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.
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 that in an ongoing way won’t lead to this overtipping
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 this 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,
because 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 discuss 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.
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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 drugs,
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 say 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 mechanism, 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?
Well, as 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 an 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, you know, I’m so depressed.
I didn’t get this job, or I’m so depressed.
I just, I 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 there’s 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,
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, you know, I was thinking about going to the shopping
today and I was, you know, and I was going to take the bus
and then I was going to do,
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.
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 confabulations 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, you say, how are things going?
How’s your rehab?
And they’ll go, oh, it’s okay.
And I don’t know, I’m just,
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,
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
because they’re trying to brush off praise.
They are viewing themselves and they are 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.
For example, in the 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 a.m. or 4 a.m. or 5 a.m.
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 there’ll 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
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 could imagine that one could have decreased appetite
because of the anhedonia, the lack of pleasure from food.
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,
hypocretinorexin and things of that sort,
ghrelin, that those would be disrupted.
And if those names of hypocretinorexin 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 read, 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, this 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 p.m. 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,
oh 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, 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
and in the 1960s and continued well until the 1980s
when new classes of drugs were discovered.
And these tricyclic antidepressants and the MAO inhibitors
largely worked by increasing levels of norepinephrine
in the brain, as well as in the body in some cases.
And they were discovered through a kind of
odd set of circumstances.
We don’t have time to go into all the history,
but suffice to say that they were discovered
because of the exploration for drugs
that alter blood pressure.
Norepinephrine impacts blood pressure
and drugs that lower blood pressure
reduce levels of norepinephrine.
And that in many cases was shown to lead to depression
or depressive-like symptoms.
And so these drugs, these tricyclic drugs
and the MAO inhibitors actually increased norepinephrine
and frankly, they do quite a good job of relieving some,
if not all of the symptoms of major depression.
However, they carry with them many side effects.
Some of those side effects are side effects
related to blood pressure itself
by increasing noradrenaline, norepinephrine as it’s called,
you raise blood pressure.
That can be dangerous.
That can be uncomfortable,
but they also have a lot of other side effects.
The reason they have other side effects
is because they impact systems in the brain
and in the body that impact things like libido,
appetite, digestion, and others.
And we’ll talk about each of those in sequence.
Okay, so the experience that clinicians had
of observing some relief for depression
with the tricyclic antidepressants
and with MAO inhibitors was terrific,
but there were all these side effects.
Side effects that people really did not like.
They didn’t like these drugs at all.
A lot of people get dry mouth.
I mentioned the low libido.
They’d have sleep issues, appetite issues,
They made some people so uncomfortable
that they preferred not to take them,
even though when they didn’t take them,
they had a worsening or a maintenance
of their depressive symptoms.
A decade or so later,
there was the discovery
of the so-called pleasure pathways in the brain.
These are pathways, literally groups of neurons
that reside in different locations in the brain,
but connect to one another.
So it’s a circuit.
And when you stimulate these neurons
with certain behaviors
or with electrical stimulation in an experiment,
believe it or not,
that’s been done in both animals and humans.
Animals and humans become very, very motivated
to get more stimulation of these pathways.
So this pleasure pathway
or these circuits for pleasure
are very what we call reinforcing.
In fact, animals and humans will work hard
to get stimulation of these brain areas
even more than they will work to obtain sex, drugs,
or even if they are addicted to a particular drug
and they are in a state of withdrawal,
the ultimate state of craving.
If given a choice, a person or an animal
will select to have stimulation of this pleasure pathway
instead of the drug itself.
And that is a major and significant finding.
This pleasure pathway, as it’s sometimes called,
involves areas like the nucleus accumbens
and the ventral tegmental area.
These are areas of the brain
that are rich with neurons that make dopamine.
And if you think to the symptoms of depression,
of anhedonia, a lack of pleasure,
a lack of ability to experience pleasure,
well, that was a smoking gun
that there’s something wrong
with the dopamine pathway in depression.
And indeed that’s the case.
So it’s not just norepinephrine,
it’s also the dopamine or pleasure pathway
is somehow disrupted.
And then in the 1980s,
there was the discovery of the so-called SSRIs.
Most people are now familiar with the SSRIs,
the Selective Serotonin Reuptake Inhibitors.
The SSRIs worked by distinct mechanisms
from the tricyclic antidepressants and the MAO inhibitors.
As their name suggests, SSRIs,
Selective Serotonin Reuptake Inhibitors,
prevent serotonin from being wiped up from the synapse
after two neurons talk to one another.
What do I mean by that?
Well, here’s some very basic neurobiology 101.
If you don’t know any neurobiology,
you’re going to know some in about 15 seconds.
Neurons communicate with one another
by spitting out chemicals into the little gap between them.
The little gap between them is called the synapse
or by the Brits, the synapse.
Those chemicals bind to the neuron on the opposite side
and cause changes in the electrical activity
of that neuron on the other side of the synapse.
Serotonin is one such neurotransmitter
or more specifically, it’s a neuromodulator.
It can change the activity of large groups of neurons
in very meaningful ways.
Selective Serotonin Reuptake Inhibitor
means when a person takes this drug,
some of those drugs include things like Prozac or Zoloft,
the more typical names or more generic names
are things like fluoxetine.
When people take those,
more serotonin hangs out in the synapse
and is able to be taken up by the neuron on the opposite side
because of this selective reuptake inhibition.
It prevents the clearance of serotonin from the synapse
and thereby more serotonin can have an effect.
So SSRIs don’t increase the total amount of serotonin
in the brain.
They change how effective the serotonin
that’s already in the brain
is at changing the activity of neurons, okay?
So they don’t increase serotonin,
they increase the efficacy or the function of serotonin
in the way that I just described.
So that was more than 15 seconds,
but now you understand how SSRIs work.
And I wouldn’t be talking about SSRIs
if they didn’t in fact work.
Yes, there are many problems with SSRIs.
They do carry certain side effects in many individuals.
Also, about a third of people that take SSRIs
don’t derive any benefit.
It doesn’t relieve their symptoms of depression.
However, for the other two thirds,
there’s often a relief of some,
if not all of the symptoms of major depression.
The problem is the side effects that accompany those SSRIs.
And so these days SSRIs are a complicated topic.
It’s sort of what I would call a barbed wire topic
because we often hear about all the problems with them,
but these drugs also have saved a lot of lives.
They’ve also improved a lot of lives.
The issue is that they tend to have varying effects
on different individuals
and sometimes varying effects over time.
So they’ll work for a while,
then they won’t work for a while.
There are also a lot of mysteries about the SSRIs.
And those mysteries bother people.
What mysteries am I referring to?
Well, SSRIs increase the amount of serotonin
or more specifically,
they increase the efficacy of serotonin at the synapse.
That happens immediately
or very soon after people start taking SSRIs,
but people generally don’t start experiencing any relief
from their symptoms of depression
if they’re going to experience them at all
until about two weeks after they start taking these drugs.
So there’s something going on there that’s not clear.
One idea is that the SSRIs
actually can improve symptoms of depression
or even remove symptoms of depression
through so-called neuroplasticity
by changing the way that neural circuits function.
And there are many studies on this,
but the main categories of studies on SSRIs
that relate to neuroplasticity fall into two camps.
One is the ways in which SSRIs might,
and I want to emphasize might,
be able to trigger the production of more neurons
in the brain, in particular areas of the hippocampus
called the dentate gyrus and others that impact memory.
This is important.
We’re going to come back to memory.
The other is that the SSRIs have been shown
in various scientific studies
to reopen critical periods of plasticity.
I’ll just briefly describe one of those studies.
It was a study done by Lamberto Maffei’s group in Pisa
that explored brain plasticity
that’s known to be present in young animals
and disappear in older animals.
And this is also true in humans.
Younger humans have a far more plastic brain.
It can change in many more ways,
more easily than can the older brain.
And what they showed was that fluoxetine, Prozac,
given to adult animals
can reopen this incredible period of plasticity,
can allow more plasticity to occur.
That was interesting.
I mean, it’s purely through increases
in serotonin transmission.
And there are other studies showing
that fluoxetine can increase the number of new neurons
that are born into the adult brain,
so-called neurogenesis, the production of new neurons.
So it’s very clear that there are at least
three major chemical systems in the brain,
norepinephrine, dopamine, and serotonin
that relate to and can adjust the symptoms of depression.
And those actually can be divided into separate categories.
So for instance, epinephrine or norepinephrine
is thought to relate to the so-called psychomotor defects,
sometimes called psychomotor retardation.
This is the lethargy.
This is the exhaustion.
This is the inability to get out of bed in the morning.
Dopamine is thought to relate to the anhedonia,
or I should say lack of dopamine in depressive patients
is thought to lead to the anhedonia,
the lack of ability to experience pleasure.
And serotonin is thought to relate to the grief, the guilt,
some of the more cognitive
or more emotional aspects of depression.
So we’ve got the norepinephrine system
related to activity and alertness,
the dopamine system relating to motivation, pleasure,
and the ability to seek and experience pleasure,
and then the serotonin system that’s related to grief.
And unfortunately, brains and organisms don’t work
in a simple mathematical way where you just say,
oh, well, this person’s experiencing a lot of grief,
but they don’t have any problems with lethargy,
and so let’s just boost up their serotonin.
On paper, it works,
but oftentimes it doesn’t work clinically.
