Understanding & Conquering Depression

- Welcome to the Huberman Lab Podcast,

where we discuss science

and science-based tools for everyday life.

I'm Andrew Huberman,

and I'm a Professor of Neurobiology and Ophthalmology

at Stanford School of Medicine.

This month, we're talking all about disorders of the mind,

things like depression, attention deficit disorders,

eating disorders, schizophrenia, and bipolar disorder.

During the course of this month,

we are going to discuss the psychological

and biological underpinnings of mood disorders of all kinds.

You'll learn a lot of science.

You'll also learn a lot about the various treatments

that exist and that are in development

for these various mood disorders.

We will talk about behavioral tools, things like exercise,

meditation, breath work, but also prescription drugs,

supplements and novel compounds that are now being tested

in various clinical trials.

Across the month, I think you'll start to realize

that there are common pathways

underlying many mood disorders.

In fact, mood disorders that look quite different

from one another often depend on the action

of the same neurochemicals or neural circuits

in the brain and body.

That actually should be a point of great relief

because what it means is that by understanding the biology

of one mood disorder or understanding how one treatment

or behavioral intervention can impact a mood disorder,

we gain insight into other mood disorders as well.

As always, we will discuss science and science related tools

that people could implement should they choose.

Before we dive into today's topic,

I'd like to discuss a very particular

set of scientific findings that relate to today's topic,

and that are important for understanding all mood disorders

and all states of motivation, happiness, and sadness,

as well as depression.

Basically, I'm going to paraphrase a brief segment

of my discussion with Dr. Anna Lembke,

who I sat down with to discuss addiction

and the biological basis of addiction

and addiction treatment.

A very important aspect of that discussion

was when Dr. Lembke described the pleasure pain balance,

literally the circuits in our brains

that control our sense of pleasure and pain,

and ultimately whether or not we remain happy

in our pursuit of pleasure or not.

This is an absolutely crucial aspect

to the way that we function in everyday life,

and especially under conditions of mood disorders.

The pathway that she was describing

is the so-called pleasure system.

However, what most people don't realize

is that the pleasure system

is also directly associated with,

and in fact is the very same system

that modulates mental or psychological anguish and pain.

Essentially what she described

is that whenever we pursue something

that we think will bring us pleasure,

and that could be anything that we think

will bring us pleasure from food, to video games, to sex,

to a particular job or goal, short-term or long-term,

that we experience release of the neuromodulator dopamine.

Now, dopamine is associated with increased levels

of motivation and drive.

It is not the molecule of reward,

it is the molecule of craving motivation and drive.

However, as Dr. Lembke pointed out,

when we are in pursuit of something,

there is a release of dopamine in our brain

that makes us feel motivated,

and in general, it makes us feel good.

But very shortly thereafter

and beneath our conscious awareness,

there is a tilt of the pleasure pain balance in the brain,

literally a shift in the neural circuits

that underlie pleasure and pain,

such that every bit of pleasure or pleasure seeking

that causes release of dopamine

will be balanced out by a little bit of pain.

And we don't experience this as physical pain,

at least not at first,

we experience it as craving for more

of the thing that brought us pleasure.

Now, that sounds pretty good.

You get pleasure and then you get a little bit of pain

to balance it out.

It's subconscious and you experience it

as the desire to seek out more pleasure.

However, it's actually more diabolical than that.

And we really need to keep an eye on this

if we are to remain happy,

if we are to remain in pursuit of our goals.

The crucial thing to understand is that if we remain

in constant pursuit of pleasure,

the pain side of the balance tips

so that each time we are in pursuit

of that pleasureful thing, activity, or substance,

we are going to experience,

we literally achieve less dopamine release

each subsequent time.

So we get less pleasure and the amount of craving increases.

Now, after a certain point or threshold,

we call that addiction.

And the way to reset the balance,

and this is very important,

the way to reset the balance

is actually to enter into states

in which we are not in pursuit of pleasure,

to literally enter states in which we are bored,

maybe even a little bored and anxious,

and that resets the pleasure pain balance

so that we can return to our pursuit of pleasure

in a way that's healthy, and then in an ongoing way,

won't lead to this over tipping or this increase

in the amount of pain or addiction.

