How Psilocybin Can Rewire Our Brain, Its Therapeutic Benefits & Its Risks | Huberman Lab Podcast

ANDREW HUBERMAN: Welcome to the Huberman Lab podcast

where we discuss science and science-based tools

for everyday life.

[MUSIC PLAYING]

I'm Andrew Huberman, and I'm a professor

of neurobiology and ophthalmology

at Stanford School of Medicine.

Today, we are discussing psilocybin.

Psilocybin is a psychedelic, meaning it modifies the psyche.

And in doing so, it changes our level of consciousness.

Psychedelics, such as psilocybin changed the way

that we perceive the outside world and our internal world,

our memories, our thoughts, our feelings, et cetera.

Not just while one is under the influence of psilocybin,

but it can also fundamentally change

all of those things afterwards and for a very long period

of time afterwards as well, which

is one of the reasons why there's

growing excitement about the application of psilocybin

and other psychedelics for the treatment

of various mental health issues, such as depression,

alcohol abuse disorder, and addictions of various kinds,

as well as things like OCD and eating disorders.

Today, we will discuss psilocybin,

talking about what it is.

In fact, you may be surprised to learn that psilocybin basically

is serotonin.

Now, for those of you that are familiar with psilocybin

and serotonin, you might think, wait, that's not true.

But, in fact, psilocybin main effect is to mimic serotonin.

But it does it in a very specific way

because it activates a subset of serotonin receptors in a very

strong fashion leading to neuroplasticity

at the level of the neural circuits, that is the brain

areas and the connections that serve things like memory

and perception.

So if any of that is confusing at this point,

I promise to make it all clear in just a few minutes.

Psilocybin is one of many psychedelics, of course.

There are things like LSD, DMT, 5-MeO-DMT.

Even MDMA while not considered a classic psychedelic

is considered a psychedelic in the general sense.

Today's episode is going to focus on psilocybin

in particular.

I will tell you what psilocybin is,

how it works at the molecular and cellular level.

I'll talk about how it changes brain circuitry.

I'll talk about the clinical effects

what's been demonstrated in controlled laboratory studies.

I'll talk about dosages and translating

from psilocybin mushrooms to actual psilocybin,

and the compound that actually exerts

the effects of psilocybin which it turns out is not psilocybin,

but something called psilocin.

Psilocin is the actual compound that

goes into the brain to create all the changes

in consciousness and all the rewiring effects

that we associate with psilocybin.

So understanding how psilocybin is converted to psilocin

has tremendous impact on the duration of a psilocybin

journey, whether or not that psilocybin journey

is going to lead to a short or longer window

for neuroplasticity.

In fact, many people don't realize this.

But much of the positive changes that are possible with proper--

and I do want to underscore proper psilocybin therapeutic

approaches, takes place after the session in which one feels

all typical or typically associated

effects of psilocybin like hallucinations and changes

in thought patterns, et cetera.

So today, we are going to talk a little bit about chemistry.

But I promise to make it accessible to anyone

and everyone, regardless of whether or not

you have a background in chemistry or biology.

We're going to talk about some cell

biology, the actual neuronal changes that occur

when one takes psilocybin.

And we're going to talk about how neural circuits change

over time and how all of that impacts the changes

that most people are interested in when they go on a psilocybin

journey.

Things such as long standing improvements

in mood, things such as tremendous insight

into themselves and to others, into their past, their present,

and their future, and even changes

in their levels of creativity, or their ability

to experience joy from music or their ability

to dissociate in a positive way from things

that formerly were depressing or triggers for depression.

In fact, we're going to talk quite a lot

about the conditions inside of a psilocybin journey that

make it actually positive and therapeutic.

This is a very important point that I'll make several times

throughout today's episode, which

is that just because something invokes

neuroplasticity changes in brain circuitry

does not mean that it's therapeutic, or I should say,

does not necessarily mean that it's therapeutic.

For neuroplasticity to be therapeutic,

it has to be adaptive, it has to allow someone

to function better in life than they did previously.

So today, we will talk about how the conditions of a psilocybin

journey, including whether or not

it's done with eyes closed or eyes open,

or whether or not people alternate between eyes

closed and eyes open phases of that journey,

as well as whether or not music is played during that journey,

and even what types of music are played

will dictate whether or not somebody

will feel better or worse in the days and weeks and years

following that psilocybin journey, as well as the dosage

level.

Because as you'll soon learn as well,

there are clinical studies showing that just

one psilocybin journey can improve mood

in a long-standing way.

But most clinical trials involve two dosages

spaced in very precise ways from one another with appropriate

follow up.

But in both of those particular journeys,

the structure of the journey who's present,

who's not present, eyes open or eyes

closed, the particular music that's played.

All of those features make up part

of a larger neuroplasticity trigger

of which psilocybin is critical.

But psilocybin is not the only variable.

So whether or not you're interested

in participating in a clinical study, or whether or not you're

interested in psilocybin for other reasons,

this is critical information to understand.

So today, we're going to talk about nearly every feature

of psilocybin possible, including what psilocybin is,

how it works at the level of chemistry cell biology,

and neural networks, and neuroplasticity.

We'll talk about the clinical studies.

We'll talk about dosages.

We will talk about conditions of clinical studies,

and we will talk about the post psilocybin journey

period in which neuroplasticity and the various activities,

including therapy or perhaps not therapy

can contribute to positive therapeutic changes

from psilocybin.

Now, as we go into this discussion,

I do want to underscore the fact that at the time of recording

this episode, meaning now, May 2023,

psilocybin is still a Schedule I drug.

It is considered illegal in the United States.

There's perhaps just one exception to that,

maybe a few others.

But the main exception is in the state of Oregon,

psilocybin has been approved in particular therapeutic settings

for use in particular conditions namely depression

and some forms of addiction.

So in Oregon, it's more or less in the domain

of a decriminalized as opposed to actually legal.

In other areas of the country, including Oakland, California,

there are some areas in which it has been decriminalized.

And perhaps there are a few others that I'm not aware of.

But, in general, psilocybin and other psychedelics

are still considered illegal.

And this is very important.

Not just saying this to protect me,

I'm saying this to protect you.

Possessing or certainly selling psilocybin,

except for rare instances, such as clinical studies

and these decriminalized areas that I

talked about a moment ago is still very much not allowed

under the law.

Today, I'll also discuss safety issues.

I'll talk about whether or not young people,

meaning people 25 or younger should consider psilocybin

given that their brain is still in a rampant period

of naturally occurring neuroplasticity.

I will also talk about dosages as it relates

to people who have formerly been on

or may currently be on different forms of antidepressants.

And I will talk about people who are

at risk for psychotic episodes either

because they know they themselves

have a propensity for psychosis or they have close family

members who have psychosis, which includes things

like schizophrenia, bipolar depression, as well as things

like borderline personality, and some related

psychiatric conditions.

So today's episode really will be a deep dive into psilocybin.

So whether or not you think you're already

familiar with psilocybin and its effects,

or whether or not you're just curious about them,

I do encourage if you're willing to try and ratchet through some

of the understanding of how psilocybin works

and what it is, leading up to some

of the therapeutic applications and different patterns

of dosing spacing of different sessions, et cetera.

Because I do believe that with that knowledge in hand,

you will be able to make far better, much

more informed decisions about whether or not

psilocybin is right for you.

Before we begin, I'd like to emphasize

that this podcast is separate from my teaching and research

roles at Stanford.

It is, however, part of my desire

and effort to bring zero cost to consumer information

about science and science related tools

to the general public.

In keeping with that theme, I'd like

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Let's talk about psilocybin.

And, again, today we're going to focus specifically

on psilocybin.

And we're going to set aside all the other psychedelics

for future episodes.

Psilocybin is what's called a tryptamine.

That refers to its chemical composition,

not to the so-called psychedelic trip.

In fact, it's spelled differently.

Tryptamine is T-R-Y-P. Trip, T-R-I-P, of course.

Tryptamines include psilocybin, but also

things like DMT and 5-MeO-DMT.

The tryptamine psychedelics very closely

resemble serotonin itself.

That's right.

Most of you have probably heard of the chemical serotonin.

And serotonin is what's called a neuromodulator, which

means your brain and body naturally make it,

and that it modifies or changes the activity of other neurons

and neural circuits.

And it does that generally by either increasing or decreasing

the activity of those neural circuits.

If I were to show you a picture of the chemical structure

of psilocybin or its active derivative psilocin,

and I were to also put right alongside it

an image of the chemical structure of serotonin,

provided that you weren't a chemist who really likes

to focus on the detailed differences between things,

you would say those look very similar.

And indeed, psilocybin in its active form psilocin

are very similar structurally and chemically

to serotonin itself.

Now, as I mentioned before, serotonin is something

that you naturally make.

And yes, it's true that about 90%

of the serotonin in your brain and body

is manufactured in your gut.

However, contrary to popular belief,

the serotonin in your brain is not manufactured

from the serotonin in your gut.

You have separate independent sources of serotonin.

That is you have particular neurons that

make serotonin in your brain.

You also have serotonin in your gut

and those work more or less in parallel separately.

Now, what does serotonin do.

This is really important to understand because

of the similarity between psilocybin

in its active form psilocin and serotonin.

Serotonin in that it's a neuromodulator

changes the activity of other neurons

and the net effects of those changes

are things that you're familiar with.

For instance, satiety or the feeling that we've had

enough of various things, such as food,

or a social interaction, or sex, or pleasure of any kind.

Serotonin is involved in all of that.

And an enormous number of other things,

such as mood regulation such as our sense of pleasure

itself, or lack of pleasure, such as whether

or not we feel motivated or not motivated.

It works in concert with other neuromodulators,

such as dopamine and epinephrine and norepinephrine.

In fact, if this were an episode about serotonin,

which it is not.

You would soon realize that serotonin

is involved in so many different functions that

impact our daily life.

And that is one reason why certain antidepressant

medications which alter either increase or decrease

the amount of serotonin transmission in the brain

will often have a lot of side effects

related to things like mood, libido, appetite, sleep, et

cetera.

It's because serotonin is involved

in so many different things.

And serotonin is involved in so many different things

because there are a lot of different so-called serotonin

receptors.

Serotonin is a chemical that we call a ligand.

And the chemical ligand is simply

the thing that plugs into the receptor for that chemical

or ligand.

The receptors, in this case, serotonin receptors,

have the opportunity to do all sorts of different things.

They can change the activity of neurons making them

more active or less active.

They can cause growth factors to be released making sure

that those neurons reinforce or even build up

stronger connections so that they're

more likely to be active in the future.

Serotonin binding to particular receptors

can even change the gene expression in particular cells

making those cells proliferate.

So make more of them.

Making those cells more robust, making those cells

interact with new elements of the brain and body.

Basically, serotonin and all these different receptors

that it binds to has dozens, if not hundreds, and maybe even

thousands of different functions.

So the fact that psilocybin so closely resembles serotonin

leads to a very important question

that we should all be asking ourselves, which is, why is it

that psilocybin, which looks so much like serotonin when one

takes it in the form of magic mushrooms,

or some other form, maybe the synthetic form of psilocybin

itself, which nowadays is manufactured in laboratories

and placed in different psilocybin containing

foods and pills, et cetera.