And in another patient,
you might get somebody who can’t experience pleasure,
but they’re kind of anxious.
They don’t have any trouble sleeping,
but they’re just much more anxious
and frustrated than they normally are,
and they meet the symptoms of depression.
Well, you might think, oh, well,
you just give that person some drug to increase dopamine
and everything will be better,
and indeed, in some cases, that’s true.
There are drugs like Welbutrin,
which function more specifically on the dopamine system
to increase dopamine,
and they also increase norepinephrine.
Many people get great relief from things like Welbutrin.
They don’t really impact the serotonin system so much,
and therefore you don’t get a lot of the serotonergic
or serotonin-related side effects.
However, some people feel far too anxious on those drugs.
Some people get addicted to those drugs in a way
because a lot of those drugs that increase dopamine
make you want more of those drugs.
So you start to realize that what makes sense on paper
doesn’t always make sense clinically,
and this is why it’s complicated,
and a really good psychologist
and a really good psychiatrist
will work with someone to try and pull and push
on these various systems to find the combination of drugs
that may be or may not be correct for them.
There’s a fourth aspect of the chemistry of depression
that’s really important to understand, and that’s pain.
We’ve talked about pain on this podcast before,
but even if you didn’t hear the episode on pleasure and pain,
I just want to emphasize that pain is something
that we experience in our body, no surprise there,
an injury, a cut, et cetera,
but that we also experience emotional pain,
and those systems are linked in very intricate ways.
There’s actually some data showing that pain relievers,
Tylenol, aspirin, these sorts of things,
can help certain people with emotional pain.
Now, I’m not recommending people run out
and take those things for emotional pain,
but actually, if you think about that,
it shouldn’t come as any surprise,
given the enormous number of people that take painkillers,
opioids, and things like them,
to try and relieve their psychological pain,
and as we know, those drugs are very, very problematic
for many individuals.
They can help certain individuals,
but they are very prone to abuse,
and they can induce addiction very easily
in a number of people.
There’s a substance that’s literally called substance P,
the letter P, that’s manufactured by neurons
in our brain and body,
which underlies our sensation of pain,
and indeed, substance P inhibitors have been used
to treat depression, and in some cases, works.
A lot of people with depression are hypersensitive to pain,
and of course, they could have multiple things going on.
They could have chronic pain or chronic injury
and major depression.
So you start to get the constellation
of the many things that could happen.
So that’s all I want to say today
about the chemistry underlying depression
or major depression.
There’s a lot more there,
but I think if you understand the norepinephrine system
and that it relates to some of these things like lethargy,
the psychomotor defects, as they’re called,
dopamine and how it relates to motivation
and lack of motivation and lack of dopamine in depression,
and serotonin and its relationship to grief,
and that low serotonin can lead to extreme grief and shame,
and higher serotonin levels can sometimes restore
a sense of wellbeing and safety
and feeling good about oneself.
If you understand that and you understand
that physical pain is somehow involved in certain cases,
I think you will know more about depression
and its underlying chemistry than most all people out there.
And if you’d like to learn more,
I invite you to pursue searching those terms
further on the internet,
and we’ll certainly go into them in more depth,
but that really sets the stage for where we’re headed next.
So next, I’d like to talk about hormones
and how they relate to depression.
And I’d also like to talk about stress
and how it relates to depression,
as well as talk about some of the genetics
or the predispositions to depression.
And for those of you that are thinking,
hey, I want the tools, I want to know how to fix depression,
I understand the desire for that.
I will just ask if you hang in here with me
a little bit longer,
not only will you learn a lot more
about how this complicated mood disorder works,
some of the more interesting things about it,
but it will also position you to get a lot more
out of the tools that we will describe.
You always have the option to skip forward, of course,
but I think it’s important to understand
some of the hormonal and stress-related aspects
So let’s talk about hormones.
20% of people that have major depression
have low thyroid hormone.
Thyroid hormone is related to metabolism.
Oftentimes we think about thyroid as only related to,
you know, having a fast metabolism,
but thyroid is related to all forms of metabolism,
including our ability to synthesize new tissues
like protein and repair injuries.
I did a whole episode on thyroid and growth hormone.
If you want to check that out,
all of that is archived at hubermanlab.com.
It’s all timestamped, et cetera.
You can find on YouTube, Apple, Spotify, all those places.
So if you’re curious about thyroid hormone
and growth hormone,
and you want to do the deep dive on those,
and you want to learn how to alter their levels
using various approaches, check that out.
But 20% of people with major depression are hypothyroidal.
They don’t make enough thyroid,
and that leads to low energy,
low metabolism in the brain and body.
And there’s a condition called Hashimoto’s,
which is essentially low thyroid output.
And again, I don’t want to get into
all the tools related to thyroid.
Sometimes a psychiatrist will prescribe thyroid medication
to increase thyroid output in people that are depressed,
and that will work to relieve the symptoms.
So there isn’t necessarily a direct problem
with serotonin, dopamine, and norepinephrine
or substance abuse.
Sometimes it’s a thyroid problem.
So there are certain situations or conditions
that can impact the thyroid hormone system
and make people more susceptible to depression
or make a preexisting depression worse.
And those are things like childbirth.
So it’s well-known that women who give birth
can often undergo what’s called postpartum depression.
It actually comes from the word post-partuition depression.
They give birth, what’s happier,
what’s more joyful than the birth of a new healthy child,
and they will lapse into a depression,
and that’s thought to be hormonally related.
Either directly to the thyroid system
or perhaps to the cortisol system as well.
We’ll talk about cortisol in a moment.
As well, women during certain phases
of their menstrual cycle experience symptoms
that are very much like clinical depression
and oftentimes are diagnosed
with clinical depression appropriately.
And of course, the menstrual cycle is associated
with shifts in hormone levels.
As well, menopause and post-menopausal women
are more susceptible to major depression
regardless of whether or not
they’ve had that major depression earlier in their life.
So these are things to be on the lookout for
and to definitely talk to a doctor
and get a blood panel that hopefully includes measures
of thyroid hormone and cortisol hormone.
Why cortisol hormone?
Well, more stress is correlated with more bouts
of major depression across the lifespan.
How many bouts?
Well, it turns out that as you go from having one
to two to three, well, when you hit four to five bouts
of really intense to stressful episodes in life,
these tend to be long-term stressful episodes,
your risk for major depression goes way up.
So whether or not you have a genetic predisposition
to depression or not,
one of the best things you can do
to try and avoid getting depressed
is to learn to control your stress system,
to not go from short-term stress,
which everybody experiences,
we all have short-term stressors,
to medium-term stress, to long-term stress,
and to not have too many bouts of long-term stress
because that probability of getting depressed
goes way, way up.
And this is something I’ve seen over and over again,
not just in my scientific career, but just throughout life,
people in all sorts of domains, young and old,
I’ve seen that people will go
through a very intense relationship, a breakup,
sometimes it’s the staying together that’s stressful,
sometimes it’s a graduate school that can be stressful,
sometimes it’s some other event,
and then some months later, they become depressed.
And that’s because the stress system is associated
with the release of cortisol.
The cortisol system can dramatically impact
the way that these different neuromodulators,
dopamine, norepinephrine, and serotonin function.
And so there’s this kind of latent
or longer lasting impact on the systems
that impact mood and wellbeing.
So learning how to control your stress is really key.
If you’re not depressed,
or you’re somebody that has not lapsed
into a depression recently,
take control of your stress system.
And we did an entire episode on how to conquer stress,
and that involves dealing with stress in the short-term,
in the medium-term, and in the long-term.
And there are a lot of different ways to do that.
One of the more important reasons
for learning how to counter stress
in order to offset depression
is that there is a genetic predisposition
that certain people carry to become depressed.
There are these studies now
of many, many thousands of individuals.
These were mainly done in New Zealand,
but these studies have now been done elsewhere,
looking at many tens of thousands of individuals
who carry particular copies of genes,
what they call polymorphisms,
in particular of a gene called 5-HTT-LPR,
which is a serotonin transporter.
So this is a gene that controls or regulates
how much serotonin is available in the brain.
If you have this gene, this polymorphism,
it doesn’t necessarily mean that you will be depressed,
but it greatly shifts your susceptibility
to depression under conditions of stress.
So I realize some people are listening to this,
and some people are watching it on YouTube.
So I’m going to describe this in a way
that doesn’t require looking at any graphs.
What I want you to imagine is a very shallow hill,
like a very mellow hill.
It’s just a ramp set at about 10 or 15 degrees, okay?
What we’re plotting there in your mind
is that with each bout of serious stress,
so that could be trying to finish a degree
or a relationship breakup or a family member that’s sick
or the loss of a loved one or a pet,
with each bout of stress,
the probability that you will experience
a major depression goes up.
However, if you carry this gene, this HTT-LPR gene,
the steepness of that curve goes way, way up,
or it’s actually more like a line,
such that you need far fewer bouts of stress
in order to lapse into a major depression, okay?
So if the typical person who doesn’t carry this polymorphism
has to experience two or three or four or five bouts
of stress before they lapse into a depression,
somebody with this gene is susceptible
to getting depression after just one bout
or two bouts of intense stress, okay?
So that’s how these genes work.
They don’t preordain or determine you to be depressed.
They raise a susceptibility.
And many genes, many things related to heritability
in general work in that way.
And we know there’s a strong genetic component
How do we know?
Well, in what are called concordant monozygotic twins.
