aggression,

which is a robust aspect of our evolution, of course,

that the mother will, an angry mother animal

of any kind protecting her young is truly dangerous,

in the best sense of the word.

- And that type of post-parturition,

period after birth aggression is all about estrogen,

progesterone, those sorts of things.

Female aggression, the rest of the time

has testosterone as a major player at a much lower level

on the average.

On the average, one always has to say,

but it's basically the same punchlines.

In females, the lower levels of testosterone are essential

for typical levels of aggression and sexual behavior.

Nonetheless, they're not causing it,

it's not sensitive to small individual differences.

Same exact thing.

You can get way over-impressed

with the importance of androgens in females

just as readily as in males.

- So in line with that,

how should we conceptualize testosterone?

I realize there isn't a single sentence

that can capture a hormone in all its effects

because hormones have so many different slow

and fast effects on the brain, on other glands on their own,

on the very glands that produce them.

But as I've heard you talk about testosterone today

and over the years, I start to get the impression

that as the most misunderstood molecule

[laughs] in human health in the universe,

it's clearly doing something very powerful.

It's shifting the way that certain neural circuits work,

adjusting the gain on the amygdala, as you described,

and certainly other things as well.

Is there any truism about testosterone like,

and its relationship to effort

or its relationship to resilience,

and in a way that maybe will help me and other people

to sort of think about how to think about testosterone?

- Yeah.

Maybe three separate answers to that.

The first one is, I think it's a fair summary to think

that when it comes to motivated strong behaviors,

what testosterone does is make you

more of whatever you already are.

And that to me, sexual arousal,

libido, aggressiveness, spontaneous aggression,

reactive aggression, things of that sort.

It's upping the volume of things

that are already strongly there.

Second way to think about it is,

well, here's like my favorite finding about testosterone.

And this was some wonderful work by a guy, John Wingfield,

who's one of the best behavioral endocrinologists out there.

And about 20 years ago he formulated what was called

The Challenge Hypothesis of Testosterone in Action.

What does testosterone do?

Testosterone is what you secrete

when your status is being challenged,

and it makes it more likely that you'll do

the behaviors needed to hold onto your status.

Okay, so that's totally boringly straightforward

if you are a baboon.

If somebody is challenging your high rank,

the appropriate response on your part

is going to be aggression.

All right, so we've just got in through the back door,

testosterone and aggression, again.

But then you get to humans,

and humans have lots of different ways of achieving

or maintaining status.

And all you need to do is go to like some

fancy private school's annual auction,

and you will see all these half-drunk alpha males

competing to see who can give the most money away

as a show of conspicuous like

property that they have.

And in a setting like that, I mean,

I haven't been able to take urine samples,

if there's times, unfortunately,

but that shows the flip side of it.

If you have a species that hands out status

in a very different sort of way,

testosterone is going to boost that also.

Okay, so that generates a totally nutty prediction.

Wow, take people in a circumstance,

say playing an economic game

where you get status by being trustworthy

and being generous in your interactions with the game.

If you give people testosterone,

does that make them more generous?

And that's absolutely the case.

Totally cool finding.

I'm showing you, I don't know,

basically if you took a whole bunch of Buddhist monks

and shot them up with testosterone,

they'd get all competitive with each other

as to who could do the most random acts of kindness.

And if we have a societal problem with too much aggression,

the first culprit to look at is not testosterone,

the first to look at is

that we hand out so much damn elevated status

for aggression in so many circumstances.

So I find that finding to be fantastic.

Third thing about subtlety of testosterone.

Okay, so like some subtler behavioral effects,

you give testosterone to people

and they become more confident,

they become more self-confident.

Well, that's good, people pay to take

all sorts of nonsensical self-help courses

that will boost your self-esteem.

And that's a good thing

unless testosterone makes you more confident,

that is inaccurate,

and you're more likely to barrel into wrong decisions.

What's shown in economic game play is that testosterone

by making you more confident makes you less cooperative

because who needs to cooperate

because I'm on top of this all on my own.

Testosterone makes people cocky and impulsive.

And that might be great in one setting,

but if and the other is,

you're absolutely sure your army is to

get over on the other country in three days.

So hell, let's start World War I,

and you get a big surprise out of it.

Testosterone altering risk assessment beforehand

probably played a big role in that kind of miscalculation.

- Super-interesting.

I always think about testosterone

and dopamine being close cousins in the brain,

not just because of their relationship

through the pituitary and hypothalamus.

That, of course, but also because of dopamine's salient role

in creating this bias towards exteroception.

When somebody takes a drug, with it increases dopamine,

or they're chockablock full of dopamine.

They tend, I want to highlight 'tend'

because this is, I'm really generalizing here,

but they tend to focus on outward goals,

things beyond the boundaries of their skin.

And testosterone seems to do a bit of the same,

it tends to put us into a similar mode of

perceiving the outside world in ways

that we're asking questions like,

how do I relate to this other of my species?

How do I relate to these goals?

Is there anything that we can do to better conceptualize

the relationship between testosterone

and dopamine and motivation?

Or would that just take us down the alleyways of,

of neural pathways and the hypothalamus?

Which is fine too.

- Well, I think it's got lots to do with

sort of this massive revisionism about dopamine.

Everyone, since the pharaohs got brought up being taught

that dopamine is about pleasure and reward.

It turns out it isn't, it's about anticipation of reward,

and it's about generating the motivation,

the goal-directed behavior needed to go get that reward.

And before you know it, you're using like elevated dopamine,

your entire life to motivate you to do

whatever is going to get you like entry into heaven

after-life kind of, it's doing that sort of thing.

So it's really about the motivation.

