Huberman Lab - Dr. Nolan Williams: Psychedelics & Neurostimulation for Brain Rewiring

Welcome to the Huberman Lab Podcast,

where we discuss science

and science-based tools for everyday life.

I’m Andrew Huberman,

and I’m a professor of neurobiology and ophthalmology

at Stanford School of Medicine.

Today, my guest is Dr. Nolan Williams.

Dr. Williams is a medical doctor

and professor of psychiatry and behavioral sciences

at Stanford University School of Medicine.

His laboratory and clinic focus on depression

and other mood disorders.

They focus specifically on the use

of transcranial magnetic stimulation,

which is a brain stimulation technique

that can either activate or quiet specific brain circuits,

as well as circuits within the body,

in order to treat depression and other mood disorders.

Other laboratories and clinics use TMS.

What sets apart the work of Nolan Williams and colleagues

is that they combine TMS with other treatments.

And some of those treatments are among the more cutting edge

that you’ve probably heard about these days,

including ibogaine, psilocybin, MDMA, cannabis, DMT,

and other drugs that at this point in time

are experimental in terms of clinical trials,

but that at least the preliminary data show

hold great promise for the treatment of depression

and other mood disorders.

In the course of my discussion with Dr. Williams,

we covered things such as the history

of each of these drugs,

how they came to be and their current status

in terms of their clinical use and legality.

We also talk about their safety profiles,

both in children and in adults.

And we talk about what the future of psychedelic research

and clinical use really looks like.

For instance, we discuss how a number of laboratories

and clinics are modifying psychedelics

to remove some of their hallucinogenic properties

while maintaining some of their antidepressant

or antitrauma properties.

You’ll also learn about some fascinating research

in Dr. Williams’ laboratory focused on ketamine,

which is a drug that is increasingly being used

to treat depression.

And contrary to common belief,

the effects of ketamine in terms of relieving depression

may not actually arise from its dissociative effects.

One thing that you’ll find extraordinary about Dr. Williams

is that not only does he have vast knowledge

of the various treatments for depression,

but that he and his laboratory

are really combining these treatments

in the most potent way.

That is combining psychedelic treatments

with brain machine interface

or combining brain machine interface

with particular learning protocols,

that is neuroplasticity protocols,

which can directly change the brain in specific ways.

So today you’re going to learn a tremendous amount

about the neural circuitry underlying depression

as well as positive moods.

You’ll also learn about all the various drugs

that I described,

and you’re really going to learn about the current status

and future of the treatment of mood disorders.

Today, you’ll also learn about a number of ongoing studies

in Dr. Williams’ laboratory.

I should mention that they are recruiting subjects

for these studies.

If you go to BSL,

which stands for Brain Stimulation Laboratory,

so that’s,

you have the opportunity to apply

for one of these clinical trials

for the treatment of depression and other mood disorders.

I confess that the conversation with Dr. Williams

was for me one of the more stimulating

and informative conversations I’ve ever had

about psychedelics,

which is simply to say that his breadth

and depth of knowledge on that topic is incredible,

and his breadth and depth of knowledge

in terms of the underlying brain science

and how it can all be combined with clinical applications

is also extraordinary.

I’m sure that by the end of today’s episode,

you’re going to come away

with a tremendous amount of knowledge

about the clinical and non-clinical uses

of those substances,

and you’re going to understand a lot more

about how the healthy and diseased brain work.

Before we begin,

I’d like to emphasize that this podcast

is separate from my teaching and research roles at Stanford.

It is, however, part of my desire and effort

to bring zero cost to consumer information

about science and science-related tools

to the general public.

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And now for my discussion with Dr. Nolan Williams.

Thanks for joining today.

I’m really excited to have this conversation.

It’s been a long time coming,

and I have a lot of questions about different compounds,

psychedelics in particular.

But before we get into that discussion,

I want to ask you about depression, broadly speaking,

intractable depression, how common depression is or isn’t.

I heard you say in a wonderful talk that you gave

that depression is perhaps

the most debilitating condition worldwide.

And yet in contrast to other medical conditions like cancer,

we actually have a fairly limited number of tools

to approach depression.

And yet the number of tools and the potency

of those tools is growing.

So if you could educate us on depression,

I would really appreciate it.

Yeah, absolutely.

So depression is a condition that

it has a lot of manifestations.

So you can have kind of a depression

that’s primarily loss of interest.

You can have folks who feel very anxious

and they’re kind of overactive.

You can have people who don’t have any anxiety at all,

and they’re very underactive,

and they have low motivation to do anything.

So you have this huge range of symptoms

that are in that umbrella of depression.

And some of our work is to actually work

with folks like Conor Liston and Cornell

and try to actually get biotypes based off of neuroimaging

to see if we can kind of parse out

the different depression kind of presentations

and see that clinically and also see that in the brain.

Depression is the most disabling condition worldwide.

What’s interesting about depression

is it’s both a risk factor for other illnesses

and it makes other medical

and psychiatric illnesses worse, right?

So recently the American Heart Association

added depression as the fourth major risk factor

for coronary artery disease, right?

So alongside the risk factors that we know,

hypertension, high blood pressure, hyperlipidemia,

high cholesterol, and diabetes, high blood sugar.

Those three have been on the list for a long time

and depression ended up being added to the list

as the fourth one.

And really interesting, right?

So in addition to taking medications

to address those other three risk factors,

we really have to be thinking about

how do you treat folks with depression

to reduce their risk of having a heart attack in the future.

And some of that’s being worked on now,

but we don’t have a complete solution

to thinking about that at this time.

And then the other thing that’s interesting

is once you have a heart attack in the individuals

that end up having a heart attack,

the risk of having depression after the heart attack

is higher than the normal population, right?

And so a lot of what we’re doing in the lab actually

is measuring kind of brain-heart connections

and we can actually with transcranial magnetic stimulation,

a form of brain stimulation,

we can actually decelerate the heart rate

and capture that heart rate deceleration

over the mood regulatory regions.

And so actually a direct probe of that connection.

So it’s interesting.

And so, as you said a second ago,

it’s a very disabling condition, moderate depressions,

about as disabling as having a heart attack,

acutely having a heart attack.

Severe depressions as disabling

as having cancer without treatment

and dying from a cancer without treatment.

And so it’s kind of underappreciated

just how disabling depression is in that way.

And I think important as stigma is consistently

kind of being reduced over the years for mental illness,

for mental illnesses,

then the idea that we can start really putting more funding

and putting more focus at the federal level,

private foundation level, whatever it is

at a given university to thinking about

developing treatments.

We’ve been very interested in a very particular

clinical set of problems around the most severe

and the most high acuity settings

that folks with depression end up being in.

And that’s in emergency settings

where they go into inpatient units.

And in the rest of medicine,

if it’s talking about heart attacks,

if I start having chest pain right now

and you bring me to a primary care doctor’s office,

they’re gonna have a certain number of tests

and treatments, right?