So this is very important.

And if this seemed vague,

what this means is we should always be cautious

of any state of mind or body or any pursuit

that leads to very large increases in dopamine.

And if it does, we should be very careful

to not pursue that repeatedly over time.

During today's episode, I'm going to give an example,

a real life example of a discussion that I've been in

with a young man who's 21 years old

who's dealing with a disruption

in this pleasure pain balance.

He is essentially depressed and he's depressed

because of his ongoing pursuit of a particular activity

that initially led to a lot of dopamine,

but over time has led to less and less dopamine

and more and more of this pain side of the balance.

We could call him addicted to that particular activity.

Whether or not he's addicted by clinical standards or not,

really, isn't important.

What is important is that he experiences this as depression,

as low affect as it's called or anhedonia,

an inability to experience pleasure from that thing

or from anything else.

And he's currently undergoing treatment

through a rebalancing of his pleasure pain pathway.

So while I can't reveal his identity to you,

that wouldn't be appropriate.

He did give me permission to reveal

the general architecture of what he's coping with.

And I spent some hours with him on the phone this week,

talking to him as well as to the various people

that he's working with to really understand

what's going on here 'cause I think it can illustrate

the relationship between dopamine, pleasure, and pain

for sake of addiction,

but also for understanding how to avoid depressive states,

how to remove ourselves from depressive states.

And as you'll see today, as we discussed depression,

many of the molecules and neural pathways

and biological mechanisms that we know can be used

to counter depression,

feed back onto this pleasure pain balance.

Before we begin, I'd like to say that this podcast

is separate from my teaching and research roles at Stanford.

It is however, part of my desire and effort

to bring zero cost to consumer information about science

and science related tools to the general public.

In keeping with that theme,

I'd like to thank the sponsors of today's podcast.

Our first sponsor is InsideTracker.

InsideTracker is a personalized nutrition platform

that analyzes data from blood and DNA

to help you better understand your body

and help you reach your health goals.

I've long been a believer in getting regular blood work done

for the simple reason that many of the factors

that impact our immediate and long-term health

can only be detected from a quality blood test.

The problem with most blood tests, however,

is that you get information back about hormone levels,

metabolic factors, et cetera,

but you don't really know what to do with that information.

Some things might be flagged as too high or too low,

but really interpreting those data and taking action

to bring those numbers into the ranges that you want

is what it's really about.

An InsideTracker makes all that very easy.

They have a platform, it's a dashboard

that will tell you for instance,

what sorts of dietary changes or supplementation changes

or exercise changes will help you bring various hormones,

metabolic factors, and other factors into the ranges

that are right for you.

If you'd like to try InsideTracker,

you can go to insidetracker.com/huberman.

And if you do that, you'll get 25% off

any of InsideTracker's plans.

Just use the code "huberman" at checkout.

Today's episode is also brought to us by Athletic Greens.

Athletic Greens is an all-in-one vitamin mineral

probiotic drink.

I've been using athletic greens since way back in 2012.

And so I'm delighted that they're sponsoring the podcast.

The reason I started taking Athletic Greens

and that I still take Athletic Greens

is that it really covers all of my foundational

nutrient and micronutrient needs.

It has vitamins, minerals,

and the thing that's especially important to me these days

is the probiotics,

because there are so many data

that show that having a healthy gut microbiome

is vital to having a healthy immune system

and for healthy gut brain axis,

literally the functioning of your brain, your mood,

various aspects of brain inflammation

or limiting brain inflammation are facilitated

by having a healthy gut microbiome.

And that's facilitated by getting the proper probiotics.

If you'd like to try Athletic Greens,

you can go to athleticgreens.com/huberman.

And if you do that, you can claim their special offer.

The special offer is five free travel packs,

which make it very easy to mix up Athletic Greens

while you're on the road or in the car,

and a year supply of vitamin D3K2.