And what testosterone does even in individuals

who are not aggressive and why testosterone replacement

is often a very helpful thing for aging males is

it increases energy, it increases a sense of thereness,

a presence of alertness that increases motivation.

So that's a whole aspect, which then takes us into

is your motivation to get up and like go,

hand out lots of soup in a soup kitchen for homeless people,

or is it to get up and go ethnically cleanse a village.

It's got much to do with what your makeup was

before the testosterone got onboard.

So it's activating in an energetic sense,

testosterone within minutes increases glucose uptake

into skeletal muscle.

You're just more awake and alert and all of that,

and that has a lot to do with what dopamine does.

And as one might predict then,

getting just the right levels of testosterone

infused into your bloodstream feels great to lab rats.

They will lever press to get infused into the range

that optimizes dopamine release.

So there is, you are absolutely right,

they're deeply intertwined.

- Yeah, such beautiful biology there.

And I love the way you encapsulate their relationship.

I want to ask about estrogen,

we don't hear about estrogen as often,

and it's always interesting to me now doing

some public facing education,

that testosterone is this very controversial molecule,

just to say it is almost controversial. [laughs]

[Robert laughs] But estrogen doesn't seem

to hold the same controversial weight,

and yet estrogen has a very powerful effects

on both the animal brain and on the human brain

of males and females.

Men do not want their estrogen to go too low.

Terrible things happen, they will lose cognitive function,

libido can drop.

So men need estrogen as well,

but perhaps maybe we can put the same filter on estrogen

as we did on testosterone.

Are there any general themes of estrogen

that people should be aware of

or that you think that are generally misunderstood?

Is it really all about feelings and empathy

and making us more sensitive?

I sense not.

- No, and it's once again very context dependent.

And if estrogen after giving birth is playing a central role

in you wanting to shred the face of somebody

getting too close to your kittens kind of thing,

we know it's not just warm, fuzzy, empathic kind of stuff.

Estrogen in lots of ways could be summarized by,

if you've got a choice in the matter

between having a lot of estrogen in your bloodstream or not,

go for having a lot of estrogen.

It enhances cognition, exactly as you said,

it stimulates neurogenesis in the hippocampus,

it increases glucose and oxygen delivery,

it protects you from dementia,

it decreases inflammatory oxidative damage to blood vessels,

which is why it's good for protecting

from cardiovascular disease in contrast to testosterone,

which is making everyone of those things worse.

This springs up this minefield with a question,

which is, so what about post-menopausal estrogen?

And all sorts of lab studies with non-human primates

suggested that you keep estrogen levels high

after a monkey's equivalent of menopause.

And you're going to keep brain health a lot better

or decreasing the risk of dementia, stroke,

every such thing.

Estrogen is a great antioxidant, all of that.

So in the 90s I think

when Healy, I'm forgetting her name,

but when there was the first female head of the NIH,

Bernadine Healy set up this massive prospective human study,

what was going to be the biggest one of all times,

looking at the pluses and minuses

of post-menopausal estrogen.

And tens of thousands of women, and this was...

And they had to cut the study short

because what they were seeing was,

estrogen was not only doing the normal bad stuff

that you expect in terms of some decalcification stuff,

but it was increasing the risk of cardiovascular disease,

and it was increasing the risk of stroke,

and it was increasing the risk of dementia.

And this ground to a halt and everybody,

they stopped the study and front page news

and everybody panned at that point.

And nobody could make sense of it

who had been spending the last 20 years studying

the exact same thing in primates

and seeing all the protective effects.

And the explanation turned out to be one of those things

where like the law of unexpected consequences.

Okay, menopause in women,

it lasts different lengths of time,

that may be a factor that's going to come.

You know what, let's not start giving our study subjects

more estrogen until they're totally past menopause.

And when you've got that lag time in between,

you shift all sorts of estrogen receptor patterns,

and that's where all of the bad effects come from.

- Wow! - All of the monkey studies

had involved just maintaining

ovulatory levels into the post-menopausal period.

And you do that and you get great effects.

Estrogen is one of the greatest predictors of

protection from Alzheimer's disease, all of that,

but it needs to be physiological.

Just keep continuing what your body has been doing

for a long time versus let the whole thing shutdown

and suddenly like try to fire up the coal stoves

at the bottom of the basement kind of thing,

and get that going,

there you get utterly different outcomes.

And that caused a lot of human health consequences

when people suddenly decided that estrogen

is in fact neurologically endangering post-menopausally.

- Wow, that's fascinating.

And I never thought that these

steroid hormone receptors could by not binding estrogen,

being devoid of estrogen binding, I should say,

could then set off opposite biochemical cascades.

Fascinating.

I guess it raises the question

about testosterone replacement too,

whether or not people should

[laughs] talk to their doctor before too long.

Men and women talk to your physicians before too long

to avoid these, whatever is happening in these periods

where there isn't sufficient testosterone and/or estrogen.

It sounds like could cause longer-term problems

even when therapies are introduced.

- Two additional misery slash complications.

So, okay, you're trying to understand,

you look at women with a history

with or without post-menopausal estrogen replacement

where it's done great.

And you're seeing 20 years later,

estrogen is a predictor of a decreased risk of Alzheimer's.

Then you got to start trying to do the unpacking

prospective type studies.

How much estrogen?

At which times?

Estrogen is a catchall term for a bunch of hormones,

estrone, estradiol, estriol.

How much of each one of them?

Natural or synthetic?

Go try to figure all of that out.

And the second complication is,

it's often hard to say anything about what estrogen does

outside the context of what progesterone is doing.

And often it's not the absolute levels of either,

it's the ratio of the two.

This is such a more complicated endocrine system

than testosterone.

And because you have to generate dramatic cyclicity

that like no male hypothalamus ever has to dream off.