But very limited because it’s an outpatient facility.

If you bring me to the emergency room after that,

there are more tests and more treatments.

If you put me in the ICU or in the cath lab

where they do invasive procedures to the heart,

there are more tests and more treatments.

In psychiatry, as we elevate the acuity of an individual,

you go from being just depressed to being depressed

and now thinking about ending your life,

the number of treatments actually go down on average.

I mean, in some scenarios they go up,

but on average they go down and there are no tests, right?

And so we’ve been very focused on that particular problem.

Somebody that maybe was doing fairly okay

with a pretty moderate depression

and their depression gets worse

and then they end up in an emergency setting

and the field really hasn’t developed a way

of consistently being able to treat that problem

and folks end up getting the same standard

oral antidepressants that they’ve been getting

from an outpatient and I came to this

because I’m dual trained as a neurologist and psychiatrist,

went back and forth between neurology and psychiatry,

saw that in neurology we have all of these ways

of treating acute brain-based problems

and really wanted to emulate that in psychiatry

and find ways to develop and engineer

new brain-based solutions.

There’s a lot to unpack there.

One thing that you said I’d like to focus on a bit more

because I think we hear that the brain

and the heart are connected, but you described,

I believe a direct relationship between areas

of the brain associated with emotion and heart rate.

And that makes perfect logical sense to me,

but I think at the same time,

many people out there probably think of the relationship

between the heart and the mind as kind of woo

or kind of a soft biology,

but here you’re talking about an actual physical connection

between what area of the brain is it?

The first place where the stimulation goes

is called the dorsolateral prefrontal cortex.

It’s kind of the sense of control,

kind of governor of the brain.

And then what we know is that when you use a magnet,

use kind of what we call Faraday’s law,

this idea of using a magnetic pulse

to induce an electrical current

in electrically conducting substances.

So in this case, brain tissue,

but not skull or scalp or any of that or hair.

You avoid all that, just the brain tissue.

Then you have a direct depolarization of cortical neurons,

you know, the surface of the brain’s neurons

in this dorsolateral prefrontal.

And if you do that in the actual scanner, which we can do,

you can see that that distributes down

into the intercingulate and the insula and the amygdala.

And ultimately the tract goes

into something called the nucleus tractus solitarius

and ultimately into the vagus nerve and to the heart.

So the heart very consistently seems to be the end organ

of the dorsolateral prefrontal cortex.

If you measure heart rate in standard ways

that cardiologists measure heart rate

and you stimulate over this left dorsolateral,

you get a deceleration of the heart rate

and it’s very time locked to the stimulation.

So it’s a two second train of stimulation.

At one second you see the deceleration,

it goes down about 10 beats per minute

and then it’ll drift back up and there’s a break

for eight seconds on the stimulation,

it drifts back up and the stimulation goes back in

and then the heart rate goes back down.

So you see the heart rate just do this,

10 beats per minute every train.

And so we know if you do that over visual cortex,

you don’t get that, or motor cortex,

you don’t get any of those findings.

It’s really specific to this kind of control region

of the brain.

So yeah, it seems to, it’s our work,

other folks work, Martin Arons in Europe,

the Netherlands work showing the same connections.

I think it’s been replicated like four or five times.

So you mentioned left dorsolateral prefrontal cortex.

Anytime I hear about lateralization of function,

I get particularly curious because obviously

we have two mirror symmetric sides of the brain.

There are rare exceptions to this,

like the pineal and things of that sort

that are only, there’s only one pineal.

What is special about the left dorsolateral

prefrontal cortex?

Does this have anything to do with handedness,

right hand or left hand?

Because we know right hand and left handedness

has a lot to do with lateralization of function

for language, a topic for another time.

But why do you think that left dorsolateral

prefrontal cortex would be connected to the heart

in this way?

Yeah, yeah, I think, so left dorsolateral

is thought to be the side that when you excite it,

when you kind of do excitatory stimulation,

potentiating sort of stimulation

that you can reduce depressive symptoms.

And a guy by the name of Mike Fox at Harvard

has demonstrated that if you have strokes in the brain

that cause depression and you put them

on the human connectome, 100,000 patient map,

and you ask the question

what they’re all functionally connected to,

left dorsolateral.

If you take lesions that cause mania in individuals

and you put those all in the human connectome map

and ask what they’re all,

the one common area they’re all connected to,

it’s the right dorsolateral.

And so there seems to be a hemispheric,

balancing of mood between these two brain regions.

And we know this from an experimental standpoint too,

because you can take individuals with depression

and you can excite the left or you can inhibit the right

and they’re both antidepressant.

You can excite the right

and that’s anti-manic in some studies.

And so this idea that there is this hemispheric balancing

of mood is quite interesting, right?

It’s incredibly interesting.

And just so people know,

if you’re curious what the connectome is,

connectome is a term that was built out

of this notion of genomes

being large collections of sequencing and mapping of genes.

They’re proteomes of proteins,

of connectomes as so-called connectomics

of connections between neurons.

So the human connectome project is ongoing.

And I find that incredible

that within the connectome project

they can identify these regularities

of right versus left dorsolateral prefrontal cortex,

especially since I’ve looked at a fair number

of brains from humans,

certainly not as many as you have.

And if you look at the architecture,

the layers, the cell types,

and even the neurochemicals of which cells are expressing,

say dopamine or serotonin,

or receiving input from areas

that make dopamine or serotonin,

they don’t look that different on the right and left side.

And yet here we’re talking about

a kind of an accelerator and a brake, if you will,

on depression and mania,

using what, at least by my eye

and I think other people’s eye,

look to be basically the same set of bits,

the same parts list, more or less.

So what gives these properties

to the right and left dorsolateral prefrontal cortex?

Is it the inputs they receive?

Is this something that we learn during development?

Or do you think that we come into the world

with these hemispheric biases?

Yeah, it’s a great question.

And it hasn’t been worked out,

which your original question was,

in a left-handed individual,

which as you know, 25% of those folks

end up having a right brain dominance,

or 1% of right-handed people have a right brain dominance

if it’s flipped, right?

And that, unfortunately,

that study still hasn’t been done at the level

because that would be probably pretty helpful

for teasing some of this out.

But it’s still being sorted out, right?

We know enough to know this phenomenon exists

because we can use TMS as a probe

and do this sort of, these sorts of manipulations.

But to my knowledge, there hasn’t been anybody

that’s gotten so interested in it

that they’ve been able to get a mechanism of why that is.

But it’s kind of empirically true

in the sense that you can push and pull on those systems,

or in the case of strokes that folks have,

and then you kind of get their brains

and their brain images

and look at where the strokes landed,

those kind of causal bits of information

point to this asymmetry.