So these will be identical twins,
and they can either be in one biological sac
or two biological sacs while in utero.
What’s called monochorionic or dichorionic.
Well, typically it’s monochorionic and identical twins
for which one of those twins goes on
to have major depression,
there’s a 50% probability that the other one
will have major depression.
So it’s not 100%.
It’s not 100% inherited.
It’s not 100% genetic, as you might say,
but there’s a much higher predisposition for depression.
Whereas in fraternal twins, that number drops.
And in siblings, that number drops to about 25%.
And in half siblings, it’s about 10%.
The numbers vary from study to study.
But basically the more closely related you are
to somebody who has major depression,
the more likely it is that you will also
get major depression.
And therefore, if you haven’t gotten major depression,
the more likely it is that you should take steps
to learn to mitigate stress,
because stress is the major factor that can trigger
one of these depressive episodes.
Okay, so we’ve covered a lot related to the stress
and the hormones and the neurochemistry of depression.
In fact, I think this is probably the deepest
I’ve ever gone into the biology of any topic
on this podcast before getting to any specific tools.
I mentioned that learning how to mitigate stress
and deal with stress, learning how to measure
and adjust your thyroid hormone, those might be useful.
But next I’d like to turn to some very specific tools
that people who both have depression
or who are prone to depression,
as well as people who don’t have depression
and simply want to maintain a good mood,
who want to maintain a positive affect
and pursuit of things in life.
What are the things that you can do?
Turns out there are things that you can do.
And all of the biology that underlies the utility
of those things, meaning the reasons those things work
will now make sense to you,
because they adjust things like serotonin and dopamine,
and they adjust them through very specific pathways.
I know for many people learning about mechanism
is kind of grueling.
I realized this podcast isn’t necessarily one
that you can listen to passively while doing other things.
Although I would hope that you could do that
and still enjoy it and extract the information.
Mechanism is so key because mechanism is a little bit
like understanding some of the chemistry of cooking.
If you read a recipe and you can follow a recipe,
you often hear people say, oh, I can follow a recipe.
That means that if you have every ingredient
in that recipe, you’re good.
You likely can make that dish.
You can make that meal.
However, if you understand a little bit of the chemistry
of why salt has to be added third and not first,
or why the heat has to be adjusted at a particular time,
well, then not only can you follow a recipe,
but that also gives you flexibility
for when salt isn’t available,
or when you want to adjust the flavor of the dish,
or when you want to try a new dish
or you want to get experimental.
So when you understand mechanism,
it puts you in a tremendous place of power
to work with your system.
So it’s not just plug and chug,
like take 12 milligrams of this,
you either feel better or you don’t.
You can really start to understand how prescription drugs,
supplements, nutrition, behavioral tools,
how those things weave together
to either work for you or not work for you
and get you to paths of healthy mind and body.
So let’s think about why any tool would work
to relieve depression.
We’ve talked about how some of the drugs
that impact these different chemical systems might work
and why they create some of the problems they create.
Problems are mainly created by the fact
that they impact lots of systems in the brain and body.
So you take a drug to increase serotonin,
but that serotonin is also related not just to mood,
but to things related to libido and appetite.
And so you start disrupting multiple systems.
You know, the same could be said for behavioral tools,
right, that any behavioral tool
that adjusts the levels of a particular chemical
ought to perhaps provide some relief
for some of the symptoms of major depression.
Let’s take an example that I’ve talked about before
on the podcast, which is if you get into a very cold shower,
you take an ice bath,
you will release norepinephrine and epinephrine
in your brain and body.
There’s no question about that.
I don’t think anyone can really escape that.
It’s a kind of a universal response to being in cold water.
Well, if some aspects of depression
are related to low levels of norepinephrine,
will taking cold showers relieve your depression?
Perhaps it might even relieve certain aspects
of that depression.
Is it a cure?
Well, that’s going to depend on the individual.
Will exercise help?
Well, if you go out for a run,
you’re going to increase the amount of norepinephrine
in your body.
If you enjoy that run,
it’s likely that you’ll increase the levels of dopamine
and probably serotonin in your brain and body as well.
Will that cure your depression?
Well, there are a lot of studies exploring
how exercise can impact depression.
And indeed, regular exercise is known to be
a protective behavior against depression.
But it also can help relieve
some of the symptoms of depression.
So you may ask yourself, why would you need drugs at all?
Why would there be prescription drugs
or the need for supplementation or other things
to alleviate the symptoms of depression?
Ah, well, that’s the diabolical nature of depression,
which is if people are far enough along in this thing,
this sometimes called disease, sometimes called disorder,
but major depression, oftentimes they can’t get the energy
to even get up and take a bath or a shower.
They have no motivation to do it.
They have no desire to go for a run.
So you say, come on, let’s go, you’ll feel better.
I know you’ll feel better.
It generates all these chemicals.
I heard on the whatever podcast,
Huberman Lab podcast or another podcast
that getting into action does all these things
and they just don’t want to do it.
And to you, a person who’s not experiencing depression,
that perhaps could just seem like the most frustrating
and confusing thing in the world.
But it’s very important to highlight the fact
that these circuits that are accessible to some of us,
the circuits for happiness, for pursuit of pleasure,
for exercise, for getting in a cold shower,
if that’s your thing,
that those circuits are present in all people.
But for certain people that are experiencing
major depression and are really in the depths
of their depression,
they can’t really access those circuits in the same way
that people who are not suffering from depression can.
So I hope that makes it clear.
It’s not offering any excuses for them.
And indeed, I think those behaviors would help
jolt them out of some of the symptomology of depression,
but they’re just not accessible to everybody.
So let’s talk about the things that people can do
to deal with depression.
And again, anytime you add a behavior or a tool
or a supplement or subtract a behavior tool,
supplement, drug, et cetera,
you absolutely should talk to your physician,
especially if you’re somebody
that’s dealing with major depression.
I want to focus on the stress system.
And I’m not just going to tell you
to get sunlight in your eyes and to get a good night’s sleep.
Although I think everybody should do that
on a regular basis, ideally every day.
Talked about those ad nauseum on this podcast.
They will help your sleep.
They will help you alleviate stress.
I think you should have tools to deal with stress
in real time, et cetera.
But let’s look at depression from the standpoint
of a deeper biological phenomenon,
which is inflammation and the immune system.
There’s growing evidence now
that many forms of major depression,
if not all of them, relate to excessive inflammation.
Now, inflammation plays an important role in wound healing
is that it is a positive aspect of our immune system,
our ability to combat wounds, combat illnesses, et cetera.
But inflammation gone unchecked,
inflammation that lasts too long
or is of too high amplitude,
meaning too many anti-inflammatory or inflammatory cytokines
and things of that sort in the body is bad.
And there’s decent evidence now
that inflammation can lead to or exacerbate depression.
And that if we want to control depression
or limit or eliminate depression,
that focusing on reducing inflammation
and its associated pathways is a really good thing to do.
And I think this is a really good thing
for everybody to do,
regardless of whether or not
you suffer from depression or not.
And today we’re going to talk about
exactly how depression comes about
through the inflammation pathway.
Okay, so first of all,
who are the major players in creating chronic inflammation
in the brain and body?
They are the inflammatory cytokines,
things like IL-6, interleukin-6,
things like tumor necrosis alpha, TNF-alpha,
things like C-reactive protein, all right?
Not all of these are cytokines,
you have interferons and your prostaglandins
and a lot of these things.
But when we are stressed, chronically stressed,
we get inflamed,
our brain and various locations in the brain
become inflamed because certain classes of cells,
in particular those glial cells,
the cells that are typically thought
to just be support cells,
those cells and their biochemistry
and their dialogue with the neurons of the brain and body
starts to become disrupted.
I may have mentioned it earlier, I don’t recall,
but I certainly mentioned it in an earlier podcast
that adrenaline, epinephrine,
when it’s released in the body,
it doesn’t cross the blood-brain barrier,
but there are certain things that are able
to cross the blood-brain barrier when we are stressed.
Things like the E2 prostaglandins,
those cross the blood-brain barrier
and our blood and our brain,
therefore our brain and our body can communicate
because certain things can pass through this barrier
we call the BBB or the blood-brain barrier.
And also we have something called the glymphatic system,
which is really a plumbing system
that links the brain and body.
It’s the link between the immune system and the brain.
Well, there is a set of actions that we can take
in order to limit inflammation.
And this has been shown in several quality
peer-reviewed studies now to reduce inflammation
and to relieve some, and in some cases,
all of the symptoms of major depression.
One of those approaches is to increase our intake
of so-called EPAs or essential fatty acids.
There’s now a very long list of papers
in quality peer-reviewed journals showing
that when people ingest a certain level
of EPA omega-3 fatty acids,
the relief from depressive symptoms matches the SSRIs.
That’s incredible, right?
That essential fatty acids could relieve symptoms
of depression as well as some
of the prescription antidepressants.
Now this doesn’t necessarily mean you run off
and stop taking your antidepressants
if you’ve been prescribed them.
Please don’t do that.
Please talk to your physician.
And I should mention that some of the same studies
have shown that increasing our intake
of these essential fatty acids,
in particular, the EPA variety of omega-3s,
can lower the effective dose of things like SSRIs,
meaning if we required a 50 milligram
or 40 milligram dose of fluoxetine,
that one can get by on a lower dose
and thereby perhaps not experience as many
or as severe side effects by taking
or supplementing with EPAs.
