Dr. Robin Carhart-Harris: The Science of Psychedelics for Mental Health | 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, my guest is Dr. Robin Carhart-Harris.

Dr. Carhart-Harris is a distinguished professor

of neurology and psychiatry at the University

of California, San Francisco.

He is one of the leading researchers

in the field of psychedelics and how they change

neural circuitry in the brain.

His laboratory is responsible for understanding,

for instance, how psilocybin, also sometimes

referred to as magic mushrooms change

neural circuitry in the brain, such that new ideas

and new forms of learning occur.

His laboratory is also responsible for carrying out

various clinical trials, some of which

have demonstrated that appropriate dosages

of psilocybin can alleviate major depression in more

than 67% of people that take the drug.

Now, this is not to say that everybody should take

psilocybin, and today's discussion describes both

the clinical trials and why treatments with psychedelics

in some cases work and in some cases

do not work in order to treat major depression.

As well as discussions around psilocybin, lysogenic acid

diethylamide, sometimes also referred

to as LSD, as well as DMT.

And how these change the brain, and how those brain changes

can relate to changes in mental health,

as it relates to depression and other psychiatric challenges,

as well as how psychedelics are being applied

in order to change neural circuitry for sake of expanding

different aspects of the human mind,

including creativity, intelligence, and much more.

During today's discussion Dr. Carhart-Harris

teaches us about the history of the study of psychedelics, as

well as how the legislature, that is the laws surrounding

psychedelics, are evolving in the United States

and elsewhere for the use of psychedelics

to treat psychiatric challenges.

By the end of today's discussion,

you will have a thorough understanding

of how psychedelics work.

Both in the short-term during the actual journey or trip.

In fact, much of my discussion today with Dr. Carhart-Harris

talks about the different aspects

of the psychedelic journey and how those

relate to therapeutic outcomes.

And, of course, by the end of today's discussion,

you will also understand the long-term effects

of psychedelics, that is, how they can actually

rewire the brain.

Before we begin, I'd like to emphasize

that this podcast is separate from my teaching and research

roles at Stanford.

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And now for my discussion with Dr. Robin Carhart-Harris.

Dr. Carhart-Harris, welcome.

I've been wanting to talk to you for a long time.

I certainly have known who you are for quite a while,

because I place you in this very small but very

special and important category of researchers

who has been pioneering the use of psychedelics

for the treatment of specific clinical conditions,

and really carrying the torch for, essentially,

the entire field.

So I want to start with a voice of gratitude

and say thank you for doing this incredibly important work.

Could you tell us a little bit about what psychedelics are?

In fact, I'm curious as to how the name psychedelic ever

came to be.

ROBIN CARHART-HARRIS: Mhm.

ANDREW HUBERMAN: And what you think they potentially

reveal about the workings of the brain.

And then we'll talk about the clinical applications.

ROBIN CARHART-HARRIS: Sure.

Well, even that one is kind of hot one,

because opinions differ on how to define psychedelic.

But perhaps, a good starting place

is to start with the etymology, where did the word come from?

And it was a Brit excommunicated living

in Canada Humphry Osmond who was due to present

a paper at a National Academy of Sciences meeting

on psychotomimetics--

drugs that mimic aspects of psychosis in their action.

And certain drugs like mescaline--

let's see, 1956-- and LSD were on the bill.

And he felt dissatisfied with them

being under this category of psychotomimetics,

and felt that the signature psychological effects

of these compounds went beyond just

mimicking psychotic symptoms.

And so he wanted to find a more apt term

to speak to, in a sense, the principal component

of their action.

And he jotted down a few different possibilities

about a dozen or so, I think.

And one of them was psychodelic, actually

it started as and ended up being psychedelic.

And he had a correspondence going on with another Brit

also living in the US, Aldous Huxley, where

they were playing with some terms

to refer to these compounds.

And in the end, Osmond won with psychedelic,

and he had this little ditty of, to fathom hell or soar angelic,

just take a pinch of psychedelic.

That's where you put the disclaimer in.

And so what does that mean?

It's two ancient Greek words psyche, means the human mind

or if we're being actually true to the ancient Greek it

means soul.

And then the other component means to make clear

or to make visible or to make manifest or to reveal.

So all of those work.

And it's a neologism.

It's a made up word.

But it does have that ancient Greek origin.

And it's speaking to this principle

that these compounds reveal aspects of the psyche,

of the human mind, the soul that are ordinarily not

entirely visible.

And so that's the etymology, and it's wonderfully poetic.

But I happen to think it's also very accurate.

It's a useful term, because it's sort of,

you might say valence nonspecific.

It doesn't say, you're going to have a great time

or that you're going to go mad.

It's more that-- it reveals a psyche, and it could be hellish

but it could be heavenly.

So that's the etymology and also a bit of the psychology.

And sort of pointing to the phenomenology,

the subjective experience.

But there's also a pharmacology here.

And quite recently, there was put out a consensus statement

about psychedelics that's really referring

to what we call the classic psychedelics to say that these

are all compounds that work on a particular receptor

in the brain, the serotonin 2A receptor.

And that's another way that we could define these compounds.

I said this one's a little hot, because I'm of the view

that while the pharmacology is really useful, how

the drugs work chemically, you can't avoid the phenomenology.

And if we're true to the etymology,

where the term came from, then we must recognize,

and we cannot neglect the subjective experience.

ANDREW HUBERMAN: Thank you for that beautiful description

of what brought us to today in terms

of using the word psychedelics.

And now, it's thrown around all the time.

ROBIN CARHART-HARRIS: Yeah.

Too much.

ANDREW HUBERMAN: Yeah.

Too much.

And I'm guessing-- well, not guessing.

I'm certain that it's also used to describe many compounds that

don't touch the 5-HT2A, the serotonin 2A receptor.

So there is a broader categorization by most people.

And it'll be interesting to see where all the nomenclature

and naming goes.

For the time being, I'd love for you to tell us

a bit more about this idea that psychedelics, however

one defines them, can reveal something about the mind that

can't be revealed otherwise.

Are you talking about the subconscious?

I mean, psychologists and most famously, Freud but also Jung

and also neuroscientists, I think, think about subconscious

processing.

I think, perhaps, the most salient example

for me that's outside the realm of anything psychedelic

would be blindsight.

This phenomenon that you take people that are blind but still

have some connectivity in their brain

and you present them a board with--

or a computer screen with different number of dots

on each side and you say how many dots

are on each side of the screen, and they say, what do you mean?

I can't see the screen.

I'm blind.

And you say, well, just guess.

And their guess rate is accurate far more

than chance would predict.

ROBIN CARHART-HARRIS: Mhm.

ANDREW HUBERMAN: So they have so-called blindsight,

and people have said, well, this is the subconscious

revealing itself.

There's no psychedelic drug involved.

But what you're describing is a pharmacologic-induced state

that reveals something that normally should we assume is

masked or that we are oblivious to--

even though it's expressing itself.

What does it mean for these drugs

to be revealing something about the workings of the mind that

would not be obvious to us, otherwise.

ROBIN CARHART-HARRIS: Yeah.

So the example of blindsight is interesting but it's different.

Blindsight would be referring to non-conscious processing, maybe

implicit processing.

So stuff going on in the mind in perception

in a sense that is below the threshold

of conscious awareness.

But yet is influencing you.

So it's sort-- it's kind of related, but it's different.

So in depth, psychology, psychoanalysis, psychodynamic,

psychology, Sigmund Freud, Carl Jung, and so on.

We talk about the unconscious.

And there, it's more about the kind of blood

and guts of the human condition, the human nature--

both the personal unconscious.

So things that you might not want

to necessarily be conscious of, because it's painful.

So that's the repression aspect pushing it out

of conscious awareness.

ANDREW HUBERMAN: Repressed memories in particular?

ROBIN CARHART-HARRIS: Yeah.

Like traumatic memories, difficult relationships.

It could be complex trauma, not necessarily

just a specific index trauma, but a series of trauma.

And then you have the collective unconscious,

which was really Carl Jung's contribution

to say that there's a transpersonal quality

to the unconscious.

There's aspects about humans, not just this individual human.

There's aspects to our minds, our psyches that

are not fully available to conscious awareness,

but can come up in certain states.

Psychoanalysis went crazy for dreaming as their royal road

to a knowledge of the unconscious.

That was Freud.

But we now with psychedelics, and this

was what drew me into the area.

Was discovering literature that was

speaking to this particular action, the psychedelic action.

And was saying that when these drugs--

like LSD, psilocybin found in magic mushrooms,

when they're used in psychotherapy,

material comes up that may be may have been repressed that

is of therapeutic value and awareness and insight

of this material seems to catalyze

the therapeutic process with strong emotional release.

These cathartic experiences and insights.

Whether they're insights that are personal

or whether they're transpersonal.

But for me, this is really where the meat of it

is with psychedelics and classic psychedelics, in particular.

The likes of compounds like LSD and psilocybin.

I would say that if it wasn't for this action

by classic psychedelics, we wouldn't be

so interested in psychedelics.

I think, if we only had compounds like ketamine, MDMA

cannabis, that could be said, broadly speaking,

to be psychedelic-like.

I don't think it necessarily would

have captured the world's attention as psychedelics

are right now.

I actually think it's a major gap to fill.

Is this principal action of the classic psychedelics.

What does this mean that I'm referring to?

Psyche-revealing.

What is that?

And I suppose where I'm going with this

is, what is that in terms of the biology as well?

What's going on in the brain and the body

when people become aware of things

that previously they weren't fully aware of.

ANDREW HUBERMAN: I'd like to talk about some

of the clinical trials that you've been involved with.

In particular, looking at psilocybin.

As you mentioned, the principal hallucinatory psychedelic agent

in magic mushrooms.

I'd like to start with a kind of nuts and bolts question

just so that everyone's on the same page.

I've read the papers that you've published

and that others have published in this area.

And typically, the dosages used in these trials

are 25 milligrams of psilocybin.

And we talk about one recent trial,

in particular, that compared 25 to 10 milligrams

to more frequent use of very small amounts.

1 milligram over 3 weeks, for instance.

However, when people talk about magic mushrooms,

they often talk about gram doses of the mushroom,

because I'm assuming that they contain milligram

dosages of psilocybin.

Here, we're not encouraging use of any kind.

These are clinical trials.

But for clarity of understanding, what

is the conversion, typically?

Like 1 gram of magic mushrooms will

contain how many milligrams of psilocybin on average.

Because what I'm trying to do here

is calibrate people to this idea of microdosing

versus macrodosing.

And that's fairly straightforward

to do with respect to the clinical trials.

But then in a lot of the lay discussion around this,

you hear about heroic doses versus microdoses.

And so I think there's a lot of confusion.

So if you would, educate us on this idea

of what's a microdose.

And perhaps, also how many milligrams of psilocybin

are contained in a gram of quote unquote, "magic mushrooms?"