Well, in that case, going with what we do know,

that stimulation of dorsolateral prefrontal cortex

slows the heart rate down transiently,

but it slows it down,

and seems to alleviate at least some symptoms of depression

leads me to the question of why would that be the case?

Is it, does it tell us anything fundamental about depression

that anxiety is inherent to depression?

I think a faster heart rate is, you know,

part and parcel with anxiety.

In my laboratory, we’ve studied fear a bit

in animals and in humans,

and we often observe brachycardia,

where somebody or an animal is afraid of something,

and rather than the heart rate speeding up,

it actually slows down,

something that most people don’t think about or recognize.

But given that stimulation

of dorsolateral prefrontal cortex slows the heart rate down

and can alleviate depressive symptoms,

and that there are other ways to slow the heart down,

I have two questions.

What do you think this tells us

about the basic architecture of depression

and its physiology at the level of the heart?

And does the circuit run in the opposite direction too?

If one were to have or find other ways

to slow the heart rate down, say with a beta blocker,

does that help alleviate depression?

Yeah, no, that’s a great question.

So I’ll answer the second question first.

So we know that in the ongoing trials of this,

if you stimulate in the vagus nerve

in an implanted vagus nerve stimulator,

you can actually, you know,

have the afferent parts of the vagus project

ultimately up to the DLPFC through the cingulate

through these anterior insulas,

so obviously the same tract, right?

And you can stimulate there and alleviate depression,

which seems very unusual, right?

You’re stimulating a cranial nerve down in the neck,

but if you can get up into the brain,

you actually can improve depressive symptoms.

And so, you know, more evidence

that this is kind of a whole tract and system.

And if you stimulate in part of that system,

it appears that you can improve mood.

And what if I were somebody

who did not have a stimulating electrode in my vagus nerve,

and I was dealing with minor depression,

and I decided I wanted to take some other approach

to slow my heart rate down via the vagus,

for instance, exhale-emphasized breathing,

or deliberately slow cadence breathing,

things of that sort.

Is there any evidence that behavioral interventions

of those kinds can alleviate depression

or some symptoms of depression?

And is there any evidence that it does indeed feed back

to the dorsolateral prefrontal cortex

to achieve some of that alleviation?

Absolutely, yeah.

So there’s a number of studies implicating the dorsolateral

in, say, meditation, mindfulness, that sort of thing.

And they’re small studies,

but pretty well-designed studies

suggesting that behavioral interventions

in mild depression actually work quite well.

There seems to be a volitional threshold for depression

where at some point you start losing,

you go from being completely in total volition

to having kind of semi-volition.

You have thoughts that you really have a hard time

controlling and that sort of thing.

And when you go through that threshold,

at some point it gets harder and harder

for those sorts of things to kind of kick in and work.

And the extreme form of that is catatonia,

where people in a very severe form of depression

get kind of stuck motorically,

and they obviously can’t, they have no control,

and so, or very limited control.

And so I think there’s a threshold

in which these sorts of interventions will work.

Exercise seems to really be a good treatment

for mild depression, and it may work

through the mechanism you’re describing, right?

As we all know, athletes hold a lower resting heart rate

than folks that aren’t.

If you were an athlete, you had a lower resting heart rate,

you stopped exercising, and a couple years later

your resting heart rate, in many cases, goes up, right?

And so maybe that’s part of the process.

I’m not aware of any studies specifically

looking at dorsolateral prefrontal physiology

pre-post-exercise, but it would be a great study.

I think that would be really helpful to understanding this,

especially if you had a correlation of changes

and kind of lowering of, say, heart rate

with mood improvements.

There’s been a lot of work with heart rate variability

and depression, and studies are, kind of point towards it.

It’s not, not every study is positive for this,

but quite a few studies say, basically,

that lower heart rate variability is associated

with moderate to severe depression,

and that may be part of that mechanism

of that heart-brain risk.

So I’m both intrigued and a little bit perplexed

by this relationship between heart rate and depression.

On the face of it, I would think of depression as depressed.

So lower heart rate might make somebody more depressed.

You even mentioned catatonia, or somebody that just

doesn’t seem motivated or excited to do anything.

I think of mania as elevated heart rate and being excited.

On the other hand, I realize that anxiety,

which brings about ideas as elevated heart rate,

is also built into depression,

which brings me back to what you said earlier,

which is that when we say depression,

are we really talking about four or five different

disorders, for lack of a better word?

And for what percentage of people that have depression,

does some approach to reducing heart rate work?

Whether or not it’s stimulation

of the left dorsolateral prefrontal cortex

by way of transcranial magnetic stimulation,

or by taking a beta blocker, or by stimulating the vagus.

Can we throw out a number, a rough number?

Does that help?

30%, 50%, how long-lasting is that relief?

Yeah, and to be clear, the deceleration of the heart rate

is in the moment when the stimulation is happening,

but it’s not something that’s necessarily

maintained chronically.

It’s more of an indicator that you’re in the right network,

more than it appears to be itself central to the mechanism.

The heart rate variability piece may be,

and there’s some studies that link the two,

but the actual deceleration seems to be

much more of a marker that you’re in the right system.

But it very well could be that the heart rate system

and the mood system just sit next to each other,

and the stimulation hits both.

If you look at how much of the variance in the mood

is explained by the heart rate deceleration,

it’s not a huge amount, right?

So it only explains a small percentage.

And so it’s unlikely that simply reducing the heart rate,

and in fact, for many years, propranolol

and these sorts of drugs actually were implicating

causing depression, and so that’s been kind of debunked,

but it’s unlikely that simply decelerating the heart rate

is gonna improve depression.

But what it does tell you is that if you’re in that area

that is the mood regulatory area,

there’s some parasympathetic cortical kind of process

that’s going on that gets in and causes this to happen.

And it’s independent of mood.

You can take a normal, healthy individual,

and you can do this,

and they’re gonna decelerate their heart rate.

I’m so glad you mentioned

the parasympathetic nervous system,

which, of course, most people think of

as the rest and digest or the kind of calming side

of the autonomic nervous system.

As I’m hearing you say all of this,

and in particular, what you just told me,

which is that it’s not as if having a lower heart rate

protects you against depression,

or a higher heart rate is associated with depression,

although at the extremes, that might be true,

but rather it’s something about the regulatory network,

the ability to control your own nervous system

to some extent.

And when I think about the autonomic nervous system,

I like to think about it as a seesaw

of alertness and calmness,

and when you’re asleep, it’s a lot of calmness,

and when you’re panicking, it’s a lot of alertness.

But that, and I don’t think this has ever been defined,

and when I teach the medical students

at Stanford Neuroanatomy,

my wish is that someday I’ll be able to explain

what the hinge in that process would be, right?

Not the ends of the seesaw.

We know what the sympathetic nervous system is

and what it’s, to wake us up and make us panic

or make us feel nicely alert and calm.

We know what puts someone into sleep or a coma

or makes them feel relaxed.