Why that leads to complex yet fairly circumscribed

sets of experience like visual and auditory hallucinations,

changes in particular thought patterns,

and neuroplasticity that, in many cases,

in the clinical setting provided things are done correctly.

Improvements in mood, relief from depression,

relief from various compulsive disorders, et cetera.

All right.

This is really what you need to understand

if you want to understand psilocybin, and how it works,

and how to make it work optimally

for a given condition or goal.

You have to understand what it's actually doing

and what allows psilocybin to do fairly specific things

in comparison to serotonin.

Even though psilocybin and serotonin are so similar

is that psilocybin mainly binds to and activates

the so-called serotonin to a receptor.

The serotonin to receptors is one

of, again, many different serotonin receptors.

But serotonin 2A is expressed in particular areas of the brain

and even on particular areas of neurons in the brain that

allow for very specific types of changes in neural circuitry

to take place, not just when one is

under the influence of psilocybin,

but afterwards as well.

So really in order to have a useful discussion

about psilocybin, we need to talk a lot about the serotonin

to a receptor.

But fortunately for you, unless you're

somebody really interested in structural biology or cell

biology, that discussion is not going

to be about the binding pocket for serotonin on serotonin 2A

receptor, or a lot of the downstream signaling

of the serotonin to a receptor.

We'll talk a little bit about that where it's relevant.

But more importantly, at least for sake of today's discussion,

we're going to talk about how the serotonin 2A

receptors really the one responsible for triggering

all the changes in neural circuitry

that lead to the changes, that is the improvements in mood,

the relief from compulsive disorders in many cases,

but really it's the serotonin 2A receptor selectivity

of psilocybin that is leading to all the excitement

that you hear about in terms of psilocybin

as a therapeutic tool.

Let me say that from a slightly different angle.

There are data that I'll talk about today, which

show that one, although in most cases,

two psilocybin journeys done with particular dosages

of psilocybin lead to maximal binding

or occupancy of those serotonin 2A receptors

in ways that lead to significant and unprecedented relief

for major depression.

In fact, you'll soon learn that the clinical trials

for psilocybin are outperforming standard therapy

and outperforming so-called SSRIs

and various other antidepressants

in terms of providing depression relief in ways that are frankly

staggering not just to me, but to the psychiatric community

at large.

And this is where so much of the excitement is coming from.

Now that statement could be taken

one way, which is to just say, OK, well,

here's a compound psilocybin that outperforms SSRIs.

And, therefore, all the attention

should be on psilocybin.

But SSRI stands for Selective Serotonin Reuptake Inhibitor.

In other words, the SSRIs of which

there is now a lot of controversy things

like Prozac, Zoloft, et cetera--

I'm sure you've heard some of this controversy.

There are people who are very pro SSRIs although there

are a growing number of people who really feel

that the SSRIs are probably most appropriate for things

like obsessive compulsive disorder where they, in fact,

can be very beneficial.

But there is a lot of leaning back from SSRIs

as the be all end all for the treatment of depression

nowadays because of the side effect profiles.

And the fact that it's not even really clear

that serotonin deficiencies are the major cause of depression

in the first place.

Now, again, we're talking about psilocybin not about SSRIs,

but you should be thinking, wait,

how is it that two molecules psilocybin

and some particular SSRI both of which

look like and/or increase serotonin

transmission in the brain are leading to either incredibly

positive and interesting outcomes

or to troubling side effect riddled outcomes?

And, again, it all boils back down

to the selectivity of psilocybin to bind

that serotonin to a receptor.

And so in order to understand how psilocybin works

and in order to understand proper dosing profiles

and spacing of sessions a.k.a. journeys,

we really need to talk a little bit more about the serotonin

to a receptor, where it is in the brain, what sorts of things

happen when psilocybin binds the serotonin to a receptor,

and how those things set in motion,

the various changes, the neuroplasticity

that allows people to feel better in terms of their mood,

and as you'll soon learn, can experience

more pleasure and joy from things like music and enhanced

creativity.

All the things that I do believe whether or not

people are thinking about or maybe even exploring psilocybin

for recreational or therapeutic purposes, all the things

that people want and are really talking about

and perhaps even doing psilocybin in order to obtain.

So before going any further, I just

want to place an image in your mind.

You can place an image in your mind whereby when serotonin

is released in the brain naturally

not having taken any compound, any drug, anything.

It's getting released a lot of different sites

binding to a lot of different serotonin receptors,

doing a lot of different things.

When somebody takes an SSRI, the net effect

of that selective serotonin reuptake inhibitor

is that there's more serotonin around to exert its effects.

Because it's a reuptake inhibitor

at the synapse, the connections between neurons,

the serotonin can do its thing more extensively

and for longer periods of time.

But it's doing it non-specifically.

So when you think about standard antidepressant treatments,

at least for sake of this discussion,

you think of a sprinkling or a spraying of serotonin

at different locations in the brain and binding

to lots of different receptors.

Whereas when you think about psilocybin, even

though the subjective effects are pretty diverse,

we'll talk about those in a few moments, what you're really

talking about is a molecule of psilocybin

that looks a lot like serotonin that

is selectively and very strongly binding to

and activating that serotonin to a receptor.

So that's the image I'd like you to embed in your mind.

And then the next image I'd like you to embed in your mind

is where these serotonin 2A receptors

are located in the brain.

Now, the serotonin 2A receptors are located

in multiple brain regions.

But they have a tremendous amount of expression

in the so-called neocortex, the outside of the brain that

includes things like our prefrontal cortex, which

is involved in understanding context, which behaviors,

thoughts, and speech patterns are

appropriate for certain circumstances,

how to switch context and category switch when you go

from playing sports, to hanging out with friends,

to being in a professional setting.

You change your behavior in the way that you speak

and perhaps even the way that you think.

You might think some things that are out of context.

But you probably keep those to yourself.

And your ability to keep those to yourself

are dependent on a functional prefrontal cortex.

There are a lot of 5-HT2A.

And by the way 5-HT is the abbreviation for serotonin.

So there are a lot of serotonin 2 receptors

in the prefrontal cortex, also in other areas

of the cortex that are associated

with sensation and perception.

That is hearing of sounds, that is seeing of particular things.

And in particular, there is a very, very, very high

expression of serotonin 2A receptors in the visual cortex.

And that is one of the reasons why psilocybin

triggers visual hallucinations.

And provided psilocybin is present

at sufficient enough concentration that

is taken at a sufficient dosage, one

will experience profound visual hallucinations regardless of

whether or not their eyes are open or their eyes are closed.

Now, that's an important fact because it explains

one of the major effects of psilocybin

that people experience while they are on the drug.

Now, as I'll talk about a little bit later

in terms of what constitutes a useful psilocybin

session, useful meaning that it's leading to adaptive

improvements in mood, adaptive improvements in creativity,

in cognition, et cetera, is that people not have their eyes open

for at least the majority of the psilocybin session,

this is something I've discussed with several experts who

are running clinical studies on psilocybin

in their laboratories, some of whom

are going to be guests on the Huberman Lab

podcast in upcoming episodes,

Again, I can't underscore this enough.

Because your visual cortex contains

so many of these serotonin 2A receptors,

and because psilocybin binds so strongly to that serotonin

to a receptor, you're going to experience

a lot of visual hallucinations when

you are under the influence of psilocybin.

There's no surprise there.

This has been known for hundreds, if not,

thousands of years.

It's one of the main reasons why people take psilocybin.

However, as I mentioned earlier, these hallucinations

occur even when the eyes are closed.

And it's now fairly well-established

that if people are to take psilocybin and have

their eyes open, much of their cognition,

much of their thinking, much of the time spent

in that psilocybin journey is focused

on the altered perceptions of things

in the outside environment.

Sometimes this looks like a fracturing of the outside world

into geometric shapes.

Sometimes it appears as a melting

of things in the visual environment,

including people's faces or a morphing of people's faces.

All of that has a strong let's just

call it a draw for a lot of people

who are looking for a highly unusual experience

inside of the psilocybin journey.

But I think if one's goal is to derive long-lasting benefit

from the psilocybin experience, it's

very clear that having an eye mask or some other eye covering

or something that ensures that one's eyes are closed

for the majority, if not, the entire psilocybin session is

going to be very useful because it's

going to limit the extent to which one is focused

on those outside changes in visual perception a.k.a.

hallucinations and rather will allow the person

to go inward to combine whatever it is that they happen

to be seeing in their mind's eye with the different thoughts

and memories and changes in their emotions

that are occurring.

And that going inward by staying in the eye mask,

at least for the majority of the time,

seems to be a very, if not, the critical feature

of making the psilocybin journey effective in

the therapeutic sense.

Now once again, I want to cue to some of the safety precautions

here.

I'm going to say this at least three times throughout today's

episode.

As I'm talking now and various other times

throughout today's episode, you may get the impression

that I'm all for everybody doing psilocybin.

And that is simply not the case.

In order for a psilocybin journey

to be therapeutically useful, it does require certain conditions

and supports.

And there are certain people for which psilocybin use

is going to be contraindicated, meaning

they should not do psilocybin.

In particular, people who have existing or have

a predisposition to psychotic episodes or bipolar episodes,

even having a first relative who has bipolar,

or schizophrenic, or schizotypal issues

can be a rule out condition, that is can get someone

eliminated from a clinical study on psilocybin

for fear of triggering psychotic episodes,

not just during the psilocybin journey,

but potentially in a long standing way.

So, again, that's really critical.

The other thing is that everything

I'm talking about today unless I say otherwise

is really focused on adults, meaning people who

are 25 years old or older.

That is their basic wiring and rewiring of the brain

that we call developmental neuroplasticity is completed.

All right.

Most of the studies today that I'll

talk about involve subjects ranging from 25 years of age

out to about 70 years of age, but no one younger.

So, again, psilocybin and its use

is certainly not for everybody.

It's still illegal, it's being used in the clinical setting

and research setting.

There are these pockets of decriminalized areas,

and potentially soon legalization of psilocybin,

but again only in the proper clinical setting.

OK.

Again, I say that not just to protect myself,

but I say that also to protect all of you.

Psilocybin is a powerful, powerful drug.

Not just to be under the influence of,

but also in terms of its long-standing changes

after the effects of psilocybin have worn off.

I'd like to take a quick break and acknowledge

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Again, that's athleticgreens.com/huberman

to get the five free travel packs and the year supply

of vitamin D3 K2.

Let's talk a little bit about dosing of psilocybin

and also about microdosing of psilocybin.

Now, this is an area that I wouldn't say is controversial,

but that there's how should we say this.

There's a lot of loose thinking around

this in the non-clinical non-research communities.

But within the clinical and research communities,

there is a lot of data that's come

out indicating what effective and safe doses provided

all other things are considered safe.

Safe doses of psilocybin actually are.

And here, we really can go back to our discussion of psilocybin

as quote-unquote magic mushrooms or mushrooms.