Vitamin D3K2 have been shown to have a number of different

positive health effects on hormones,

on cardiovascular health, and so on.

Again, that's athleticgreens.com/huberman

to claim their special offer.

Today's episode is also brought to us by Belcampo.

Belcampo is a regenerative farm in Northern California

that raises organic, grass fed, and finished

certified humane meats.

I don't need a lot of meat.

Typically my diet regime is one in which I fast

until about noon,

and then I have a lunch which is fairly low carbs.

So I'll have some piece of meat or chicken or fish

and some salad typically.

And then in the evening is when I tend

to emphasize carbohydrates.

That helps me be really alert during the day

and sleep well at night.

When I do eat meat, I insist that the meat

be of the very highest quality

and that it is sourced in humane ways.

Belcampo's animals graze on open pastures

and seasonal grasses,

and that results in meat that is higher in nutrients

and healthy fats.

There are now a lot of data pointing to the fact

that high levels of omega-3 fatty acids are vital for mood,

for cardiovascular health and various aspects

of maintaining what's called a healthy Inflammatone,

the various things in our brain and body

that maintain a healthy inflammation response,

but one that doesn't go out of whack or get unchecked

in any way that is detrimental to us.

If you'd like to try Belcampo, first-time customers

can get 20% off by going to belcampo.com/huberman

and using the code "Huberman" at checkout.

That's belcampo.com/huberman for 20% off

and use the code "Huberman" at checkout.

Today we're discussing depression.

In particular, we're going to talk about major depression.

The phrase major depression is used to distinguish

one form of depression from the other,

the other one being bipolar depression.

Bipolar depression, sometimes called bipolar disorder,

is really characterized by manic highs.

So where people aren't sleeping

and they're talking very fast,

and they're buying things and pursuing resources

that they can't afford,

they're starting relationships left and right,

they're manic,

followed by periods of crashes of feeling very low,

lethargic, and so on.

Bipolar depression is an absolutely crucial thing

for us to discuss.

And therefore we are going to have an entire

separate episode related to bipolar depression.

Today, we're going to talk about major depression,

also sometimes called unipolar depression,

just because it doesn't have the highs and lows.

It's more characterized by the lows.

We're going to talk about the biology,

the psychology, and the various treatments,

behavioral, drug, supplementation, diet, exercise,

all of that.

Before we go forward into the material,

I just want to emphasize that any discussion

about mood disorders carries with it

a particular sensitivity,

and that sensitivity is one related to self-diagnosis.

Today's episode, and indeed in the future episodes

for this month on mood disorders,

you're going to hear various symptomologies that are used

to diagnose and characterize these disorders.

If you recognize some of these symptomologies in yourself

or in others that you know,

that's an important thing to take note of.

However, accurate diagnosis really should be done

by a qualified healthcare professional.

So at once I'm saying, keep your eyes and your ears up

for things that sound familiar to you

that might be of concern.

And at the same time,

I'm saying don't necessarily leap to conclusions.

Take those flags of concern if they're there

and bring them to a qualified healthcare professional,

and they'll be able to properly diagnose you

as having a particular mood disorder or diagnose somebody

as having a particular mood disorder or not.

And that's an essential step.

I don't say this to protect us,

I said this really to protect you.

Okay, let's have a fact-based discussion about depression.

And I promise you that where we don't know certain things

about depression, I will be clear to tell you.

In fact, we are going to talk about some treatments

for depression that are looking very promising,

and that right now are actually being used more and more.

And from my read of the mechanistic literature,

we're still a bit in the dark as to how these work.

That's actually a common theme of medicine.

Many times there are treatments that seem promising

or that look really terrific.

And there isn't a lot of understanding about mechanism.

However, any good discussion about neuroscience

and in particular about mood disorders,

has to get into mechanisms.

So we're going to do that.

And in doing that, we're going to frame the discussion

for the tools of how to keep depression at bay

and how to deal with it

if you happen to find yourself depressed,

or if you know somebody else who's depressed.