But what shifts from one side of the seesaw to the other

and the tightness of that hinge

seems to be what you’re describing,

that depression is sort of a lack of control

over inner state so that when I’m stressed,

I can’t get myself out of it.

But when I’m feeling completely collapsed with exhaustion,

I can’t get out of bed and get motivated

to do the very things that would help me

get out of depression, like a workout or social connection

or eat a quality meal, these kinds of things.

So this is perhaps the first time

that I’ve ever heard about a potential circuit

for the hinge as I’m referring to it.

Does that make any sense at all?

Yeah, absolutely, absolutely.

Okay, I just want to make sure

that I’m framing this correctly in my mind.

Yeah, absolutely, and in some studies,

if you do the same identical stimulation

on the right dorsolateral, you can get an acceleration.

Just kind of further confirming

this idea of lateralization, right?

That even, it appears that even the prefrontal cortex,

you know, cortical areas seem to be lateralized

in this way, and I, you know, it’s less,

the right finding is more variable

depending upon the study.

The left’s very consistent in this way, so.

So we’ve talked about transcranial magnetic stimulation

for getting into these networks.

And I also just want to take a brief tangent and say,

because I’ve heard you say this before,

I think it’s so vital what you’re saying

that it’s really not about stimulation of areas,

or any specific brain area or vagus nerve

being important per se.

It’s really about a network, a connection,

a series of connections.

I think that’s really important for people to understand,

and is kind of a new emerging theme, really.

The other thing that, to me,

seems extremely important for us to consider

is what are these lateral prefrontal cortices doing?

Are they involved, for instance, in sensation,

sensing the heart rate?

Are they involved in thinking and planning?

And this gets down to a very simple question

that I know a lot of people have,

which is, can we talk ourselves out of depression

if it’s mild?

Can we talk ourselves into a manic state,

or an excited state, a positively excited state

that doesn’t qualify as mania?

You know, other areas of the brain,

I think is responsible for perception,

or for motor control.

But here we are in this mysterious frontal cortex area,

which people say executive function, planning, et cetera.

Are we talking about thoughts?

Are we talking about structured thoughts?

Are we talking about dreamlike thoughts?

What in the world is going on in the prefrontal cortex?

And here I’ve spent my career in neuroscience,

and I still can’t really understand what it’s doing,

and maybe it’s doing 50 things.

Yeah, no, it’s a great question.

So one of the studies that we’ve been working on,

in addition to the depression work,

is actually trying to change trait hypnotizability.

So David Spiegel and I have been working on this,

and he’s found, and published this 10 years ago,

that a different part of the left dorsolateral

is functionally connected

with the dorsal anterior cingulate,

with a lot of functional connectivity in high hypnotizables,

and not much in low hypnotizables.

And that’s a different, kind of a different sub-region

within this bigger brain region

we call left dorsolateral prefrontal cortex,

than the part that seems to be important

for regulating mood.

And so the left dorsolateral seems to have connections

that are location-specific

within the overall kind of named brain region

that connect to various parts of the cingulate

and seem to regulate it, right?

And so if you knock out

the left dorsolateral prefrontal cortex,

and you have people do the Stroop task, for instance,

which is a task where you have, it’s a simple task,

probably know this,

you have people name the color of words.

And so if I look at one of the cards that they’ll show you,

it’ll have the word red in red, and that’s very easy,

and that’s called a congruent.

And then the incongruent is red in the color blue,

and you have to name, you have to say the word,

you don’t name the color.

So you have to suppress a response.

Yeah, yeah, exactly.

And so, I’m sorry, you name the color

and you see the word written in a different way.

And so basically, if you stimulate in a way

that inhibits the left dorsolateral prefrontal cortex

or either one, you can actually knock out

the ability to do that well,

and it’ll take longer for people in the incongruent cards

to be able to name it.

And so they have a kind of a time delay

that’s greater than they had before they got stimulated.

So that’s a part of the prefrontal cortex

that’s different than the part of the prefrontal cortex

that’s involved in mood regulation.

The nice thing about TMS is that you can go through

and you can find these areas that are functionally defined

through brain imaging, and you can perturb them

and answer the question you’re talking about.

How do I understand this part of the prefrontal cortex

and its function, this part?

And so we were able to stimulate in an inhibitory way

within the left dorsolateral prefrontal cortex

that’s involved with this sort of cognitive control area,

and we were able to knock that area out

and increase trait hypnotizability.

So people had greater hypnotizability

after they got active stimulation

versus when they got sham.

And so it suggests that that brain circuit

is involved in the process

of what therapeutic hypnosis ends up being,

but it’s a very different region

within the left dorsolateral than say we do

when we do these very intensive stimulation approaches

to treat severe depression,

and we’re able to get people out of depression

with the part of the dorsolateral

that seems to be lower in the kind of more lateral

and inferior on the DLPFC

and connected with the subgenual anterior cingulate,

so the part of the anterior cingulate

that processes emotion.

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Based on what you told us about the Stroop Task

and the role of the prefrontal cortex in the Stroop Task,

to me, the Stroop Task is a rule-switching game.

You’re saying in one moment,

the rule is you read whatever the word says,

and then you switch, and then you say,

the rule now is you tell me what color

the word is written in,

and you suppress whatever it is the word says.


Okay, a rule, in some sense, like that,

is a transiently adopted belief system.

So I could imagine that in depression,

which has all sorts of backstory to it,

that of course the psychiatrist or psychologist

or friend can pull on that thread.

Like for instance, somebody might believe that they are bad,

or that they don’t deserve love.

I’m trying to bring this into the typical language

that people talk about, or that they will never succeed,

or that even if they keep succeeding,

it’s just going to get harder and harder,

and it will never feel good.

These are sort of rules like the Stroop Task.

At some level, there are rules that are more pervasive

over time, unfortunately.

But I could imagine that if the PFC

is also contains some sort of maps or algorithms

related to rules of emotionality or self-representation,

or things that we’ve heard,

I think there must be data out there

that’s saying that whatever we heard in middle school,

when someone made fun of us, we can remember that.

Because I can remember things that people said

about a jacket I wore one day

or something in the fourth grade, like crazy.

I didn’t even like the jacket.

Now I think it was kind of cool.

But anyway, the point being that we have an intense memory

for these things that set up a sort of rule or a question,

like maybe I don’t really know how to dress, for instance.

Maybe that’s why I always wear the same black shirt.

But in all seriousness,

it seems like the dorsal out prefrontal cortex

is in this amazing position to access rules,

which are beliefs and beliefs are rules.

And then for moments or longer to switch those rules.

And so for somebody who’s depressed

to just simply look themselves in the mirror and say,

you are great, you are fantastic.

It feels like a lie if you feel like garbage to say that.

It doesn’t fit with the rule.

It’s like saying that card is not red.

That card is green when your eyes tell you that it’s red.