Now, the threshold level seems to be about one gram,
1,000 milligrams of EPA.
So you will sometimes see on a bottle of krill oil
or fish oil or any other source,
even plant source or other source of EPA,
that it’s 1,000 milligrams or 1,200 milligrams.
But what’s really important to look at is
whether or not there’s more than 1,000 milligrams of EPA,
because the EPA in particular is what’s important here.
And actually, in exploring some of the literature
on the effects of EPAs on cardiovascular health, excuse me,
as well as their effects on depression,
there’s some interesting dose-dependent responses,
such that people who took anywhere from 400 milligrams
to 5,000 milligrams of EPAs,
achieved a variety of different benefits.
And in some cases, some side effects,
we’ll talk about those.
And it does seem that this 1,000 milligrams
is the critical threshold for benefiting
or getting some relief from depressive symptoms.
But people who took two grams seem to do better.
And in the cardiovascular health realm,
there it’s a little more complicated.
Some studies point to a very positive effect
on cardiovascular health by taking increasing amounts
of EPA, others, not so much.
The current data point to the fact
that for every gram of EPA that one ingests,
there’s about a 9% improvement in cardiovascular health.
The same dose-dependent improvement on psychological health
in combating depression can’t really be stated.
I wouldn’t say that the more EPA you take,
the better you’re going to feel, so to speak.
I don’t think the data point to that.
However, it does seem that if you take a gram,
1,000 milligrams or 2,000 milligrams of EPA,
there does seem to be some substantial relief
for many people, I should emphasize many, not all,
for many people in major depressive symptoms.
So how would this work?
Well, it turns out that these inflammatory cytokines,
they impact neurons and the circuits of the brain
that relate to things like serotonin,
dopamine, and norepinephrine.
These inflammatory cytokines act
in a variety of different ways,
but they mainly act to inhibit the release
of serotonin, norepinephrine, and dopamine,
or the synthesis of serotonin, norepinephrine, and dopamine.
And I’ll give you one example
of how EPAs can positively impact this process,
and then it points to a second tool,
which is the proper utilization of exercise
to offset the effects of depression.
So now you should understand why having healthy levels
of serotonin is important for maintaining healthy mood.
It’s not responsible for all the aspects
of having a healthy mood.
There’s also dopamine and norepinephrine,
but it is a very important one.
Dopamine, also called 5-HT,
essentially derives from a precursor called tryptophan.
Tryptophan arrives into our system through our diet, okay?
Tryptophan is an amino acid.
Tryptophan is found in turkey, it’s found in carbohydrates,
and that should therefore raise the idea,
hmm, I wonder if one of the reasons
why people who are depressed have such an appetite
for carbohydrate-laden foods
is because they’re trying to get more tryptophan,
and therefore more serotonin.
And indeed, that’s the case.
Tryptophan is eventually converted into serotonin.
However, if there’s excessive amounts of inflammation,
these inflammatory cytokines cause tryptophan
to not be converted so much into serotonin,
but to be diverted down a different pathway.
The pathway involves something called IDO.
IDO-lamine, which converts tryptophan into kynurine, okay?
Kynurine actually acts as a neurotoxin
by way of converting into something
called quinolinic acid, okay?
And quinolinic acid is pro-depressive.
So if that seems like a complicated biochemical pathway,
what’s basically happening here is that the tryptophan
that normally would be made into serotonin
under conditions of inflammation
is being diverted into a neurotoxic pathway.
And ingestion of EPAs,
because it limits these inflammatory cytokines,
things like IL-6, C-reactive protein, et cetera,
can cause more of the tryptophan that one ingests
or has in their body to be diverted
towards the serotonergic pathway.
Exercise, it turns out, also has a positive effect
on the tryptophan to serotonin conversion pathway.
And the way it does it is really interesting.
You now know that tryptophan
can either be converted into serotonin
or it can be converted into this neurotoxin,
which is a bad thing.
Exercise, the activation of the muscles
through rhythmic repeated use,
in particular aerobic exercise,
but also resistance training has been shown
to do this to some extent,
tends to sequester or shuttle the kynurine into the muscle
so that it isn’t converted into this neurotoxin
that is pro-depression, okay?
There are a lot of steps in the pathway
leading to depression,
but what this essentially means
is that hitting a certain threshold level of EPA intake,
whether by supplementation with fish oil or krill oil
or through some plant source,
if you’re not into ingesting fish or krill,
or trying to get up above that 1,000 milligram threshold
for EPA by ingesting particular food sources,
you certainly can do it through food,
you don’t have to supplement,
but it’s easier to do with supplements,
that doing that will limit the inflammation
that diverts tryptophan into this neurotoxic pathway.
And exercise as well augments this conversion
of tryptophan into serotonin
because it takes this thing
that would potentially be a neurotoxin
and it sequesters it, it pulls it away
so that it can’t actually go have its pro-depressive effects.
So you’ve got multiple steps here,
we’re describing two tools,
increasing EPA and regular exercise
as a way of increasing serotonin somewhat indirectly,
it’s by limiting this bad pathway
to promote the activity of a good pathway.
But from the data that are published
in quality peer-reviewed journals,
it really appears that this inflammation pathway
does function to increase depression
through these pathways.
And so knowing that there are behavioral steps
and supplementation-based steps,
or if you prefer getting your EPAs from typical food,
from nutritional approaches,
I find that very reassuring
that the mechanisms all converge on a common pathway,
serotonin, that gives me great peace of mind
that when people say, hey, go out for a run
or you should get outdoors, exercise,
or you should take fish oil or like the Scandinavians do,
I have Scandinavian family members
and they are known to,
or I should say they are quite open about the fact
that during the winter months in particular
when depression is more likely,
but throughout the year really,
they make an effort to regularly ingest high levels of EPA,
either through ingesting fatty fish and its skin,
I’m not a particular fan of ingesting
the skin of fatty fish,
or by supplementing with cod liver oil
or other types of fish oil,
sardines and things of that sort, sardine oils.
There are a number of different things out there
that one could use.
So I find it very reassuring
that there’s a common biochemical pathway
that can explain why these things not just work,
but why they should work.
They should work because they operate
in the very same biochemical pathways
that antidepressants that are prescribed to people do.
So what does this mean for you?
Well, if you’re somebody who suffers from major depression,
again, don’t stop taking your prescribed medication,
talk to your doctor,
but talk to them perhaps about the EPAs and exercise
and how these things can impinge
on the same biochemical pathways.
If you’re somebody who’s not suffering from major depression,
I still think these pathways
are really important to understand.
And actually knowing these pathways
is additional motivation to get regular exercise.
I think we all know that we should be getting
anywhere from 150 minutes to 180 minutes per week
of so-called zone two cardio for cardiovascular effects.
Zone two is the kind of mellowish cardio
where you can sort of hold a conversation if you needed to,
but it’s a little bit tough.
You’re kind of sucking for air a little bit.
And that’s going to limit these depressive like symptoms.
I think in all of us,
I don’t think that we should think of depression
as a strict threshold.
I’m somebody who personally has made the choice
to take a thousand milligrams of EPA per day.
I do that by supplementing fish oil.
There’s debate out there as to whether or not
it’s better to take EPA and DHA in particular ratios
and whether or not DHA can impact the LDL,
which is the so-called bad cholesterol.
That’s getting really down into the weeds.
And we can talk about that in a future episode.
But for myself,
I notice a pretty substantial positive effect
of taking anywhere from a thousand milligrams
to 2000 milligrams of EPA per day.
I do that through supplementation
and I do strive to try and eat some fish,
even though frankly I’ve never liked the taste of fish.
For those of you that would like a little more detail
or perhaps a lot more detail into the effects of EPA
on depression and in relieving depressive symptoms.
And if you want to get into the nitty gritty of it,
I invite you to go to examine.com,
put in depression, EPA.
They list off and have links to 28 studies
on the effects of EPA on major depression.
If you go to PubMed,
there are many, many studies on this now
that date back several decades, really.
If you’re interested in the specific effects of EPA
as opposed to DHA,
I want to point you towards a particular study entitled,
not surprisingly, EPA but not DHA,
appears to be responsible for the efficacy
of omega-3 long chain polyunsaturated fatty acid
supplementation in depression,
evidence from a meta-analysis of randomized control trials.
This is a really wonderful paper.
The author is Julian Martins, M-A-R-T-I-N-S.
It was published in 2009.
We will provide a link to this study in the caption.
That study is really the one that at least to me
points to why EPA in particular is what’s effective
and that whether or not DHA is problematic or not
is a separate issue,
but it’s really the EPA that one wants
to hit a certain threshold level of
if one’s goal is to get relief from depression
or to keep depression at bay by keeping mood elevated,
which is why I take high dose EPA.
So we’ve got EPA, we’ve got exercise.
Now you understand how they work to adjust mood.
Now I want to talk about something that at least for me
was quite surprising when I first learned about it
for sake of treatment of mood disorders,
and that’s creatine.
Creatine has a number of very important functions
throughout the body.
For those of you that are into resistance training,
and actually for those of you that are
into endurance training as well,
creatine has achieved a lot of popularity in recent years
because supplementation with creatine
can draw more water into muscles
and can increase power output from muscles.
So it’s something that does indeed work.
There have been debates about whether or not
it’s unhealthy for the kidneys
to take long-term creatine supplementation at high doses.
