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- 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.
This month, we're talking all
about disorders of the mind,
things like depression,
attention deficit disorders,
eating disorders, schizophrenia,
and bipolar disorder.
During the course of this month,
we are going to discuss the psychological
and biological underpinnings
of mood disorders of all kinds.
You'll learn a lot of science.
You'll also learn a lot
about the various treatments
that exist and that are in development
for these various mood disorders.
We will talk about behavioral
tools, things like exercise,
meditation, breath work,
but also prescription drugs,
supplements and novel compounds
that are now being tested
in various clinical trials.
Across the month, I think
you'll start to realize
that there are common pathways
underlying many mood disorders.
In fact, mood disorders
that look quite different
from one another often
depend on the action
of the same neurochemicals
or neural circuits
in the brain and body.
That actually should be
a point of great relief
because what it means is that
by understanding the biology
of one mood disorder or
understanding how one treatment
or behavioral intervention
can impact a mood disorder,
we gain insight into other
mood disorders as well.
As always, we will discuss
science and science related tools
that people could implement
should they choose.
Before we dive into today's topic,
I'd like to discuss a very particular
set of scientific findings
that relate to today's topic,
and that are important for
understanding all mood disorders
and all states of motivation,
happiness, and sadness,
as well as depression.
Basically, I'm going to
paraphrase a brief segment
of my discussion with Dr. Anna Lembke,
who I sat down with to discuss addiction
and the biological basis of addiction
and addiction treatment.
A very important aspect of that discussion
was when Dr. Lembke described
the pleasure pain balance,
literally the circuits in our brains
that control our sense
of pleasure and pain,
and ultimately whether
or not we remain happy
in our pursuit of pleasure or not.
This is an absolutely crucial aspect
to the way that we
function in everyday life,
and especially under
conditions of mood disorders.
The pathway that she was describing
is the so-called pleasure system.
However, what most people don't realize
is that the pleasure system
is also directly associated with,
and in fact is the very same system
that modulates mental or
psychological anguish and pain.
Essentially what she described
is that whenever we pursue something
that we think will bring us pleasure,
and that could be anything that we think
will bring us pleasure from
food, to video games, to sex,
to a particular job or goal,
short-term or long-term,
that we experience release of
the neuromodulator dopamine.
Now, dopamine is associated
with increased levels
of motivation and drive.
It is not the molecule of reward,
it is the molecule of
craving motivation and drive.
However, as Dr. Lembke pointed out,
when we are in pursuit of something,
there is a release of
dopamine in our brain
that makes us feel motivated,
and in general, it makes us feel good.
But very shortly thereafter
and beneath our conscious awareness,
there is a tilt of the pleasure
pain balance in the brain,
literally a shift in the neural circuits
that underlie pleasure and pain,
such that every bit of
pleasure or pleasure seeking
that causes release of dopamine
will be balanced out by
a little bit of pain.
And we don't experience
this as physical pain,
at least not at first,
we experience it as craving for more
of the thing that brought us pleasure.
Now, that sounds pretty good.
You get pleasure and then
you get a little bit of pain
to balance it out.
It's subconscious and you experience it
as the desire to seek out more pleasure.
However, it's actually
more diabolical than that.
And we really need to keep an eye on this
if we are to remain happy,
if we are to remain in
pursuit of our goals.
The crucial thing to
understand is that if we remain
in constant pursuit of pleasure,
the pain side of the balance tips
so that each time we are in pursuit
of that pleasureful thing,
activity, or substance,
we are going to experience,
we literally achieve less dopamine release
each subsequent time.
So we get less pleasure and the
amount of craving increases.
Now, after a certain point or threshold,
we call that addiction.
And the way to reset the balance,
and this is very important,
the way to reset the balance
is actually to enter into states
in which we are not in
pursuit of pleasure,
to literally enter states
in which we are bored,
maybe even a little bored and anxious,
and that resets the pleasure pain balance
so that we can return to
our pursuit of pleasure
in a way that's healthy,
and then in an ongoing way,
won't lead to this over
tipping or this increase
in the amount of pain or addiction.
So this is very important.
And if this seemed vague,
what this means is we
should always be cautious
of any state of mind
or body or any pursuit
that leads to very large
increases in dopamine.
And if it does, we should be very careful
to not pursue that repeatedly over time.
During today's episode, I'm
going to give an example,
a real life example of a
discussion that I've been in
with a young man who's 21 years old
who's dealing with a disruption
in this pleasure pain balance.
He is essentially depressed
and he's depressed
because of his ongoing pursuit
of a particular activity
that initially led to a lot of dopamine,
but over time has led to
less and less dopamine
and more and more of this
pain side of the balance.