And it seems like there’s something

about prefrontal cortex that in principle

gives flexibility to rules

based on what we know about this group task.

So given its connectivity,

can we assume that the talk therapy that occurs

in the psychiatrist’s office or with a friend

or through journaling out something,

because we do know that reporting things about trauma

or difficult circumstances or the rules that we contain

and tend to hide inside of us

about how we feel miserable about ourselves

or anything really,

that in re-scripting that,

that somehow it allows us to do a sort of stoop task

on our beliefs, is that a tremendous leap?

I’m just really trying to frame this in the context

of what I and most people think of as depression.

Because the network components are vitally important,

but I guess what I’m trying to figure out is like,

what are the algorithms that govern prefrontal cortex?

Yeah, absolutely.

So in a kind of standard cognitive behavioral

therapy session, right?

What the therapist is trying to do

is identify those beliefs

and kind of determine how fixed they are,

if they’re flexible, as you’re saying,

and then help folks to find another explanation for them

and to kind of reintegrate that potential other explanation

into their memory system, right?

Where I think TMS is really interesting, actually,

we’ve had a lot of patients who’ve told me,

like, my therapist told me that I wasn’t trying hard enough

in therapy, and I really am trying hard,

but these are moderate, pretty severe depressed patients.

And as soon as we get them well with the TMS approaches,

you know, kind of rapid five-day approach,

and the next week we come in and see them,

and they’ll say, you know what I did all weekend

is I looked at my therapy books

and now I can understand it.

And so, you know, I actually see TMS

as a way of having kind of exogenous

sorts of cognitive functions

that in milder forms of depression

we can pull off with psychotherapy.

You know, this idea of being able to kind of turn

that prefrontal cortex on

and have it govern these deeper regions.

In depression, the deeper regions

govern the prefrontal cortex.

They precede the prefrontal cortex timing-wise.

We’ve got some data in review now

where we’re seeing that in depressed individuals

that are responsive to our rapid TMS approach,

we call Stanford Accelerated

Intelligent Neuromodulation Therapy,

or S&T, or SAINT,

if you look at the brain before people get this,

they will have a temporal delay

where the cingulate is in front of the DLPFC.

And in people that are normal, healthy controls,

no depression, the dorsolateral prefrontal cortex

is temporally in front of the anterior cingulate.

With effective treatment,

we can flip the timing of things

so the dorsolateral is in front of the anterior cingulate

just like in a normal person.

So you’re not talking about

obviously physically moving these structures,

you’re talking about in time, their activation.

So in one case, it’s like the coach

telling the player what to do,

and in the other case, it’s like the player

telling the coach what to do,

and you restore order to the game.

You restore order to the game.

And what it looks like is depression, to your point,

is a bunch of kind of spontaneous content

that’s semi-volitional,

that’s being kind of generated out of this

conflict detection system, the cingulate,

that seems to sense conflict

and kind of feed that information,

gets overactive in depression.

And then in depression,

it looks like the left dorsolateral

does not sufficiently clamp down on it.

And what therapy appears to do is to kind of restore that.

What we see with TMS over that region

is that we just exogenously do the same sort of thing.

We restore the governance of the left dorsolateral

over the cingulate area,

and that is correlated with treatment improvement.

So the degree in which you can re-time,

re-regulate in time,

the left dorsolateral over the cingulate,

the more of an antidepressant effect you have.

Can we therefore say in crude terms

that the dorsolateral prefrontal cortex

really is the governor of how we interpret

physiological signals and spontaneous thoughts?

It places a lens

that the rest of the brain sees things through.

And you can do these experiments

where you can put a normal, healthy control person

in the scanner and you can make them feel

like they have a loss of control,

and then you can see that region come offline.

So you can experimentally manipulate the system.

And so kind of buffing it up,

I mean, it’s like almost,

TMS is almost like exercise for the brain, right?

You’re kind of exercising this region over and over again

with a physiologically relevant signal

and kind of turning that system on.

And what’s interesting,

I think really interesting for this show is to,

you know, we had a couple of folks,

you know, probably five or six folks

that have actually told me this,

where if they remit early enough in the week,

we have this very dense stimulation approach

where we can stimulate people really rapidly

over a five-day block.

We don’t discriminate when they get better

to when they stop.

So if they get better on day one,

we still give them the other four days

because it’s in the protocol to do that.

We’re getting to a point where we can tell

how long it’s going to take,

but we’re not there yet.

And so, you know, every time somebody gets better

at day one or two,

at the beginning when we first started doing this,

we’d say, you know, we’re not sure,

you know, we think this is safe to keep going,

but you know, what do you want to do?

And everybody was like, no, I want to keep going.

And so, you know, by Wednesday,

they’re like totally zero down on the depression scales,

you know, even better than most people walking around,

like really no anxiety, no depression or anything.

By Thursday, the first guy that told me this,

he came in and he said, you know,

I was driving back to my hotel

and I decided to go to the beach

and I just sat there and I was totally present

in the present moment for an hour.

And he’s like, I read about this in my mindfulness books,

but I experienced it last night

and I’ve never experienced anything like this before.

And I was like, hmm, that’s interesting,

but kind of wasn’t sure.

And then I didn’t tell any, you know,

obviously any more patients about that.

And then about five over the last couple of years

and they get, they were met early in the week.

By the end of the week, they’re like going to the beach

and they’re like totally having what people describe

as a pretty mindful present moment sort of experience,

which is really interesting, you know, what that is.

I mean, I don’t have full on scientific data to tell you,

but it’s just, it’s an interesting anecdote, right?

That folks, when you push them through this point

of feeling kind of clinically well,

that some people end up reporting

this additional set of features, so.

Yeah, you mentioned the cingulate

and the anterior cingulate in particular,

because now I feel like for the first time in my career,

I have some sense of what prefrontal cortex

might actually be doing besides providing a bumper

for the rest of the brain.

The cingulate, it seems, is a more primitive structure

in the sense that it’s under the,

ideally it’s under the regulation of this top-down control

from prefrontal cortex, but what’s mapped in the cingulate?

And for the non-neuroscientists out there,

when I say mapped, if we were to put someone in a scanner

and focus in on cingulate or put an electrode in there,

what makes the neurons in there fire?

What sorts of things in the body and in the mind

and out in the world light up,

for lack of a better phrase, the cingulate?

What does the cingulate like?

Yeah, yeah, so that strip task,

those incongruent word color associations,

the dorsal part of that,

for obsessive-compulsive disorder patients,

certain kind of triggers you’ll see.

Some of the neuroimaging studies

will point to anterior cingulate.

In the kind of very crude psychosurgery world 50 years ago,

the anterior cingulotomy was a way

of treating obsessive-compulsive disorder, right?

Because that area seems to be overactive

in people who are experiencing

obsessive-compulsive disorder.

You can kind of walk, the cingulate wraps around

this white matter track, like bundles,

it wraps around that.