ROBIN CARHART-HARRIS: Sure.

Well, a microdose is neither of these are that.

Simple.

But they're fun.

It's a fun challenge.

But microdose, one definition is that it's

a dose of typically a classic psychedelic like LSD

or psilocybin that has some perceptible psychedelic

effects.

It doesn't put you into a noticeable altered state

of consciousness that feels like you're tripping.

And if that was LSD, it looks as though the threshold

is around about, let's see, 10, 11, 12 micrograms.

ANDREW HUBERMAN: Micrograms.

ROBIN CARHART-HARRIS: Micrograms.

ANDREW HUBERMAN: Want to be very clear here.

Micrograms.

ROBIN CARHART-HARRIS: Yeah.

ANDREW HUBERMAN: So 10 micrograms of LSD,

are you saying will not induce visual hallucinations in most

people?

ROBIN CARHART-HARRIS: So that's threshold level.

That's about the level that some people who are sensitive

could feel it.

But if you were to talk to the microdosing gurus,

they might say that that's the ballpark for an LSD dose

that you would consider a micro dose,

and then you would take semi-regularly.

It's typically something like one day

on, one day off or one day on, two days off.

This kind of thing.

There's different protocols.

And yeah.

So some like Jim Fadiman--

one of the popularizers of microdosing, I think

would say that a true microdose should be sub-perceptible.

You shouldn't feel it, yet the assumption

is it's going to change you in some way on a kind of trait

level more than a state level, and maybe behaviorally.

And the typical story goes, it will improve well-being.

And maybe, maybe, it could improve

certain aspects of cognition, say,

related to creative thinking.

I emphasize the maybe there because that's

another angle with microdosing.

We're waiting for some compelling evidence.

As things stand right now, I'd say,

we lack that compelling evidence.

There's some suggestive stuff, but often the study designs

aren't that strong.

It's really hard to do a study with microdosing,

because you need to have permission to give people

a microdose that for practical reasons,

they would go home with, otherwise, you're requiring

them to be in the lab, say three times a week for x number

of weeks to meet the criteria of a course of microdosing,

which might be two or three times a week for say, a month.

And that's a hard thing to do in a lab study.

It's expensive.

You'd need to do that against a suitable control,

so a placebo control.

And there is a study that's been done

in New Zealand that has some interesting preliminary data

that did--

I think did the design right.

But it hasn't been published yet.

I've seen some positive findings presented

around improvements in mood.

But it's a bit early to get too excited about that.

It needs to go through peer review and all that.

But as things stand, the evidence is pretty thin.

And we have to be honest about that.

We did quite a creative study with my colleagues at Imperial.

The guy leading that, Balazs Szigeti, a Hungarian chap,

did a really creative design.

Very much his brainchild.

He instructed people to do their own blinding,

their own placebo-controlled blinding

of their own microdosing.

So this was a classic citizen science study

like do it yourself science where they would get their LSD

tabs and chop them up, put them into gel capsules,

opaque, and have other capsules that are the placebos that they

just close empty capsule.

And then there was a whole barcode scan technique

so that you kind of shuffle them up.

But they've got the barcode in, the QR code.

So you can break the code later on,

but once you've shuffled them up,

you no longer know which ones had the microdosing

and which ones are empty.

ANDREW HUBERMAN: Was this LSD?

ROBIN CARHART-HARRIS: This was LSD.

Also tried it with mushrooms, but the issues

with the mushrooms was people would burp sometimes.

They'd belch.

And then they'd have this mushroom taste.

So then he instructed people to get

some non-psychoactive mushroom material to put in.

So it's really--

ANDREW HUBERMAN: Not an easy study.

ROBIN CARHART-HARRIS: --not an easy study.

And it was-- I love that kind of science.

Real creative first mover kind of science.

And the results were fascinating,

because the short story is that the microdosing didn't

compellingly beat the placebo.

ANDREW HUBERMAN: It did not.

ROBIN CARHART-HARRIS: It didn't.

And he controlled, because he asked.

He controlled for expectancy.

So people's positive expectancy, which is, in a sense,

the vehicle that carries the placebo response.

It's why you have a placebo.

Is that positive expectancy can drive a therapeutic effect

to a large extent.

So you measured that pre-trial and then used

it to correct for the response.

And how did it work?

Those who got a placebo but thought

they got a microdose did as well as those

who thought they got a microdose and did get a microdose.

So it was the bigger effect--

the majority of the effect was in thinking

that you got a microdose.

So in a sense, it was a victory for the power of the placebo

response.

And it's created all sorts of controversy.

People don't want to believe it, that kind of thing.

But that's the beauty of science, isn't it?

That science is not about what you want to believe.

That right there is the beauty of science.

ANDREW HUBERMAN: I love that experiment.

Kudos to them.

I'm not going to attempt to say his last name correctly.

ROBIN CARHART-HARRIS: I tried.

Yeah.

Probably you made a mess of it--

ANDREW HUBERMAN: No.

No.

I think you got it.

You were involved in a clinical trial that

was published last year comparing

25 milligrams of psilocybin to 10 milligrams of psilocybin

to a drug called escitalopram.

ROBIN CARHART-HARRIS: Yeah.

ANDREW HUBERMAN: Yeah.

ROBIN CARHART-HARRIS: Lexapro.

Yeah.

ANDREW HUBERMAN: Lexapro?

ROBIN CARHART-HARRIS: Mhm.

ANDREW HUBERMAN: And this 1 milligram over a 3-week dosage.

I'm wanting to discuss the results of that study a bit

and some of the other trials that you've

done involving psilocybin for depression,

the treatment of depression.

Could we calibrate ourselves?

25 milligrams of psilocybin, is that what--

it's going to be a perceptible dose presumably.

Hallucinations and all that.

And is that what one would find in--

I'm guessing here, if I'm accurate,

this does not mean that I have experience here.

But 2 grams of mushrooms?

ROBIN CARHART-HARRIS: It's more than that we think.

Yeah.

Sorry.

I missed that--

ANDREW HUBERMAN: No, no.

ROBIN CARHART-HARRIS: I missed that one.

Went off on a tangent.

But yeah.

25 milligrams of psilocybin would be--

we don't know, and it's important

that I say that because I wouldn't want people

to hear my answer here, and then use

it to calibrate their own dosing of mushrooms

and get it way off.

So it's guesswork.

And I would love to see someone do a proper study on it.

And look at the psilocybin content

in a given mass of psilocybin mushrooms, magic mushrooms.

But to my knowledge, that hasn't really been done.

Someone like Paul Stamets would give a better answer here.

But I think the percentage within the mushroom mass is--

of psilocybin in the mushroom mass and psilocin

which is the metabolite of psilocybin

is something in the 1%, a little bit higher, maybe, range.

ANDREW HUBERMAN: OK.

So 1 gram, 1000 milligrams of magic mushroom

would contain about 10 milligrams of psilocybin.

Is that right?

ROBIN CARHART-HARRIS: Broadly speaking, yeah.

ANDREW HUBERMAN: OK.

Great.

That helps calibrate.

And I think, again, just allows the layperson

to understand a bit more of where

we're headed with these psilocybin

trials and the results.

So we don't have to restrict our discussion

to just that I clinical trial.

But if we include that one and compare it

to some of the other trials that you've done,

I mean, your laboratory is seeing phenomenal--

in my opinion, phenomenal results

in the treatment of, otherwise, intractable depression,

major depression, which so many people suffer from.

From two-- I suppose there two sessions

of using psilocybin in these ranges of 10 to 25 milligrams.

Do I have that correct?

ROBIN CARHART-HARRIS: Yes.

ANDREW HUBERMAN: OK.

Could we talk a little bit about what people typically

experience during those sessions that

allows this phenomenal transformation of mood

and state and trait as well?

And I'm especially interested in whether or not

it is the experience during those sessions that

is the trigger that's necessary for the transformation

from a depressed to a non-depressed state.

Because the impulse is to think it is.

That what one thinks and sees and hallucinates is--

and hears is so vital.

But of course, these drugs can create neuroplasticity changes

in our neural wiring, presumably for long periods of time.

So what are your thoughts on the experience itself?

And maybe for those who have not done these compounds before,

you could explain a little bit about what's

typical for people, and what you think

is leading to that incredible positive and pervasive change

in mood, state, and trait.

ROBIN CARHART-HARRIS: I would say that it's more than impulse

that is leading us to think that the experience is important.

It's really data and converging evidence now.

So independent teams, independent studies

are converging on the magnitude of certain kinds of experience

rated, yes, with subjective rating scales

is predicting therapeutic outcomes.

Pretty strongly and very reliably.

And so that's guiding us.

Now, could you say, well, maybe those experiences

are some kind of epiphenomenon of say, a central brain action?

Well, absolutely.

But then all experience are epiphenomenon

by that principle.

And yet we care about it, you know?

And it matters to us and in our human relations

with each other.

So I think it does matter to a human being

when they're in say, a psilocybin therapy session,

and as the drug effects begin to come on

and the body starts to feel a little strange and tingly

and there's some initial anxiety.

And then in their mind's eye, they

start to notice patterns and maybe colors

and then, maybe, those patterns deepen and they're dynamic

and they have this fascinating organic quality.

ANDREW HUBERMAN: Are they--

patients in your studies typically using an eye mask?

ROBIN CARHART-HARRIS: Yes.

ANDREW HUBERMAN: So they're in the eye mask?

So eyes closed?

ROBIN CARHART-HARRIS: Yeah.

ANDREW HUBERMAN: That's why you said mind's eye as opposed

to looking out into the clinical setting.

ROBIN CARHART-HARRIS: Yes.

And that's one of the major differences

to psychedelic therapy versus taking a psychedelic.

Is you shut your eyes.

And it's a world away from taking a psychedelic.

Yeah.

A rave or something.

In a sense, good luck with that.

But in psychedelic therapy, yeah.

It's settled conditions.

There's music playing.

And what I'm describing here is very much the default.

There's actually very little variability

between the different sites that have done

this work on these conditions.

Typically, it's two people.

Ideally, mental health professionals, at least one

who's a psychiatrist or a clinical psychologist

or some other kind of psychotherapist or psychiatric

nurse.

But ideally, two who meet those criteria

with a individual who's ingested the drug and music playing

throughout.

A kind of runway into taking the drug and then throughout,

so there's continuity.

ANDREW HUBERMAN: They're music with lyrics or without lyrics?

ROBIN CARHART-HARRIS: Without lyrics, to begin with,

and the music typically is spacious to begin with.

And then builds and becomes atmospheric.

There might be, I don't know, some tribal drums

in the distance or something as it develops

or like the sound of a bird in the distance.

A call.

And then as it gets into more stronger drug effects,

the music starts to coax emotion,

and very intentionally, strings, for example, would come in

and it would be an interesting experiment and one

that we'd love to do actually to see whether if you were

to pull that out, whether the psychedelic experience would

be as emotionally intense as it is in psychedelic therapy

when you have music there as a default.