We could call him addicted
to that particular activity.
Whether or not he's addicted
by clinical standards or not,
really, isn't important.
What is important is that he
experiences this as depression,
as low affect as it's called or anhedonia,
an inability to experience
pleasure from that thing
or from anything else.
And he's currently undergoing treatment
through a rebalancing of
his pleasure pain pathway.
So while I can't reveal
his identity to you,
that wouldn't be appropriate.
He did give me permission to reveal
the general architecture
of what he's coping with.
And I spent some hours with
him on the phone this week,
talking to him as well
as to the various people
that he's working with
to really understand
what's going on here 'cause
I think it can illustrate
the relationship between
dopamine, pleasure, and pain
for sake of addiction,
but also for understanding how
to avoid depressive states,
how to remove ourselves
from depressive states.
And as you'll see today,
as we discussed depression,
many of the molecules and neural pathways
and biological mechanisms
that we know can be used
to counter depression,
feed back onto this pleasure pain balance.
Before we begin, I'd like
to say 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 about science
and science related tools
to the general public.
In keeping with that theme,
I'd like to thank the
sponsors of today's podcast.
Our first sponsor is InsideTracker.
InsideTracker is a
personalized nutrition platform
that analyzes data from blood and DNA
to help you better understand your body
and help you reach your health goals.
I've long been a believer in
getting regular blood work done
for the simple reason
that many of the factors
that impact our immediate
and long-term health
can only be detected from
a quality blood test.
The problem with most
blood tests, however,
is that you get information
back about hormone levels,
metabolic factors, et cetera,
but you don't really know what
to do with that information.
Some things might be flagged
as too high or too low,
but really interpreting
those data and taking action
to bring those numbers into
the ranges that you want
is what it's really about.
An InsideTracker makes all that very easy.
They have a platform, it's a dashboard
that will tell you for instance,
what sorts of dietary changes
or supplementation changes
or exercise changes will help
you bring various hormones,
metabolic factors, and other
factors into the ranges
that are right for you.
If you'd like to try InsideTracker,
you can go to insidetracker.com/huberman.
And if you do that, you'll get 25% off
any of InsideTracker's plans.
Just use the code "huberman" at checkout.
Today's episode is also brought
to us by Athletic Greens.
Athletic Greens is an
all-in-one vitamin mineral
probiotic drink.
I've been using athletic
greens since way back in 2012.
And so I'm delighted that
they're sponsoring the podcast.
The reason I started
taking Athletic Greens
and that I still take Athletic Greens
is that it really covers
all of my foundational
nutrient and micronutrient needs.
It has vitamins, minerals,
and the thing that's especially
important to me these days
is the probiotics,
because there are so many data
that show that having a
healthy gut microbiome
is vital to having a healthy immune system
and for healthy gut brain axis,
literally the functioning
of your brain, your mood,
various aspects of brain inflammation
or limiting brain
inflammation are facilitated
by having a healthy gut microbiome.
And that's facilitated by
getting the proper probiotics.
If you'd like to try Athletic Greens,
you can go to athleticgreens.com/huberman.
And if you do that, you can
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The special offer is
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Vitamin D3K2 have been shown
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Again, that's athleticgreens.com/huberman
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Today's episode is also
brought to us by Belcampo.
Belcampo is a regenerative
farm in Northern California
that raises organic,
grass fed, and finished
certified humane meats.
I don't need a lot of meat.
Typically my diet regime
is one in which I fast
until about noon,
and then I have a lunch
which is fairly low carbs.
So I'll have some piece
of meat or chicken or fish
and some salad typically.
And then in the evening is when I tend
to emphasize carbohydrates.
That helps me be really
alert during the day
and sleep well at night.
When I do eat meat, I insist that the meat
be of the very highest quality
and that it is sourced in humane ways.
Belcampo's animals graze on open pastures
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and that results in meat
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There are now a lot of
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that high levels of omega-3
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for cardiovascular health
and various aspects
of maintaining what's called
a healthy Inflammatone,
the various things in our brain and body
that maintain a healthy
inflammation response,
but one that doesn't go out
of whack or get unchecked
in any way that is detrimental to us.
If you'd like to try
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Today we're discussing depression.
In particular, we're going to
talk about major depression.
The phrase major depression
is used to distinguish
one form of depression from the other,
the other one being bipolar depression.
Bipolar depression, sometimes
called bipolar disorder,
is really characterized by manic highs.
So where people aren't sleeping
and they're talking very fast,
and they're buying things
and pursuing resources
that they can't afford,
they're starting
relationships left and right,
they're manic,
followed by periods of
crashes of feeling very low,
lethargic, and so on.