And I invite you to go down that rabbit hole.
I think most people now accept the idea
that for most people, not all, but for most people,
low dose creatine supplementation of anywhere
from one gram to five grams per day
can have a number of positive effects
on physical performance.
People with kidney issues, et cetera,
need to be especially cautious,
but creatine is interesting for that purpose.
However, there’s also a so-called phosphocreatine system
in the brain, and that phosphocreatine system
has everything to do with the dialogue between neurons
and these other cell types called glia,
and glia comprise several cell types,
microglia, astrocytes, et cetera.
But the phosphocreatine system in the forebrain
in particular, in the front of our brain,
has been shown to be involved in regulation of mood
and some of the reward pathways, as well as in depression.
And there are now several studies, at least three,
although there are probably more by time this comes out
because they’re coming out very quickly now,
at least three quality studies pointing to the fact
that creatine supplementation doesn’t just have
these positive effects on physical performance,
but can also be used as a way to increase mood
and to improve the symptoms of major depression.
This has been now done
in several double-blind placebo-controlled studies.
These studies have looked at women, have looked at men,
have looked at adolescents, some of whom were taking SSRIs,
some of whom were not.
They’ve done magnetic resonance spectroscopy.
So spectroscopy is a way that you can look at
the concentrations of particular compounds in the brain
in real time in humans.
It can be used for other things as well, of course.
And basically what’s been observed is that
increasing the activity of the phosphocreatine system
in the forebrain can be beneficial,
or at least as correlated with improvements in mood.
So let’s just talk for a moment about what’s involved
with using or supplementing creatine
in order to improve mood and perhaps even treat depression.
First of all, when I talk about creatine,
I’m talking about creatine monohydrate.
There are a number of different forms of creatine.
Here I’m talking about creatine monohydrate.
The American Journal of Psychiatry in 2012
published a study which was a randomized
double-blind placebo-controlled trial
of oral creatine monohydrate.
And what it found is that it could augment
or enhance the response to a selective serotonin
reuptake inhibitor, in particular in women
with major depressive disorder.
So like EPA, creatine supplementation seems to either
lower the required dose of SSRI
that’s required to treat depression,
or can improve the effectiveness of a given dose of SSRI.
However, there are other studies that have looked directly
at creatine supplementation in the absence of SSRIs,
and those are interesting as well.
There’s a wonderful and very comprehensive review
on creatine for the treatment of major depression
that includes beautiful tables of all the subjects
and the dosages, et cetera.
I’m not going to read off every line
and every column in that review,
but we will provide a link to that review as well.
One of the things that’s really striking
about the lists of studies that they include
is that most of them used dosages
that are pretty reasonable for most people,
anywhere from three grams to five grams,
sometimes up to as many 10 grams per day of creatine.
Many of these also were shown to increase activity
of this phosphocreatine system in the forebrain.
And some show a relationship
between that phosphocreatine system
and a particular category of receptors in the brain
called the NMDA receptor, N-methyl-D-aspartate receptor.
The NMDA receptor is one of the first things
that every budding neuroscientist learns about
because it is the receptor
that has particular electrical and chemical properties
that make it a critical gate for so-called neuroplasticity.
So it’s not a receptor that’s activated in the brain
typically for just the functioning of the brain
on a day-to-day basis.
It’s a receptor that’s activated
when circuits are going to change,
when they are inspired to change
by some very strong stimulus, meaning some experience,
or in some cases a drug, or in some cases something else.
But the NMDA receptor is a kind of a key node
for shifting brain circuitry.
And so while the details aren’t entirely clear,
it seems that creatine supplementation
leads to increases in the phosphocreatine system
in the forebrain,
and that increases in the activity of the forebrain
phosphocreatine system relate to changes
in the way the NMDA receptors function
and may lead to some of the plasticity,
the changes in neural circuits that underlie the shift
from negative mood and affect to positive mood.
Now, there are a lot of gaps.
Those are, you know, there are a lot of little boxes
or bins in the diagram I just laid out for you.
And some of them are still truly black boxes, as we say,
meaning we don’t really know what’s in them yet
and more mechanistic data are coming.
However, when you look over the data in this review,
or when I look over the data in this review,
what you find is that
they’re pretty striking positive effects of creatine.
And one of the more interesting effects
is that creatine has actually been shown to increase mania
in people that are already manic.
And that’s interesting.
We’re not talking about bipolar depression today,
but it seems that creatine elevates levels of activation
and kind of mood overall.
And you could see why that would be a problem
for somebody that’s already in a manic phase,
but it actually might be beneficial
for somebody who is very low affect
and has a major depression.
So should you supplement with creatine?
Well, as always talk to your healthcare provider,
but if you’re somebody who is thinking about things
that you can do and things that you can take
in order to improve your mood, keep depression at bay,
maybe even support other treatments for major depression,
the creatine system seems like a logical one.
There’s at least strong studies
and a good number of them to look to,
to determine whether or not that’s right for you.
I personally take five grams of creatine for other reasons.
I take it for the physical performance enhancing effects,
but it’s kind of nice to think that perhaps
it’s also helping me improve my mood.
That’s a choice that I’ve made for me
as in within the margins of safety for me in my life.
I don’t know that it’s right for everybody,
but I find it very interesting.
And again, I find it particularly interesting
because there’s a logical biochemical pathway
to support the finding that it improves mood
and can offset the effects of major depression
in some cases,
or can improve the effects of antidepressant medication
in many cases.
When I see mechanism and I see effectiveness
and the mechanism and the effectiveness map
to a lot of the same mechanisms
that are involved in prescription drugs,
that gives me great reassurance
that this isn’t just some sort of mysterious pathway
or mysterious compound by which creatine might be working.
So now we’ve kind of clustered together EPA’s exercise
and their relationship to inflammation,
creatine and its relationship to forebrain function
and the phosphocreatine system and this NMDA receptor.
And as you’ll see in a few minutes,
that NMDA receptor turns out to be vitally important
and is actually one of the main nodes of action
for some of the more novel and exciting therapeutics
that are being explored now in psychiatric clinics.
So let’s talk a little bit more about this NMDA receptor
and how it relates to some of the more experimental
or novel therapeutic compounds
for the treatment of major depression.
And the compounds that we’re going to be talking about,
you may have heard of before,
one is ketamine, which is getting increasing interest
in psychiatric clinics
and in various experimental and clinical studies.
And the other is PCP.
Both ketamine and PCP are known drugs of abuse.
For many years, people have abused these drugs,
go by the street name Special K, et cetera.
And they create dissociative anesthetic states.
So dissociative states where people don’t feel
as closely meshed with their emotions and their perceptions.
It’s an odd state, I hear.
And it’s an odd state that clinicians are now leveraging
for the treatment of depression.
And we’ll talk about why that is.
But let’s talk a little bit about this NMDA receptor
and why ketamine and PCP might work
for the treatment of depression
or how they even could work.
I want to be very direct that this is an area
that still needs a lot of data.
There are, however, some excellent papers
from really terrific groups.
One of them is a paper that was published
in Nature last year, 2020.
First author is Vesuna, Sam Vesuna, V-E-S-U-N-A.
And the last author and the lead on the study
was Dr. Karl Deisseroth,
who was a guest on the Huberman Lab podcast
a few months ago.
He’s a world expert in neuroscience.
He’s a psychiatrist.
And this paper from Sam Vesuna and Karl and colleagues
explored how these dissociative states come about.
And they looked at this both in animals and in humans
and found that there was essentially a common mechanism
whereby a particular layer of cortex,
so your brain has this outer shell of tissue
that is called the neocortex.
It’s where our perceptions lie.
It’s where our associations lie.
It’s a very important area for processing,
decision-making and planning, et cetera.
It’s literally stacks of cells.
And one of those layers in the stack of cells is layer five.
And the layer five neurons in particular
went into a particular rhythm of electrical activity,
this one to three Hertz rhythm
after mice or humans were administered ketamine or PCP.
There was activation of a particular area of the brain,
this retrosplenial cortex as it’s called.
And the dissociative state that emerged
was an interesting one.
And clinically what’s described in the trials for ketamine
and things like it,
that people who are depressed will take ketamine,
will experience a kind of separateness from their grief
and from their emotions.
And that possibly there’s plasticity,
there actually shifts in the neural circuitry
such that their emotions don’t weigh on them so heavily.
I’m using very loose language here,
but that they don’t feel as overridden
or as burdened by their own emotions
as they did previously to the ketamine therapy.
Now, absolutely in no way, shape or form,
in my suggestion that people run out
and take ketamine in order to treat their own depression.
These drugs are still very much experimental,
although they are approved in certain contexts,
at least in the US by prescription
for the treatment of depression.
What’s interesting to me is that these dissociative states
sound at least at the outset to be more of a separateness
It sounds a little bit like depression itself.
It’s sort of like anhedonia,
an inability to experience pleasure.
And then one takes a dissociative anesthetic
and somehow is able to get relief
by getting even further away from an experience.
To me, that doesn’t make sense,
but that just speaks to the fact that these drugs
and these receptors and these pathways
operate through very cryptic means.
And we really don’t understand all the pathways
in the brain that relate to motivation and mood
and so forth.
And the results with these ketamine trials
are looking very promising.