It's a much, much more complicated system,

thus, it's a lot more complicated to understand,

let alone like figure out what the ideal benefits are of it.

- Yeah.

I don't know what to make of the literature on

dropping rates of testosterone and endocrine disruptors.

I was at Berkeley when Tyrone Hayes

published his data on these frogs

that were drinking water from various locations

throughout the United States, not just in California,

and seeing very severe endocrine disruption

through blockade or,

and of androgen receptors and all sorts of issues.

And you hear this all the time now

that sperm counts are dropping,

that there are all these endocrine disruptors

that there's birth control in the water,

in the drinking water.

It all starts to sound a little crazy,

and yet I've also been fooled before by,

I guess a good example would be,

there's a lot of crazy stuff in the world online

about all the terrible stuff in highly processed foods.

And yet you've got very respectable people,

endocrinologists at UCSF like Robert Lustig saying,

yeah, a lot of these hidden sugars

and these emulsifiers, they're causing real problems.

So I've become more open-minded about the question.

And so, are we suffering from drops in sperm counts

and testosterone and estrogen and fertility

as a consequence of endocrine disruptors

in the environments and food,

or because of social reasons?

Is there anything that we can hang our hat on

like real data that you're confident in?

Or is it just a mess?

- No, the phenomenon does appear to be quite real.

Cross-sectional studies, human populations,

or I still don't understand why this was

one of the first things that Hayes spotted.

Decreasing testicle size in crocodiles.

[Andrew laughs]

Go figure why that was

one of the first contributions to this.

And I think the phenomenon is absolutely real.

And what you're then left with is two classic challenges,

which is this is correlated with

something broad environmental toxins.

Which ones, how much, when, etc.?

And the other one always being, well, okay,

dropping is a dropping enough to make a difference.

How big of an effect is this?

And those are where the juries are still out.

- Yeah, it's an area that I know

there's a lot of interest in,

and you've got groups of people

who won't touch a receipt at a store

because of the BPAs that are on the inks of the...

And then [laughs] you've got people

who don't care about those things.

It is a fascinating area.

I hope that more biology will be done there soon.

I'd like to briefly return to stress.

You described a study once about two rats,

one running on a wheel voluntarily,

one who is basically stuck in a running wheel,

and it's forced to run anytime, rat number one runs.

So in one case the rat is voluntarily exercising. [laughs]

And in the other case, the rat is being forced

to go to PE class, so to speak,

but really, and seeing divergent effects on biology.

And I'd like to just touch into this and use it

as kind of a case study for stress mitigation in general.

I'm rather obsessed in our colleague, David Spiegel,

Associate Chair of Psychiatry at Stanford

is obsessed with this question of,

how humans can start to mitigate their own stress?

What do you think about stress mitigation

and what should we do as individuals and as families

and as a culture to try and encourage people

to mitigate their stress, but in ways

that are not going to turn us into rat number two,

where we're being forced to mitigate our own stress

and therefore it becomes more stressful. [laughs]

- And what you see is, rat number one gets

all the benefits of exercise.

Rat number two gets all the downsides of severe stress

with the same exact muscle expenditure

and movements going on.

Perfectly yoked, great example

that it's the interpretation on your head.

And I haven't kept up with that literature,

but I'll bet you, rat number two

is having a whole lot more activity in its amygdala

than is rat number one.

Okay, so stress mitigation.

Anything I should say here I should preface with,

I'm reasonably good at telling people

what's going to happen if they don't manage their stress,

but I'm terrible at actually like managing stress

or advising how to manage that.

I'm much better with the bad news aspect of it.

But what you see is, by now just a classic literature,

half a century old, sort of showing

what are the building blocks of stress.

Not, ooh, you step outside

and you've been gored by an elephant,

and can you grow from your experience?

And what doesn't kill you makes you stronger.

In that you could have a stress response,

but you're in the realm of the gray zone

of ambiguous social interactions, that sort of thing.

Some people have massive stress responses,

others not at all, in between, enjoy it.

Like what are the building blocks of,

what makes psychological stress stressful?

And the first one is exactly

what is brought up by that running study.

Do you have a sense of control?

A sense of control makes stressors less stressful.

And the running wheel shows that or studies where you,

you lab rat or you college freshman volunteer

have been trained that by pressing a lever,

you're less likely to get a shock.

And today you're at the lever they're working away

and unbeknownst to you the lever has been turned off,

and it has no effect on shock frequency,

but because you think you have some control,

you have less of a stress response.

If you were a rat and doing this day-in and day-out,

you're less likely to get an ulcer.

So a sense of control.

And related to that is a sense of predictability.

Rat get shocked, human gets shocked, whatever,

and the scenario either is the shocks come now and then,

or the shocks come now and then,

and 10 seconds before a little warning light comes on.

And when you get the warning light,

the shocks are distressful.

You got predictability

because if you're not getting warning lights,

any second you could be a half second away

from the next shock.

You get a warning light,

and you know that if there isn't one,

you've got at least 10 seconds worth of relaxation.

You know what's coming,

you can prepare your coping responses,

and best of all afterward you know when you're finally safe,

when you can recover from it.

And that's enormously protective.

Others outlet for frustration,

you take a rat who is getting shocked,

and if it could run on a running wheel,

that's a protective thing, that's doing it voluntarily.

If you've got a rat and he can gnaw on a bar of wood,

a stressor is less stressful.

Unfortunately, if you have a rat or primate or human

and they're stressed, the ability to aggressively dump on

somebody smaller and weaker

also reduces the stress response.

And the fact that displacement aggression reduces stress

accounts for a huge percent triggers like unhappiness.

So all of those are variables, get social support as well.

That's a good one.