Bipolar depression is an
absolutely crucial thing
for us to discuss.
And therefore we are
going to have an entire
separate episode related
to bipolar depression.
Today, we're going to talk
about major depression,
also sometimes called unipolar depression,
just because it doesn't
have the highs and lows.
It's more characterized by the lows.
We're going to talk about the biology,
the psychology, and
the various treatments,
behavioral, drug,
supplementation, diet, exercise,
all of that.
Before we go forward into the material,
I just want to emphasize
that any discussion
about mood disorders carries with it
a particular sensitivity,
and that sensitivity is one
related to self-diagnosis.
Today's episode, and indeed
in the future episodes
for this month on mood disorders,
you're going to hear various
symptomologies that are used
to diagnose and characterize
these disorders.
If you recognize some of these
symptomologies in yourself
or in others that you know,
that's an important thing to take note of.
However, accurate diagnosis
really should be done
by a qualified healthcare professional.
So at once I'm saying, keep
your eyes and your ears up
for things that sound familiar to you
that might be of concern.
And at the same time,
I'm saying don't necessarily
leap to conclusions.
Take those flags of
concern if they're there
and bring them to a qualified
healthcare professional,
and they'll be able to
properly diagnose you
as having a particular mood
disorder or diagnose somebody
as having a particular
mood disorder or not.
And that's an essential step.
I don't say this to protect us,
I said this really to protect you.
Okay, let's have a fact-based
discussion about depression.
And I promise you that where
we don't know certain things
about depression, I will
be clear to tell you.
In fact, we are going to
talk about some treatments
for depression that are
looking very promising,
and that right now are actually
being used more and more.
And from my read of the
mechanistic literature,
we're still a bit in the
dark as to how these work.
That's actually a common
theme of medicine.
Many times there are
treatments that seem promising
or that look really terrific.
And there isn't a lot of
understanding about mechanism.
However, any good discussion
about neuroscience
and in particular about mood disorders,
has to get into mechanisms.
So we're going to do that.
And in doing that, we're
going to frame the discussion
for the tools of how to
keep depression at bay
and how to deal with it
if you happen to find yourself depressed,
or if you know somebody
else who's depressed.
What is this thing we call depression?
Was I mentioned before, it has two forms,
bipolar depression, which
we're not talking about today,
and major depression, also
called unipolar depression
is the other.
Major depression impacts
5% of the population.
That is any enormous number.
That means if you're in
a class of 100 people,
five of them are dealing
with major depression
or have at some point.
Look around you in any environment
and you can be sure that a
good portion of the people
that you're surrounded by
is impacted by depression,
or will be at some point.
So this is something we
really have to take seriously
and that we want to understand.
It is the number four cause of disability.
A lot of people miss work, miss school,
and before then likely perform
poorly in work or school
due to major depression.
Now there's a very serious
challenge in having a discussion
about depression and it relates
directly to the challenges
in diagnosing depression.
Earlier, I did an episode
with Dr. Karl Deisseroth,
who is indeed a medical doctor and a PhD.
He's a psychiatrist.
And he made a very important point,
which is that the field of
psychiatry and psychology
are confronted with a challenge,
which is they're trying to
understand what's going on
within the stuff that's in our brains
that's deep to our skulls.
We don't have access to
that without brain imaging
and electrodes and things like that.
Someone just comes into the
office and the dissection tool
for depression so to speak is language.
In order to determine if
somebody has depression or not,
we have to use language,
how they talk about things,
also how they carry their body.
Also some general patterns of health.
So let's talk about depression
the way that clinicians
talk about depression,
because one of the issues is that
we use the word depression loosely.
A lot of people say,
"Oh, I'm so depressed.
"I didn't get this job
or I'm so depressed.
"I just don't know, I
had a really rough week
"or I'm exhausted.
"I'm so depressed or I'm so depressed
"I thought I was going to go on vacation
"and then they canceled the flight." Okay.
That is not clinical depression.
That's called being bummed
out, being sad or disappointed.
Now that person might be depressed,
but clinical depression
actually has some very specific criteria.
And those criteria are
mainly characterized
by the presence of certain things
and the absence of a
few particular things.
So let's talk about the
things that are present
in somebody that has major depression.
First of all, there tends
to be a lot of grief.
There tends to be a lot of sadness.
That's no surprise.
The threshold to cry is often
a signature of depression.
Now that doesn't mean
that if you cry easily,
that you're depressed.
Some people cry more easily than others,
but if you're somebody who
typically didn't cry easily
and suddenly you find
yourself crying very easily,
that could be a sign of depression.
And I want to emphasize, could.