And across the board, people should find this remarkable,

because it kind of is.

All of the published studies that

are now having such an impact on psychiatry and beyond

have music there as a staple component.

And we just take it as assumption that it needs to be.

I tend to share that assumption.

But it's remarkable that it hasn't been tested properly.

But it's there.

And if you were to run with that,

and if you had a critical agenda, you would say,

well, this is music therapy.

Why are you making all this fuss about psychedelics

when it's music that's there in all of these trials with all

these fantastic findings.

So there is something to that.

And this will tee me up probably to talk

about psychedelic-therapy being a combination treatment.

We have a hyphen between the two,

because I share the hypothesis.

The assumption that should be tested better.

There is a positive interaction between the two.

That there's a synergy between the two.

ANDREW HUBERMAN: That's why it's psychedelic-therapy

with a hyphen, just like Carhart-Harris.

ROBIN CARHART-HARRIS: OK.

Yeah.

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This is extremely useful to hear because I

think most people think, OK.

Psychedelic.

Whether or not they have experience

with psychedelics or not, get some visual hallucinations,

some auditory hallucinations, some synesthesia,

some visual auditory blending, somatosensation, you know?

Rubbing a surface and being able to elicit

the sounds in one's mind.

Of course, et cetera.

But so seldom do we actually hear

about the specifics of these clinical trials in a way that,

for instance, points to music as one of the, perhaps,

key variables.

Now, you mentioned that as people

enter these psychedelic states, that there's a little bit

of initial anxiety.

About a year and a half ago, I had a discussion

with Dr. Matthew Johnson who's running some psilocybin trials

at Johns Hopkins, as you know.

And he mentioned the critical importance,

at least in his mind, to this idea

of the patient, quote unquote, "letting

go" or allowing the experience to take them someplace mentally

as opposed to trying to constrain

their sensory and cognitive experience.

I'm curious what your reflections are on that idea.

And why it might be so valuable clinically.

And this ties back to this earlier discussion

we were having about the unconscious

or about psychedelics revealing something that's

there all the time but that we don't have access to.

And again, I'm struggling to find the right language

for this, because we don't really

have a neural mechanism like top-down inhibition

or something like that to explain how

this unconscious might be uncorked

in the psychedelic experience.

But to make it quite simple and direct, how important do you

think it really is for the patient

to feel like they are, quote unquote, "letting go"

and what in the world is "letting go"

in biological terms?

ROBIN CARHART-HARRIS: Yeah.

Yeah.

Well, I think we'll get there in terms

of having the neural correlates of the mind

revealing itself to itself.

The emergence of the unconscious into consciousness

or unconscious material into conscious awareness.

It's a wonderful challenge.

It's a huge challenge, but it's a challenge to embrace.

And letting go very much is, again,

a staple component of how the different teams

do this work in terms of encouraging a willingness

to let go.

And when we started out doing our depression work

and did that first trial, it was the first trial

of psychedelic in a formally diagnosed depression, you know?

Where that was the target population.

A depressed population.

It was the first modern study to do that.

And we visited Hopkins, friends there

and were mentored on how to do the guiding Bill Richards, Mary

Cusumano.

They were just so brilliant and wise in their guidance to us

as how to do the guiding in our trial.

And so this phrase of trust, let go, be open, you'll hear a lot.

I don't know who fairly it should be attributed to,

but I would attribute it to Bill Richards.

Yeah.

Everything's borrowed.

You probably got it from someone else.

But it's such a key principle.

And it's almost like a mantra that you're

trying to instill in people.

Trust, let go, be open.

And those different components where the trust

is about the therapeutic rapport that, again, this

goes beyond just intuition now.

We formerly measured therapeutic rapport.

We do it even with just a single item, a visual analog scale

item, a subjective rating scale item on the morning of dosing,

and we find that it's a significant predictor

of the quality of the experience that you

have under the drug in the psychedelic therapy,

and then the therapeutic outcomes x weeks or months

later.

So very powerful chain of predictive components

there, but trust, essentially, important.

And again, not just to intuition but the data pointing to that.

Let go, there's a readiness to surrender, to let go,

to not resist.

And we do measure that too and see that it's

predictive of response.

And then the being open is about a willingness to go there,

to confront, to be inquisitive.

Something that's easier said than done.

Can be terrifying.

When you're dealing with a very vulnerable population,

it's probably more--

the rule then, the exception that they're

carrying some significant adversity, life adversity

or frank trauma that they've suffered.

And so that message of be open, be willing to confront

and to go there is really powerful.

And that's how it plays out.

And often, there is struggle.

There's something going on that is I

don't want to be feeling this.

Make it stop.

That can be nightmarish at times,

but it's very, very strong.

And with these big doses that we give, it's very strong.

And actually, a student that I've

worked with, I think now doing a PhD, at Harry Brouwer

is working on a fantastic project characterizing

the different phases of the psychedelic experience

where the early phase is dominated

by negative emotions and negatively-valenced feelings

of anxiety and struggle.

And then it's a different story in the latter half.

ANDREW HUBERMAN: Could I ask about that?

First of all, I think that's fascinating and important

to analyze the different phases and, again, I'm delighted

here because people typically hear

about a psychedelic journey but we never

really hear about the stereotypic components

of the beginning, middle, and end of that journey.

We know that there's a peak and that there's a parachuting

down and et cetera.

But when you say that typically there's an anxiety, maybe

some negative valence in the early stage,

do you mean about the sensations people are experiencing

or about some prior event that's being called to mind

that they're remembering?

Likewise, for the positive phase of the psychedelic

journey or trip are people--

do they still call it a trip?

ROBIN CARHART-HARRIS: Yeah.

ANDREW HUBERMAN: All right.

For the-- I guess, we'll use trip.

For the psychedelic trip.

Are people feeling positive about the experience like, uh.

Like there's been some sort of breakthrough

or they're in a calmer state, or is it

that they tend to be focusing on prior events

that were positive.

So in other words, is there a threading

through of some concept that comes to mind for people?

Maybe about an earlier trauma or maybe about a sense of self

or a sense of other forgiveness.

It could be any of these things.

But what do we know about the finer details of all that?

ROBIN CARHART-HARRIS: Mhm.

I would say, the initial struggle

is more against the general drug effects

than pinning it on something specific.

It's more that normal waking consciousness.

We have a sense, generally speaking,

if we're well or well enough, a sense of assuredness about what

is a table here and so on.

And we have that assuredness to an extent about ourselves

as well.

It might be illusory, but we have it.

And what the drug's doing is it's breaking down all of that.

And it's scary as hell.

And if it's a big dose, it's just like human nature

to rage against that a bit and a bit like dying.

I don't want this.

It feels like I could be dying.

ANDREW HUBERMAN: I might lose my mind.

ROBIN CARHART-HARRIS: Yeah.

That too.

ANDREW HUBERMAN: I'd never come back.

ROBIN CARHART-HARRIS: Those two are the classics.

Is oh, but I might know that I've taken a psychedelic

and I might even know a bit about psychedelics,

but I still fear that I'm going to go mad

or I know that generally speaking,

these drugs don't have a high fertility risk.

I still think I'm going to die.

And it's very palpable and that comes up.

So yeah.

I mean, those are the core fears.

That those two and very reliably, that comes up.

And it's really like a basic drug action.

It's dose-dependent but it's a basic drug action

that is forcing something about the nature

of the mind and the way it's made up

that makes it feel that way, but it feels like I'm losing

my mind or it feels like I could lose my mind

or that I could go insane or that maybe I'm dying here

and this is bad.

Yeah.

ANDREW HUBERMAN: You've talked many times before

and have done really wonderful work looking

at the changes in communication between different brain areas

while people are under the influence of psychedelics.

And I think the gestalt of those data, correct me if I'm wrong,

is that compared to the non-psychedelic state, that

under psychedelic influence.

There is far more--

let's just call it interconnectivity

or communication between brain areas that typically aren't

communicating, which probably is not

surprising to people given the subjective effects

of these drugs.

What is the evidence that after the psychedelic journey

is over, that some or perhaps all

of that enhanced communication across brain areas

is maintained?

And if so, what role do you feel that could

play in these incredible positive therapeutic outcomes?

ROBIN CARHART-HARRIS: Yeah.

So we've had some recent findings in that direction

where, yes, it's true.

And picture says a thousand words

that some people might be familiar with are these two

circles project that we did in collaboration

with some researchers where ordinarily, the communication

is going on within systems like other regions

of the visual system will be speaking mostly

within the visual system.

There'll be a kind of cliquishness or a modularity

to the quality of the communication in the brain.

And then the cool finding with psilocybin was the first paper,

is that the communication, yes.

It transcends these modules and becomes much more inter-modular

crossing different modalities and that effect correlated

with the magnitude of the subjective effects

and then we replicated it with LSD using different methods.

And a new paper will come out soon

with DMT showing a similar effect.

It's a bit of a debate about what regions are most

implicated.

But the general effect of an increase in global functional

connectivity is what we call it or global communication

in the brain.

ANDREW HUBERMAN: And this is while under the influence

of these drugs.

ROBIN CARHART-HARRIS: This is under the--

ANDREW HUBERMAN: So putting people into a brain scanner

while they are under the influence of the drug.

Is that right?

ROBIN CARHART-HARRIS: Yes.

ANDREW HUBERMAN: That itself must be quite an experience,

given that these scanners are small tubes.

You're in a bite bar, you've got a bite bar in your mouth.

That's quite a study.

ROBIN CARHART-HARRIS: You don't always

have a bite bar, at least with the psychedelics.

But yeah.

You've got to keep your head still.

And you have the loud MR scanner noise going.

But because it's regular, there aren't too many surprises.

So it's actually surprisingly tolerable.

ANDREW HUBERMAN: You're in a hospital setting.

So you're not worried about what would happen if you had

a cardiac event or something.

ROBIN CARHART-HARRIS: Yeah.

You got professionals around, and most people generally

tolerate that setting quite well, surprisingly well.

But yeah.

We do all that.

And yes, we do see the opening up

of the communication across systems in the brain.

And it does speak to intuition about

the subjective experience.

The different modalities might be blending with each other.

ANDREW HUBERMAN: Sorry for interrupting,

but I have to ask, is it thought that the activation

of the serotonin 2A receptors what's

responsible for the increased communication between brain

areas that under normal circumstances

would not be communicated?

ROBIN CARHART-HARRIS: Yes.

So there's a few reasons why some modeling work that--

computational modeling work that first identifies where the 2A

receptor is and then looks at--

models its basic effect on neural activity.

Will recapitulate the-- or recreate the effect

that we see actually in the data with the scanning.

So doing the computational modeling.

You can see the same effect by knowing where the key receptors

are and then making them do a certain thing that we

know psychedelics do.

ANDREW HUBERMAN: I can imagine two possibilities.

And I think it's important to distinguish between these two.