Interpreting circumstances is being

good news rather than bad.

Hurray, so you've got this very simple

sort of like take home recipe of go out

and get as much control and as much predictability

and as many outlets and as much social support as possible,

and you're going to do just fine.

And you go out and do that,

and that's a recipe for total disaster

because it's much, much more subtle than that.

In one great example, okay, so you're getting shocks,

you want a warning beforehand,

get a little warning light 10 seconds before each shock,

it's wonderfully protective.

Get a warning light one second before the shock

doesn't do anything.

There's not enough time for you to get

the psychological benefits of the anticipation.

Now instead, gets the little warning coming on

two minutes before each shock,

and it's going to make things worse

because you're not going to be sitting there like reveling

and sort of your sense of predictability,

and it's soon going to be, oh.

You're going to be sitting there for two minutes saying,

damn, here it comes.

Predictive information only works in a narrow domain.

Similarly, control.

Do you want to have a sense of control on the face of stress?

And the answer is, only if it is a mild to moderate stressor

because what's happening then,

your sense of control is completely independent

of the reality of whether you have control or not,

but in the face of mild to moderate stressors,

a sense of control gets interpreted as,

wow, look how much worse things could have been.

Thank God, I have control,

I'm on top of this to master my fate.

In contrast, if it's a major stressor,

all that arbitrary sense of control does

is make you think,

oh my God, look how much better it could have been.

I could have prevented it.

And we all know that intuitively

like we do that in the face of people's worst stressors.

Nobody could have stopped the car

the way the kids suddenly jumped out.

It wouldn't have mattered

and if you had gotten them to the doctor a month ago,

instead of now, it wouldn't have made any...

You didn't actually have any control.

And what you see is,

you absolutely want to have a huge sense of control

over mild to moderate stressors,

and especially ones that result in a good outcome.

Hooray, for me, and in the face of horrible stressors,

what you want to do is like self-deception,

and like truth and beauty don't necessarily go

hand-in-hand at that point.

And that's why stress management techniques impact control

and predictability wind up being far worse than neutral

if you're preaching that to somebody homeless

or somebody with terminal cancer,

or somebody who is a refugee.

Tell a neurotic middle-class person

that they have the psychological tools

to turn hell into heaven.

And there's some truth to that.

Do the same thing to somebody

who is going through a real hell,

and that's just privileged heartlessness

to do that because that doesn't work.

More and more outlets, if your outlets are damaging,

that's not a good way to mitigate stress.

Social support, if you're confusing mere acquaintances

for real social support,

you're going to have the rug pulled out

from under you at some point.

If you're mistaking social support for being,

going and bitching and moaning and demanding supportiveness

from everyone around you rather than you doing

some of that reciprocally,

that's not going to work very well either.

It's not simple.

It's not for nothing that lots of us are really lousy.

It, like being good friends and things like that,

and why it takes a lot of work to do it right?

Because you do it wrong

and it may temporarily seem like a great thing,

but when it turns out to be completely misplaced faith,

you're going to be feeling worse than before you started.

- Interesting.

These days, there's a lot of interest in

using physical practices to mitigate stress,

trying to get out of the ruminating,

and to some extent take control of neural circuits

in the brain by using exercise

and using breathing and hypnosis.

And, of course, hypnosis has a mental component as well.

What are your thoughts on stress mitigation

from the standpoint of,

okay, so we don't want to be rat number two,

we want to select something for ourselves,

so we have to take the initiative for ourselves.

Being forced into exercising is not,

it could actually have negative health effect perhaps.

So we need to pick something that we like,

we need to take control of it.

In terms of supporting other people,

you touched on that a bit.

What is the best way to support other people?

Is it to talk about the stressful thing?

I mean, I'm not asking you to play psychologist here,

but I find divergent data on this.

We can spin ourselves up into a lather

by ruminating on something.

And language seems to me like it's a wonderful tool,

but it's also a fairly deprived tool

because it doesn't really get into

the core of our physiology

like something like breathing would.

So what are your thoughts on more,

for lack of a better way to put it, more head-centered,

cognitive approaches to stress mitigation

versus kind of going at the core physiology.

Cold showers now are even a thing to some extent

just to get people stress acclimated,

voluntarily taking cold showers.

- That makes some sense physiologically,

preconditioning for when the real stressors come.

In terms of what you bring up,

oh, transcendental meditation, mindfulness, exercise,

prayer, sort of reflecting on gratitude,

all that sort of thing.

Collectively they work on the average,

they work in terms of, they can lower heart rate

and cholesterol levels and have all sorts of good outcomes,

but they compromise us.

One is exactly the caveat

that comes out of the running wheel study is,

it doesn't matter how many of your friends swear

by the stress management technique.

If doing it makes you want to scream

your head off after 10 seconds,

that's not the one that's going to work for you.

So read the fine print and the testimonials,

but it's got to be something that works for you.

Another one is the stress management type techniques

that work, you can't save them for the weekend,

you can't save them for when you're stuck on

hold on the phone with Muzak for two minutes.

It's got to be something where you stop what you're doing

and do it virtually, daily or every other day,

and spend 20, 30 minutes doing it.

And what you see coming out of that is this

like 80/20 rule from economics.

80/20, 80% of the complaints in the store come from

20% of the customers, things like that.

What you see is, if your entire life consists of

every single thing on your shoulders,

that you can't say no to 24/7.

If you've stopped that and finally said,

my wellbeing is important enough

that I'm finally get to say no to some of the stuff

that I can't say no to.

And I'm going to do it every day for 20 minutes,

whatever stress management technique

you then do in those 20 minutes sort of who knows what,

you're already 80% of the way there

simply by having decided your wellbeing is important enough

that you're going to stop every single day

and have that as a priority.