What is this thing we call depression?

Was I mentioned before, it has two forms,

bipolar depression, which we're not talking about today,

and major depression, also called unipolar depression

is the other.

Major depression impacts 5% of the population.

That is any enormous number.

That means if you're in a class of 100 people,

five of them are dealing with major depression

or have at some point.

Look around you in any environment

and you can be sure that a good portion of the people

that you're surrounded by is impacted by depression,

or will be at some point.

So this is something we really have to take seriously

and that we want to understand.

It is the number four cause of disability.

A lot of people miss work, miss school,

and before then likely perform poorly in work or school

due to major depression.

Now there's a very serious challenge in having a discussion

about depression and it relates directly to the challenges

in diagnosing depression.

Earlier, I did an episode with Dr. Karl Deisseroth,

who is indeed a medical doctor and a PhD.

He's a psychiatrist.

And he made a very important point,

which is that the field of psychiatry and psychology

are confronted with a challenge,

which is they're trying to understand what's going on

within the stuff that's in our brains

that's deep to our skulls.

We don't have access to that without brain imaging

and electrodes and things like that.

Someone just comes into the office and the dissection tool

for depression so to speak is language.

In order to determine if somebody has depression or not,

we have to use language, how they talk about things,

also how they carry their body.

Also some general patterns of health.

So let's talk about depression

the way that clinicians talk about depression,

because one of the issues is that

we use the word depression loosely.

A lot of people say, "Oh, I'm so depressed.

"I didn't get this job or I'm so depressed.

"I just don't know, I had a really rough week

"or I'm exhausted.

"I'm so depressed or I'm so depressed

"I thought I was going to go on vacation

"and then they canceled the flight." Okay.

That is not clinical depression.

That's called being bummed out, being sad or disappointed.

Now that person might be depressed,

but clinical depression

actually has some very specific criteria.

And those criteria are mainly characterized

by the presence of certain things

and the absence of a few particular things.

So let's talk about the things that are present

in somebody that has major depression.

First of all, there tends to be a lot of grief.

There tends to be a lot of sadness.

That's no surprise.

The threshold to cry is often a signature of depression.

Now that doesn't mean that if you cry easily,

that you're depressed.

Some people cry more easily than others,

but if you're somebody who typically didn't cry easily

and suddenly you find yourself crying very easily,

that could be a sign of depression.

And I want to emphasize, could.

There's also this thing that we call anhedonia,

a general lack of ability to enjoy things,

things that typically or previously we enjoyed.

Things like food, things like sex, things like exercise,

things like social gatherings,

a kind of lack of enjoyment from those things.

Sometimes that lack of enjoyment is sad,

and sometimes it's just flat, it's just kind of neutral.

It doesn't feel good because nothing there.

It's like bland food.

It's like these experiences are analogous

to biting into your favorite article of food

and it just not tasting very good.

It just doesn't taste like anything at all.

And that's a common symptom of major depression.

The other one is guilt.

Oftentimes people with depression will feel very guilty

about things they have done in the past,

or they'll just generally feel badly about themselves.

And we're going to talk about this because it relates

to some of the more serious symptomology

seen in depression sometimes,

things like self harm, mutilation, or even suicide.

But for the time being, we want to frame up anhedonia,

this lack of ability to achieve or experience pleasure,

or kind of a flat affect as it's called.

Sometimes even delusional thinking,

negative delusional thinking,

and in particular anti-self confabulation.

What is anti-self confabulation?

Well, first of all, confabulation is an incredible aspect

of our mind and our nervous system.

You sometimes see other forms of confabulation

in people who have memory deficits

either because they have brain damage

or they have age-related dementia.

A good example of this would be someone

with age related dementia sometimes will find themselves

in a location in the house and not know how they got there.

And if you ask them, "Oh, what are you doing here?"

They will create these elaborate stories.

"Oh, I was thinking about going to the shopping today,

"and I was going to take the bus,

"and then I was going to do this."

They create these elaborate stories, they confabulate.