In fact, there are a number of trials that show
that a fair number of people that take ketamine
in a therapeutic setting legally
with a psychiatrist guiding the experience
are able to get relief from their symptoms
without the need for many, many treatments with the drug.
Just how many treatments varies
from individual to individual,
but it’s not like people have to take this stuff on going.
This is really an attempt to tap into this NMDA receptor
that is related to neuroplasticity.
Both ketamine and PCP essentially act as antagonists,
which means they block the NMDA receptor.
They do it through different methods,
non-competitive and competitive for you,
chemists and pharmacologists out there.
You can look it up if you like.
But what’s therefore even more surprising
is that every neuroscientist learns
that activation of the NMDA receptor,
not antagonism or blocking of the NMDA receptor
leads to changes in neural circuitry in very profound ways.
In fact, experimentally,
and I’ve done these experiments myself,
if you want to prevent plasticity,
you want to prevent an experience
from reshaping neural circuitry,
you give an NMDA receptor blocker.
I’ve done that many times
in the course of my experimental neuroscience career,
not to myself, obviously,
but in the course of doing experiments.
So it’s still a bit mysterious to me
how this could work.
A couple of things.
One is this layer five activation is pretty interesting.
We’re going to come back to layer five
when we talk about yet another emerging treatment
for depression, which is psilocybin,
so-called magic mushrooms,
and the effects of psilocybin on layer five neurons
in the cortex.
So there’s a common theme emerging here,
which is that layer five activity in the cortex
may be important for rewiring the brain in certain ways
that can lead to recovery
or to an alleviation of some of the symptoms
of major depression.
So if this is sounding a little bit vague to you,
it’s because this is still truly experimental
and new and still very much on the cutting edge
of what’s happening now.
We don’t have all the answers.
So if it sounds like I’m moving slowly through this
and I’m being extra careful about what I say,
you are correct.
Your antennae are correct in this case.
I never want to misstep and say something that’s not true,
but that’s especially the case
when we’re talking about experimental therapies and drugs,
which formerly were taken as drugs of abuse,
which are now being used as drugs
for therapeutic treatment in the clinic.
There is a very interesting study.
This was published in Science in 2019.
So these are very recent studies.
The last author on this is Liston, L-I-S-T-O-N.
The title of the paper is
Sustained Rescue of Prefrontal Circuit Dysfunction
by Antidepressant Induced Spine Formation.
And here, when we hear spine,
we’re not referring to spine as in your vertebrae
running down your spinal column.
We’re talking about the spines,
which are these little protrusions on neurons.
Neurons are not smooth by any stretch.
If you zoom in on a neuron,
if you were to come to my lab
and look down the microscope at a neuron
and zoom in on it,
you’d find that some neurons are smooth,
but most neurons have these little protrusions.
And those little protrusions are called spines.
And those little spiny protrusions
are little sites where neurons can reach out
and form and receive new synapses from neighboring neurons.
So they increase the surface area of a neuron
and allow new connections to be formed.
And so spine formation is synonymous with neuroplasticity,
which is synonymous with changes in circuit function,
which is synonymous with changes in the ways that we think,
we feel, and we behave.
And what was shown in this study is really interesting.
What they showed is that ketamine
can relieve depressive symptoms rapidly
by changing or increasing, in this case,
the spines on these neurons in the prefrontal cortex.
And if that word prefrontal rings a bell,
well, now you remember.
The phosphocreatine system,
the ingestion of creatine monohydrate,
and the forebrain, activation of the forebrain,
were related to, in some way or another,
to relief or improvement of major depressive symptoms.
So we’re starting to converge on a picture here
whereby these drugs, ketamine, PCP,
used in a therapeutic context,
may be increasing neuroplasticity,
literally the changing of neural circuits in the forebrain,
somehow through dissociative states.
And I don’t want to speculate too much
about how that might come about,
but one of the things that’s such a resounding
or repeating theme of major depression
is that when you talk to somebody who has major depression,
it is a real downer.
And I’m not being disparaging of those people,
but if you’ve ever had a conversation
with someone who’s depressed,
they’re always talking about how exhausted they are,
or in really severe cases,
they are not even responsive at all.
They just kind of stare at you blankly,
or they fall asleep.
I mean, they’re truly depressed.
Their system is lowered in terms of its activation state.
So I think that it’s interesting
that the application of drugs
that allow people to separate from that state
of not caring or being uninterested
or unwilling to do anything
is actually one of the paths to treatment.
It’s not always about just getting people peppy
and excited and happy.
There also seems to be a requirement
for getting them distanced from their own grief.
And this brings us back to something that we talked about
way back at the beginning of this episode,
which was this particular feature
of the anti-self confabulation,
that everything that happens is a reflection
that I should say for the depressed person,
that everything that happens is a reflection
of how life is bad and their experiences
just point to the fact that nothing is going to get better.
This is the common language of depression.
If this is very depressing to hear me talk about,
it is heavy and that’s what it’s like to hear these things.
It’s even heavier, of course,
for somebody to experience them.
And those beliefs, those patterns of guilt and grief
and anhedonia and delusional anti-self confabulations,
those are the things that eventually,
if they get severe enough,
start to convert into things like self-harm, mutilation,
and in the most tragic of cases, of course, suicide.
And so I think we can look to these treatments
such as ketamine and PCP,
but in particular ketamine and its use in the clinic
as ways for people to get distanced
from the negative affect that they feel
isn’t just inside them or overwhelms them,
but that for the very severely depressed person,
they feel is them.
And we hear this sometimes, you are not your emotions.
You know, that’s a statement
that I’ve always been a little bit challenged by.
I mean, yes, indeed,
emotions are not who we are.
They are states that we go into and out of,
including happiness and sadness,
but they are very much a part of us when we experience them.
We don’t experience them as next to us or behind us
or across the room from us.
We experience them as our emotions.
They are so much part and parcel
with our experience of ourself
that a statement like we aren’t our emotions
is a very hard statement to digest,
especially for the depressed person.
And so I think that the NMDA receptor
and its capacity to induce neuroplasticity circuit changes,
the fact that PCP and ketamine
are both showing activation of neural circuits
by way of suppressing activity of the NMDA receptor
and some of the positive or exciting therapeutic outcomes
that are coming from this really point to the fact
that ketamine and PCP and removal of negative experiences
or the experience of a negative experience,
sort of getting meta there,
but the experience of a negative experience
may be an important path by which people
treat their depression,
especially in its most severe forms
where people are veering towards
self-harm mutilation and suicide.
So you may have noticed a theme,
which is that certain categories of approaches
that we’ve been discussing for offsetting
the symptoms of depression, such as exercise,
ingesting EPAs, reducing inflammation,
or even the SSRIs for increasing serotonin,
focus on changing some core biological function,
like raising the amount of a chemical, serotonin,
or reducing the amount of inflammatory cytokines
in the brain and body.
And yet things like ketamine
focus more on rewiring circuitry,
changing neural circuitry so that it functions better
in the immediate and hopefully in the long-term as well
and keep people with major depression
in what they call remission, away from major depression.
Another category of treatments
that’s being actively explored now in laboratories
and in the psychiatry realm are the psychedelics.
And that’s a huge category of compounds.
However, one in particular, psilocybin is one
that’s being most intensely and actively pursued
for its capacity to treat major depressive disorder.
I want to be very clear that the work
that I’m going to describe is work
that’s being done in university settings,
university hospitals by scientists and psychiatrists.
And these are clinical studies,
clinical trials leading to peer-reviewed data.
And those are the data that we’ll be discussing.
Some of the major luminaries in this area include,
of course, aren’t limited to,
but include people like Matthew Johnson,
who’s at Johns Hopkins.
We’ll discuss some of his work now.
And fortunate to say that he will be coming on the podcast
as a guest to describe the studies
in a variety of laboratories,
working on a variety of different psychedelic compounds.
But let’s focus on psilocybin for its capacity
to rewire neural circuits and alleviate depression.
There have been anecdotal data or evidence over the years
that psilocybin has this capacity.
How does psilocybin work?
Well, psilocybin magic mushrooms, as it’s sometimes called,
mainly works on what’s called the serotonin 5H2A receptor
with some affinity for the 5HT1 receptor.
What does that mean?
Well, basically you’ve got a lot of different kinds
of serotonin receptors,
just as you have a lot of different kinds
of dopamine receptors or other types of receptors.
The advantage of having different receptors
expressed in different parts of the brain and body,
even on different parts of individual cells
in the brain and body,
is that the same compound serotonin
can have a diverse set of effects
on different cells and tissues.
This is also the basis of some of the side effect profiles
of SSRIs, because maybe, for instance,
we know that taking Prozac fluoxetine
will increase serotonin in one area,
but also in another area,
and then they will go have diverse effects
on different brain circuits
because of the variety of receptors.
Receptors are just like parking slots
where the molecule serotonin parks and has different effects.
Well, psilocybin engages or increases
meaning it increases the amount of serotonin,
mainly by acting at these 5H2A receptors.
But where in the brain does it happen
and what are the major effects?
First, let’s talk about the major effects,
because I think that’s what people are interested in.
The study that I’d like to highlight
is a fairly recent one.
It was published in May of 2021 in Journal,
Journal, excuse me,
of the American Medical Association Psychiatry,
so JAMA Psychiatry,
and it’s entitled
Effects of Psilocybin-Assisted Therapy
on Major Depressive Disorder,
a Randomized Clinical Trial.