And that's exactly the same finding

that you find people with chronic depression untreated

that merely calling and getting an appointment

to see a mental health professional,

people start feeling better already

because it's evidence that you've been activated,

and you matter enough to do this,

and you could conceive that this would actually

have a good outcome rather than a hopeless one.

Just doing something meditative

or reflective every day or so,

and it hardly even matters which one you're doing.

And what comes out of that is thus another warning,

which is do not trust anybody who says,

it has been scientifically proven

that their brand of stress management

works better than the other ones.

Just watch your wallet at that point.

- Yeah, amen.

I think one of the core goals of my lab

and David Spiegel's lab,

and I know you've worked with David

and published papers with David as well

is to really try and find out

what are the various entry points to this thing

that we call the autonomic nervous system

and the stress system,

and these systems that when gone unchecked

really can take us down a dark path.

And the idea that there are so many entry points

is really the one that keeps,

what the data keep telling us over and over again.

So there's no magic breathing tool or exercise,

it's any variety of those or one of those.

And, again, we come back to this idea

that it's the one that you select

and the one that you make space for,

and it's the one that you hopefully enjoy

that's going to work best in terms of physiology.

- And [mumbles] benign for those people

who were stuck around you.

- Right, right, absolutely.

And that brings me to this question of,

I find it amazing that how we perceive an event,

and whether or not we chose to be in that event or not

can have such incredible different effects

on circuitry of the brain and circuitry of the body

and biology of cells.

And in some ways it boggles my mind,

like how can a decision made presumably

with the prefrontal cortex,

although other parts of the brain as well,

how can that change essentially the polarity

of a response in the body.

And, I mean, you've talked before

about Type A personalities in there.

We don't have to go into all the detail there

for sake of time, but it is interesting

that the effects of endothelial cells.

I mean, literally of the size of, [laughs]

of the portals for blood are in opposite direction,

depending on whether or not somebody

wants to be in a situation as a highly motivated person.

Maybe you could just give us the top contour of that

because I think it really illustrates

this principle so beautifully.

And then maybe if you would, you could just speculate on

how the brain might have this switch to turn

one experience from terrible to beneficial

or from beneficial to terrible, it's really fascinating.

- Well, all you need to do is like tonight

before you're going to sleep

and you're lying in bed and you're nice and drowsy

and your heart's beating nice and slow,

you start thinking about the fact that

that heart isn't going to beat forever.

[Andrew laughs]

And imagine your toes getting cold afterward

and imagine the flow of blood coming to a halt

and all of you clotting.

You're going to be doing something with your physiology

at that point that 99% of mammals out there only do

if they're running frantically.

And you're going to be turning on your

sympathetic stress response with thought,

with emotions, with memory.

And the measure of that is just how much the cortex

and the limbic system sends projections down

to all the autonomic regulators in the brain.

You can think autonomic regulatory neurons into action

in ways that only other animals can do

with like extremes of environmental circumstances.

And given that and the autonomic rule,

I mean, the other big challenge in understanding it

is gigantic individual differences.

And that's,

when you talk about the optimal amount of stress,

the counts of stimulation,

and in general that stress that's not too severe

and doesn't go on for too long

and there is overall in a benevolence setting.

And under those conditions, we'd love being stressed

by something unexpected and out of control predictability

like a really interesting plot turn

in the movie you're watching.

That's great, but you get the individual differences

that somehow has to accommodate the fact

that for some people, the perfect stimulatory amount

of stress is like getting up early

for an Audubon birdwatching walk next Sunday morning.

And for somebody else, it's signing up to be

like a mercenary in Yemen. [Andrew laughs]

And tremendous individual differences

that swamp any simple prescriptions.

- Yeah, the prefrontal cortex, this thinking machinery

that we all harbor, it's such a double-edged sword.

And what's remarkable to me is,

how the areas of the brain like the hypothalamus

and the amygdala, they're sort of like switches.

I mean, there is context and there is gain control.

You talked about the gain control by testosterone, etc.,

but they're really like switches.

I mean, if you stimulate ventromedial hypothalamus,

you get the right neurons,

an animal will try and kill even an object

that's sitting next to it.

You tickle some other neurons,

it'll try and mate with that same object.

I mean, it's really wild.

I think there are probably rules to prefrontal cortex also,

but it sounds like the context plural

from which prefrontal cortex can draw from

is probably infinite, so that we could probably learn

to perceive threat in anything.

Whether or not it's another group

or whether or not it's science

or whether or not it's somebody's version of

the shape of the earth versus another.

I mean, it's like, you can plug in anything to this system

and give it enough data,

and I think it sounds like you could drive a fear response

or a love response.

Is that overstepping?

- Or [laughs] a mixed horribly ambivalent one

that is changing by the millisecond,

and then like could be mutually contradictory.

No, that's absolutely the case

in the prefrontal cortex,

I more than once have regretted having like wasted 30 years

of my life studying the hippocampus

then I shoot him and studied the prefrontal cortex

because it's so much more interesting what it does,

and it's all this contextual stuff.

It's all the ways in which

it's not okay to lie in this setting,

but it's a great thing in another.

It's not okay to kill unless you do it to them,

and then you get a medal.

It's not, all of this social context

and moral relativity and situational ethic stuff,

that's the prefrontal cortex

that's got to master that.

And that winds up meaning that's the place in your brain

more than anywhere where you say your perception of things

can powerfully influence the reality

of what's coming into you. - Yeah.

- I mean,

a great example, just harking back to testosterone.

Okay, so exercise boosts up testosterone levels.

Does exercise and success do it more

than exercise and failure?

A literature back in the 80s or so

looking at outcomes of marathons.