And yet that person hasn't left the house in weeks

and that person doesn't have a driver's license.

And so they're really just creating this stuff.

They're not lying to get out of anything,

they're confabulating.

It's as if a brain circuit that writes stories,

just starts generating content.

In major depression,

there's often a state of delusional anti-self confabulation,

where the confabulation are not directly

or completely linked to reality,

but they are ones that make the self,

the person describing them,

seem sick or in some way not well.

A good example would be somebody

who experiences a physical injury perhaps.

Maybe they break their ankle, maybe it's an athlete,

and they also happen to become depressed.

And you'll talk to them and say, "How are things going?

"How's your rehab though?"

And they go, "Oh, it's okay. And I don't know.

"I feel like I'm getting weaker and weaker by the day.

"I'm just not performing well."

And then you'll talk to the person

that they're working with,

their kinesiologist or whoever the physical therapist is.

And they'll say, "No, they're actually really improving.

"And I tell them they're improving,

"but somehow they're not seeing that improvement,

"they're not registering that improvement."

You notice that sometimes it's subtle

and sometimes it's severe, but they'll start confabulating.

You'll say, "I actually heard you're doing much better.

"You're getting better, you're taking multiple trips

"around the building now

"before you could barely get out of bed."

And they'll say,

"Yeah, well basically, they changed some things

"about the parking lot that make it easier to move around.

"So it's not really me."

And these aren't people that are just explaining away

their accomplishments

'cause they're trying to brush off praise.

They are viewing themselves

and they're confabulating according to a view

that is very self-deprecating

to the point where it doesn't match up with reality.

It's not what other people see

and it's actually not matched up with reality.

And that's a symptom of depression

that I think we don't often think about

or conceptualize enough.

So it's not just telling people,

"oh yeah, it's not as good as it seems. Everything's bad."

These people really believe that

and it becomes disconnected from reality.

So it's if they're sort of sinking into a pit

and they're losing touch with the realities of the world,

including data about themselves,

their ability to move and get around it,

for example, in that particular instance

that I used as an example, but there are others as well.

The other common symptomology of major depression

is what they call vegetative symptoms, okay?

So vegetative symptoms are symptoms that occur

without any thinking, without any doing,

or without any confabulation.

These are things that are related to our core physiology.

The word vegetative,

you might know it sounds like vegetable.

It actually relates to a system in the body

that nowadays is more commonly called

the autonomic nervous system.

The vegetative nervous system

and the autonomic nervous system,

historically were considered sort of one in the same.

And it relates to things like the stress response

or to our ability to sleep.

So vegetative symptoms

be things like constantly being exhausted.

The person just feels exhausted.

It's not because they exercise too much,

it's not necessarily because of a life event, it could be,

but they're just worn out.

They don't have the energy they once had.

So it's not in their heads, it's probably,

and now I think we have good data to support the fact

that there's something off,

something is disrupted in the autonomic

or so-called vegetative nervous system.

And one of the most common symptoms

of people with major depression,

one of the signs of major depression is early waking

and not being able to fall back asleep

despite being exhausted.

So waking up at 3:00 AM or 4:00 AM or 5:00 AM

just spontaneously and not being able to go back to sleep.

I want to emphasize that that could happen

for other reasons as well, but it is a common symptom

or warning sign of major depression.

So let's talk more about sleep and depression.

It's well-known that the architecture of sleep

is disrupted in depression.

What's the architecture of sleep?

I've done entire episodes about this,

but very briefly in two sentences,

although they're probably be run on sentences,

early in the night,

you tend to have slow wave sleep more than REM sleep

or Rapid Eye Movement sleep.

As the night goes on,

you tend to have more Rapid Eye Movement sleep.

That architecture of slow wave sleep

preceding Rapid Eye Movement sleep

is radically disrupted in major depression.

In addition, the pattern of activity in the brain

during particular phases of sleep is disrupted.

Now this is during sleep.

So this can't be that people

are creating this situation for themselves.

These are real physiological signs that something is off

in this so-called autonomic or vegetative nervous system.