One possibility is that the activation of this serotonin 2A

receptor leads to increased connectivity

and thereby auditory and visual hallucinations emerge,

changed patterns of thinking emerge, et cetera.

That's the obvious interpretation.

But the scientist in me has to ask,

is it possible that all of that increased connectivity

is occurring, and yet that is a distinct phenomenon layered

on top of some other effect of the psychedelic drugs

impacting access to the unconscious, hallucinations?

In other words, is it the increased connectivity

that's leading to the subjective experience,

or are those two things happening in parallel?

ROBIN CARHART-HARRIS: Well, they happen in parallel

and they map to each other.

But the question of causality, what causes what,

is the tricky thing where I would suggest

that the causality is circular.

That they influence each other.

And this gets a bit philosophical.

But it matters, because otherwise, there's

a trap that it's easy to fall into where you're thinking

that it's all about the brain action

causing the subjective experience.

And that's typically what we do in cognitive neuroscience.

It's like the first port of call materialist approach.

But one can be a materialist, essentially, but still

appreciate that circular causality that mind also

interacts with brain.

And it's so hard to pick the two apart.

And there is a kind of essential dualism

where subjective experience is a thing in and of itself.

But that's not to divorce it from what's

going on the biological level.

ANDREW HUBERMAN: The reason I ask

is because as I understand it, nowadays, there's

a bit of a movement within the scientific community

that studies psychedelics to develop drugs that can,

essentially, cure or alleviate many

of the symptoms of depression or trauma

that are built off our understanding of how

psychedelics like psilocybin and here I'll throw MDMA in there,

although classically not a psychedelic, it gets lumped in.

We can get back to that later.

But that do not produce hallucinations

or massive changes in subjective experience.

Actually, I think this is what initially got us

into conversation on Twitter as I

had learned about this paper published out

of a group at UC Davis.

That essentially modifying psychedelics

so that they have potential therapeutic application

for the treatment of depression but zero

hallucinogenic properties.

And I thought, wow.

This is going to be a very controversial thing

in the world, right?

Because the history of psychedelics,

as you pointed out, has been one of people

accessing different modes of thinking, feeling.

Seeing things and letting go.

Trust, et cetera.

A therapeutic relationship.

And here we have--

I don't want to say pharma because it's not really pharma,

but we have laboratories who are trying to tease apart

the activation of receptors independent of all

that subjective experience in order

to, essentially, treat the same conditions.

I'd love for you to comment on this, where

you think it might be going.

And whether or not you think that's

the right or the wrong approach, if it has any validity at all.

ROBIN CARHART-HARRIS: It is pharmas, just smaller pharma,

sort of startup pharma.

But--

ANDREW HUBERMAN: OK.

So because pharma would like to have

drugs that can cure depression but don't make people

hallucinate.

Is that correct?

ROBIN CARHART-HARRIS: Oh, they would.

And patients might and the system

would love it, because the system is used to it.

It's medicine.

ANDREW HUBERMAN: Right.

And it doesn't give this mental imagery of the Summer of Love

in San Francisco or of kaleidoscope eyes, right?

It's more of--

ROBIN CARHART-HARRIS: Yeah.

ANDREW HUBERMAN: You can imagine, the more--

I have to be careful with my wording here.

Those who would not be inclined toward that

might embrace a therapeutic that is strictly

effective at treating depression with no hallucinations.

ROBIN CARHART-HARRIS: Yeah.

And it doesn't look like an individual lying on a sofa

crying their eyes out about the life that they've lived.

And that deep catharsis being life-transforming.

Is very different from that model.

I'm skeptical of it for a few reasons.

And one is that I can't see the logic--

I can't see the pieces fit in a way that's compelling.

And I'm also skeptical, because I think it could easily

be wishful thinking, because of that point that patients

would like it and the system would like it.

And you got to bear that in mind as well.

So wouldn't it be convenient if it were true

and you could get the therapeutic action

without the psychedelic effects?

ANDREW HUBERMAN: Well, in a way, that's

a little bit of what microdosing seems to be designed to do.

Like you said, take dosages that are below that perceptual

or awareness of some effect threshold

over a longer period of time in an attempt to ping the circuits

or alter the circuits but not hallucinate.

Not have a catharsis.

ROBIN CARHART-HARRIS: So if microdosing can do that,

and it's sub-perceptible, then microdosing

isn't a psychedelic action, because whereas

the psychedelic action.

When psychedelic, when defined, means psyche revealing.

You're not getting that effect.

You might be getting the pharmacology,

you might be getting some direct serotonin to a receptor

agonism that could be driving a therapeutic response,

but you can get that with SSRIs as well.

And so my point is, what's new?

OK.

Maybe it's a bit new and people are now

developing direct 2A agonists rather than indirect

through a serotonin releaser like the selective serotonin

reuptake inhibitors, the SSRIs like Lexapro.

ANDREW HUBERMAN: Are there any SSRIs

that selectively agonize, which folks by the way means,

activate, in a good way.

Agony sounds terrible.

Those not informed might think that mean that disrupt.

But that can activate the serotonin 2A receptor.

Are there any drugs that will do that are not psychedelic?

I'm not aware of any, but then again I'm

not a psychopharmacologist.

ROBIN CARHART-HARRIS: Well, there are.

I mean, are there any that are licensed and used

as medicines in psychiatry?

I actually had this debate recently on social media,

and I couldn't see a compelling example.

I saw 2A agonists that were used for other things.

You have a compound like Lesuride

used in treating Parkinson's, but actually it's

more of a dopamine agonist.

ANDREW HUBERMAN: Right.

So they're always hitting other things, right?

ROBIN CARHART-HARRIS: Yeah.

Yeah.

ANDREW HUBERMAN: They're always tapping

other neurotransmitters--

ROBIN CARHART-HARRIS: All that being used for other things.

So is there a selective serotonin

2A receptor stimulator, an agonist,

that isn't psychedelic, that is therapeutic in psychiatry

and the answer firmly is, no.

I haven't seen it yet.

Will they develop one?

Well, for patients sake, I hope so.

Because it would be great.

Let's wait and see.

If they do, I doubt it'll be psychedelic

and I doubt it would have much to do with psychedelic therapy.

And it would be much more like the system we're used to

of chronic pharmacotherapy.

Take your drug every day.

Let's hope they find it and it works for patients sake.

But as things stand right now, I'm a little skeptical.

Now, some of the findings that are

being seen that are really exciting, fantastic

work being done, showing things like increases

in the communication components of neurons,

dendritic growth, spine growth, synaptic spine growth.

ANDREW HUBERMAN: Yeah, by the way, folks,

just I'll interrupt for not necessarily spine--

not the cerebral column but spines

are these little tiny twigs with bulbs

on the end of neurons that allow for communication

points between neurons.

So neuroplasticity is often associated

with growth of dendrites and spines

and so forth, which is what Robin's referring to.

That reminds me, and I just want to make sure

that we close the hatch on the earlier answer,

because I interrupted you.

Is the increased connectivity between--

or communication between brain areas

that's observed while people are under the influence

of the psychedelic also observed later

after the effects of the drug wear off?

ROBIN CARHART-HARRIS: Yeah.

ANDREW HUBERMAN: And then I'll just

throw in another question there, because we're on to this topic

now.

To what extent do we think that neuroplasticity, structural

changes in neurons, functional changes in neurons

are responsible for that?

And how long does that last?

Let's say I come into your clinic,

I'm a subject in your experiment, I take--

come in the morning, I do my psychedelic journey

five or six hours later.

I'm parachuting back to reality, as we call it,

and then I go home.

Increase connectivity lasts for how long,

and how long are the structural brain changes occurring?

ROBIN CARHART-HARRIS: Well, you're

asking fantastic questions, and partly because we

don't have the answer yet.

But we do have some data.

And so we have looked at, first of all,

in a sense, the functional plasticity of what we assume

it to be or at least the functional

changes, the increase in communication across systems

that increase in global connectivity,

functional connectivity.

Do we see it after the trip?

We know we see it during the trip pretty well replicated

correlating with intense drug effects.

Do we see it after the trip?

Well the answer is, we've seen it

in two different depression cohorts, psilocybin therapy

for depression.

In one study where we looked the next day, we saw it.

A kind of residual effect similar to what you see acutely

being seen the next day.

And then in a subsequent study, we

saw it also three weeks later.

So we've seen it in two independent data sets.

This decrease in modularity is how we measure it.

It's the same thing, essentially.

Broadly speaking, it's the same thing.

An increase in global connectivity,

functional connectivity.

And actually, unpublished we've seen it

in healthy volunteers on a correlational level.

Not on an absolute change level, but if you

look at its relationship to a mental health outcome,

and this is an important thing to stress with the depression

work, we saw a relationship between the magnitude

of that change, the decrease in modularity or increase

in global connectivity, and the improvement

in symptom severity.

ANDREW HUBERMAN: So interesting.

ROBIN CARHART-HARRIS: Yeah.

ANDREW HUBERMAN: And just to state it a different way,

so what Robin is referring to is when you say modularity,

as neuroscientists, we think of the different modular networks

of the brain.

The eye talks to a region of the thalamus involved

in vision, which talks to the visual cortex, which eventually

converges with auditory information, of course.

But there's a separation or modularity of function.

This increased connectivity is cross-modular

in during the trip, but afterwards as well.

And you're saying that that correlates very strongly

with the strength of the therapeutic outcome

for depression.

I mean, the logical extension of that

is that extreme modularity of brain function

is depressive in some way.

Now, we don't want to go too far,

but what does that mean that increasing

crosstalk between different modules of the brain

is so strongly correlated with a positive therapeutic outcome?

ROBIN CARHART-HARRIS: We don't other

than there's a relationship.

I mean, this is the thing.

We need to be a little careful not to run with it too far.

I mean, there's some things that it suggests.

I think it suggests a more flexible mode of brain

functioning, if you're not getting stuck in modules

or the modules aren't excessively

cut off from each other.

But you see different things with different presentations

if you were to look at cognition.

Sharper cognition is actually associated

with more modularity.

So it's a rule that's a little slippery.

And we need to be careful with it.

ANDREW HUBERMAN: Again, forgive me for interrupting,

but I think I have friends who are--

I would say, are on the spectrum.

Who are very linear in their thinking

and extremely intelligent in the kind

of classic sense of being able to ratchet

through hard problems to arrive at a solution.

And then I have friends who are-- let's

just call them what they are.

From the creative communities outside of science

that are very expansive, they see connections

between many different things, but sometimes, you

have to-- not all of them, but you

have to catch their ideas with a butterfly net.

And oftentimes, what they're saying sometimes

it just doesn't make any sense.

Now, they also produce incredible creative works.

But to have a conversation with them

is anything but a linear experience.

They are not random thought generators,

but there's a non-linearity or randomness to their processing

that's distinct from these other folks

that I'm describing on the spectrum.

And of course, it's a spectrum.