Did testosterone rise more in the people

who win than the losers?

Wrestling matches.

Things of that sort with a simple prediction

and the answer wound up being,

you didn't see a simple answer.

Okay, you win the marathon,

that's not necessarily a predictor

of increased testosterone.

What's that about?

And then you find like the winner testosterone decreases,

and you find out the guy who came in 73rd

is having a massive testosterone increase.

Whoa, what's that about?

What's that about is far more human subtlety.

The guy who won the race has a decline in testosterone

because he came in three minutes later

than he really, really was expecting.

And everybody now is going to be writing it up

about how he's over the hill.

And the guy who came in 73rd

is having a boost of testosterone

because he was assuming he'd be dead from a heart attack

by the third mile, [Andrew laughs]

and instead he managed to finish.

It's this interpretive stuff going on in there,

and that's what prefrontal cortex is about.

- Amazing, it raises this question of cognitive flexibility,

Can we tell ourselves that something is good for us

even if we're not enjoying it?

And can we wriggle around these corners of

choosing the exercise or doing the...

Personally I'm not a big fan of long bouts of meditation,

but I've benefited tremendously from things like

dedicated breathing and shorter rounds of meditation.

Can I tell myself that it's good for me

and wriggle around the corner

and get my physiology working the way I want?

Do we have cognitive flexibility?

Can I be that third place runner and tell myself,

well, at least I came in, I wanted to win so badly.

That was my primary goal,

but another goal was to beat my previous time,

and I did do that.

And so, [laughs] I mean, it's...

To what extent can we toggle this relationship

between the prefrontal cortex

and these other more primitive systems?

- Well, an enormous amount.

For example, being low in a hierarchy

is generally bad for health in like every mammal out there,

including us, but we do something special,

which is we can be part of multiple hierarchies

at the same time.

And while you maybe low ranking in one of them,

you could be extremely high ranking in another,

you're like have the crappiest job in your corporation,

but you are the captain of the softball team

this year for the company.

And you better bet that's somebody

who is going to find all sorts of ways

to decide that nine to five Monday to Fridays,

just stupid paying the bills.

And what really matters is the prestige on the weekend.

You're poorer, but you're the deacon of your church here.

And so we can play all sorts of

psychological games with that.

One of the most like consistent, reliable ones that we do

and need to use the frontal cortex like crazy is,

somebody does something rotten

and you need to attribute it.

And the answer is, they did something wrong,

hmm, because they're rotten.

Always have been

or always will be this constitutional explanation.

You do something rotten to somebody,

and how do you explain it afterward?

A situational one.

I was tired, I was stressed in this sort of setting,

I misunderstood this.

We're best at excusing ourselves from bad things

because we have access to our inner lives

and we've got prefrontal cortexes

that are great at coming up with a situational explanation

rather than, hey, maybe you're just

like a selfish rotten human, you need to change.

And that's all prefrontal cortex, and we do that every time,

we don't let somebody merge in the lane in front of us,

even though you curse somebody

who does the same thing to you and...

Endlessly.

- I love it.

Your statement about the fact that we can select

multiple hierarchies to participate in.

To me it seems like a particularly important one nowadays

with social media being so prevalent.

I know you're not particularly active on social media

although you might be pleasantly,

or I don't know unpleasantly surprised to find out

that there's a lot of positive discussion about you

and your work, so you don't even need to be on there.

We'll just continue to discuss [laughs] your work.

But what's interesting about social media I've found

is that the context is very, very broad.

I mean, one could argue that who one selects to follow

and which news articles you're reading, etc.

can create a kind of a funneling of information

that itself can be dangerous.

More verification of crazy ideas

or even just less exposure to new ideas.

But there's also this idea

that social media is an incredibly broad context.

So as you scroll through a feed, it's no longer

like being in your eighth grade classroom

or your office or your faculty meeting.

You are being exposed to thousands,

if not millions of contexts, this meal, that soccer game,

this person's body, this person's intellect.

YouTube is another example.

It's a vast, vast landscape.

So the context is completely mishmash

whereas I'm assuming we evolved.

I think we did evolve under contexts

that were much more constrained.

We interacted with a limited number of individuals

and a limited number of different domains,

seasons tended to be constrain us all.

Of course, then we got phones and televisions,

and this started to expand,

but now more than ever, our brain, our prefrontal cortex

and our sense of where we exist

in these multiple hierarchies

has essentially wicked out into infinity.

How do you think this might be interacting

with some of these more primitive systems

and other aspects of our biology?

- Well, I think what you get is,

in some ways the punchline of,

what's most human about humans,

which is over and over we use the exact same blueprint,

the same hormones, the same kinases, the same receptors,

the same, everything were built out of the exact same stuff

as all these other species out there,

and then we go and use it in a completely novel way.

And usually in terms of being able to

abstract stuff over space and time in dramatic ways.

So, okay, you're a low ranking baboon

and you can feel badly because you just like killed a rabbit

and you're about to eat

and some higher ranking guy boots you off

and takes it away from you,

and you feel crummy and it's stressful and you're unhappy.

We are doing the exact same things with like our brain

and bodies when we're losing a sense of self-esteem,

but we can do it by watching a movie character on the screen

and feeling inadequate compared to like how wonderful

or attractive they are.

We can do it by somebody driving past us

in an expensive car, and we don't even see their face,

and you can feel belittled by your own socioeconomic status.

You can watch like the Lifestyles of the Rich and Famous

or read about what Bezos is up to.

And for some reason, decide your life is less fulfilling

because you didn't fly into space for 11 minutes.