And if one were to translate from the mushroom

form of psilocybin to the psilocybin that's actually

used in various studies-- because frankly,

in these studies, people aren't eating mushrooms.

They're typically taking synthetic psilocybin

either intravenously injected into a vein or orally.

And that's how the researchers are able to tightly control

the amount of psilocybin.

And the typical dosage that's used in clinical studies

ranges from 1 milligram often given repeatedly

from day-to-day over long periods of time,

so-called microdosing.

And really that 1 milligram per day or even up

to 3 milligrams per day repeatedly over time

is what people generally think of as microdosing.

As compared to say a 10-milligram dose given once,

maybe twice in two separate sessions, or a 25 to 30

milligram dosage that's given once or twice.

Now, those amounts of 1 to 3 milligrams or 10 milligrams,

or 25 to 30 milligrams might not mean

much to those of you that don't think

about these things in the research terms.

Perhaps, you've heard of microdosing

and you've also heard of macro or quote-unquote heroic dosing.

OK.

That's common or I should say popular nomenclature

for psychedelics.

And I'll circle back to that in a few minutes.

But I think one of the questions that I hear a lot is,

how much psilocybin is present in a given amount of mushrooms?

And so the way this typically works

is that mushrooms are often discussed in terms of grams,

or ounces.

So an 1/8 of mushrooms refers to an 1/8

of an ounce of mushrooms, or x number of grams of mushrooms.

The breakdown is actually quite simple.

1000 milligrams equals 1 gram.

And the concentration of psilocybin

in most so-called magic mushrooms is about 1%.

So 1 gram of mushrooms being 1000 milligrams

means that it contains approximately.

And, again, it's approximately 10 milligrams of psilocybin.

And in most of the clinical studies,

it's been shown that the dosage of 25 to 30mg given--

or I should say, taken once or twice--

and we'll talk about the spacing of sessions a little bit later,

taken once or twice is what's leading to the most pronounced

therapeutic outcomes.

But, of course, with enhanced therapeutic outcomes,

one also observes enhanced side effect profiles or what

are called adverse events.

So there's an important nuanced conversation

that has to take place.

But right now, we're talking about the conversion of grams

of mushrooms to psilocybin.

So 1 gram of mushrooms being 1000 milligrams containing

1% psilocybin means that it contains

10 milligrams of psilocybin.

Now, the so-called heroic doses that you've heard about.

And this is something that's discussed.

More with the let's call them traditional or classic

Psychonauts.

These are people that may have an advanced degree,

but typically are not running laboratories

exploring the effects of psilocybin

in controlled clinical trials.

These are people who have been long time explorers, and often

writers, and people who have been

spokespeople for psilocybin and other psychedelics.

And they will often refer to the so-called heroic doses.

It's a little bit hard to translate

from that informal community to the scientific data.

But in discussing that topic with various researchers who

run laboratories at major universities

focused on psychedelic therapies, what I was told

is that the quote-unquote heroic dose that's

often discussed really refers to a 5-gram or so dose

of mushrooms.

So what that translates to is 50 milligrams of psilocybin.

So when you hear someone talk about a quote-unquote heroic

dose, they're probably referring to ingestion

of 50 milligrams or so of psilocybin,

but in its mushroom form.

So about 5 grams of mushrooms.

And, again, it's important to point out

that the concentration of psilocybin

in different strains of mushrooms

and in different batches, and depending

on the age of those mushrooms, and how they've been stored,

et cetera, can vary tremendously from batch to batch.

In fact, there are some laboratories

that have explored the range of psilocybin concentration

in different mushroom strains and different so-called magic

mushrooms.

And that range is pretty broad.

It's anywhere from 1/2% all the way up to 2%.

What that means is that someone might

get a hold of 1 gram of mushrooms thinking that they're

taking 10 milligrams of psilocybin

in those mushrooms when, in fact, they're actually

taking 20.

Or somebody could take 3 grams of mushrooms thinking

they're taking 30 grams of psilocybin

and in fact they're only taking 10

or 15 milligrams of psilocybin.

So the sourcing is really key obviously

as things become more legal, and more regulated, and more used

in the therapeutic setting.

And this is what's happening more and more.

Or as people start to rely on synthetically made psilocybin

as opposed to using mushrooms to ingest psilocybin.

Then certainly, the dosage thing is

going to be more consistent from batch to batch

because we're not talking about batches of mushrooms,

we're talking about batches of psilocybin itself.

So now, I'd like to take a step back

from all this chemistry and cell biology

and talk a little bit about the structure of a psilocybin

journey itself and relate that to what we now

know about what's happening in the brain

during the psilocybin journey.

And then a little bit later, we will return to that serotonin

to a receptor.

When we talk about some of the more lasting changes in brain

chemistry and brain wiring, that occur after the psilocybin

journey is over.

So let's take a couple of minutes

and just discuss the various components

of an effective therapeutic psilocybin journey.

And here I'm not detailing a menu of things

that people should do in order to pretend that they are

a psilocybin assisted therapy coach,

or to do self-administered psilocybin therapy.

That is not what I'm doing.

What I am trying to do is to share with you

the consistent components that are

present in the clinical trials that have demonstrated

the effectiveness of psilocybin for the treatment of depression

and for other compulsive and addictive disorders.

And those data, meaning the specific data

related to those trials and the references themselves,

we'll get into a little bit later.

But we can't really have a conversation about psilocybin

and what it does without talking about the so-called set

and setting as it's often referred to.

That is known to at least bias the probability of the journey

being beneficial and not a so-called bad trip.

So what are the variables that make up an effective and safe

psilocybin journey?

And, again, when we say safe we're

referring to people who are not prone to psychotic episodes,

that don't even have a first relative that's

prone to psychotic episodes.

We're talking about people that are 25 years or older.

We're talking about people that, for instance, are not

taking antidepressants that impact the serotonin system.

This is very important to understand.

I think a lot of people don't know this.

But as far as I know, all of the studies

that have explored psilocybin for its ability

to positively impact brain chemistry and mood and function

have required that people either not be on

or abstain from antidepressants in the weeks

leading up to the psilocybin journey.

Now, that is not to say that if you are currently

taking SSRIs or something similar that you should

cease taking them and do psilocybin,

I'm absolutely not saying that could be very, very, very

dangerous if not catastrophic.

Anytime you're going to take anything or stop

taking anything for that matter, you

do need to consult with your physician.

In this case, a psychiatrist as well.

So let's talk about psilocybin journeys

from the subjective side and from the structural side.

And when I say the structural side, what I mean

is what is a psychedelic journey actually include?

And here are the words set and setting

become extremely important.

Some of you may have heard that set and setting are

the foundation of a well done or even therapeutically beneficial

psychedelic journey.

And all of that really hinges on safety and outcomes.

So set refers to mindset.

The mindset of the person taking the psychedelic.

And setting refers to--

as the name suggests, the setting

in which they're taking it in and the people

that are present there.

So let's talk about setting first.

The setting for a psychedelic journey

needs to be one in which the person

under the influence of the psilocybin or other psychedelic

is safe.

That means no windows they can jump out of,

that means no streets of moving cars, they can run out into.

That means no opportunity for getting lost.

That means no opportunity for getting into bodies of water.

In other words, it requires that there be at least one,

and perhaps even two or more other individuals

who are not also taking psychedelics who are not also

taking psychedelics present in that setting to ensure

that the person taking the psilocybin

is not going to harm themselves or others.

I say this not to sound like a school teacher,

even though technically I'm a school teacher,

but because, of course, I don't want anyone to get harmed.

And I'm also aware that there's a lot of interest nowadays

in psychedelics, such as psilocybin becoming

legal or decriminalized for their therapeutic applications.

And if we look back to the late 1960s and early 1970s

when the Controlled Substances Act was invoked

to make psychedelics like psilocybin illegal,

one of the bases for that was not just

the geopolitical unrest at the time

and things like the Vietnam War, but also some

highlighted instances in which people did not

take set and setting into consideration,

took things like LSD, stared at the sun, went blind.

Or took psilocybin, went out, and harmed somebody else.

Again, these are very, very isolated instances.

But these are the exact instances

that lead to criminalization or the fact

that things like psilocybin, and LSD, and MDMA for that matter

are considered illegal.

Again, I completely acknowledge that there

are a number of different factors making them illegal.

We could have a whole discussion about that.

We talk about the drug trade, the war on drugs.

But right now, it's such a critical time in the history

and the use of psychedelics for therapeutic and other reasons.

And getting setting correct, meaning making it absolutely as

safe as possible for the person taking the psychedelic

is absolutely key.

And one of the best ways to ensure that it's safe

is to have responsible individuals who

are not under the influence of psychedelics

present in that environment.

So that's one component of setting.

The other component of setting that we talked

about earlier, which turns out to be very important

is the opportunity and perhaps even

the bias toward the person on the psychedelic being

seated or ideally lying down and being in the eye mask

or at least having their eyes covered

so that they can combine any spontaneous visual

hallucinations that occur with the various thought

processes that are occurring while

under the influence of psychedelics.

This is far and away different than quote-unquote taking

mushrooms and going into the woods

or taking mushrooms and going to the beach.

What we're talking about today is the use

of psychedelics for particular brain rewiring outcomes

that yes can involve things like changing one's relationship

to nature, or changing one's relationship to somebody else

by interacting with nature or somebody else.

And while I'm not trying to diminish the potential value

of those sorts of psychedelic journeys,

if we look at the scientific data, the vast majority of it,

not just in the clinical setting,

but in terms of understanding the safety, and efficacy,

and positive rewiring of brain circuitry,

that allows people to feel better

to understand themselves better and to interact with life

in more adaptive ways going forward

out of the psychedelic journey involve these very,

let's say, subdued settings that are typically in one room,

a closed environment with one or two other individuals

acting as guides or helping the individual

by talking to them from time to time if they feel like they

have to sort through a particular aspect

of the psychedelic journey that's creating anxiety.

And we'll talk about the contour of the psychedelic journey

that almost everyone who takes psilocybin

at somewhere between 20 and 30 milligram dosages

tends to experience.

But the setting that I'm describing

is not just a list of things to make sure you're safe,

but they're really the list of things

that also ensure that one can get the maximum benefit out

of the psilocybin journey.

Now, other things included in setting that are known, again,

from scientific literature to be very influential in terms

of the experience that one has and to bias

things towards a positive experience

are, again, safety, eye mask, but also the presence of music.

Now, when I first heard about this from one of the Premier

researchers on psilocybin and other psychedelics which

is Robin Carhart-Harris, he's a professor

at University of California San Francisco, who's

one of the major pioneers in the studies of psychedelics.

And when he first started telling me

about the critical role that music plays,

I thought, OK, that makes sense you know.

Music can impact our emotion, impact the way that we think,

and could, therefore, impact what one experiences

during the psychedelic journey.

But he really underscored for me the extent to which music

is not just an incidental feature of the setting

in psychedelic set and setting, but that it

is one of the major drivers of the actual cognitive and

emotional experience that somebody

has on something like psilocybin that allows the psilocybin

journey to be looked at or viewed, not just as beneficial,

but, and this is quoted in the scientific literature as one

of the most profound and important positive experiences

that one ever experienced in their life.