There's a whole range in between.

It sounds to me like there is some therapeutic value

to being able to move along this continuum from the more

linear to the nonlinear.

Is that correct?

ROBIN CARHART-HARRIS: Well, I think so.

Yeah.

It's resonating what you're saying.

It's speaking to my intuition.

That you could be very passy, passing things up,

chopping things up like an analytical scientist like I'm

doing a bit.

ANDREW HUBERMAN: A splitter as we say in science.

You're either a lumper or a splitter.

Yeah.

ROBIN CARHART-HARRIS: The way I'm

being very particular about when to call something psychedelic.

That kind of passy analytical way of thinking you

might associate with a more modular system.

Whereas the system that's more globally, interconnected,

and open, yeah.

Might be more flexible and creative and divergent

in the associations and so on so.

Yes.

That's speaking to my intuition to how you're describing it.

And I imagine, if you take severe psychopathology, severe

mental illness like a depression,

I've always thought that there's something intuitive

about the term itself.

Like a depression in a landscape, which is a halt.

ANDREW HUBERMAN: Physical depression.

ROBIN CARHART-HARRIS: A physical depression

that is easy to fall into.

And if you do, it's hard to get out of.

ANDREW HUBERMAN: So almost--

if I understand what you're saying correctly,

almost like getting stuck at one location on this continuum.

Because most people don't reside at one extreme

or the other full time.

They can kind of migrate back and forth

between expansive states and more linear states.

ROBIN CARHART-HARRIS: Like you do with low mood.

If you're "healthy" in inverted commas,

you can feel your low mood, your disappointment.

But you can spring back.

But someone with--

ANDREW HUBERMAN: And you know you can spring back.

ROBIN CARHART-HARRIS: Yeah.

ANDREW HUBERMAN: Right.

Whereas the suicidal depressive person or suicidally

depressed person, somehow, at least in my understanding,

there's something about that extreme depressive states

and extreme anxiety states, something my laboratory is

a bit more familiar with anxiety, which

alters the perception of time such that people feel

like that negative state is going to go on forever

or that if it goes away, that it's going to return at random.

ROBIN CARHART-HARRIS: Yeah.

ANDREW HUBERMAN: Kind of a vulnerability

to the time domain.

ROBIN CARHART-HARRIS: Yeah.

Yeah.

And it's so tragic, that cognitive bias in depression

that everything's hopeless and that there

is no light at the end of the tunnel.

Yeah.

Yes.

So if you were to get stuck in that rut and have that bias,

then you're cut off from other things,

other sensory modalities or modules,

cut off from the world, cut off from other people.

Stuck in your inner rut.

So yes.

I think we're sharing this intuition

that a decrease in modularity or an opening

up of the system, the brain could relate to an opening

up of the mind that is enduring after the psychedelic dosing

session.

And yeah.

And the third replication was to see in healthies

an improvement in well-being.

Because they're healthy, we don't look at depression.

ANDREW HUBERMAN: So these are people

that are healthy walking into the trial?

ROBIN CARHART-HARRIS: Yeah.

ANDREW HUBERMAN: Take psilocybin twice?

ROBIN CARHART-HARRIS: Well, actually they do.

But the first dose is 1 milligram, which they

don't feel it's a placebo dose.

ANDREW HUBERMAN: Quote unquote, "micro dose."

Yeah.

ROBIN CARHART-HARRIS: Yeah.

We stick EGG on their heads to measure their brainwaves

during each dose.

And 1 milligram, you see no change.

ANDREW HUBERMAN: I think that, you microdosers.

No, I'm just kidding.

I mean, nothing against the micro doses.

I've always just been a little bit skeptical

based on my conversations with the scientists

actually doing the work with psychedelics.

It seems like the answer keeps coming back.

1 or 2, maybe 3 macro doses in a controlled safe setting.

ROBIN CARHART-HARRIS: Well, that's compelling.

The evidence for that is compelling.

And that's what's making all the difference right now.

Microdosing is just appealing, but again,

science isn't about what we want to believe,

it's about what's actually coming through

and what seems to hold up to testing.

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Would you say that's right?

That one or two or three sessions, and how far

apart are those typically spaced in time?

ROBIN CARHART-HARRIS: Yeah.

Typically, one to three weeks across the sites

is the way people are doing the psychedelic therapy

dosing sessions.

Two sessions, you know, Hopkins, Imperial, NYU.

That's been a kind of default to--

we actually use three in a current anorexia

trial, psilocybin therapy for anorexia.

Two patients left to see after 19

who've gone through the trial.

Very exciting results there.

ANDREW HUBERMAN: You're seeing an alleviation

of the obsessive thought about food and a willingness

to consume healthier amounts of food.

ROBIN CARHART-HARRIS: Yeah.

Even improved weight at the long follow-up.

ANDREW HUBERMAN: So critical.

When we did an episode on eating disorders,

I learned that anorexia nervosa, which by the way folks,

the rates are not increasing.

It's been pretty stable through time

despite what's said about social media, and et cetera.

But anorexia nervosa being the most

deadly of all psychiatric illnesses,

which is a big statement, because manic depression,

so-called bipolar depression, has a 20 to 30 times

the typical suicide rate.

Basically, many people with anorexia, I think is how it's--

is what one says, not anorexics.

But people with anorexia often die.

Many of them die.

ROBIN CARHART-HARRIS: Yeah.

So tragic.

So often young people as well.

And similarly, with suicide in terms of premature death.

So the tragedy with psychiatry is so strong.

It's so rewarding to be doing that trial

and to be seeing good results.

I have to check myself a little bit

that I'm reporting on it in this really promisory way

and the trial isn't yet publicly released and published.

So it's still ongoing as well.

ANDREW HUBERMAN: But that was three sessions.

ROBIN CARHART-HARRIS: It is three sessions.

And I can't say what the dosage is, because we still have--

there is a blinding component.

But there are three dosing sessions in there.

Let's see now.

I think they're two weeks apart and we do the follow-up.

Yes.

ANDREW HUBERMAN: I'd like to close out

this description of the journey and the trip

by extending past the day when people actually

take the drug into this-- what I've described

as the integration phase.

You have to re-integrate.

All this increased connectivity during the session.

Hallucinations, insights, anxiety, letting go.

Maybe revelation, maybe epiphany.

OK.

Great.

At what point is that consolidated?

Meaning, are these patients or subjects

in studies having daily conversation

with their therapist?

Are they journaling every day?

And I want to keep in mind that most people are not going

to be part of a clinical trial.

And of course, here we're not suggesting

what people do or not do.

But let's just put it this way.

Were people to use psychedelics, what is the way that people can

maximize on the neuroplasticity and the brain changes

in a positive way in the days and weeks afterwards?

In other words, how long does this so-called integration

last?

And how far can we take this?

I mean, I could imagine that how often one

chooses to think about the insights

could also have an impact.

ROBIN CARHART-HARRIS: Yeah.

ANDREW HUBERMAN: Right?

Because clearly people went to raves, clearly

people did psychedelics in the '60s.

We don't know if clearly people do psychedelics now.

But we don't have data on those people.

You have access to the understanding of how they're

spending their time and the therapeutic outcomes,

which we haven't gotten to the numbers yet, but again,

are incredibly impressive.

In upwards of, as I understand it,

60% or more people getting relief from depression.

ROBIN CARHART-HARRIS: Yeah.

70%, yeah.

ANDREW HUBERMAN: 70%.

Incredible, especially when compared

to the typical antidepressant treatments and so on.

So what is this business of integration?

How is it done properly?

ROBIN CARHART-HARRIS: Yeah.

Yeah.

Gosh.

Well, how long does it last as well?

A lifetime?

You know?

Life is a journey like a trip is a journey.

And there's always work to do.

As Jack Kornfield says, after the, ecstasy the laundry.

And you know?

ANDREW HUBERMAN: I love that.

ROBIN CARHART-HARRIS: Yeah.

Yeah.

There'll be other good ones as well, but forget them.

But yeah.

So the work is ongoing, and yeah.

But this gives you a foot up.

It enables people to do the work more easily, and that's true.

The classic psychedelics is also true.

Very true of MDMA therapy for post-traumatic stress disorder.

It's really giving you a leg up, making it easier

to do very, very difficult work going back to a trauma.

Trying to digest it, process it, integrate it.

So it's such an essential component

of the treatment model.

But one has to be realistic as well by saying, oh,

integration lasts a lifetime.

Well, people delivering a service

can't be there for a lifetime.

So what's the answer there?

And people are wrestling with that issue right now.

And I think one of the solutions might be that it's, in a sense,

on you to appoint.

The therapeutic team can treat you to a point

and then it becomes what you might call practice.

In a similar way, that meditation is a practice.

It's something that you have to keep up.

And if it slips, then things could slip.

And that's the way it is.

Or you have another psychedelic treatment.

So people have even used this term of practice

in relation to psychedelics, where

there's a psychedelic practice like there's a meditation

practice.

But I'm using meditation intentionally here because they

actually think that meditative practice, elements

of spiritual practice could be a very important complement

to psychedelic therapy.

And I think it's probably doing something similar

in terms of promoting an ability to sit with--

a former colleague of mine said it quite well.

In relation to psychedelic therapy

versus chronic pharmacotherapy or like SSRIs

being on them all the time.

Says psychedelic therapy allows you

to sit with rather than sit on.

And so that's quite good.

Yeah.

So the meditation, the mindfulness, the ability to,

yes, be present-centered but also present-centered

and accepting so if things come up,

you can watch and process and then let go.

ANDREW HUBERMAN: That Holy Grail of mindfulness.

ROBIN CARHART-HARRIS: Yeah.

ANDREW HUBERMAN: Awareness without reactivity, respond.

I grew up in the Bay Area and you'd

hear this language, right?

And I'm not being disparaging this.

I have friends that are on the board of Esalen and work

down there.

And I've gone there.

And yet you hear these terms, right?

Be responsive, not reactive, which to a neuroscientist

is like grates on me, which probably just means

I have issues.

And surely, I do.

But what does that mean?

It's saying like, oh, to be the observer

but not be drawn into the experience.

And again, I don't want to be overly reductionist,

but what I find so compelling about the emerging data,

because it really is data, on psychedelics as treatments

for depression and trauma, namely psilocybin and MDMA

is that it really seems to allow people this space that

is so commonly thrown around.

Giving space between stimulus and reaction.

Viktor Frankl talked about this.

But I've been reading a wonderful book

called The Prince of Medicine.

Dates back to the origins of medicine.

Very dense book.

People have been talking about this stuff

and thinking about this stuff for thousands of years.

Psychedelics seem to give people access to that better version

of self, which is remarkable.

What's also remarkable, it's, perhaps, worth pointing out

is that, five years ago, I never would

have been comfortable having this conversation.

I would have been afraid to lose my job.

Stanford Magazine, this week, just published an entire issue

about psychedelics with how ketamine works, MDMA,

psilocybin with the appropriate cautionary notes in there.