And so there’s a part that’s above that,

around that, and below that.

And depending upon how much of the conflict task

has an emotional component,

the more ventral and subgenual that activation is.

So the dorsal part of the anterior cingulate

seems to be kind of more of a pure cognitive,

maybe obsessive-compulsive disorder sort of area,

whereas when you start getting into mood sorts of triggers,

like facial expression conflicts,

where you’re supposed to,

you know, there’s an emotional strip task

where you show the word happy,

and then you have a face of a person that looks mad,

then that’s another way of having

the same sort of stroop conflict.

That seems to be more perigenual, subgenual areas, right?

So you can kind of, you can trigger the cingulate

based off the level of emotional valence

from none down to a lot.

And that seems to be how it’s distributed.

There are heart rate kind of components to it,

autonomic components in there too.

There’s something called aconetic mutism.

You know, I’m a board-certified neuropsychiatrist,

behavioral neurologist,

and I’ve seen a lot of these,

what we call zebra cases in neurology,

where people have these unusual neurological presentations,

and one of them is aconetic mutism.

So if you have a glioma

sitting in the inner hemispheric fissure

and kind of having pressure on the cingulate,

people can get into an almost catatonic-looking state

where they kind of get stuck and they don’t speak.

And so that tells you something about how the cingulate works

as well, right?

It’s like, if it’s not functioning,

then people have a hard time kind of connecting with reality.

It seems to need to be constantly online

to be able to interact with the exterior world.

Is it involved in some of the dissociative states

that sometimes people who are very stressed

or depressed experience?

You said catatonia being an extreme one,

but I know someone, for instance,

that when they get really stressed

and it can even be if someone yells at them

or someone’s angry, even if someone’s angry with them

or they perceive someone’s angry with them,

there’s a developmental backstory

to why they likely feel this way.

They sort of just kind of can’t,

this is a high, high-functioning individual normally,

and they just sort of can’t function.

They can’t complete simple things like email

or groceries or things for a short while.

It’s almost like a catatonia,

and they refer to it as a dissociative state.

Do you see that in depression?

I mean, we’re speculating here

as to whether or not that involves a cingulate,

but what you’re saying holds a lot of salience for me

in thinking about this example.

Yeah, yeah.

So you see catatonia as an extreme outcome of depression

and sometimes of schizophrenia and other illnesses.

Dissociation is an extreme outcome,

or even in some cases, a less extreme outcome

of PTSD and trauma.

And it’s also a phenomenon that happens naturally

in some people that are highly hypnotizable.

And so if you ask David Spiegel,

he’d say that some of the work that he’s been working on

is around posterior cingulate

and the capacity to dissociate.

But yeah, with our stimulation approach to DLPFC,

dorsal anterior cingulate,

one of the subscales that moved the most

was the dissociative subscale for hypnotizability.

So even in a normal individual,

you see that change in that kind of experience

of dissociation.

I am highly hypnotizable.

David’s hypnotized me a number of times.

In fact, we have a clip of that

on our Huberman Lab channel.

I’ve always, well, always, starting in my early teens,

I started exploring hypnosis.

I’m extremely hypnotizable.

And self-hypnosis or assisted hypnosis.

I don’t know that I ever go into dissociative states.

I’ll try and avoid forcing you

into running a clinical session right now,

but to assess anything like that.

But this brings about something really interesting,

I think, which is I’m aware

that some of the more popular emerging treatments

for depression include things like ketamine,

which is a dissociative anesthetic, is that right?

And my assumption is that as a dissociative anesthetic,

that it leads to dissociative states

where people can sort of third-person themselves

and feel somewhat distanced from their emotions.

I’ve also been hearing that there are emerging treatments,

psilocybin being one of them,

but some other treatments, MDMA, et cetera,

that we’ll parse each of these in detail,

that lead to the exact opposite state

during the effect of the drug,

which is a highly engaged emotionality

and heart rate and sense of self,

and can also lead to relief of depression.

Now, whether or not this, again,

reflects that depression is many conditions

as opposed to just one,

or whether or not somehow tickling,

or in some cases pushing really hard

on the opposite ends of the scale really matter,

I am absolutely fascinated,

and again, also perplexed by this.

Why would it be that a drug

that induces dissociative states

and a drug taken separately

that induces hyper-associative states

would lead to relief of the same condition?

Yeah, no, that’s a great question.

Yeah, so for ketamine,

the level of dissociation appears to be correlated

with the therapeutic effect.

It appears to be necessary,

but not sufficient to produce an antidepressant effect,

and so folks that don’t have any psychological change

from the ketamine or don’t experience any dissociation

typically tend to have less potent

antidepressant effects from ketamine.

We did a study a couple of years ago.

It was really interesting.

So we gave folks naltrexone,

which is an opiate antagonist,

a mu and kappa opiate receptor antagonist,

and we gave the same individuals a pill of that

or a pill of placebo,

and they had no idea which one they were getting.

Was this low-dose naltrexone?

50 milligrams, so it’s a pretty high dose.


Yeah, and so we gave a typical ketamine therapeutic dose,

and then we gave 50 milligrams of naltrexone or placebo,

and then in the same individuals,

we gave two infusions,

one with each of those conditions,

and if they had an antidepressant effect,

we waited until they relapsed,

and then we gave them the other condition,

and then we looked to see

what effect of blocking the opioid receptor,

what effect would you see on the antidepressant effect

of blocking the opioid receptor,

with the idea that if ketamine works the way

that a lot of researchers at the time thought

that it completely worked in,

which is the glutamate system,

then you would have no effect of naltrexone,

because naltrexone just interacts with the opiate system.

It doesn’t do anything with any other systems.

Ketamine has a lot of effects over,

you know, it has clear opiate effects in mice

and various ways of looking at that,

and NMDA receptor antagonism and glutamate effects,

and so if it’s just that the glutamate part

is the part driving the antidepressant effect,

you shouldn’t have any difference

in the antidepressant effect between the two conditions.

If, however, the antidepressant effect is primarily,

the opioid properties of ketamine are necessary

for the antidepressant effect,

then you should have a loss of antidepressant effect

during the ketamine plus naltrexone condition

that you observed in the ketamine plus placebo condition,

and what we saw was that there was a dramatic blockade

of the antidepressant effect when naltrexone was present

in the people that had an antidepressant effect

with ketamine plus placebo alone,

and then some friends of mine did a TMS study with pain

and they stimulated over the left dorsolateral

prefrontal cortex and they gave IV naloxone,

which works basically the same way as naltrexone,

and they were able to block the anti-pain effects of TMS

with an opiate blocker, so this idea that,

another kind of convergent point, right,

this idea that the opioid receptor may have a role

in mood regulation, what’s also interesting is

if you look at people that are getting

a total knee operation, a very painful operation, right,

total knee replacement, and you age, sex,

everything matched the individuals

that are going through that,

but you have a group of people that don’t have depression

and a group of people that do have depression,

the presence of depression triples

the oral opioid dose by day four.