There's also this thing
that we call anhedonia,
a general lack of ability to enjoy things,
things that typically or
previously we enjoyed.
Things like food, things like
sex, things like exercise,
things like social gatherings,
a kind of lack of enjoyment
from those things.
Sometimes that lack of enjoyment is sad,
and sometimes it's just flat,
it's just kind of neutral.
It doesn't feel good
because nothing there.
It's like bland food.
It's like these experiences are analogous
to biting into your
favorite article of food
and it just not tasting very good.
It just doesn't taste
like anything at all.
And that's a common symptom
of major depression.
The other one is guilt.
Oftentimes people with
depression will feel very guilty
about things they have done in the past,
or they'll just generally
feel badly about themselves.
And we're going to talk
about this because it relates
to some of the more serious symptomology
seen in depression sometimes,
things like self harm,
mutilation, or even suicide.
But for the time being, we
want to frame up anhedonia,
this lack of ability to
achieve or experience pleasure,
or kind of a flat affect as it's called.
Sometimes even delusional thinking,
negative delusional thinking,
and in particular anti-self confabulation.
What is anti-self confabulation?
Well, first of all, confabulation
is an incredible aspect
of our mind and our nervous system.
You sometimes see other
forms of confabulation
in people who have memory deficits
either because they have brain damage
or they have age-related dementia.
A good example of this would be someone
with age related dementia
sometimes will find themselves
in a location in the house and
not know how they got there.
And if you ask them, "Oh,
what are you doing here?"
They will create these elaborate stories.
"Oh, I was thinking about
going to the shopping today,
"and I was going to take the bus,
"and then I was going to do this."
They create these elaborate
stories, they confabulate.
And yet that person hasn't
left the house in weeks
and that person doesn't
have a driver's license.
And so they're really
just creating this stuff.
They're not lying to get out of anything,
they're confabulating.
It's as if a brain circuit
that writes stories,
just starts generating content.
In major depression,
there's often a state of
delusional anti-self confabulation,
where the confabulation are not directly
or completely linked to reality,
but they are ones that make the self,
the person describing them,
seem sick or in some way not well.
A good example would be somebody
who experiences a physical injury perhaps.
Maybe they break their
ankle, maybe it's an athlete,
and they also happen to become depressed.
And you'll talk to them and
say, "How are things going?
"How's your rehab though?"
And they go, "Oh, it's
okay. And I don't know.
"I feel like I'm getting
weaker and weaker by the day.
"I'm just not performing well."
And then you'll talk to the person
that they're working with,
their kinesiologist or whoever
the physical therapist is.
And they'll say, "No, they're
actually really improving.
"And I tell them they're improving,
"but somehow they're not
seeing that improvement,
"they're not registering
that improvement."
You notice that sometimes it's subtle
and sometimes it's severe, but
they'll start confabulating.
You'll say, "I actually heard
you're doing much better.
"You're getting better,
you're taking multiple trips
"around the building now
"before you could barely get out of bed."
And they'll say,
"Yeah, well basically,
they changed some things
"about the parking lot that
make it easier to move around.
"So it's not really me."
And these aren't people that
are just explaining away
their accomplishments
'cause they're trying to brush off praise.
They are viewing themselves
and they're confabulating
according to a view
that is very self-deprecating
to the point where it doesn't
match up with reality.
It's not what other people see
and it's actually not
matched up with reality.
And that's a symptom of depression
that I think we don't often think about
or conceptualize enough.
So it's not just telling people,
"oh yeah, it's not as good as
it seems. Everything's bad."
These people really believe that
and it becomes disconnected from reality.
So it's if they're sort
of sinking into a pit
and they're losing touch with
the realities of the world,
including data about themselves,
their ability to move and get around it,
for example, in that particular instance
that I used as an example,
but there are others as well.
The other common symptomology
of major depression
is what they call
vegetative symptoms, okay?
So vegetative symptoms
are symptoms that occur
without any thinking, without any doing,
or without any confabulation.
These are things that are
related to our core physiology.
The word vegetative,
you might know it sounds like vegetable.
It actually relates to
a system in the body
that nowadays is more commonly called
the autonomic nervous system.
The vegetative nervous system
and the autonomic nervous system,
historically were considered
sort of one in the same.
And it relates to things
like the stress response
or to our ability to sleep.
So vegetative symptoms
be things like constantly being exhausted.
The person just feels exhausted.
It's not because they exercise too much,
it's not necessarily because
of a life event, it could be,
but they're just worn out.
They don't have the energy they once had.
So it's not in their heads, it's probably,
and now I think we have good
data to support the fact
that there's something off,
something is disrupted in the autonomic
or so-called vegetative nervous system.