But clearly, times are changing.

Speaking of which, I know you're doing a trial on first-time use

of psychedelics.

What inspired that?

And what are you observing?

And as you tell us that, please give us

a few of the key contours.

What's the dose, how old are these subjects?

I'm assuming it's men, women.

Are they suffering from depression or not?

What's the landscape of that study?

And I realize this is still early days of the study

or maybe it's close to completion.

It's not yet published, however, correct?

ROBIN CARHART-HARRIS: It's not published, it's not submitted,

it is completed.

So this was another one of our COVID studies, in a sense,

meaning COVID hit and we had to finish the study.

And it was hard to finish the study because of COVID.

That was true of our psilocybin therapy versus escitalopram.

Lexapro trial, which is published in The New England

Journal of Medicine.

But the--

ANDREW HUBERMAN: This was '20-- that paper, by the way, folks,

we'll provide a link to in the show note captions

as well as some of Robin's other papers.

I think the 2022 New England Journal paper is really

fabulous given the different dosages and the comparison

to, essentially, what is microdosing

and the comparison to citalopram.

ROBIN CARHART-HARRIS: Mhm.

Yeah.

That's interesting that you link the way

we gave small doses of psilocybin to microdosing.

We didn't think of it that way.

We thought it was just a necessary placebo

for the big dose, the 25 milligrams.

Yeah.

So that we could say to everyone we're giving you psilocybin

and not be lying.

Yeah.

For those who got escitalopram, Lexapro for six weeks,

they got a very, very low dose of psilocybin.

But it allowed us to standardize all the psychotherapy and so

on.

But the other study that you're referring to

was in healthy volunteers.

Middle-aged.

Average age, I think, was 40.

So not your typical student study

that is so often the case in psychology research.

All the undergrads end up volunteering for your study.

So this is more of an age range and also--

I think it was an equal proportion of male and female.

All the staff actually were female,

which the staff were very proud of them.

ANDREW HUBERMAN: Although, it produces its own potential

confound, right?

To become all one sex of staff.

ROBIN CARHART-HARRIS: Possibly.

ANDREW HUBERMAN: Yeah.

ROBIN CARHART-HARRIS: They did a good job in the sense

that we saw significant improvements in well-being

at the end of the trial.

So let me describe the design.

It was a repeated measures design, meaning people come in,

you collect your baseline data and do a brain scan,

and you give people a placebo.

We gave people a placebo.

And actually let me rewind a little bit.

Everyone's healthy volunteers, middle-aged never taken

a psychedelic in their life.

None of them.

Entirely fresh, virgin people coming in.

And the plan is to give them their first ever psychedelic

experience.

So that's what we did in this study.

But to do it, we have this repeated measures design where

they'll first get a placebo.

And we have the placebo so that we

can do all the procedures, all the therapy, all the music

listening but not give a whopping dose of psilocybin.

Again, we gave them a placebo dose of psilocybin.

1 milligram.

We stick EEG headsets on during the experience

to record the brain activity from the scalp, the oscillating

electrical activity.

And we do the MRI scanning before and after to see deeper

into the brain, and we can look at the functional connectivity

that we were referring to earlier, and also properties

of brain anatomy, which we did in this study.

So the short story is that all of the changes that we

saw both psychologically and neurobiologically

were seen with the 25 milligrams.

It all happened with that big whopping dose.

And what did we see?

Well, we did see significant improvements

in psychological well-being.

We saw what I call the entropic brain effect, which is actually

formerly quite accurate.

We see an increase in the informational complexity

of ongoing brain activity recorded with the EEG

on the dose of psilocybin.

The activity becomes more complex.

It's harder to predict across time.

It's more informationally rich.

And that effect correlates as it does

very reliably with the magnitude of the subjective effect.

So the bigger the trip, the bigger this entropic brain

effect.

Now, pretty well replicated finding.

But then the MRI, seeing deep into the brain

was probably our most exciting result

where we didn't just see some functional brain changes,

but we've seen some anatomical brain changes as well.

And we used a technique called diffusion tensor imaging that

looks at the cabling of the brain, the white matter tracts.

And we saw a change in major tracts.

So we limited our search space to really thick tracts.

Really thick fibers.

And the fibers that came through as changing

were ones that traveled between the prefrontal cortex

and the thalamus and the striatum.

There were two tracks, two prefrontal tracks that changed.

And they changed in the direction of a decrease

in axial diffusivity, which could be interpreted

as tract integrity where a decrease would be

an increase in tract integrity.

It is something that you see in the developing brain.

The axial diffusivity decreases as the brain goes

from being a baby to being an adult.

Axial diffusivity goes down.

And then in aging and pathologies of aging,

axial diffusivity goes up.

ANDREW HUBERMAN: This is in the opposite direction

of the results you talked about earlier in terms

of brain connectivity of increased

communication across areas.

If I understand correctly, and I'm

perfectly happy to be wrong, by the way, that this decrease

in axial diffusivity translates to a higher

fidelity of communication between the prefrontal cortex

and the thalamus and striatum as opposed to less.

And your description of this as somewhat

like the transition from babyhood and childhood

to adulthood.

Speaks to the same where we know that there's

a massive culling of connections as opposed

to growth of connections.

So in other words, as we get older,

we get better at doing certain things

and less good at doing potentially most everything

else.

Is that right?

ROBIN CARHART-HARRIS: Ish.

Because the change was anatomical and not functional.

So the other stuff was is really measuring communication

in the brain by looking at how the activity fluctuates

across time and whether those fluctuations in activity

are synchronous between regions.

And if they are, we say they're functionally connected.

And we infer that they're talking to each other,

because they go up and down in synchrony.

But when it comes to the anatomy,

we're talking about the just static material stuff.

And so we're seeing the fibers and a property of the fibers

change.

At least that's what we think.

And recently, we had an independent person

come in and reanalyze the data, because one of those things,

incredible finding requires credible evidence,

really strong evidence.

And I would say, the evidence at the moment is one study.

So we need to be cautious on that.

But we did re-analyze it and use this correction

procedure-free water correction to be more sure that it

was a change in the actual microstructure

rather than something to do with the extracellular space.

The water surrounding the fibers.

And it came through.

In fact, the change was strengthened

by doing this correction step.

ANDREW HUBERMAN: So this is neuroplasticity

as the consequence of one first time session with 25

milligrams of psilocybin.

ROBIN CARHART-HARRIS: Yeah.

Yeah.

So we're excited and the two--

ANDREW HUBERMAN: Understandably so.

ROBIN CARHART-HARRIS: --the two different-- the second analyst

coming in wasn't sure she believed it

and then she thought this correction technique might

kill the result and then it came through, and she's like, OK.

Now, I'm excited too.

So we'll see.

We don't know what it means.

What does it mean functionally?

We don't know.

How did the people change?

Well, psychologically, as I said, well-being improved.

We did look at their cognition, and we

used a cognitive flexibility paradigm that

looks at people's ability to notice a rule change

and then flexibly adapt their behavior based on noticing

this rule change and people improved after the 25

milligrams and didn't significantly improve

after the placebo dose.

There weren't correlations with the DTI change, the cabling

change and these psychological outcomes.

But with these studies and smaller sample sizes,

you don't always see those correlations come through.

So it's something.

We don't know what it means.

But it's a change in brain anatomy

that's in the opposite direction to what

you see in an aging brain or with pathology of aging.

And it's what you see in a healthy brain

as it goes from normal neurodevelopment

into adulthood.

ANDREW HUBERMAN: Very, very exciting and intriguing.

And I appreciate that you highlighted

that it's just one study, although from everything you've

said, it sounds like it's been done with immense rigor.

So we will eagerly await the publication of that study

so we can peruse all the data and the subsequent studies.

I want to hear a bit about the study

that you have been carrying out on the use of psilocybin

for the treatment of fibromyalgia.

I'm intrigued by fibromyalgia, because I

have a good friend who also--

I won't reveal who it is.

No.

It's not me.

This isn't the "I have a friend thing."

Who also is a scientist who sits at a fairly high position

in the National Institutes of Health who quietly

has expressed to me that they are incredibly

frustrated with the fact that the standard medical community

has largely ignored fibromyalgia.

And that for many years, it was lumped with things like chronic

fatigue syndrome and other so-called--

again, so-called.

I'm not saying this.

But people often refer to these as, oh.

It's psychosomatic.

That's all in your head.

Which, as a neuroscientist, is a ridiculous statement to hear,

because it's all in your head.

Your brain is in your head after all.

Your physiology and your psychology

are influencing each other.

Of course.

And the world is starting to appreciate that more.

But first of all, maybe you could

tell people what fibromyalgia is,

what inspired you to do a study on fibromyalgia

using psilocybin of all things because that's

surprising to me.

And if you are allowed to or if you have access

to the data in mind, share with us

a little bit about what you're discovering in that study.

ROBIN CARHART-HARRIS: Sure.

Yeah.

Happy to.

So again, it's psilocybin therapy and the population

is fibromyalgia syndrome.

So this is people presenting with

a generalized chronic pain.

So unlike some other pain disorders

where the pain is focused.

You can say, it's my lower back, which is very common.

Chronic lower back pain.

This is more generalized.

And for that reason, it's hard to know what it is.

And that's why it's been a controversial space in medicine

and it's been-- yeah.

It's had that charge thrown at it that maybe it's

psychosomatic, and just to your point,

is anything ever independent of the mind, anyway.

But this is actually a fascinating space

for how subjective experience, the lived experience,

and the mind can influence the body.

Because there's some really interesting literature

around the etiology.

How the pain has come about.

In a sense like what caused the pain.

What's the story there?

And the head of the trial, I would say to my colleagues,

let's just be careful.

Because there is some fascinating literature

around things like a background of trauma

and how that can relate to issues related to inflammation

and how that can express into things

like fibromyalgia syndrome.

I just said, be very careful there,

because if you go in with an assumption

that there's some buried trauma, for example,

then there's that whole other side

of psychoanalysis that massively tripped it up

around false memory and so on.

And so please don't hold prior assumptions

that you're going to uncover buried trauma in every case.

Now, the team of treated, I think,

eight people and it is going very well.

Again, I just want to be careful with how

I describe it to manage expectations and not

get too carried away.

But I check in with the team every week,

and they're still based in London doing the work.

And it's remarkable what I hear about the profound experiences

that people have under the drug.

In this study, we only give one dose.

It's a very mechanistic study.

We actually have the EEG cap on in the sessions

like in the healthy volunteer study,

but this time now taking it into a clinical population.

And--

ANDREW HUBERMAN: So they are wearing an eye mask

under the influence of 25 milligrams of psilocybin.

Most of them probably have not done psilocybin before.

So it's a little bit like the first time study in some sense.

They have fibromyalgia that's debilitating in some way.

They don't want it, obviously.

And during the session, are they thinking about their pain?

Are they being told to think about their pain?