That’s required.

That’s required to cover the pain,

but what may be happening is it’s not just treating

physical pain, it may be treating emotional pain as well,

right, at least transiently it seems to have

an antidepressant effect, chronically it seems

to have a very pro-depressant effect,

it can make people treatment resistant,

but it’s an interesting phenomenon,

but yeah, the opioid system seems to be pretty involved,

but what’s interesting there with the ketamine trial

is that we didn’t see any effect on the dissociation,

and so the dissociation was the same each time,

so the psychological effect of what we call the trip

or the kind of dissociative effect

where people are having a psychological phenomenon

from ketamine, that was identical both times,

and so it kind of, it also challenged this idea

that the psychological experience of the psychedelic effect

may be all that’s necessary to produce an effect

and that the pharmacology doesn’t matter

as long as you can achieve that state,

and so we think we pretty clearly debunked that idea

that the underlying pharmacology and the state

seem to be important.

We don’t know for sure if you can,

and a lot of people are working on this,

if you can take out essentially the psychological effect

and still have a drug that works to treat the illness

that you’re trying to target,

and a lot of, there was a mouse study out this week

where they had an LSD analog,

and they were able to see some animal-level data

to suggest that could be true,

but until we figure that out in humans,

it’s kind of to be determined,

but it is curious, right,

being able to kind of use experimental manipulations

to try to separate some of these phenomenon apart

and really understand what’s doing what.

It’s so critical, and it’s so critical

to the other conversation that we’ll surely get to,

which is the progression of psychedelics

from illicit illegal drugs to clinically validated

and presumably at some point either decriminalized

or legal drugs, which has not yet happened,

at least not in the US,

but just to make sure that people are getting this

and how crucial this is,

what we’re really talking about here

is the fact that if somebody takes a multigram dose

of psilocybin or somebody takes MDMA

or they take ketamine and they experience relief

from their trauma, their depression, their addiction,

or any number of the other things

that indeed those compounds have been shown to be useful for

in certain contexts, clinically supported, et cetera,

there’s this gravitational pull to the idea that,

oh, it was the hallucinations,

it was the dissociative state,

it was the feeling of connectedness,

and what we’re really saying is that

while that certainly could be true,

it may be the case that a major source

of the positive shift that occurs after the effect

of the drug is some underlying biology

like shifts in the mu opioid receptor,

a la your experiments with naltrexone,

or a change in the underlying neuromodulation

that had anywhere from nothing to something

to do with the real shift.

And I know there’s a group up at UC Davis

that published a paper in Nature about a year ago,

also looking at, there’s a chemistry lab,

essentially modifying psychedelics

to remove the hallucinogenic properties,

the mood-altering properties,

and actually seeing some pretty impressive effects

in shifts in mood after the drug wears off.

And I know this gets people upset when they hear it,

a lot of people, this gets a lot of people upset, really,

because people think,

oh, no, it’s the intense experience that matters.

But in fact, that may not be the case at all.

In fact, it’s so powerful for people

that sometimes I liken it in my mind to,

you know, it’s like somebody,

it’s like the birth of a new child,

and it’s such an incredible experience,

and then people feel so much connection,

and then they sort of connect the experience

of the actual birth to the connection,

when in fact, that’s true, it turns out,

but there are a bunch of other things happening too

that’s simply the reflection of the fact

that you’re holding a child

and the pheromonal effects, et cetera.

So anyway, I think it’s very important

that these different variables be figured out.

Along those lines, I want to make sure

that before we dive a bit deeper

into ketamine and psilocybin,

that we do touch on a really important topic

that has been in the press a lot lately,

which is SSRIs, selective serotonin reuptake inhibitors,

because we can’t really have a discussion about depression

without talking about SSRIs.

And then I want to circle back to ketamine and psilocybin.

It seems that there are now data

that essentially state that there’s no direct link

between serotonin levels and depression,

although my understanding is that the SSRIs

are powerfully effective for certain forms

of obsessive-compulsive disorder

and may also be effective for treatment of depression,

but it may, again, be, through some effect,

unrelated to serotonin itself.

Is that right?

And how should we think about SSRIs?

Are they useful?

Are they not useful?

What’s going on with SSRIs in your patients

and in other people as well?

Yeah, so that experiment that I described a bit ago

around the naltrexone and ketamine

is the first time I’m aware of

where we were able to essentially eliminate

an antidepressant’s effect by using a second drug

as kind of a blockade.

And it highlights a bigger issue, right?

The issue that we haven’t had a good way

of really understanding how these drugs work.

And so it’s the difference.

I think a lot of the controversy there

is that it’s been difficult, I think,

for folks to see that something can, on one hand, work,

and on the other hand, we don’t know how it works, right?

And so SSRIs clearly work.

Many, many meta-analyses kind of proving that out, right?

That in a subpopulation of individuals,

they achieve great benefit from depression,

for depression, for obsessive compulsive disorder,

for generalized anxiety disorder, panic,

all these things, you can see an improvement

in those symptoms with what we call SSRIs,

or selective serotonin reuptake inhibitors.

The issue there is that these selective serotonin

reuptake inhibitors end up blocking

the reuptake of serotonin, leaving the serotonin

in this kind of in-between between two neurons for a while,

and allowing for more serotonin to kind of be there.

The issue is that they don’t work immediately, right?

So they don’t work like the same day you start taking them.

And that suggests that probably it’s not exactly

the serotonin being in there that’s directly driving it,

that it’s much more likely that it may have some,

say, brain plasticity effects, right?

We know that things like brain-derived neurotrophic factor

get upregulated with chronic oral antidepressant use.

And so that’s kind of the idea,

is that these things work, but what’s powerful,

and I think what the authors of this paper,

it was an extremely controversial paper,

were in part trying to say was that

there’s not a deficit of serotonin.

You’re not born with what people call a chemical imbalance.

And psychiatry has known this.

This is not actually new information to anybody.

It’s kind of a rehashing of a bunch of information

we’ve known for a while now, but in the lay press,

it’s kind of hit in a way that it didn’t seem

to grab attention before with previous publications,

but this idea that this chemical imbalance idea is wrong.

I really think that part’s important

because I think that for a while, I think psychiatry,

what I’ll call psychiatry 1.0, right,

this kind of idea of Freud and psychotherapy

and its origins, it was a lot around your family,

and those experiences, and psychotherapy

kind of going in and correcting,

or helping you to figure out,

or you being able to see, or people hear you

so that you can eventually come to the conclusion

of certain cognitions that aren’t helping you, right?

And there’s a huge importance there,

but there’s a history where things

like the schizophrenogenic mother and all of that,

that was a concept at some point, right?