So let's talk about the sorts of music

that have been used in these clinical studies.

Well, first of all, we need to think

about how long the psilocybin journey itself is going to be.

And the typical duration of the psilocybin journey

is anywhere from 4 to 6 hours.

It's going to depend somewhat on dose.

It's going to depend somewhat on variability in people's liver

metabolism, and it's also going to depend somewhat

on how much food people have in their gut.

In all the clinical studies that I read,

it was advised that people not have any food in their gut

at the time in which they ingest or are

injected with the psilocybin.

That's particularly true if people

are going to be taking psilocybin, mushrooms, in order

to get their psilocybin.

And that has been done in a few studies.

Most studies however use synthetic psilocybin

taken orally.

Again, that's converted to psilocin in the gut

by the acidity of the gut.

And the acidity of the gut is going

to be impacted by the various foods that people eat.

And so that's one of the major reasons why people are advised

to not eat for at least four hours

prior to the psilocybin journey.

So here we've got this 6 hour, what we're calling,

journey because that's what everyone calls it or trip.

That people start experiencing about 30 to 45 minutes

after ingesting psilocybin or taking psilocybin.

There's a peak component in which there's

a maximal intensity of emotion and often that's

also associated with anxiety.

And this is very important to understand.

The anxiety component is part of what

in the therapeutic setting, they refer to as ego dissolution.

And that anxiety around the peak--

and I think most people would probably hear peak experience

and think, oh, we're talking about a peak positive

experience.

But no, we're referring to a peak experience and anxiety

that people stay with and then come down from gradually

as one goes from the second or third hour

after taking psilocybin.

And that tapers off slowly toward the 6-hour mark

what, sometimes people refer to as parachuting back in.

Of course, hopefully, I would very much

hope people aren't actually parachuting back

in while on psilocybin.

But I think you get the idea.

The music that's typically played in the clinical studies

using psilocybin for the treatment of depression,

or for compulsive disorders, or addiction

tends to have a particular contour that

matches with and can also drive that contour of the psilocybin

journey that I just described.

Again, we're talking about people

wearing an eye mask with guides present.

So people who are not taking psilocybin there as well

to ensure that the person feels supported and is safe.

The person is typically lying down, sometimes sitting

down, but more often than not lying down,

wearing an eye mask--

and the music that's played at the beginning of the psilocybin

session tends to be music that doesn't have

a lot of vocalizations, it tends to be

things like classical music, it tends to be fairly low volume.

But then transitions into music that has a lot of percussion.

So often drums that tends to be higher

volume, that has a lot of intensity.

At about the time that one would be experiencing the peak

in emotion and perception, that so-called peak of the journey.

That intense music tends to be played for about 45 minutes

to 90 minutes, depending on the study one looks at.

And then tends to transition into softer music, again.

Sometimes choral type or more melodic music, often female

voices in particular, and then transition

into nature sounds and things that more or less mimic

the outside natural world and less so

synthetic things like drums, or instruments, and vocalizations,

and things of that sort.

So why would it be so important that music match

and even contribute to the subjective experience

that people have on psychedelics?

And here, we should probably take a couple of moments,

and just talk about what those subjective experiences are

like.

So for people that haven't done psilocybin or any psychedelics,

it's a little hard to describe.

But one way to describe it is that there's

a lot of so-called perceptual blending.

So, for instance, people in the eye mask

will report seeing some geometric shapes and colors.

But perhaps the music they're listening

to will then start to change the intensity or the movement

of whatever it is that they're seeing,

hallucinating inside of the eye mask in ways that are linked.

This is referred to as synesthesia

or the merging of different senses

that are not ordinarily merged.

In addition, people under the influence of psilocybin

or other psychedelics for that matter

often will report that their pattern of breathing

becomes linked to the perceptions of things

that they are hearing, or seeing, or feeling.

So, for instance, if they take a big deep breath in and then

a long exhale out, they may find that during a long exhale

out, that the notes of music that they're

hearing in those moments are also

drawn out for the duration of the breath in they'll inhale

and that they're getting at least what they perceive

as control over the music which, of course,

they are not actually controlling

by using their breath.

And that perhaps their visual perceptions are also

being merged with that.

So those are just a couple of examples

of how perceptual blending a.k.a.

synesthesia can occur while under the influence

of psilocybin.

And this really is highly individual from one person

to the next.

Some people, for instance, will find

that if they take their fingertips and rub them

across the couch or the chair that they happen

to be lying down or sitting on, that they will experience

a change in the music.

Maybe even if they move their hand up,

they hear an increase in frequency of sound.

They move their hand down, they hear a decrease

in frequency of sound.

And all of this is linked to their emotional state

at the same time and vice versa.

So we're talking about a lot of perceptual and emotional

blending and some sense of control

over one's perceptions and emotions

in a way that's very unordinary, even extraordinary.

We can step back from all of this very subjective

description of the psychedelic journey and ask,

what is going on that would allow these sorts of things

to occur?

And there you are already equipped with an understanding

of the cell biology and the chemistry that

makes all of this possible.

And that is that when psilocybin is ingested and then converted

to psilocin, it's the psilocin that crosses the blood brain

barrier, and then even though psilocin

looks a lot like serotonin, psilocin

has this incredible ability to predominantly activate

the serotonin to a receptor.

Well, we can understand much of what's

happening at a subjective level during the psychedelic journey,

even right down to the sorts of emotions,

and perceptual blending, the synesthesia.

We can understand a lot of that by understanding

where the serotonin 2A receptors are expressed on neurons,

and what those particular neurons are doing.

And the simplest way to describe this

is that there's a category of neurons

that we call pyramidal neurons.

Pyramidal neurons are found lots of places in the brain.

But they're called pyramidal neurons

because they're sort of shaped like a pyramid.

They have a cell body, which is the part of the cell that

has the DNA in it and a lot of other important things

like the organelles, mitochondria, et cetera.

And then they also have what are called dendrites.

Dendrites are the little branches or processes

that reach out both from the bottom of these cells.

And then these pyramidal cells are

interesting because they also grow a branch up, up, up, up,

up into layers of neural tissue above them.

And they have what's called an apical branch.

That's the part that grows up.

And then they fan out at the top.

And that fanning out at the top allows

them to communicate with other neurons in their environment.

So if you're not getting a good picture of this in your mind

from my description, I apologize.

But simply think about putting your arms out to the side.

And by doing that, you're able to interact

with things that are some distance from your body,

an obvious thing in that case.

These cells are effectively doing the same thing

by extending little processes out into layers above them

and to the sides.

And this is really important because much

of the serotonin to receptors that are present on neurons

in the brain are present in those apical dendrites,

those branches of these pyramidal neurons

that are above and that extend out

to the side of those neurons.

And so when somebody is under the influence of psilocybin,

that means that psilocin has bound to the receptors

on those apical dendrites.

And it's increasing lateral communication

across brain areas.

In fact, this is perhaps one of the most

well-documented effects of psilocybin and other

psychedelics, which is that there's

a shift from the brain being more modular,

meaning more segmented like auditory neurons are

communicating electrically and chemically largely

with other auditory neurons.

Of course, they'll communicate with other types of neurons,

too, right?

When I hear something off to my right, like a snap of a finger

is off to the right, I'll turn my head.

And my ability to do that depends on my auditory neurons

being linked up with things like my motor

system and my visual system.

But the key thing to understand is

that when there is psilocybin present in one system,

that the communication of any of these pyramidal neurons,

the ones involved in hearing, the ones involved in thinking,

the ones involved in memory, the ones involved

in visual perception or in the generation

of visual hallucinations with eyes closed,

those are all talking to many, many more other neurons more

extensively.

So what happens effectively is that there's

a reduction in the modularity, the separateness of function

in the brain, and an increase in what's

called integration of communication

across what would otherwise be disparate brain regions.

We can say that really simply by saying psilocybin increases

communication across the brain.

Now, in addition to that, there's

a reduction in what's called the hierarchical organization

of the brain.

Typically sensory information comes in

from the outside environment.

So we hear something, we see something, we taste something,

we smell something.

And in what's called a bottom up fashion meaning bottom

from the periphery up, meaning it propagates up

through the eyes, through the nose, through the ears

through the skin, or the senses in those regions,

I should say, up into areas of the brain that

sit deep to the cortex like the thalamus.

And then the thalamus is a way station,

it's like a switchboard that sends

visual stuff to the visual centers,

and auditory stuff to the auditory centers,

and touch stuff to the touch centers,

and things that maybe trigger a memory off

to the memory centers of the brain, et cetera.

That's the typical organization.

It's hierarchical because it goes from the periphery

up to the more complex processing

regions of the brain that make decisions, that

link all of that stuff to prior experience,

maybe plans about the future.

When psilocybin is present in the system,

there's a broadening of the flow of that information

from the bottom up as well.

And that has to do with what's called thalamic gating.

The thalamus is a very interesting structure.

We probably don't want to go into it in too much detail

right now.

But it really is like a switchboard

in a way station saying, hey, pay attention

to the visual stuff, pay attention

to the auditory stuff, or just to the visual and auditory

stuff, and ignore touch sensation for the time being

or vice versa.

When psilocybin is present in the system,

and when serotonin 2A receptors are activated very strongly,

there's a tremendous broadening of the flow of information

up and through the thalamus.

So not only is there more communication

of so-called higher order brain centers,

we refer to them as higher order because they're

involved in thinking, and decision making, and emotion,

et cetera.

But there's also a shift in the flow of sensory information

into the brain that can generally

be described as broader and including more blending

of the different senses.

And when I say blending of the senses,

I'm also referring to blending of the sense of interoception

of our sense of our body and what's

happening inside of our body.

And this without question, at least

partially explains when under the influence of psilocybin,

one's breathing can be linked to a sound,

and then suddenly the sound one thinks

is being controlled by one's breathing,

or that the sound itself can be linked to something that we

see in our mind's eye while in the eye mask.

Essentially, what I'm describing here

is that serotonin to a receptor activation

allows for more broad, less precise, and less hierarchical

activation of brain circuitry.

And when I say hierarchical, what I mean

is that normally things go from periphery, from eyes,

to thalamus, to visual cortex.

However, when under the influence of psilocybin,

as I mentioned before, even in the eye mask,

the visual cortex is going to be very activated

even in the absence of any visual input.

So then if one hears a sound, perhaps

from music, a particular motif or voice,

and that's linked to a particular emotional state,

that is now being blended with visual phenomenon occurring

within the brain that have no external stimulus.

And so while the patterns of activation

in the brain while under the influence of psilocybin

aren't random, they are far less channeled, far less modular,

and far less hierarchical than would ever be the case when

not under the influence of psilocybin

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Now in all fairness to the scientific literature,

there are not one, not two, not three,

but four prominent theories of which brain networks are

most activated during a psilocybin

or other psychedelic journey.

And so for those of you that are interested

in those different models, first of all, please

know that they are not competing models.