ROBIN CARHART-HARRIS: They're not

being told to think about the pain.

In fact, as I understand it, while there is a therapeutic

model around acceptance of the pain, it isn't--

unlike some of the PTSD work, you

aren't encouraging them to focus on the index trauma

and then work through it and try and digest it.

We don't do that with the pain.

So the pain is there, but there isn't an invitation

to focus on it.

And that's probably one of the differences

with classic psychedelic therapy versus MDMA therapy.

Arguably, MDMA therapy is more like it's a bit closer

to traditional talk therapy where there is more dialogue.

People are able to talk on MDMA.

ANDREW HUBERMAN: In the MDMA trials, do you

know whether or not they used eye masks or--

because this seems to be an important distinction

between, as you described, the therapeutic trip

versus the trip that one does going into the woods

and taking psilocybin in the woods or at a party

or while staring at a poster or a leaf.

Again, I'm not trying to trivialize those experiences.

I mean, obviously, they can be profound.

So I'm told.

But the MDMA trials seem to involve,

as you said, more directed dialogue.

And sometimes, even empathic connection

between people by they're actually

looking at one another, the eyes and eye contact

being such a key part of the human social cognitive

connective networks.

So do you know if they put eye masks on people

during the therapeutic session?

ROBIN CARHART-HARRIS: I'm pretty sure that they

have the eye masks there.

ANDREW HUBERMAN: Right.

Because a lot of the MDMA work, and I

was part of an MDMA trial.

Was, as I understand geared toward developing,

because it's an empathogen empathy toward the self.

ROBIN CARHART-HARRIS: Yeah.

I'm pretty sure they have the eye masks there,

but they probably-- and it's a great question,

because you could formally test this.

It probably don't use them as much.

ANDREW HUBERMAN: Mhm.

ROBIN CARHART-HARRIS: The thing is with the classic

psychedelics, if you're looking at your guides

or your facilitators and their faces are melting or--

ANDREW HUBERMAN: On MDMA, you just

might really start to feel more connected to you.

ROBIN CARHART-HARRIS: Yeah.

They might look especially beautiful and you know--

ANDREW HUBERMAN: sure.

Yeah.

ROBIN CARHART-HARRIS: And yeah.

There's that fascinating effect of loving the people

that you're with.

And so yeah.

I imagine they talk more and use the eye shades less.

And it is more interpersonal rather than like intrapersonal

or going inside.

They do use a fascinating terminology

that some people have critiqued, but it is a very interesting

phenomenon.

And it's this notion of the inner healer.

They use that language a lot.

It's been critiqued because it sounds very suggestive.

You know?

And that's probably one of the vehicles here.

Driving the therapeutic process is suggestion.

I think we have to be honest about that.

So when they go inside, that's another term

that we use very much in the classic psychedelic therapy

work.

You go inside.

You put the eyeshades on, and people

are encouraged to go inside.

But when they do that in the MDMA work,

especially, they might be told explicitly

and listen to the inner healer and that language.

So you could see how a cynic or a skeptic

could come in and see that as some kind of like suggestive

priming or biasing.

I think they have a point.

Skeptics often do, but I don't think it's all of the story.

And just briefly, because it's an interesting point,

speaking to that point a bit in our psilocybin

therapy versus escitalopram trial,

we measured pre-trial expectancy.

And we did it for both conditions.

So what kind of improvement do you

expect with the Lexapro, the escitalopram

at the end of the trial?

And what kind of improvement if you go into the psilocybin arm

and get two big doses of psilocybin.

What kind of improvement do you think you'll see in that arm?

And of course, it was a coin flip

as to what arm people went into and there was no crossover.

What we found was that it was true that we had a sample bias,

so most people had higher expectation stations.

On average, there were higher expectations for psilocybin

and its efficacy or effectiveness

versus the SSRI, the Lexapro.

However, when we looked at the correlation

or the predictive relationship between pre-trial expectancy

and response, we saw that pre-trial expectancy

for the escitalopram predicted response

to escitalopram across virtually every single measure, all

these different measures of depression and anxiety

and well-being, and I think none of the scales.

I'm pretty sure it was none of about 12 or so mental health

rating scales.

Was there a relationship between pre-trial expectancy?

Even though it was high, it didn't predict--

pre-trial expectancy didn't predict response

to the psilocybin therapy.

So that was a bit of a smash on the head for the idea

that the classic psychedelic therapy is

some kind of placebo response.

And I think it's so important to address that question.

Because if it doesn't come through

as it didn't come through, then it

opens up even more intrigue about, well, what is it then?

If it's not just a placebo response or a super placebo

response like an amplification of the placebo response,

then it must be something else.

And how intriguing?

It has a direct therapeutic action.

It must be something.

And we don't yet know what it is.

I talked about the residual increase

in global connectivity.

That's one possibility.

But the truth is, we're just scratching the surface.

ANDREW HUBERMAN: And yet the therapeutic outcomes

are, again, just so marvelously impressive.

I'm curious as to why as--

well, there are that many labs.

But the laboratories that are focused on classic psychedelics

for the treatment of depression and now as you

mentioned, promising results for anorexia and fibromyalgia

as well.

Although preliminary very promising.

Why the lack of attention toward LSD?

Is it that the LSD trips are just too long?

Is it that they are qualitatively different?

Are there any data on non-microdoses of LSD?

And here I want to be very careful,

because I learned through my interactions on social media

that this term microdose is very misleading.

And in some cases, can be dangerously misleading,

because, as you mentioned earlier,

the effective psychedelic dose or the--

effective meaning that can induce

a real trip with hallucinations, et cetera, of LSD

is actually in the microgram range.

So some people hear microdose, and they think microgram of LSD

is a-- micrograms is a microdose when, in fact,

a macrodose of LSD can be measured in micrograms, right?

So this is where in the absence of scientific training,

people can really go astray.

Or even just in lack of understanding

of the metric system.

And since now you're a recent arrival to the US,

fortunate for us.

Sorry.

England's loss is the US's gain by--

Robbins Lab moved from England to the United States recently.

So score 1 for us.

But why isn't there more use of LSD in these trials?

ROBIN CARHART-HARRIS: I think it probably

is the duration of the trip.

It used to be stigma and it was easier

to get your psilocybin study through,

because others were, they were getting that through.

So there was the likes of Franz Vollenweider in Zurich

in Switzerland and then Roland Griffiths

coming along and doing the psilocybin work at Hopkins.

So you could appeal to that precedence

and say, well, they're doing it over there.

Can we not do it in little England?

So that's how it worked for us.

We did actually go on and do an LSD study

once we'd laid the foundations for doing this kind of work.

And it was a brain imaging study.

It was a really extensive one actually

where we used both MRI and another modality

called MEG, sort of super EEG in a sense.

But you know, why didn't that turn our heads

to think, oh, should we not be doing our trials with LSD?

It does have something to do with the pragmatics

like a study day with psilocybin is long enough.

ANDREW HUBERMAN: So four to six-hour trip?

ROBIN CARHART-HARRIS: Yeah.

And the FDA asked us to have the people in the lab

until eight hours post-dose, which personally I think

could be quite excessive, especially if it's a low dose.

And if you have that in the placebo condition as well,

it becomes impractical.

ANDREW HUBERMAN: Yeah.

Scientists are not paid nearly enough

to warrant the-- there's no such thing as overtime

for the graduate students and postdocs.

ROBIN CARHART-HARRIS: Yeah.

It's often those more junior members

that are doing that really hard work.

ANDREW HUBERMAN: It was described very well to me

by a student when I was-- a graduate student said to me,

they really can't afford to pay us by the hour.

Because we used to work.

He was a electrophysiologist, so he would run experiments.

No joke, folks.

Three to five-day experiments.

Sleeping in bouts of two hours here or there

in a dark room with a bunch of equipment and recordings.

So these are long, long acute electrophysiological

recordings.

So yeah.

No scientist does it for the money, I promise you.

There is money in pharma, there is not

money in personal income.

It's not lucrative for the basic scientist.

So yes.

LSD is what?

Anywhere from 8 to 15 hours, something like that.

ROBIN CARHART-HARRIS: Yeah.

15 would be a little long.

You'd be a bit worried if you were still

tripping at that time, maybe with a really big dose.

ANDREW HUBERMAN: Oops.

No.

Just kidding.

ROBIN CARHART-HARRIS: Yeah.

Eight hours plus-- and dose dependent, yeah.

If it's a bigger dose, it's a longer experience.

But if you're going to dose say, 10:00 AM

in the morning, which is more or less how it often goes, then

that's 6:00 PM still feeling the effects.

And then how long do you wait now to close things out

before they can go home.

Even with psilocybin, you have people still at work

into the evening.

And the staff are always there later,

of course, because they've got to pack up and yeah.

So these are long days.

And it's too much, you know?

ANDREW HUBERMAN: That makes sense.

Practical constraints.

I learned from a recent guest on this podcast

that we recorded with, Dr. Satchin Panda who

is a colleague of mine when I was down at the Salk Institute.

Pioneered a lot of the studies on

so-called intermittent fasting.

That the reason that the eating period in these studies--

in animals and now on humans is 8 hours,

the feeding window in these studies

is because the graduate student was going to, otherwise,

lose their relationship.

Because their significant other says, listen,

you can be in the lab for 12 hours, that

meant some hours before the experiment, then 8 hours,

and then some hours afterwards.

But you can't stay in there longer.

And many people use the eight-hour feeding window

as a consequence.

So the scientist has to exist and be carried out

in real-world frame.

ROBIN CARHART-HARRIS: It does.

ANDREW HUBERMAN: Yeah.

ROBIN CARHART-HARRIS: It does.

ANDREW HUBERMAN: MDMA is a little bit shorter, right?

It's about a four to--

it's also about four to six hours, correct?

ROBIN CARHART-HARRIS: Yeah.

It's kind of similar to psilocybin.

Yeah.

It is.

And actually, in the maps work, they

redose after a certain point.

ANDREW HUBERMAN: The booster.

ROBIN CARHART-HARRIS: They have a booster or optional booster,

yeah.

So there is that.

And now, people are thinking, well,

even the psilocybin sessions are long and expensive.

And if you have to have two staff members there

all the time, that's expensive.

That's where most of the expense is.

Is in the staffing.

So can we abridge the experience, make it shorter,

and get away with it, and get similar therapeutic outcomes?

So there's a lot of interest in that direction.

ANDREW HUBERMAN: May I ask about--

sorry to interrupt, but I want to make sure

I don't forget to ask about combination psilocybin MDMA

therapies.

The reason I ask about this is--

and here, truly not me, but I know

people who do self-administered combination

psilocybin and MDMA.

I think I heard this right.

I think it's called a hippy flip.

There's another one that involves LSD too.

Again, I'm not suggesting people do these drug combinations.

But the way it was described to me

was that the psilocybin, because it's so serotonergic,

sometimes can be not a downer but can have a bit of kind

of a murky feel to it.