It’s an absolutely beautiful study,
a very important study.
It includes some of the luminaries in this area,
like Matthew Johnson,
We will provide a link to this study.
It is available in its full form at zero cost
if you want to read it.
It’s got a lot of detail,
so I’m just going to summarize a few things,
but basically what they did
was they screened for patients to come into the clinic.
These were people that suffered
from major depressive disorder.
And administered either one or two rounds of psilocybin.
They used particular dosages.
They’re listed in the study,
so you can look it up
if you’re really interested in that level of detail.
Typically it was 20 milligrams per kilogram of body weight,
so it depends on body weight,
or 30 milligrams of psilocybin
per 70 kilograms of body weight.
They were given in capsule form,
so people weren’t eating the mushrooms.
This is obviously a very controlled study,
and they want to control the dosages appropriately.
They were randomized to begin the treatment immediately,
or after an eight-week delay.
They had all the appropriate control groups
that one would like to see.
What’s really striking about this study
is that there was a very significant improvement
in mood and affect and relief from depressive symptoms
in anywhere from 50 to 70% of the people
that were subjects in the study
who received the psilocybin treatment.
And whether or not it was 50,
or whether or not it was 71%,
varied according to how long after the study
they maintain these antidepressive effects,
or whether or not they stayed in remission
from the depression.
But these are really enormous and significant effects,
and very exciting,
and are pointing in the direction of psilocybin
very soon becoming a treatment
for various forms of depression,
including major depression.
Now, of course, this is limited to the laboratory at present.
There are a number of elements of these studies
that are important to take into consideration too,
which is that there are highly trained guides,
meaning people to direct people through the experience.
As Matthew Johnson has told me,
there is the occurrence from time to time
of people having so-called bad trips,
of having anxiety attacks
during the hallucinations and all that.
And they have ways to mitigate that and deal with that
because the guides are trained.
They have all the sorts of medical monitoring devices
for heart rate and temperature
and things that one would like to see
for a study like this,
because these are very powerful compounds.
I don’t want to give away any elements of the discussion
with Matthew Johnson,
because it will be released in podcast form
reasonably soon here, the Huberman Lab podcast.
But one of the things that came up,
and is a fundamental question that I had,
that I think probably many of you are asking is,
does the experience that one has on these compounds
make a difference for whether or not
somebody gains relief from depression
from these psilocybin journeys or not?
In other words, does it matter what they talk about?
Does it matter what they think about?
Does it matter if they have a good trip or a bad trip?
And I don’t want to hold you in too much suspense.
I’ll let Matthew provide the more thorough answer.
But what’s really interesting is
there are some common themes to psilocybin administration
and experience that lead to relief from depressive symptoms,
but they are subjectively, excuse me,
subjectively very varied.
Meaning that whether or not people feel
they had a good experience or a bad experience,
whether or not people thought about their parents
or thought about the color of the ceiling
doesn’t seem to have too much of an impact
on whether or not they receive relief
during these studies, in these clinical studies.
It seems like different people
can have lots of different experiences
and still receive benefit.
And that points to something deeper.
It points to the fact that these drugs,
which is really what they are,
are rewiring neural circuitry in a common way
despite a diversity of experience while on the drug.
And that itself is really interesting.
And it takes us back to a place that we’ve been before
in this discussion, which is layer five of the cortex,
this area that ketamine seems to impact as well
by generating rhythms of the,
I mentioned one to three Hertz activity
in layer five of certain areas of the cortex.
Well, the 5-HT1A receptor is known to be enriched
in layer five of the cortex.
And layer five of the cortex is a very interesting area
because it’s an area in which
there’s a lot of lateral connectivity.
So connections between different brain areas,
laterally generally is what allows us
to merge different senses.
So for instance, when we hear a sound off to our right,
over here, we turn to our right,
there’s a very hardwired response.
And typically we hear something off to our right,
we don’t look to our left.
That’s how hardwired some of these circuits are.
What appears to be happening is that the activation
of the serotonin system in 5-HT1A receptor in layer five
is offering up or providing an experience
whereby the lateral connections are able to engage
much more broadly than they would normally.
Now that also could be a bad thing.
And I asked Matt about this,
that sounds kind of spooky.
I don’t know that when I hear something off to my right
that I want to look off to my left,
that could be highly maladaptive,
especially if it’s a car coming at me from my right.
That doesn’t seem to be what’s happening.
It’s not really rewiring these deeply reflexive circuits.
It’s somehow rewiring associations between events,
emotional events, past events, current events,
and future events in ways that allow people
to get some sort of relief or distance from these narratives,
these depressive stories about their past and present,
and allow them to see new opportunity
and optimism in the future.
That’s really a fascinating thing
if you really think about it,
because I would have thought that simply by ramping up
laterality of connections,
meaning the cross associations,
that things could either be rewired randomly
in ways that don’t serve us,
or would perhaps just cause no effect at all.
So it’s either going to be bad or neutral,
but that’s not really the way things are turning out.
Again, these are highly controlled studies.
I do want to emphasize that ketamine, psilocybin,
these things are still illegal, most all places.
There are some regions and cities in the United States
where they are locally decriminalized,
but they are not legal, they’re still illegal.
So what we’re referring to here are indeed clinical studies
in which people are taking them legally.
I think it’s very likely we will see a shift
in the legislature around psychedelics,
and in particular psilocybin in the not too distant future.
And I think that for now,
what we should know is what Matt told me,
and what you’ll hear far more about,
which is that psilocybin,
this one, or in most cases, two-dose treatments
done in a highly clinical setting, controlled setting,
with patients that are carefully selected,
can, in many cases, the majority of people receive
and maintain relief from their depressive symptoms
simply through the experience of this psychedelic journey.
I did ask him about microdosing.
I made it sound as if I’d never heard about it before.
Microdosing, not microdosing.
Microdosing, and his answer was interesting.
His answer was that the microdosing effects
don’t seem to be nearly as impactful as some of these,
let’s just call them what they are,
these kind of high-amplitude sessions
that there are just one or two.
There are some studies ongoing where there’s more than two,
but that the microdosing doesn’t seem to compare
to these macrodosing, I mentioned the dosages before,
this 20 milligrams per 70 kilograms
or 30 milligrams per 70 kilograms dosages
given several weeks apart.
So you’ll hear more about microdosing and other psychedelics
and their impact on depressive states
and major depression in the episode with Matt,
but for the time being, it really seems as if, again,
we’re looking at neuroplasticity,
we’re coming back to layer five,
just like with ketamine and PCP,
we’re hearing about layer five,
we’re hearing about rewiring of circuitry,
we’re hearing about a dissociation
or a distancing of oneself from these negative moods
and affects and narratives,
but there’s a key distinction between the ketamine work
and the psilocybin work,
which is that in the ketamine work,
it really is about dissociating from experience
during the session with the psychiatrist,
whereas during the psilocybin journey,
it’s really about immersing oneself in the experience
and being fully present to that experience.
That does seem to be an important component.
And what the difference is there
and why they both seem to provide some relief
from major depression isn’t clear.
I think most likely it takes us back to the fact
that this thing we call major depression
clearly involves serotonin, dopamine, and norepinephrine,
and in some individuals,
they may be more deficient in one or several of those
or all of those, whereas in other individuals,
it might be a different collection of chemicals.
And of course, there are a tremendous number
of other psychedelic compounds that people are exploring
for treatment of major depression,
but really psilocybin is the one
that we have the most data on.
MDMA has mainly been explored in the clinical realm
for treatment of trauma.
There are some trials ongoing for treatment of depression,
but the big breakthroughs seem to be happening
in the realm of trauma treatment,
the so-called MAPS group that’s doing this,
again, legally in a clinical setting,
and there are other groups
that are starting to do it as well.
We are going to do an entire podcast episode
about MDMA and some related compounds,
so I’ll save that discussion for then.
One of the most common questions I get for this podcast
is about different diets, different regimes,
different nutritional plans,
things like keto, ketogenic diet, or vegan diets,
or intermittent fasting, or the all-meat diet,
the so-called lion diet, et cetera.
There are actually really interesting data
relating nutrition and diet to major depressive disorder,
and I think we just need to frame this
by returning to something that was said earlier,
which is that the ingestion of carbohydrates,
in particular, carbohydrates and some meats, like turkey,
that are rich in tryptophan, this precursor to serotonin,
are in many ways the self-medicating version
of depression treatment.
Now, to be clear, I’m not saying that people
should use food to medicate their depression.
Many people do that reflexively, however.
They reach for carbohydrate-rich foods
to blunt their cortisol, because that’s indeed what it does.
It blunts cortisol when you ingest high-carbohydrate foods,
in particular, starchy foods,
and it does increase serotonin,
in particular, if those foods, rather,
are rich in the amino acid tryptophan.
Now, ingesting food is wonderful, and important, and great,
but ingesting excessive foods of any kinds,
carbohydrate or otherwise, is not healthy, of course.
There have been some explorations
of whether or not a vegan diet
can improve symptoms of depression.
Not a lot of data, not impressive data.
There have been very few controlled studies
looking at the carnivore, all-meat diet.
On that, I think there are now some
that are starting to spin up,
meaning the studies are starting to spin up.
However, the ketogenic diet has been explored
for its ability to relieve certain symptoms of depression,
in particular, to what’s called maintain euthymia.
Euthymia is the kind of state of equilibrium
between a manic episode and a depressive episode
in a manic bipolar person.