While some of them disagree about some of the details.

It's very likely that all of these models are true.

They include things like changes in the so-called default mode

network.

There's a lot of interest in this.

I've talked about it before on this podcast.

The default mode network is the network

in the brain that's thought to be responsible

for spontaneous imagination, for daydreaming,

and that reflects the base activation

state of the brain when there's no drugs in our system.

And the default mode network is one of the systems or networks

rather that is thought to be required

under conditions of psilocybin or other psychedelics.

Again, if you're interested in these models

and comparing and contrasting them,

there's a very nice review from Brian Roth's Lab

at Duke entitled, The Neural Basis of Psychedelic Action.

We'll provide a link to this in the show note captions.

And, again, I just want to emphasize

that all of these models have been shown to be

true in different studies.

And what they all point to is more extensive communication

between areas of the brain that normally are not

as active at the same time while under the influence

of psychedelics, such as psilocybin.

The controversy in the field relates

to which of these networks is the one that changes the most

to explain the therapeutic outcomes that have been

discovered in recent years.

So, again, check out that review if you're interested

and that sort of thing.

In the meantime, we can cut a broad swath

through all of those models, and just

say that psilocybin expands the functional

connectivity of the brain while one

is under the influence of psilocybin.

And it does seem that some of that expanded functional

connectivity persists after the effects of psilocybin

have worn off.

And that statement about the functional connectivity

of the brain being more expanded,

not just during the psilocybin session, but after as well,

has been substantiated in a number of papers.

But one of the key papers in this area

is one that I recommend people check out

if they're interested in this sort of thing,

is entitled, The Effects of Psilocybin and MDMA

on Between Network Resting State Functional Connectivity

in Healthy Volunteers.

And I like this paper for a number of reasons.

First of all, it's a very high-quality paper

carried out in the laboratory of Robin Carhart-Harris at UCSF.

Again, one of the Premier researchers

in this area of psychedelics and their function,

what they do in the brain, and also

their therapeutic applications, but also

because it focused on healthy volunteers.

They explored using brain imaging.

What brain areas are active in a resting state?

So things like default mode network.

Then they had people take psilocybin or MDMA.

And then they looked at the connectivity

between those brain areas in those same individuals

when they were not under the influence of these drugs

and found more extensive connectivity.

All of which pointed to an enhanced lateral connectivity,

less hierarchical organization effectively more

interconnection and communication

between different brain areas.

I think not only is the fact that they looked

at healthy volunteers very interesting and important,

but also that they looked at this resting state

of the brain.

They weren't providing a particular auditory

or visual stimulus for people to hear or look at

while they were in the brain imaging scanner

as it's called rather, they were simply

looking at how the brain was behaving at rest.

And so it's very clear that for people that do two or even

just one of these psilocybin journeys at a particular dose,

that the brain is actually getting rewired.

We hear this a lot.

Psilocybin or other psychedelics lead to plasticity.

They rewire your brain.

Let's go back to what we said at the beginning.

Rewiring of the brain is not the goal.

Adaptive rewiring of the brain is the goal, right?

Rewiring that leads to new ideas that are interesting,

that are accessible after the psychedelic journey.

New ideas and new ways of thinking or feeling that

allow people to function better in their lives.

That's the goal of effective psychedelic therapies.

Not simply rewiring of the brain.

A brain injury for that matter will

lead to rewiring of the brain.

But that's maladaptive rewiring.

The use of things like amphetamines

or methamphetamines, in particular,

will lead to rewiring of the brain.

But that is strongly maladaptive rewiring

So now, there are really dozens of studies conducted

in humans using brain imaging and other techniques

have evaluated how things like psilocybin

change connectivity in the brain.

And I think the take home message is

it expands that connectivity.

However, it seems to do so in ways

that still allow people to function in their daily lives.

And one of the key things that I gleaned from the literature

on the therapeutic use of psilocybin

for the treatment of depression is

that very seldom, do people who take psilocybin experience

long-term issues with memory.

Why is that so critical?

Well, you could imagine that increasing connectivity

in the brain reducing modularity,

reducing hierarchical organization of the brain

would lead to disruptions in memory, right?

It's as if you're shuffling books on the bookshelf

so to speak.

But that doesn't seem to be the case.

Rather it seems that the increase in connectivity

is leading provided set and setting are correct,

provided safety protocols are followed

to positive rewiring or adaptive rewiring of neural tissue.

So that's one of the things that makes

psychedelics and psilocybin, in particular,

very exciting from the therapeutic standpoint.

And of course, we have to acknowledge

it's also it has a lot of people excited about psychedelics, not

just for the treatment of depression,

but for expanding the brain's capabilities more generally.

So along those lines, I want to touch

on the issues of creativity and the experience

of life outside of psychedelic journeys

is impacted by psychedelic journeys.

And here this relates to a question that I heard a lot.

When I put the call out on social media

that I was going to do this episode, and I asked people,

what do you want to know about psilocybin?

And one of the more common questions that I got was,

does it increase creativity?

Does it increase our experience of life

in ways that are beneficial aside from its now documented

positive effects in treating depression

and compulsive disorders and addiction?

And the short answer to this is yes.

But that the positive effects of psychedelics,

psilocybin, in particular, on creativity,

and our experience of life have only

been explored in a fairly narrow set of dimensions.

However, where it's been explored,

there's some really interesting findings.

So one of the more interesting findings

I think is a paper entitled increased low frequency brain

responses to music after psilocybin therapy

for depression.

I think this is a really interesting paper.

Because what the authors did is they took advantage of the fact

that in these therapeutic psilocybin sessions

that were carried out for the treatment of depression,

music is being played.

And there are prior studies showing

that when music is played, you activate different brain

areas depending on what music is being played.

It's somewhat obvious perhaps.

Sad music versus intense.

You can think about heavy metal, versus choir music,

versus Gregorian chants, versus punk rock music,

and on, and on.

It makes sense that different brain areas

would be activated when different patterns of music

are played.

However, there do seem to be some universal features

of brain activation in response to music.

This should probably be the topic of an entire episode

of the Huberman Lab podcast.

And indeed it will be.

For instance, there are areas of the auditory cortex

that are activated.

No surprise there.

And areas of the brain's reward circuitry,

the so-called ventral striatum and the so-called mesolimbic

reward pathway.

I talked a lot about these in the episodes about dopamine

that I've done previously.

These are brain areas that lead to the release of dopamine

in other brain areas, and that reinforce certain experiences,

and that tend to give us the subjective feeling of, yes, I

like this.

I want more.

So in this particular paper, what the authors did

is they took advantage of the fact

that people are in the clinic, they're on psilocybin,

they're listening to music.

And as you recall, the music played

at different stages of the psilocybin journey

are different.

They have a different emotional component.

And music is a really nice stimulus in the laboratory

as we say.

Because like with visual stimuli,

you can break it down into high frequency, low frequency.

Sounds like dum, dum, or ah, ah.

These kinds of things that was my attempt

at low frequency versus high frequency auditory stimuli.

Or at the spatial frequency, or what in the auditory domain

would be called the temporal frequency

is it boom, boom, boom.

Or is it boom, boom, boom, boom.

All we've changed there is the temporal frequency.

The sound was somewhat the same, but the distance

between those sounds was different.

You get the idea.

So they have access to these people

and these different conditions.

And they can put them in the brain scanner.

And they can do that before and after having taken psilocybin.

And the long and short of this study

is that psilocybin changes one's experience of music, not just

during the psilocybin journey itself, but thereafter.

And, in fact, it changes one's emotional response

to music in very interesting ways.

For instance, one of the more common features

of major depression is that people

don't derive as much pleasure from different types

of experiences, whether or not it's

food, or sex, or social experiences to the point where

sometimes they just stop trying to seek out those experiences.

People with depression often feel as if music no longer

has the same impact.

It just doesn't really lift them up very much.

This study found that people who have taken psilocybin,

according to the parameters we talked about earlier,

can get a return of the elevated emotionality,

the positive emotions associated with music that formerly

made them feel good.

In other words, they can feel music again.

They can feel good in response to music again.

Now, this is interesting because, in theory, it

could be that psilocybin simply allowed

them to access the emotions around music, again,

more generally.

But that's actually not what this paper

and some other papers that have been published report.

Rather, it seems that taking psilocybin

can increase one's positive perception of music

that one likes and can tone down or reduce

the depressiveness or the sadness of music that

tends to make one sad, even after the psilocybin has

worn off and for a long period of time afterwards.

Maybe even forever.

Although no study, of course, can be carried out forever

because forever is forever.

What we do know, however, is that psilocybin

can rewire the connections between the emotion centers

in the brain and the networks that control

auditory perception of music.

And leads to this condition in which people

who felt like, I was depressed, or I couldn't feel the music,

I just wasn't getting the same lift and joy from it again,

they can start to experience more joy from that music again.

And that music that made them feel sad and depressed

has a diminished capacity to make

them feel sad and depressed.

And there's a lot of neuroimaging data

in this paper that point to the specific brain areas that

include areas like the ventral tegmental area that

can explain why these sorts of effects would occur.

So this isn't just subjective reports of people saying,

oh, yeah, I was depressed.

And music didn't feel really good and now it feels great.

Or that used to make me feel so sad.

And now, I feel like I have a capacity

to listen to that without being crushed by feelings of sadness.

The paper included some subjective reports

of that sort.

But then was able to link those to changes in brain circuitry

and brain activation in response to music using neuroimaging.

So in that way, it really points to both the subjective,

and structural, and functional changes

that psilocybin can bring about through that expanded

connectivity between brain areas.

Because remember during the psilocybin session,

it's not as if music or the perception of music

is specifically being looked at or focused on in these studies,

rather music is playing.

People are in the eye mask, they're

feeling all sorts of things, they're breathing,

they're hearing their touch.

It's all happening all at once.

There's a peak.

It's long.

There's a long taper.

The music's changing.

OK.

All of that took place in this study as well.

But it is after the session when comparing brain activation

states to music of a particular type, sad or happy.

And comparing that to the patterns of brain activation

that occurred before the psilocybin journey

that they discover that people's brains

have rewired during the psilocybin session

in a way that allows them to experience joy

in response to music again.

So that's one of the more rigorous studies

I was able to find.

That addresses this question of whether or not psilocybin

really does rewire the brain in ways

that allows us to be more creative

and experienced life differently after the psilocybin session.

Now, that paper didn't focus specifically on creativity.

I did an entire episode on creativity

that talked about different types of meditation,

like open monitoring meditation, it

talked about different patterns of thinking

that one can actually practice to increase creativity.

We had arguably one of the most creative people on the planet.

Rick Rubin came on this podcast talked

about the creative process from the perspective of music

and his role in producing music.

So you can check out those episodes

if you're interested in the neural circuitry related

to creativity.

At least at the time of recording this episode.

There haven't been a lot of studies looking specifically

at the brain networks that we think

are involved in creativity and how

those change in response to psilocybin and other

psychedelics.

I imagine those studies are either happening now

or will happen in the future.