And so you can feel miserable about yourself in ways

that no other organism can,

simply because we can have our meaningful social networks

include like the party you're reading about on Facebook

that you weren't invited to

because it's taking place in Singapore,

and you don't know any of those people,

but nonetheless, somehow that could be a means for you

to feel less content with who you've turned out to be.

Do you take steps in your own life

to actively restrict the contexts

in which you think and live and contemplate

in order to enhance your creative life,

your intellectual life?

Are those steps that you actively take?

- Well, I very actively don't know how to make use

of anything [laughs] with social media.

So I guess that counts as my having thus

actively chosen not to learn how.

So that's the case certainly for the last year and a half,

like lots of people, I've gone through stretches

where I've managed to sort of enforce a moratorium

on looking at the news, and that was wonderfully freeing.

I think in the larger sense though,

in addition to me being a neurobiologist,

I'd sort of spent decades spending part of each year

studying wild baboons out in a national park in East Africa.

And I'd spend three months a year without electricity,

without phone calls, with going 12 hours a day

without saying a word to somebody.

And when I finally would, it would be somebody

nomadic pastoralist guy in a different language.

Yeah, I did 90% of my like insightful thinking

about anything in the laboratory

during those three months each year,

and not one in the lab, and not when inundated with stuff.

- Well, I think there is a shifting trend

towards trying to create a narrowing of context that...

And I like what I see, I have a niece, she's 14-years-old

and she and her friends are very good

at putting their phones away.

They say, we're not going to have our phones

for this interaction, especially after...

And I realized we're still somewhat in this.

It's unclear where it's headed,

but 2020 was so restrictive

and she was so separated from her friends.

Now it's, let's really focus on being together

and not bring in all these other elements from our phones.

And that brings me great hope for

that generation, [laughs] maybe they will...

Or who knows, maybe they'll run off and study baboons,

we need more field researchers.

So along the lines of choice,

I'd like to shift gears slightly

and talk about freewill,

about our ability to make choices at all.

- Well, my personal way out in left field

inflammatory stance is,

I don't think we have a shred of freewill

despite 95% of philosophers.

And I think probably the majority of neuroscientists

are saying that we have freewill

in at least some circumstances.

I don't think there's any at all.

And the reason for this is,

you do something,

you behave, you make a choice, whatever.

And to understand why you did that,

where did that intention come from?

Part of it was due to like the sensory environment

you were in the previous minute.

Some of it is from the hormone levels

in your bloodstream that morning.

Some of it is from whether you had a wonderful

or stressful last three months

and what sort of neuroplasticity happened.

Part of it is what hormone levels

you were exposed to as a fetus.

Part of it is what culture your ancestors came up with,

and thus how you were parented when you were a kid.

All of those are in there,

and you can understand where behavior is coming from

without incorporating all of those.

And at that point,

not only are there all of these relevant factors,

but they're ultimately all one factor.

If you're talking about what evolution

has to do with your behavior,

by definition you're also talking about genetics.

If you're talking about what your genes

have to do with behavior, by definition you're talking about

how your brain was constructed

or what proteins are coded for.

If you're talking about like your mood disorder now,

you're talking about the sense of efficacy

you were getting as a five-year-old.

They're all intertwined.

And when you look at all those influences,

basically like the challenge is,

show me a neuron that just caused that behavior,

or show me a network of neurons

that just caused that behavior.

And show me that nothing about what they just did

was influenced by anything from the sensory environment

one second ago to the evolution of your species.

And there's no space in there to fit in a freewill concept

that winds up being in your brain, but not of your brain.

There's simply no wiggle room for it there.

- So I can appreciate that our behaviors

and our choices are the consequences of a long line

of dominoes that fell prior to that behavior.

But is it possible that I can intervene in

the domino effect, so to speak.

In other words, can my recognition of the fact

that genes have heritability,

there is an epigenome that, there is a hormonal context,

there is a historical context.

Can the knowledge of that give me some

small shard of freewill?

Meaning, does it allow me to say, ah,

okay, I accept that my choices are somewhat predetermined,

and yet knowing that gives me

some additional layer of control?

Is there any philosophical or biological universe

in which that works?

- Nah.

All of that can produce the wonderfully positive belief

that change can happen.

Even a traumatic change, even in the worst of circumstances,

most unlikely people, and change can happen,

things can change.

Don't be fatalistic, don't decide

because we're a mechanistic, biological machines

that nothing can ever...

Change can happen,

but where people go off the rails

is translating that into, we can change ourselves.

We don't, we can't because there's no freewill.

However, we can be changed by circumstance.

And the point of it is,

like you look at an Aplysia, a sea slug

that has learned to retract its gill

in response to a shock on its tail,

you can do like conditioning, Pavlovian conditioning on it,

and it has learned, its behavior has been changed

by its environment.

And you hear news about something like

horrifically depressing going on,

and refugees in wherever.

And as a result, you feel a little bit more helpless

and a less of a sense of efficacy in the world,

and both of your behaviors have been changed.

Okay, okay, yeah, I guess that,

but the remarkable thing is,

it's the exact same neurobiology.

The signal transduction pathways that were happening

in that sea snail incorporate the exact same kinases

and proteases and phosphatases

that we do when you're having mammalian fear conditioning,

or when you're alert, it's conserved.

It's the exact same thing, it's simply playing out

in obviously a much, much fancier domain.

And because you have learned

that change is possible

despite understanding mechanistically

that we can't change ourselves volitionally,

but because you understand change is possible,

you have just changed the ability of your brain

to respond to optimistic stimuli.

And you have changed the ability of your brain

to now send you in the direction of being exposed to

more information that will seem cheerful

rather than depressing.

Oh my God, that's amazing,

what Nelson Mandela and Martin Luther king

and all these folks did.

Wow, under the most adverse of circumstances,

they were able to do.