We’ll return to this more in a future episode,
but basically, manics have highs, and they have lows.
Bipolars either cycle back and forth really quickly,
so rapid cycling bipolars, or some people,
so really quickly can be day-to-day.
Other people, it’s month-to-month or week-to-week.
They’re going highs and lows.
And you hear about mania, and you hear about dysphoria.
Euthymia is that kind of place in the middle
where people feel neither too high nor too low.
And there are some interesting studies
looking at the ketogenic diet
for maintaining euthymia in manic depressives,
but also in people with major depressive disorder.
Why would this work?
Well, we have to remember that the ketogenic diet
wasn’t discovered so that self-appointed nutrition gurus
could talk about it online,
or so that people could make money
selling anything related to ketosis.
And here, I’m not disparaging of the ketogenic diet.
It’s helped a lot of people.
The ketogenic diet was actually shown
to be medically relevant for its use to treat epilepsy.
It turns out that in epilepsy,
or in particular, pediatric epilepsy,
that a ketogenic diet and the shift of brain metabolism
to predominantly one in which ketones are being metabolized
rather than more standard glucose type metabolism
can greatly reduce the number of epileptic seizures
that these children experience.
It’s not always the case, but it’s often the case.
And so you talk to a neurologist or a neurosurgeon
who’s specialized in epilepsy,
in particular, pediatric epilepsy,
and they’ll tell you this.
Oh yeah, the ketogenic diet, in many cases,
not all can be very effective for this treatment.
How is it that a ketogenic diet reduces seizures?
Well, the way it reduces seizures
is by increasing what’s called GABA transmission.
GABA is a substance that is naturally released in our brain.
It’s an inhibitory neurotransmitter,
meaning that when it’s released into the synapse,
it has the tendency to reduce the firing,
to reduce the electrical activity of the next neuron
or sets of neurons.
There are various compounds that increase GABA,
in particular, GABA in the forebrain.
One common example would be something like alcohol.
Drinking alcoholic drink or two
will increase GABA transmission,
will, ironically, will lower your social inhibitions
by increasing your neurochemical inhibition.
It basically suppresses the self-monitoring pathways.
And if people drink enough,
it will suppress all pathways
and people will urinate themselves and fall over.
It will eventually inhibit all sorts of pathways.
So the GABA system has a rich array of effects
all over the brain and body,
but alcohol tends to activate the release of GABA.
You might say, well, then why not just take alcohol
to suppress seizures?
Well, that would be a terrible idea
because there tends to be a rebound excitability
after alcohol stops having its effects
on the GABA receptors.
And so then there’s an excitability
which in epilepsy would be terrible.
The reason why the epileptic diet is useful for epilepsy
is that increases what we call the tonic level,
sort of the tide, the level of GABA in the brain,
and that suppresses some of the hyper-excitability
that is the characteristic feature of epilepsy.
And there are other drugs, for instance,
the benzodiazepines and things of the Xanax variety,
Valium and so forth, those increase GABA transmission.
Those drugs also have a lot of potential
for abuse and addiction, et cetera,
and they’re problematic for other reasons.
But the ketogenic diet,
by way of increasing ketone metabolism
or shifting brain’s metabolism over to ketones,
tends to modulate GABA such that GABA is more active
and adjust the so-called GABA glutamate balance.
This is getting technical,
but glutamate is an excitatory neurotransmitter,
GABA’s inhibitory neurotransmitter,
and their balance is vital for neuroplasticity,
for maintaining healthy levels of activity in the brain,
And so there is decent evidence
that people with major depressive disorders,
in particular, the people with major depressive disorders
that are refractory,
meaning they don’t respond to classical antidepressants,
can benefit, it seems, from the ketogenic diet.
Now, this is not always the case,
but for those of you out there
who are struggling with major depression
and for which drugs have not worked,
please talk to your psychiatrist.
I don’t know how many of them are up on the literature
about the ketogenic diet or the EPAs and the rest.
You know, psychiatrists are very,
in terms of how involved in the current literature,
they tend to be,
but there are many excellent psychiatrists out there.
Most of them, in my experience,
are actually quite avid learners
about what’s happening and what’s new
in this realm that they call psychiatry.
So it’s really interesting that eating in a particular way,
lowering carbohydrates to the point
where you rely on ketogenic metabolism in the brain
increases GABA and can provide some relief
for depressive symptoms.
And that, in particular,
that seems to have positive effects
in people that are refractory
or don’t respond to classic antidepressants.
And that would include things like fluoxetine, et cetera.
I’ll make one final point about ketogenic diets
and GABA and depression,
which is that it’s also been shown
that for people that respond well to these drugs
that impact the serotonin system, dopamine system,
or norepinephrine, the ketogenic diet there
may improve the ability for those drugs
to work at lower dosages,
which is reminiscent of what we saw
with the EPA supplementation.
So today we’ve covered what at least feels to me
like a tremendous amount of material.
This topic of depression is indeed an enormous topic
to try and get our arms around.
We talked about the symptomology.
We talked about some of the underlying neurochemistry
and biology, and then we talked about approaches
to deal with it that are really grounded
in the neurochemistry and biology.
I just want to recap a few of those tools
and what those things are.
First of all, we talked about making the effort
to not overwhelm the pleasure system.
That might seem counterintuitive
to not overly seek out pleasure
or else one can find themselves in a place of depression.
I mentioned way back at the beginning of the episode,
a young man who I know to be really struggling
with depression, and it is thought,
and we don’t know for sure,
but it is thought that some of that depression
was probably triggered by an overindulgence in video games
and other highly dopaminergic activities
to the point where those activities
eventually were countered by the pain balance
that Dr. Anna Lembke described.
And he now has to do those activities repeatedly
and for many, many hours each day just to feel okay,
not even to derive pleasure from them.
And worse, many other activities,
practically all other activities have lost their zest,
they’ve lost their excitement
and his sense of pleasure for them.
And so there’s a really active campaign now
to reset that system.
So number one, don’t overwhelm your pleasure centers
either through activities or compounds.
It might seem counterintuitive,
but you’re setting yourself up for anhedonia and depression
if you do that.
It’s not just about addiction, that too,
but it’s also about setting yourself
for anhedonia and depression.
How often can you engage in these activities?
Well, that’s going to differ from person to person,
everyone’s slightly different,
but you should really mind your extreme highs
and your extreme lows and be cautious about those.
We’ll probably have Dr. Lembke on again at a future time
to try and get some more specifics about that.
But if you do feel like you need to reset that system,
it really does seem like a 30-day complete detox
from whatever activity or substance that is,
and ideally it doesn’t continue after that 30 days,
especially in conditions of drugs of abuse.
Second of all, talked about the norepinephrine system
and how the norepinephrine system is really deficient
in many forms of major depression and in depression.
There is now more deliberate pursuit
of norepinephrine-inducing activities that are healthy,
that aren’t adrenaline-seeking per se,
things like cold showers,
things like particular patterns of breathing
that engage and tend to make us more alert,
things like exercise that will increase
our levels of noradrenaline.
I’d be remiss if I said that these activities
could completely eliminate depressive symptoms
in people with major depressive disorder.
I don’t think that’s the case.
And again, I want to acknowledge that people
with major depressive symptoms often don’t have the energy,
the willingness, or the capacity to engage
in some of these activities,
but things like cold showers, deliberate cold showers,
things like regular exercise,
they aren’t just feel-good activities.
They actually engage the norepinephrine system
and keep that system tuned up
and allow us to increase our norepinephrine levels
at will on a regular basis.
And their mood-enhancing effects are real effects
that at the level of neurochemistry.
Then we talked about EPAs.
These essential fatty acids.
And it’s clear that for most people,
getting above 1,000 milligrams
and probably even closer to 2,000 milligrams per day
of EPAs can be beneficial for mood,
especially in attempts to treat
or offset major depressive disorder.
Are there side effects?
Well, you need to explore those for yourself
and with your doctor.
Everyone has a different health background.
The margins of safety for most people
will probably be quite large,
but for some people that might not be the case.
So definitely check with your physician.
We also talked about exercise
and how EPA and exercise on a regular basis
can offset these inflammatory pathways.
I want to mention something I’ve mentioned
on a previous podcast,
but in terms of keeping the inflammatome,
all these molecules that create inflammation,
and then the inflammation can limit the amount of serotonin
through the pathways we described.
In order to do that,
it’s also very, very useful to ingest two to four servings
of fermented foods on a daily basis or near daily basis.
These are data that were published
by the Sonnenberg Lab at Stanford,
recently in the journal Cell,
Cell Press Journal, excellent journal,
that ingestion of these fermented foods
really keeps the gut microbiome tuned up, so to speak,
well in order to offset these inflammatory cytokines.
Keeping inflammation at bay,
it just turns out to be a really good thing
in order to keep our mood in a good place.
So EPA, exercise, fermented foods,
creatine as a potential source of relief from depression
or offsetting or keeping us away from major depression
or relapse into depression.
And then we talked about the prescription compounds
and the compounds that are being used mainly
in the course of studies and of psychiatry and depression,
things like ketamine, PCP, psilocybin and related compounds.
And then lastly, we talked about ketosis,
which may not be right for everybody,
but might be right for certain individuals out there
who are grappling with this.
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And last but not least,
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How does it work and how to treat it?
And thank you for your interest in science.