And then there are some other things that relate

to the autonomic nervous system,

but that we normally think of as more voluntary in nature.

And these are things like decreased appetite.

So you can imagine that one could have decreased appetite

because of the anhedonia,

the lack of pleasure from food, right?

If you don't enjoy food,

then you might be less motivated to eat it.

That makes sense.

As well because of these disruptions

in the autonomic nervous system,

these vegetative symptoms, as they're called,

you can imagine that someone would have decreased appetite

because some of the hormones associated with appetite,

hypocretin orexin and things of that sort, ghrelin,

that those will be disrupted.

And if those names of hypocretin orexin and ghrelin

don't make any sense to you, don't worry about it.

What those are just hormones that impact when we eat,

when we feel hungry, and when we crave food more,

as well as when we feel full,

we have enough so-called satiety.

If you want to learn more about those,

we did entire episodes on eating and metabolism.

So you can see that the symptomology of major depression

impacts us at multiple levels.

There's the conscious level of how excited we are generally.

Well, that's reduced.

There's grief, there's guilt, there's crying,

but then there's also these vegetative things.

There's disruptions in sleep,

which of course make everything more challenging

when we're awake.

We know that sleep is so vital for resetting.

You're waking up early, you can't get back to sleep.

That's going to adjust your affect,

your emotions in negative ways.

We know this.

And appetite is off.

And there are hormones that get disrupted.

So cortisol levels are increased.

In particular, there's a signature pattern of depression

whereby cortisol, the stress hormone that normally

is released in a healthy way

only in the early part of the day

is shifted to late in the day.

In fact, a 9:00 PM peak in cortisol

is one of the physiological signatures

of depressive like states.

It's not the only one, but it is an important one.

So there are a lot of things going on in major depression.

And by now you're probably thinking,

goodness, this is dreadful.

Like there's all this terrible stuff.

And indeed it is terrible.

It is a terrible thing to find oneself

in a mode where things feel sad, you feel guilty,

you're exhausted.

And oftentimes there's also an association

with the anxiety system.

So just because people are exhausted

and lethargic and they don't enjoy things,

doesn't necessarily mean that there's an absence of anxiety.

There can also be a lot of anxiety

about what's going to happen to me.

Am I going to be able to achieve my goals in life?

Will I ever get out of this state?

And so things really start to layer on.

And if this sounds depressing to you,

it is indeed depressing.

This is really the place that many people find themselves.

And it's a pit that they just don't know

how to climb out of.

So let's just take a few minutes

and talk about some of the underlying biology

that creates this cloud or this constellation

of symptomology.

I think that's really important to do

because if we want to understand the various treatments,

how they work and why they work and how to implement them,

we have to understand some of the underlying biology.

So let's spend a few minutes

talking about the biology of depression,

what's known and what's not known.

Because in doing that,

I think you'll get a much clearer picture

about why certain tools work to relieve depression

and why others might not.

So one of the most important early findings

in the search for a biological basis of depression

was this finding that there are drugs

that relieve some of the symptoms of depression.

Those drugs generally fall into three major categories,

but the first set of ones that were discovered

were the so-called tricyclic antidepressants,

and the MAO inhibitors, the monoamine oxidase inhibitors.

You don't need to understand that nomenclature,

but I'm going to give you a little bit of detail

so that if you want to understand it, you can.

Most of this work took place in the late 1950s

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 increase 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 the 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, weight gain.

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, 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 Re-Uptake Inhibitors.

The SSRIs worked by distinct mechanisms

from the tricyclic antidepressants and the MAO inhibitors.

As their name suggests, SSRI,

Selective Serotonin Re-Uptake 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,

can change the activity of large groups of neurons

in very meaningful ways.

Selective serotonin re-uptake 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 re-uptake 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 awhile 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 neuro-plasticity

by changing the way that neural circuits function.

And there are many on this,

but the main categories of studies on SSRIs

that relate to neuroplasticity fall into two camps.

One is that 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.