But the studies I just described referring

to the changes in emotionality and responses to music,

I think provide a nice template for what's

likely happening both during psilocybin journeys

and after those psilocybin journeys.

When we talk about less hierarchical organization,

more connectivity between brain areas, what it's pointing to

is the fact that during the psilocybin journey,

people have the opportunity to learn

new relationships between different sensory and emotional

states.

And those new relationships seem to persist

long after the psychedelic journey has been finished.

And a lot of people researching psilocybin

in the clinical setting think that that's

one of the major reasons why psilocybin and other

psychedelics can rewire our relationship to things more

broadly.

It allows for new learning, new contingencies.

And when we look at depression, we often think diminished mood,

people don't have an appetite, they're not

interested in social relationships,

or romantic relationships.

They're really struggling.

And all of that, of course, is true.

But another lens to look at depression through

is that a lot of that thinking and a lot

of those emotional states that are negative

are somewhat habitual.

They relate to implicit understanding

and living out of the idea that A leads to B

leads to C. You seek out a relationship,

it doesn't work out.

Try a new job, you don't get the job.

You get the job, it's no good.

All these negative outcomes of if A, then B, then C.

And it does seem that psilocybin can

have this effect of invoking new patterns of learning.

New considerations about what might be possible.

And indeed, may even lead to actual rewiring of the emotion

centers in the brain with these other brain areas and vice

versa in ways that eject people from the psilocybin session

thinking, oh, yeah, I used to feel this way about something,

work, relationships, myself, et cetera.

But I'm willing to consider this other possibility.

Or this other possibility seems at least partially

true to the extent that I'm willing to go out and evaluate

that.

Now, here I'm speaking very subjectively.

But remember, we have to tie back the subjective experiences

and changes of things like music,

and emotion, and our relationship to life,

and jobs, and relationships back to the cell biology

and chemistry of psilocybin.

Because, ultimately, it really is just a chemical

activating receptors.

Those receptors changing networks in the brain.

And the journey itself seems to be

the time when all of those changes are put in motion.

It's like a boulder that gets rolling.

In fact, I think the best way to think about psilocybin

and other psychedelics is that they initiate

the neuroplasticity process, but they are not

the neuroplasticity process itself.

And the journey itself is not where all the neuroplasticity

occurs.

We know that for sure.

In fact, if you want to imagine how

psilocybin and other psychedelics work

to change the brain, think about them

as a wedge that gets underneath the boulder, that

is the neuroplasticity that gets rolling forward.

And then think about whether or not

the plasticity is adaptive or maladaptive, whether or not

it actually serves you in your life on a daily basis,

or not, depending on whether or not

you're using your conscious brain to move

that Boulder in a particular direction.

Not just bulldozing through things and destroying them,

but clearing a path through old ineffective maybe,

even destructive patterns of thoughts, or emotions, et

cetera.

I give you that analogy because I

think it more accurately captures what psychedelics

like psilocybin are doing.

Rather than the typical discussion around

psychedelics that we tend to hear which is that, oh,

it creates plasticity.

And plasticity is what you want.

For the next couple of minutes, I'd

like to focus on some of the key and stereotype that

is characteristic experiences that people tend to have

during a psilocybin journey.

Because there's some really interesting research on this.

These are phrases that perhaps you've heard before.

Things like letting go, ego dissolution,

feelings of connectedness.

Well, all of that is very subjective on the one hand.

Those words are heard often enough and repeatedly enough

in psilocybin sessions and after psilocybin sessions,

along with this description of the psilocybin

experience as one of the most profound of one's life,

or one of the most positive in the ideal case of one's life

that they are worth exploring.

We should also, of course, explore the so-called bad trip,

the possibility that someone will

have a not good time or even very frightening time while

under the influence of psilocybin.

So there have been some scientific studies

that have explored what sorts of subjective experiences.

That is thoughts, and feelings, insights that people have,

that relate to positive therapeutic outcomes,

and more generally with the sense

that the psilocybin journey was positive or maybe

even tremendously positive in one's life.

So while there's a century or more

of writings about psychedelics that

describe things like enhanced feelings of connectedness,

or dissolution of the ego, the loss of one sense of self,

and then the regaining of one's sense of self, and so on.

There's a particular paper that describes

some of those things in terms of rating scales, that

is the sorts of tests that people can take in which they

answer particular questions, and that link back to things

like feelings of connectedness and ego dissolution,

that allows us to put some numbers to those m

and to look at some of the statistics associated

with those experiences.

And this is really what's important

about scientific studies, whether or not

a measure is subjective.

So if someone's self-reporting, how they felt or feel,

or whether or not it's measure of blood pressure,

or of a chemical in the bloodstream, et cetera.

It's the use of numbers and statistics

that allows comparison between different groups.

And that can be compared between studies

that allows us to make some firm conclusions about what

sorts of things psilocybin may or may not be doing

when it's effective or not.

So the paper I'd like to highlight

is entitled quality of acute psychedelic experience

predicts therapeutic efficacy of psilocybin for treatment

resistant depression.

I'll put a link to this paper in the show note captions.

But the basic contour of this paper

is that they looked at subjects that underwent two

different psilocybin sessions.

One, at a relatively low ish dose

of 10 milligrams of psilocybin.

And that would be equivalent to about 1 gram

of psychedelic mushrooms more or less.

And a second session involving subjects

taking 25 milligrams of psilocybin,

or what's roughly equivalent to somebody

taking 2.5 grams of psilocybin mushrooms.

Those people then answered what's

called the altered states of consciousness questionnaire,

which allowed them to address.

And here I'm paraphrasing the quality

of experiences in the 25 milligrams psilocybin session.

So without going into too much detail,

it's often the case in these two session studies

that subjects will take a slightly lower dose

of psilocybin, to familiarize themselves with the experience.

And then the higher dose that leads

to the more intense experience.

Intense meaning a bigger, more intense peak, a longer session

overall, greater distortions in emotionality,

and perceptual experience, all the stuff

we talked about before.

So what this study found is that one of the key features,

if not, the key feature of a positive quote-unquote

psychedelic experience is this sense

of oceanic boundlessness occurring at some point

during the psychedelic journey.

Now, oceanic boundlessness doesn't necessarily

mean anything to any of us.

It probably means different things to different people.

Is this idea that one is experiencing something

extremely unusual, even mystical beyond this world and one's

normal experience.

But that it's not aligned with any specific outcome

in the moment.

It's not directly attached to any one feeling, or memory,

or thought process.

It's a little bit tough to describe

because I can guarantee you.

I'm not on psilocybin or any psychedelics right now.

And I can only imagine that you're not.

Although some of you might be.

I can't even imagine what this podcast

would be like for somebody on psilocybin at this moment.

But in any case, oceanic boundlessness,

a feeling of the experience being mystical,

and not really heading in any one particular direction.

Just a feeling of massive connectedness with one's

environment both in the room and session.

Perhaps with the guides with oneself, with one's past,

with one's present, people outside the room

with the entire world, maybe even the universe,

that sort of thing.

The intensity of that experience of oceanic boundlessness,

the mystical experience seems to be positively correlated

with positive therapeutic outcomes.

That is relief from major depression.

Now, during the psychedelic journey,

as we talked about before, there are

a number of steps that one typically goes through.

So there's the build up to first experiencing

the effects of the drug about maybe

20 to 45 minutes into the journey or trip.

Then the peak.

And it is during that peak that people often

feel the sense of oceanic boundlessness.

However, it's also often the case

that it is during the peak or the maximum intensity

of emotion.

And we know based on direct measurements

also increases in blood pressure and heart rate often

very significant increases in anxiety and fear as well,

that people will experience things like ego dissolution.

And the guide's role at that point

is, of course, to keep the person safe,

make sure they don't run out of the room, jump out of a window,

run into traffic.

Sadly, these are things that have

happened outside of a strong, healthy, safe set and setting.

But the guide's role is to keep the person safe,

but also to encourage them to let go and move

through that experience to experience the anxiety,

allow it to peak, allow them to see that they're not

going to die from that anxiety, they're not going to dissolve.

They won't lose their sense of self completely,

or they may temporarily feel as if they

lose their sense of self.

But then they feel it restored at various intervals

during the peak or as they exit that peak

and move toward the say second, third, fourth, fifth hour

of the session.

So when exactly these feelings of oceanic boundlessness

and ego dissolution occur?

It varies from person to person.

But typically, it's during the peak

that the ego dissolution, the fear, and the need

to quote-unquote let go is most typical.

I think perhaps the best way to describe the data

in this paper in a way that's meaningful to everybody

is to refer you to figure 2, which

if you're not looking at the paper,

won't mean anything to you.

But I'll describe it.

And if you do want to take a look at figure 2 again,

you can access the paper in the show note captions.

What they did is they looked at a number

of different subjective measures, things

like experience of unity, the feeling

that one is connected to others and to the world.

Things like spirituality, whether or not

the whole thing felt like a spiritual experience,

whether or not it was a blissful state, whether or not

there were insights, whether or not somebody felt disembodied

out of body, whether or not somebody had a lot of anxiety,

whether or not they had these synesthesia, these blending

of visual, auditory, touch, and breathing, and things

of that sort.

And they addressed, which of those measures

related to the positive clinical outcomes that

were observed later after the psilocybin wore off.

And while I'm not going to go point

by point through each one of these measures,

there's a general feature to emerge from the study, which

is that the experience of unity, the sense that the psilocybin

journey was spiritual, an experience of bliss

at some point inside of the psilocybin journey.

The sense that there were insights,

that there were learnings about one's life and one's self.

When those things were experienced very strongly,

that correlated with the person being

what was called a responder to the psilocybin treatment,

meaning they got relief from their depression.

Whereas people who felt less of that--

OK, so the non-responders as they're called,

the people who do not benefit so much

in the long run from the psilocybin treatment

tended to report less of an experience of unity,

less of a spiritual experience, less of a blissful state,

less insightfulness, and so on.

Whereas there were very few differences between the people

that derived benefit from the psilocybin treatment and those

did not along the dimensions of synesthesia,

this blending of different perceptions

that ordinarily doesn't occur for most people.

Or complex imagery, right?

Put simply everyone who took psilocybin in this study at 25

milligrams saw a complex imagery,

they saw a lot of hallucinations.

But just seeing hallucinations did not

lead to the positive clinical outcomes in terms of mood.

Anxiety was a very interesting measure here.

Because ordinarily, we think of the ego dissolution,

the letting go is such a key component

of the psychedelic journey in terms

of the positive therapeutic outcomes.

This has been discussed quite a lot.

And in full disclosure, Robin Carhart-Harris

has already come on to record an episode of The Huberman Lab

podcast.

That episode hasn't been released yet,

but it will be released soon.

And he talks about the importance

of this letting go in terms of the positive clinical outcomes

of the psilocybin journey.

And indeed that is true.

And I should also mention that Dr. Matthew Johnson

from Johns Hopkins who also runs a laboratory exploring

psychedelics and their role in treating things

like eating disorders, and depression, et cetera.

Also, doing incredible work.