And one of the most common symptoms
of people with major depression,
one of the signs of major
depression is early waking
and not being able to fall back asleep
despite being exhausted.
So waking up at 3:00 AM
or 4:00 AM or 5:00 AM
just spontaneously and not
being able to go back to sleep.
I want to emphasize that that could happen
for other reasons as well,
but it is a common symptom
or warning sign of major depression.
So let's talk more about
sleep and depression.
It's well-known that the
architecture of sleep
is disrupted in depression.
What's the architecture of sleep?
I've done entire episodes about this,
but very briefly in two sentences,
although they're probably
be run on sentences,
early in the night,
you tend to have slow wave
sleep more than REM sleep
or Rapid Eye Movement sleep.
As the night goes on,
you tend to have more
Rapid Eye Movement sleep.
That architecture of slow wave sleep
preceding Rapid Eye Movement sleep
is radically disrupted
in major depression.
In addition, the pattern
of activity in the brain
during particular phases
of sleep is disrupted.
Now this is during sleep.
So this can't be that people
are creating this
situation for themselves.
These are real physiological
signs that something is off
in this so-called autonomic
or vegetative nervous system.
And then there are some
other things that relate
to the autonomic nervous system,
but that we normally think of
as more voluntary in nature.
And these are things
like decreased appetite.
So you can imagine that one
could have decreased appetite
because of the anhedonia,
the lack of pleasure from food, right?
If you don't enjoy food,
then you might be less
motivated to eat it.
That makes sense.
As well because of these disruptions
in the autonomic nervous system,
these vegetative symptoms,
as they're called,
you can imagine that someone
would have decreased appetite
because some of the hormones
associated with appetite,
hypocretin orexin and things
of that sort, ghrelin,
that those will be disrupted.
And if those names of
hypocretin orexin and ghrelin
don't make any sense to
you, don't worry about it.
What those are just hormones
that impact when we eat,
when we feel hungry, and
when we crave food more,
as well as when we feel full,
we have enough so-called satiety.
If you want to learn more about those,
we did entire episodes
on eating and metabolism.
So you can see that the
symptomology of major depression
impacts us at multiple levels.
There's the conscious level of
how excited we are generally.
Well, that's reduced.
There's grief, there's
guilt, there's crying,
but then there's also
these vegetative things.
There's disruptions in sleep,
which of course make
everything more challenging
when we're awake.
We know that sleep is
so vital for resetting.
You're waking up early, you
can't get back to sleep.
That's going to adjust your affect,
your emotions in negative ways.
We know this.
And appetite is off.
And there are hormones that get disrupted.
So cortisol levels are increased.
In particular, there's a
signature pattern of depression
whereby cortisol, the
stress hormone that normally
is released in a healthy way
only in the early part of the day
is shifted to late in the day.
In fact, a 9:00 PM peak in cortisol
is one of the physiological signatures
of depressive like states.
It's not the only one, but
it is an important one.
So there are a lot of things
going on in major depression.
And by now you're probably thinking,
goodness, this is dreadful.
Like there's all this terrible stuff.
And indeed it is terrible.
It is a terrible thing to find oneself
in a mode where things
feel sad, you feel guilty,
you're exhausted.
And oftentimes there's also an association
with the anxiety system.
So just because people are exhausted
and lethargic and they don't enjoy things,
doesn't necessarily mean that
there's an absence of anxiety.
There can also be a lot of anxiety
about what's going to happen to me.
Am I going to be able to
achieve my goals in life?
Will I ever get out of this state?
And so things really start to layer on.
And if this sounds depressing to you,
it is indeed depressing.
This is really the place that
many people find themselves.
And it's a pit that they just don't know
how to climb out of.
So let's just take a few minutes
and talk about some of
the underlying biology
that creates this cloud
or this constellation
of symptomology.
I think that's really important to do
because if we want to understand
the various treatments,
how they work and why they
work and how to implement them,
we have to understand some
of the underlying biology.
So let's spend a few minutes
talking about the biology of depression,
what's known and what's not known.
Because in doing that,
I think you'll get a much clearer picture
about why certain tools
work to relieve depression
and why others might not.
So one of the most
important early findings
in the search for a
biological basis of depression
was this finding that there are drugs
that relieve some of the
symptoms of depression.
Those drugs generally fall
into three major categories,
but the first set of
ones that were discovered
were the so-called
tricyclic antidepressants,
and the MAO inhibitors, the
monoamine oxidase inhibitors.
You don't need to understand
that nomenclature,
but I'm going to give you
a little bit of detail
so that if you want to
understand it, you can.
Most of this work took
place in the late 1950s