There 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 that younger humans

have a far more plastic brain that 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, epinephrin 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 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,

do you just give that person some drugs increase dopamine

and everything will be better?

And indeed, in some cases that's true.

There are drugs like Wellbutrin,

which function more specifically on the dopamine system

to increase dopamine and they also increase norepinephrine.

Many people get great relief from things like Wellbutrin.

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, 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 it,

that 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 and 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 of depression.

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 is only related

to 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 hypo thyroidal.

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 psychiatrists 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 pre-existing 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 parturition 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, certain 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, menopausal 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, 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 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,

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 5HTTLPR,

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 about 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 about of stress, the probability

that you will experience a major depression goes up.

However, if you carry this gene, this HTTLPR gene,

the steepness of that curve goes way, way up

where 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 about 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

to depression.

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 sack

or two biological sacks 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% generic, 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.

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?

It 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.

Why mechanism?

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.

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 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.

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.

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, alright?

Not all of these are cytokines.

You have interferons and prostoglandins

and a lot of these things.

But when we are stressed, chronically stressed,

we get inflamed, our brain and various locations

of 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 epinephrin, 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 prostoglandins,

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 review 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,

1000 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 1000 milligrams

or 1200 milligrams.

But what's really important to look at

is whether or not there's more than 1000 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 1000 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 ingest,

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,

1000 milligrams or 2000 milligrams of EPA,

there does seem to be some substantial relief

for many people, should emphasize many, not all,

for many people in major depressive symptoms.

So how would this work?

Well, 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 5HT,

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 late in 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, Indoleamine,

which converts tryptophan into kynurenine.

Kynurenine actually acts as a neurotoxin

by way of converting into something called quinolinic acid.

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 serotoninergic 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 contouring 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 1000 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, right?

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 Review 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 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 is 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 melowish 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 1000 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 NDHA 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 1000 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 pub med,

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 acids supplementation and 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.

And 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

as 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 a high-dose EPA.

So we've got EPA, we 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, glial,

and glial comprise several cell types,

microglia, astrocytes, et cetera,

but the foster creatine 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 they're probably more by the 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.

The studies have looked at women,

have it 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 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 is 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

re-uptake 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 creating 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 neuroscientists 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.

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 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

is 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 a creatine might be working.

So now we've kind of clustered together EPAs,

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,

who was Dr. Karl Deisseroth,

who was a guest on the Huberman Lab podcast

a few months ago.

He's 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 a,

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 retro splenium 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 over written

or as burdened by their own emotions

as they did previously to the ketamine therapy.

Now, absolutely in no way, shape or form

am I suggesting 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 U S,

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

from everything.

It sounds a little bit like depression itself.

That's sort of like anhedonia and 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 ongoing.

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 MDA 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 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 has 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 antenna 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 the 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 neurocircuits 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 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,

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 confabulation,

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.

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 experienced 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 as 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 just scribe 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 serotonin transmission,

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

'cause 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

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, Patrick Finan,

Roland Griffiths, and others.

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 that are 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 wanted 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 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,

whether or not they stayed in remission from the depression,

but these are really enormous insignificant 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 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 5HT1A 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 and 5HT1A 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.

It'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 that 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 where 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 them about micro dosing.

I made it sound as if I'd never heard about it before.

Microdosing, not micro dosing.

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,

well, 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 breakthrough seemed 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 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 it's 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 or all meat diet.

On that, I think there are now some

that are starting to spin up,

meaning those 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 it basically, maniacs have highs and they have lows,

bipolars, either cycle back and forth really quickly.

So rapid cycling bipolars or slow, 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 tight 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?

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,

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 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

for which an epilepsy would be terrible.

The reason why the epileptic diet is useful for epilepsy

is that increases what we call the tonic level,

the sort of the ti, the level of GABA in the brain,

and that suppresses some of the hyperexcitability,

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 increased 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 is inhibitory neurotransmitter,

and their balance is vital for neuroplasticity,

for maintaining healthy levels of activity in the brain,

et cetera.

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.

Psychiatrists vary 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 in 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 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.