Also talked about the importance of letting

go during the psilocybin journey.

This ego dissolution, this ability

to move through the anxiety.

And, again, I can't underscore this enough

because it's been told to me over and over again

by the top researchers in this area.

That people head into that peaking phase of the psilocybin

journey, and oftentimes it is not pleasant for them,

they're feeling like it's uncomfortable, it's scary,

and their heart rate is up, and their blood pressure is up,

and they're having a hard time calming down,

and they want to calm down.

But it does seem that while the guides should not ramp them up

and get them more stressed, that the ability

to move through that stressful period

to somewhat guide oneself or to be encouraged to guide oneself

through that peak.

And that anxiety and the fear of losing oneself

and the so-called ego dissolution that occurs

is an important feature for an effective therapeutic session.

In this study, anxiety itself was inversely

correlated with a positive therapeutic outcome.

So this is important and somewhat nuanced.

On the one hand, I'm telling you that the letting go,

the ego dissolution does seem to be

important in terms of reporting a psychedelic experience

as effective as having accomplished something.

And perhaps even explaining some of the long-term positive

effects to emerge from that psychedelic journey.

In this case, psilocybin journey.

However, non-responders, that is people

who did psilocybin, but did not have

a positive therapeutic outcome in comparison

to the responders, those non-responders

tended to have higher subjective ratings of anxiety

than did the responders.

So this is important.

And what it speaks to is the fact

that while yes letting go during the session,

experiencing some anxiety, perhaps even ego dissolution,

and the dissolving of self, and then the return of self

is important.

It is also important it seems that anxiety not be so, so high

or subjectively experienced as so high.

That one does not experience the positive neuronal rewiring

that leads to a more pervasive elevated mood.

So I'm definitely saying two things at

once because I'm trying to capture the data accurately.

It would not be fair for me to say, just let go, experience

as much anxiety as is possible.

And that's part of the process.

Yes.

Letting go-- again, in air quote seems

to be important for one's experience

of the psychedelic journey, in particular, around the peak.

That occurs about two hours in or so.

However, extreme levels of anxiety

seem inversely correlated or negatively correlated

would be the better way to put it

with the positive therapeutic outcome or relief

from depression.

So this takes us back to all of the things

we've been talking about thus far.

Not just the chemistry and biological action

of psilocybin, but the key importance

of getting dosage right, the key importance of making sure

that you're in a safe environment,

but also one in which the guides really know what they're doing.

I think this is one of the biggest and most important

reasons for having well-trained guides who really understand

the contour of the psychedelic journey,

but are also trained in how to help somebody

with their anxiety in real-time while they're

under the effects of psilocybin.

And, of course, to help people integrate those feelings

of high anxiety and maybe guide them

back down to a calmer state during the psychedelic session

itself.

And here I can just mention some unpublished data and studies.

And, again, these are very preliminary.

But through discussions with Dr. Matthew Johnson who's

running these psilocybin and other sorts

of psychedelic trials at Johns Hopkins,

he and I discussed the importance

of having a real-time tool to adjust to anxiety while

under the influence of psychedelics like psilocybin.

And there he asked, and they've started to incorporate,

as my understanding, some of the real-time respiration tools

that is breathing tools that we know based on work

in my laboratory, Dr. David Spiegel's laboratory,

can reduce anxiety very quickly in real-time.

And that involves the use of the so-called physiological sigh.

I've talked a lot about this before on previous podcasts.

So rather than explain it to you again here now,

we'll put a link to the physiological sigh.

I do a demonstration of it in the show note captions.

I'll also link to a recent paper that we published

in Cell Reports Medicine.

This was a collaborative work that my laboratory

did with Dr. David Spiegel's laboratory

at Stanford School of Medicine.

Showing that the physiological size

among the different deliberate respiration techniques, one

of the fastest and most effective ways

to reduce levels of autonomic arousal a.k.a.

anxiety or stress.

And Dr. Matthew Johnson's laboratory

has started to incorporate physiological size

within these psychedelic sessions as a tool

that the guides can refer people to before the session begins,

teaching it to them.

So they realize they can calm themselves

down if necessary in real-time.

It works the first time, it works every time.

This is not because it's some magic breathing technique

that I created.

It certainly is not.

This is a naturally occurring pattern

of breathing that occurs in sleep and in waking.

But that when done deliberately, leads

a very rapid and quite significant

decreases in stress and anxiety.

And then when people are inside of the psychedelic session,

if they feel their anxiety levels are going too high,

they're heading toward what might be called

a quote-unquote bad trip.

They're starting to panic or really

think they're going to have a panic attack or die.

Again, the subjective experience is

going to be layered on top of the physiological experience

of one's heart rate being really elevated,

saw a stress and agitation.

By using the physiological sigh inside

of the psychedelic session, Dr. Johnson's laboratory.

And I believe, at least one other laboratory

are starting to use breathing techniques

such as the physiological sigh as a way

for these people who are under the influence of psilocybin

to self-direct their own calm.

And to bring that level of anxiety

down so that they can continue to move through the peak

and move through the other phases

of the psychedelic journey in ways that could

be most beneficial for them.

So to close out the description of this really wonderful

study--

and by the way, it's another one from the Carhart-Harris

laboratory, about the subjective experience of ego dissolution

or oceanic boundlessness, this mystical state

as so key as a component of a positive psilocybin journey.

I'll just read for you the final sentence of this paper

because it captures it so well.

Quote, it seems vital that appropriate consideration

is paid to the importance of promoting a certain experience

as the quality of that experience

may be the critical determinant of therapeutic success.

Now, before we move into what will

be a very brief description of some

of the other rewiring phenomena, that psilocybin

can induce, and then into some of the therapeutic applications

of psilocybin as they relate to these recent really exciting

clinical trials for depression, and addictive disorders,

and things of that sort.

I just want to cue everybody to a paper

that I think many people will want

to take a look at in thinking about psilocybin.

And I'll provide a link to this paper

as well in the show note captions.

This paper is entitled therapeutic use

of psilocybin, practical considerations

for dosing and administration.

And this is a wonderful paper because it really

goes step by step through the pharmacology of psilocybin

of which you now understand a bit.

But it goes into a bit more detail.

But then it also really nicely describes

the contour of a psilocybin session

and what's happening at the level of chemistry

early, middle, peak, and toward the end of the psilocybin

session.

And then also importantly, it gets

into issues of dosage and translating

from mushrooms, to psilocybin itself, to psilocybin,

things I talked about earlier.

But in a bit more detail, if you'd like to see that detail.

And then perhaps most importantly,

there's a section on contraindications where

it points out that of course, women

who are pregnant or breastfeeding,

people who have a predisposition to psychosis,

those people should really avoid the use

of psilocybin and other psychedelics entirely.

It also talks about where the evidence is strong, moderate,

and weak for the use of psilocybin for treatment

of various disorders.

And I can just summarize that very quickly

because it's where we're going to head in a few minutes, which

is that the most evidence for positive therapeutic outcomes

in response to psilocybin taken and conducted in the manner

that we've been describing today in terms of dosage, and journey

set, and setting is for cancer-related depression,

cancer-related anxiety, and treatment resistant depression.

That's where most of the evidence resides.

There's also some evidence for the use of psilocybin journeys.

And, again, this is typically one or two psilocybin journeys

spaced in the cases of two journeys anywhere

from one to two weeks apart.

And, again, with all of the same contour

of supports and set and setting that we've

been talking about today.

And there there's some evidence for improvement

in terms of outcomes in alcohol use disorder, and dependence,

and tobacco addiction.

And then finally, there's the least amount of evidence.

Although there is clinical trial support for relief

or partial relief for obsessive compulsive disorder,

cluster headaches and migraines, and demoralization

due to AIDS diagnosis.

So this paper has a lot of really interesting information

in terms of different conditions, in terms of dosage,

and again, contraindications, and what's

called adverse events, what sorts of bad things

can and do happen as a consequence of psilocybin

and other types of psychedelic journeys

both during and after those psilocybin or psychedelic

sessions.

And we'll talk a bit more about this

when we go into some of those clinical studies.

Because adverse reactions is always

a key measure in any clinical study.

So very soon, we'll get into the more recent clinical studies

related to psilocybin for the use of treating depression

and some other conditions.

But before we do that, I'd be remiss

if I didn't talk about how psilocybin does and does not

change the brain, what is and what is not known about that.

In fact, when I put out the call for questions about psilocybin,

many of the questions related to these issues.

The first thing to understand is that a psilocybin journey

is really a way to try and put that wedge under the boulder

as I described it to try and invoke neuroplasticity

of a particular kind.

And in that way, it's remarkable,

if you think about it, that everyone has different lives

different experiences.

Psychedelics, in this case, psilocybin

are activating these brain networks that each of us

has more broadly than they would normally be activated.

These are very abnormal patterns of thinking, and perceiving,

and experiencing our emotional and physical life, et cetera.

And yet so often, the outcomes are positive.

Not always, but the outcomes are positive.

The experience is positive, even though it

might have these anxiety moments or components within them.

It's very important to understand that psilocybin

and the journey while important are not really what all of this

is about.

It's really about neuroplasticity.

So researchers, in particular, neuroscientists

are very intensely interested in understanding

what sorts of neuroplasticity psilocybin creates.

Because it turns out there are lots

of different types or processes involved with neuroplasticity.

For instance, brain networks, behavior, thinking, emotion, et

cetera can change because of the addition of new neurons.

That's one form of neuroplasticity

that's referred to as neurogenesis, the production

of new neurons, most typically in the so-called dentate gyrus

or other subregions of the hippocampus,

a brain area involved in learning and memory.

Neurogenesis in other regions of the adult human brain

are exceedingly rare.

And to be honest, may not occur at all.

This is a debated area.

We could do an entire episode about this.

But for the most part, neuroscientists

don't really believe that your neocortex, your striatum,

your cerebellum has that much neurogenesis that's

related to learning and memory of new things,

or new experiences.

And we don't actually think that occurs as a consequence

of taking psilocybin either.

Now, some of you who are familiar with,

for instance, the cerebellum.

You might be saying, wait, what about granular cell

proliferation in the cerebellum?

Or what about the rostral migratory stream

from the subventricular zone where there are neuroblasts

spitting out little new neurons that

migrate in through the nose to replenish the olfactory neuron

population?

Yes, that's all true.

That does occur.

It's been observed in mice, it's been observed in monkeys.

And to some extent, it's been observed in humans.

But, again, I repeat it is not a prominent feature of learning

and acquisition of new skills, new ideas,

or new emotional states.

Perhaps the best supported evidence

for neurogenesis underlying new thoughts, experiences,

abilities, emotions, et cetera is the production

of new neurons in that dentate gyrus

subregion of the hippocampus.

And that probably does occur in humans.

But neurogenesis is not really the dominant mode

of changing neural circuitry in adult humans.

It might be a player in adolescence,

in young childhood.

It is certainly a player before we are born

when we are still in utero.

But then the brain is being wired up

in many different ways, including

the addition of new neurons and changing of connections.