Some real deep introspection, sometimes

in the darker realms of one's psyche depressive thoughts,

et cetera.

Not that it necessarily stays that way throughout the trip,

but that the MDMA, because it has

a very strongly serotonergic but also dopaminergic--

I mean, it has an amphetamine component.

Cocaine-like, in fact.

If you've ever seen someone on MDMA,

their pupils are about the size of a quarters.

For a reason, they're extreme autonomic arousal

compared to a sedative, which by the way,

would constrict the pupils.

So they describe the use of MDMA to balance out

the affect component of it.

What are your thoughts on combination psilocybin MDMA?

Does this hold any therapeutic potential?

This is, obviously, backyard chemistry in the sense

that people are cowboying this stuff on their own,

which again, I don't really recommend.

I'd like to see the science go first,

but I understand this is how it works in the real world.

Yeah.

What are your thoughts on combining compounds?

ROBIN CARHART-HARRIS: Yeah.

Well, I guess, they're cowboying it in recreational context,

but also underground therapists do work with this combo.

ANDREW HUBERMAN: That's what I'm referring to.

So I'm not talking about people partying with this stuff.

I'm talking about there are thousands now of therapists

that offer psychedelic therapies illegally,

really, because it's not legal at least, not in the US,

to possess or sell.

But that are doing this.

ROBIN CARHART-HARRIS: Yeah.

ANDREW HUBERMAN: So that's really why I'm asking.

ROBIN CARHART-HARRIS: Yeah.

And I think there's something to be said for--

one has to be careful with this as a scientist.

But if they're doing it, are they using

some kind of trial and error?

The same is true, of course, with longer history

of psychedelic plant medicine use if by plants, we

include the fungi as well.

So in the extended sense plants.

There will have been trial and error there.

It might not be as systematic as the science we do today,

but maybe there's been a learning process.

And maybe what they do, they've come

to because they found it works.

So by that principle, I'm interested in that combination

and whether it does offer some advantages, maybe,

in certain patients.

One of the buzz terms in medicine

these days is precision medicine.

A precision medicine and personalized medicine.

So maybe there are certain cases where

introducing say, psilocybin after the MDMA or the other way

around could offer some advantages.

And the differences are interesting.

Psilocybin can get you to deep places.

Maybe the kernel of your suffering and major life

experiences and complexes that are causally

linked to whatever the pathology that you're presenting with.

But it can do it, sometimes, quite aggressively.

And if it say, post-traumatic stress disorder,

it can be overwhelming.

And you can fight it.

And really, it's that.

The resistance is really challenged,

and they fight back.

And the therapeutic breakthrough and the progress

isn't happening because you've agitated the defense

mechanisms.

Whereas what MDMA offers is something arguably

more directionally reliable in terms of the valence.

It's more directionally positive generally, an MDMA experience.

ANDREW HUBERMAN: Hard to have a bad time on MDMA.

ROBIN CARHART-HARRIS: Yeah.

ANDREW HUBERMAN: To be quite blunt, I mean.

But one of the concerns I had with MDMA,

I've never done it recreationally.

I have had not and have not ever done it recreationally.

But when it was done in this therapeutic setting,

I realized, because there was a music on at the beginning,

I actually asked them to turn it off,

because I realized that the music was becoming

such an attractor to my attention

that I suddenly was starting to think about music

and my love of music, which was not

the focus of the session that was there for.

And I'm glad that they did turn the music off,

because the moment they did, I was

able to drop in within the eye mask to this sort of go inward

and address some certain issues that at least to me

felt key and productive.

So that seems to be the kind of hazard with MDMA.

Is that it's such an empathogen that one could start to-- you

could go down any number of different rabbit holes.

ROBIN CARHART-HARRIS: Yeah.

But it's also-- it's a strength, because you well,

the classics like psilocybin can take you there very reliably

but maybe a bit aggressively.

MDMA makes it easier to go there.

And that's its strength.

And that's why that marriage of MDMA therapy for PTSD,

in particular, is a good combo.

It works, because you are going to go there.

In a sense, you have to really make the therapeutic progress.

You're going to have to go back there.

But we're going to set it up so that you can go back there

and feel safer and more trusting and be

able to go back there whereas you've never, otherwise,

been able to go back there without dissociating or having

horrible flashbacks and so on.

So that's the strength that it offers.

I guess the limitation would be that, maybe, it

doesn't take you as deep as the classic psychedelics.

And I tend to think I'm biased on this one,

that there's a kind of honesty to the classics

in that it is hell as well as heaven.

And that's the psyche.

It isn't all roses.

ANDREW HUBERMAN: I really appreciate

that you bring that up.

Because I think that there's such a fear

of so-called bad trips.

There's such a fear in non-psychedelic states

to avoid the painful and everything we know from trauma

and the treatment of trauma.

And we've had several guests on here.

And my close colleague, close, close colleague at Stanford,

Dr. David Spiegel, our Associate Chair of Psychiatries,

Clinical Hypnotist.

Amazing human being and scientist and clinician,

has really just embedded this in my mind.

That the only way to deal with trauma

is to get right up next to that trauma to the point

where some relief is experienced.

There is no other real way.

And so, I really appreciate that you're

saying that the classic psychedelics may offer

with a very strong nudge, perhaps,

the opportunity to get into the uncomfortable in a way

that MDMA or some non-classical psychedelics, perhaps, do not.

We were talking about time frames or duration of trips

and these different compounds and how they differ

and how they're similar.

I'd love for you to educate me on DMT and some of the work

that you're doing with DMT.

My understanding is that it's a very brief trip minutes.

People I know who have done this.

Again, therapeutically, actually, I'll

just point to one very exciting, I think,

group and initiative which is the Veterans Solutions

Initiative, which is a group--

this is carried out in Mexico, but in conjunction

with laboratories at Stanford and elsewhere who are

evaluating the neural changes.

And this involves ibogaine, which

is iboga, which is a very long duration psychedelic.

22 hours or more, followed by I think one or two doses of DMT.

This is for veterans to deal with any number of issues.

Appears to be working with great success.

And I've spoken to several people

who've gone through this.

And the way that they described DMT, almost across the board,

was quote, here I'm just pulling quotes, right?

Anecdata.

The most profound experience of my entire life,

even greater than the birth of my children,

quote, "like being attached to the shockwave of an atom bomb."

Quote.

"There's no way I would do another dose,

because the first one was so unbelievable."

Interesting, by the way.

I think most of us, including me,

would think, why wouldn't you want to do it again then?

But this idea that that was just beyond anything.

So these are significant-- excuse

me these are significant statements coming

from individuals who have existed

at the extremes of human experience to begin with.

These are so-called tier 1 operators

within special operations who exit and may or may not

have trauma.

But DMT sounds like a big deal.

ROBIN CARHART-HARRIS: Yeah.

ANDREW HUBERMAN: Short duration, really big deal.

What do we know about its chemistry?

What do we know about how it's impacting brain networks?

And what in the world is going on

that people are describing it as the ways

I just mentioned a few moments ago?

ROBIN CARHART-HARRIS: Yeah.

It's a rocket ship.

If the psilocybin is like a ship leaving port, then yeah.

This is a rocket ship into craziness.

ANDREW HUBERMAN: Is it serotonin 2A?

ROBIN CARHART-HARRIS: It is.

Yeah.

So it is a classic psychedelic.

It's a direct agonist, a direct stimulator of the serotonin 2A

receptor.

It's an order of magnitude less potent than psilocybin.

But potency is a funny thing, because it's dose-dependent.

So that doesn't mean that the experience with DMT

is less than that of psilocybin.

It's just that you give more of the drug.

But that's matched by it's stickiness

for the serotonin 2A receptor, which

is this kind of golden rule in psychedelic sciences

that it was discovered in the mid 1980s.

This tight relationship between the affinity or the stickiness

or the binding potential of a psychedelic for 2A receptor,

in particular.

Serotonin 2A and its potency.

And the stickier the drug, the more potent.

So LSD really sticky.

Very, very potent.

You only need those tiny microgram doses.

So DMT, by its affinity, is a little less potent,

but by its effects when you give a standard dose,

it's just wild.

And DMT, because there's another compound called 5-methoxy DMT,

which is a bit different pharmacologically

and subjectively, it's similar in terms of its kinetics.

It's another rocket ship.

Both compounds in the wild, so to speak, are smoked often.

DMT and 5-MeO.

People are vaping both actually now.

There are vape pens that are being developed for people

to administer this, but more traditionally,

it's been a smoking thing.

ANDREW HUBERMAN: This is clinically not recreationally

or both.

ROBIN CARHART-HARRIS: Both no.

I mean, underground practitioners

are using the vape pens.

They like them because people titrate the dosage.

They get a feel for what it is to be going into this state

so that they feel they can let go and go into it.

And actually, I think some of the veterans work

might be giving 5-MeO after the ibogaine.

Phenomenologically, if there's a difference between DMT

and 5-MeO, people might put it on 5-MeO

being more of a reliable ego dissolution experience.

Less visual and more all round immersion

in the greater whole loss of self-identity

and just immersion in everything.

ANDREW HUBERMAN: Yeah.

Maybe we could just talk about ego dissolution for a second,

because it's such a sticky, interesting idea.

I can take a step back as a neuroscientist and say, OK.

Ego dissolution.

This idea that-- from a very early age,

we have a concept of self and that I wake up every morning

and I know I'm me and not somebody else.

And presumably, you do the same.

And most people do the same, I would hope.

And that there are objects in the world

and people in the world beyond us.

But every time I hear about ego dissolution,

it sounds like it's kind of a temporary elimination

of the idea that things start and stop

between us and everything else.

Almost like in a kind of a-- here I'm not

trying to sound philosophical or metaphysical,

but there's the molecular continuity of life, right?

We're all just little bits--

ROBIN CARHART-HARRIS: Which is true.

ANDREW HUBERMAN: --which is true, right?

Not a functional way to go through the day, right?

Because you want to make a cup of coffee,

you don't really want to get lost in that

if your goal is to make a cup of coffee.

But what is the power of ego dissolution?

Is it the idea that we belong, is it a sense of meaning?

Is it the sense that we're not as important as we think,

which, of course, could be a wonderfully useful way

to go through life?

To think that we're not as--

like we are vitally important, but we're not the only thing,

right?

Because I do believe connection is vital as most people do.

What is ego dissolution?

And why would this serotonin 2A activation cause that?

That's remarkable.

ROBIN CARHART-HARRIS: Yeah.

Great questions.

I mean, what is it?

You alluded to it with the start/stop, I think.

Because you could define it by boundaries.

In a sense what isn't me is as valid here

as the a developing sense of what

is me that a child develops at whatever age.

And so a major characteristic of the ego dissolution

experience rather than just a negative, a thing going away.

My sense of self going away is the positive.

Oh.

Now, I feel interconnected with other people and the world