Maybe I can also, maybe I can go read more

about people like them to get even more data points

of change the neurochemistry,

so that your responses are different now.

And you're tilted a little bit more in that direction

of feeling like you can make a difference

instead of it's all damn hopeless.

So enormous change can happen,

but the last thing that could come out of a view of,

we are nothing more or less than the sum of our biology

and its interactions with environment,

is to throw up your hands and say,

and thus it's no use trying to change anything.

- So we can acknowledge that change is extremely hard

to impossible, that circumstances can change,

and yet that striving to be better human beings

is still a worthwhile endeavor.

Do I have that correct? - Absolutely.

Because simply the knowledge, either from experience

or making it to the end of the right neurobiology class

has taught you that change can happen

within a framework of a mechanistic neurobiology.

You were now more open to being made optimistic

by the good news in the world around you.

You are more likely to be inspired by this or that,

you were more resistant to getting discouraged by bad news,

simply because you now understand it's possible.

- Mm-hmm, yeah, somebody who spent

much of his career working on the hippocampus,

I have to assume that you are a believer in neuroplasticity,

that neural circuits can change in response to experience,

and that some of the same so-called top-down mechanisms

of prefrontal cortex that we were talking about before

can play a role there,

that the decision to try and change

and the pursuit of knowledge and the pursuit of experience

can shape our circuitry,

and therefore make us different machines, so to speak.

- Yeah.

And not only can say prenatal hormone exposure

changed the way your brain is being constructed,

but learning that prenatal hormone exposure

can change the construction of your brain

will change your brain right now,

and how you think about where your intentions came from.

Wow, maybe that had something to do with it.

The knowledge of the knowledge is an effector

in and of itself.

- That's such an important and powerful statement to hear.

I think that many people think that if a tool,

if it doesn't involve a pill or a protocol,

that it's useless.

And certainly there are pills and protocols

that are very useful in a variety of context

for a variety of things, but the idea that knowledge itself,

whereas you put it, knowledge of knowledge is itself a tool,

I think is a very important concept for people

to embed in their minds.

And, listen, I'm so grateful for this discussion

and for you raising these topics.

I think that people,

many people know your work on testosterone, on stress,

and we've covered some of that today,

the work on freewill and this idea that we are hopeless

or that we are in total control.

I think I'm realizing in listening to you

that it's neither is true, and that the solution resides

in understanding more about freewill

and lack of it, [laughs] and also neuroplasticity.

You're working on a book about freewill,

are you willing to tell us a little bit about that book

and where you are in that process

and what we can look forward to?

- Yeah, it's going really slow.

Title is, "Determined: A Science of Life Without Freewill."

And essentially the first half of the book is

trying to convince a reader,

okay, if not that there's no freewill whatsoever,

but at least there's a lot less than is normally assumed.

And I'm going through all the

standard arguments for freewill,

and why that doesn't make sense with 21st century science?

And that has led to reading a lot of very frustrating

philosophers who basically are willing to admit

that stuff is made out of like atoms and molecules.

And like there's a physical reality sort of world,

they're not just relying on magic,

but that they believe in freewill for magical reasons,

and where it doesn't make sense.

Okay, so the first half of the book is to

hopefully convince people that there's much less freewill

than we used to think.

And then the second half is this gigantic juncture

built around the fact that I haven't thought

there's any freewill since I was like an adolescent.

And despite thinking that way,

I still have absolutely no idea

how you're supposed to function with that belief.

How are you supposed to go about everyday life

if anything you feel entitled to isn't true?

If any angers and hatreds you feel aren't justified,

if there's no such thing as appropriate,

blame or punishment or praise or reward,

and none of it makes any sense,

and somebody like even compliments you on your haircut,

and you've been conditioned to say, oh, thanks,

as if you had something to do.

How are we supposed to function with that?

And so the second half is wrestling with that,

and what the punchline there is,

is it's going to be incredibly hard.

And if you think it's going to be hard

to subtract a notion of freewill

out of making sense of like serial murderers,

it's going to be a thousand times harder

making sense of when somebody says "good job" to you.

[Andrew laughs] And because it's the exact

same on reality of sort of our interpretations.

It's going to be incredibly hard,

but nonetheless when you look at the history

of how we have subtracted the notion of agency

out of all sorts of realms of blame, starting with thinking

that witches caused hailstorms 500 years ago

to the notion that psychodynamically screwed up mothers

cause schizophrenia, we've done it.

We've done it endless number of times,

we've been able to subtract out a sense of volition

in understanding how the world works around us.

And we don't have murderers running amuck on the street,

and society hasn't collapsed into a puddle,

and in fact, it's a more humane society.

So the good news is it's possible

because we've done it repeatedly in the past,

but it's going to be hard as hell.

And it's hard as hell to try to write about that coherently,

[laughs] I'm discovering, so it's going slowly.

- Well, I speak for many, many people when I say

that we're really excited for the book when it's done

and we will patiently wait,

but with great excitement for the book, "Determined".

You said it's the title, correct?

- Yeah, "Determined: The Science of Life Without Freewill".

It seems like you can't publish your book these days

without a sub-title, so that's it?

- Fantastic.

Well, very excited to read the book.

I'm very grateful to you for this conversation today,

I learned a ton.

Every time you speak I learn,

and for me it's really been a pleasure

and a delight to interact with you today

and over the previous years, I should say, as colleagues.

And thank you again, Robert, for everything that you do

and all the hard, hard work and thinking

that you put into your work

because it's clear that you put a lot of hard work

and thinking, and we all benefit as a consequence.

- Thanks, and thanks for having me, this was a blast.

- Thank you for joining me for my conversation

with Dr. Robert Sapolsky.

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