All of this is to say that while neurogenesis is a really

sticky idea and it makes great headlines,

the addition of new neurons is not really the way

that the brain changes under psilocybin, other psychedelics,

or just generally.

It's perhaps responsible for maybe 1% to 2%,

and I'm being generous there, of the rewiring events

that are going to be most important for all of us.

So we need to set that down and cement that there.

Until further evidence comes out to the contrary,

that's certainly where I and here

I feel comfortable speaking for the majority of neuroscientists

out there, professional neuroscientists.

That is the paper showing adult neurogenesis are interesting,

but they don't really explain most

of the plasticity that occurs in the adult human brain.

So if neurogenesis ain't it, what is?

Well, it's very clear that psilocybin, other psychedelics

and any behavioral or drug intervention that

can induce neuroplasticity does so largely through the addition

or strengthening of new neural connections

or through the elimination or weakening

of other neural connections.

And if you look at the data exploring the mechanistic basis

for psilocybin induced neuroplasticity,

it's mostly focused on animal brains, animal models, mice

and rats, in particular.

A little bit on primates, but mostly mice and rats

because that's where the interventions can

be done of knock out animals, of imaging the brain in real-time.

Of course, there are the beautiful studies

of Robin Carhart-Harris and others exploring

neuroplasticity at the level of brain imaging,

at the level of ultrasound measurements,

of how active are certain brain areas in humans, how extensive

is the modularity or not extensive

is the modularity, et cetera, the stuff

we talked about earlier.

So in other words, there are neuroplasticity studies,

the effects of psilocybin in humans.

But in terms of underlying mechanisms of neuroplasticity,

I think the predominant theory is that psilocybin induces

neuroplasticity through the addition of novel connections

in those pyramidal neurons of the frontal cortex,

elsewhere in the cortex, and certainly

also in the visual cortex.

Probably also subcortical as well below the cerebral cortex

in areas like the thalamus, maybe even in the brain

stem as well.

And that those neuroplasticity events

are structural and functional.

And they involve a couple of basic events.

The most prominent of which is the growth of dendrites.

Dendrites are those little branches or processes

that come out of the neurons, not just the pyramidal neurons,

but other neurons as well.

But since we're talking mainly about pyramidal neurons today.

Both the apical, those ones that top.

They're called the apical tufts.

They're the ones that reach laterally to connect

with other neurons, communicate with other neurons

that we talked about before.

As well as the dendrites that come out

of the base of those pyramidal neurons.

Those processes grow in response to psilocybin,

as well as the addition of what are called dendritic spines.

So the dendrites are the branches.

The spines are these little protrusions that grow out.

Actually, here, I don't know if this is coincidence or not.

Again, I always say I wasn't consulted at the design phase.

But these little protrusions actually

look like little mushrooms.

They have a little stalk and they have a little head,

a little spine, head.

And those little spines-- so think

of these as like little tiny mushroom appearing.

OK.

They aren't actual mushrooms.

OK.

The first person that puts in the comments, oh, my goodness.

I learned today that mushrooms grow out of our neurons.

When we take magic mushrooms, that is not what I'm saying.

What I'm saying is that these little mushroom shaped

protrusions that we're calling dendritic spines

do in fact grow out of dendritic branches of neurons

when animals ingest psilocybin or are

injected with psilocybin.

And that those little mushroom shaped protrusions

are the sites of new excitatory connections, new locations

for input from other neurons to activate

those neurons that have those little mushroom-shaped

protrusions.

If you'd like to see examples of this, both movies and still

shots, it's pretty remarkable.

There's a paper that I'll provide a link to in the show

note captions.

This was published in the Journal Neuron, Cell Press

Journal, Excellent Journal, entitled Psilocybin Induces

Rapid and Persistent Growth of Dendritic Spines

in the frontal Cortex In Vivo.

So these measurements were done in the mouse equivalent

more or less of the prefrontal cortex.

There are some interesting details in this paper,

for instance, that those new connections persist.

So they don't just grow out during the psilocybin being

active in the bloodstream and brain of the animal,

they persist.

OK.

So this may again.

May explain some of the persistent changes

that occur in people after psilocybin journeys.

They may too grow new spines.

I should also mention that a reduction

in the number of dendritic spines, these little mushroom

shaped protrusions in the frontal cortex

neurons of humans occurs in depressed patients.

We know that from postmortem tissue.

And that drugs that relieve depression

or that treatments including behavioral treatments, that

provide some relief from depression do

seem to be correlated with increases

in spine growth in frontal cortex neurons as well.

So this raises a very interesting idea,

which is perhaps it's the growth of new connections,

these new dendritic spines in particular neurons.

That's created by administration of psilocybin.

That explains the relief from depression

that people experience.

So this is just one paper.

But it's one paper of a growing body of work showing that, yes,

indeed, psilocybin induces both structural and functional

plasticity in the human and animal brain.

It does that in the human brain at therapeutic doses

of anywhere from 10 to 25, perhaps even

30 milligrams per session, one or two sessions.

I should mention that the mouse studies tended to use

quite high doses of psilocybin.

I wasn't shocked, but I was somewhat wide eyed for a moment

to realize that most of the studies looking at changes

in plasticity in the mouse brain in response to psilocybin

use the equivalent of 1 milligrams per kilogram

of body weight, which is if you do the math,

and you translate what we were talking about before in terms

of dosages, I'll just spare you all the time,

it's about double, the sorts of dosages that are typically

used in humans.

Maybe even triple in some cases.

Now, it's often the case in animal studies

because of the metabolism of animals

being different, but also because seeing effects of drugs

in animal studies can be difficult.

They did use a dose response anywhere from 0 to 0.25

to 0.5 to 1 to 2 milligrams per kilogram

of psilocybin in the study.

So they had a dose response curve.

But focused mainly on this 1 milligrams per kilogram dosage.

In any event, the point is that many

of the studies that describe these pretty

dramatic structural changes in the animal brain,

most typically the mouse brain in response

to psilocybin use dosages of psilocybin

that if translated to humans would

be about double the human therapeutic dose.

So that is something that we need

to take into consideration.

Nonetheless, it's very clear that in both animal studies

and humans, psilocybin is inducing

both structural and functional changes in brain circuitry.

And that in humans, the network connectivity

is being changed dramatically.

We talked about those data earlier.

And that the underlying basis for that might be,

again, might be.

We don't know for sure.

The addition of new dendritic spines on these pyramidal

neurons that we've been talking about repeatedly

throughout today's episode.

Although neurogenesis perhaps and other modes

of neuroplasticity, such as the elimination

of certain connections.

Perhaps related to unhealthy maladaptive thoughts,

or feeling that a particular sad song is overwhelmingly sad.

It could be the case that those sorts of things

change subjectively because of the removal

of neural connections.

If you're going to think like a neurobiologist or scientist

for that matter, you don't ever want

to think that one mechanism can explain

all the effects of a given drug or a given experience.

It's almost certainly likely to be

the consequence of multiple mechanisms acting in parallel.

And because I know there are people out there who

would like to even more about the neuroplasticity induced

by psychedelics, including psilocybin,

there's a wonderful review that I provide a link to

in the show note captions entitled, Psychedelics

and Neuroplasticity: A Systematic Review Unraveling

the Biological Underpinnings of Psychedelics.

This review is great because it goes a step

beyond just psilocybin and psilocin

binding to the serotonin to a receptor, and things like brain

derived neurotrophic factor.

It actually talks a lot about the intracellular signaling

and exactly how neurons change their excitability patterns

based on this activation of the serotonin 2A receptor.

It's probably more detail than most of you

out there are interested in.

But if you are interested in that level of detail,

this is a wonderful open access review.

So a few minutes ago, I talked about where

there is strong, modest, and somewhat weak

or rather, I should say, minimal evidence

for the therapeutic use of psilocybin

to treat various disorders.

And across the board, it really appears

that major depression and so-called intractable

depression, in some cases, is where

we're seeing the most exciting research to date.

Now keep in mind that because of the Controlled Substances

Act being invoked in 1970 in the United States,

and because it was only just a few years ago really,

only about five years ago, that psychedelics including

psilocybin received what's called a breakthrough

status at the FDA.

That there are now a lot of clinical trials

exploring how psilocybin can impact

various things like mood disorders, addictive disorders,

and so on.

Prior to 2018, when that therapeutic breakthrough

potential was established in the United States,

I think a lot of people in the so-called psychedelics

community had the sense, and really the belief

that these drugs had enormous potential.

But they just weren't being explored that extensively.

So I do want to give a nod to the incredible researchers

such as Robin Carhart-Harris, but also Matthew

Johnson, Roland Griffiths, Nolan Williams, and many others.

OK.

I'm certainly not listing off everybody.

That would take hours.

But those researchers have really pioneered

both the legal efforts, and the funding efforts,

and most importantly, the research

efforts defining the clinical data

that I'm about to describe.

And here, I'm going to summarize the clinical data

in a bit of a top contour fashion

just giving you the kind of highlights.

We will, of course, provide links to the papers

if you'd like to look into it further.

But I'm only giving you the top contour

because I've had the great fortune of having Matthew

Johnson on this podcast before.

You can find that episode at hubermanlab.com.

Just simply put Matt's name or psychedelics into the search

function.

It'll take you to that episode in all formats

or links to all formats rather.

I've also had the great fortune of sitting down recently

with Dr. Robin Carhart-Harris to talk about his work

at University of California San Francisco on psilocybin, LSD,

Ayahuasca, and DMT as it relates to depression

and other disorders.

And that episode, which also will

be released at hubermanlab.com and on all platforms YouTube,

Apple, Spotify.

Really goes in depth into these clinical studies

and what those studies really look like, who's in the room,

whether or not people just get one

dose or two doses, how far apart those are separated.

All of that is covered in extensive detail

in that what I found to be wonderful discussion with Dr.

Robin Carhart-Harris.

So if you're interested in all of the details

as it relates to clinical application of psychedelics,

stay tuned for that episode soon.

Again, you can find that at hubermanlab.com

and on all platforms.

In the meantime, I would be remiss

if I didn't include a bit of discussion

about what has been observed in terms of using psilocybin

journeys as a way to treat depression because the data are

just oh, so exciting.

Again, these data really started to surface

as the consequence of studies that

were initiated around 2006 in just a few select laboratories.

And then really picked up in terms

of the number of laboratories and number

of studies between 2018 and now.

So what you'll notice is that most

of the papers I'm about to describe were published in,

for instance, Phenomenal Journals,

New England Journal of Medicine in 2021,

and New England Journal of Medicine November 2022, Journal

of the American Medical Association Psychiatry

just very recently, 2021.

So these are very recent papers.

Essentially, all of these clinical studies

involve either one or two psilocybin sessions.

The dosages that were explored range from 0 milligrams.

So placebo, if you will.

10 milligrams, in some cases, 25 milligrams,

in some cases, 30 milligrams.

And most typically, people received the same dosage

for both sessions if indeed they did both sessions.

However, there's at least one study

looking at just one single episode

of psilocybin administration.

So this is the paper entitled.

No surprise single dose psilocybin for treatment