And so we’ve transitioned from that

to the, for a long time, the chemical imbalance,

which I’ll call psychiatry 2.0,

this idea that there’s something chemically missing,

and I think that the trouble there

for a patient who’s not a physician,

who’s not someone who’s steeped in these sorts of ideas,

who’s more of kind of a person,

kind of average American out there, right,

is that it’s sending a message

of there’s something missing with me,

whether it be my experiences I had no control over

when I was a child, or a chemical in my brain.

What I think’s really powerful with TMS,

really powerful with TMS, and a level even powerful

with the psychedelic story,

is it’s saying something different.

You know, TMS works, and there’s no serotonin

coming in or out of the brain, right?

And we’re doing a rapid form of TMS

that works in one to five days,

so there’s no, it’s very unlikely

that there’s some long-term kind of upregulation

of serotonin that’s driving that.

So our work actually kind of pushes back

on this serotonin hypothesis

as being kind of the center of depression,

because it says, look, we’re not giving anybody

any serotonin, we’re simply turning these brain regions on,

and we’re focused on the circuitry,

and that’s Psychiatry 3.0.

It’s not just like neuromodulation.

Neuromodulation’s a really nice use case for Psychiatry 3.0,

because it’s a way to focally and directly perturb

brain regions in whatever modality you’re using,

but there are a lot of groups

that are actually doing neuroimaging before and after,

and they’re able to see circuit-level changes

for something like psilocybin or ketamine

long after the drug is gone,

suggesting in those same brain regions converge,

so the subgenual default mode network connection

that we see is changing

with our Stanford neuromodulation therapy technique.

It’s that same set of brain regions

that ketamine and psilocybin seem to act on,

act on these connections between brain networks

that seem to shift,

and so it refocuses the story

on something that’s highly correctable,

and it’s basically electrophysiology,

and it’s basically kind of recalibrating a circuit

that is recalibratable,

instead of I have something missing

or I have some set of experiences early in life

that are gonna forever trap me

in these psychiatric diagnoses,

and so it kind of challenges that idea,

and I think that’s what’s so powerful

about Psychiatry 3.0,

this idea of focusing on the circuit

because it gets us into thinking about psychiatry

and psychiatric illnesses as something that are recoverable.

People can get better.

We’ve seen with our TMS techniques,

we’ve seen it with some of the psychedelic work

that we’ve done where people are actually

in normal levels of mood for sustained periods of time.

Within five days.

Within five or less days,

and in the case of the psychedelics,

within a few days, right?

So we can get people out of these states.

They’re totally well.

There’s no drug in their system at that point.

In the case of psychedelics,

there was never a drug in their system

in the case of TMS,

and it just tells us that it’s fixable.

It’s just like the heart.

It’s just like an arrhythmia in the heart.

It’s just like these other illnesses

that it’s like a broken leg.

We can go in and do something

and we can get somebody better,

then I think what’s empowering

and what a lot of patients have told me

is they say,

some people will relapse and need more stimulation

or need more psychedelics or whatever it is,

but they’ll tell me I’ve relapsed

and I’m depressed again,

but I’ll never think about killing myself again

because I know that if I go get stimulated again,

it improves.

It gets better.

I will be able to reach it

and I don’t fear that I’m chronically broken.

I don’t fear that the chemical imbalance

is still imbalanced.

I don’t fear that these things

that I couldn’t control in my childhood

are gonna be there and drive this problem forever

and I think that’s what’s so powerful about this.

The sense of control.

The sense of control.

The sense of,

they’re not doing the stimulation themselves.

They’re not administering the drug

in these trials themselves.

They probably never will.

These will probably be medical treatments,

but they are choosing to do it

and in that sense,

they are in control.

I have a good friend.

I won’t out him for reasons

that will become clear in a moment

who was quite obese

and lost a lot of weight

and was really proud of himself

and then I guess we could say

he sort of relapsed in a sense.

Not all the way,

but far along,

but his tone around it was very different.

He knew he had accomplished his goal once before.

He was disappointed in himself,

but he knew exactly why he had relapsed.

It was very clear.

He had essentially relapsed

to the previous set of eating behaviors

and lack of exercise behaviors

and has now brought himself back again.

And it just resonates with your story

that once somebody understands they can do it

because they’ve been there before.

This idea again of considering new rules.

And that brings me to this question about psychedelics

and the, frankly,

the altered thinking and perception

that occurs in high-dose psilocybin clinical sessions.

It seems that the disordered thinking,

even though it could be random, right?

Hearing colors and seeing sounds

is always the kind of cliche statement

of the Timothy Leary era.

Also, right there, that’s a Stroop task of sorts.

It’s a synesthesia.

It’s a combining of perceptions,

but it’s sort of Stroop task-ish

in that it’s a new set of rules for the same stuff, right?

And many people do report improvements

in trauma-related symptomology and depression,

as I understand it,

from my read of the clinical trials after taking psilocybin,

because during those sessions,

something comes to mind spontaneously.

As you and I were talking about earlier,

they will report, for instance,

a new way of seeing the old problem.

And the old problem could be the voice

that they’re no good, nothing will ever work out,

or it could be even more subtle than that.

So that raises two questions.

One is about the basic functioning of the human brain,

which is, why do you think the brain

would ever hold on to rules that don’t serve us well?

That’s one question.

And then the second question is,

what is it about psilocybin and related molecules

in terms of their neurochemistry,

in terms of the ways they disrupt thinking and feeling,

et cetera, during the session,

that allow this novel rule consideration phenomenon?

Yeah, so the first question,

I think it’s an evolutionary neurobiology answer, right?

I think that at the individual person level,

it doesn’t make a whole lot of sense

that when we’re really stressed out,

some of us want to eat more, right?

At the individual person level,

because that’s not particularly that good

for my health in the long term.

But if you think about it in some 500 years ago,

1,000 years ago, if I’m highly stressed out,

it’s most likely that I’m about to not have food

at some point, and I should eat a bunch of food

that is high-fat, high-sugar, high-carb food

to put on weight for that next phase,

where in this stress, I may be in battle

and I don’t have food and I have enough fuel on board,

right, and so we end up being a result

of probably a lot of biology that’s not that useful

in the modern era, and I think in the brain

for, let’s say, PTSD, right?

A lot of veterans come back

and they experience these PTSD symptoms,

and they’re not at all useful back home, right?

They hear some loud noise and all of a sudden,

they’re behind a car or they’re behind a,

I’ve heard of folks jump and run behind a trash can

or whatever in the middle of San Francisco

when they hear a loud noise,

but if you put them back in the battlefield,

you have that.

That’s highly adaptive, right?

And so I think what’s interesting

is that we, in the absence

of using substances like psychedelics,

we end up having these very persistent memories

that are attached to negatively valence to motion

predominantly, as you were saying earlier,

the jacket in elementary school,

we had various things like that for me, too, right?

You remember these things,

and we hold onto those things

from, I think, an evolutionary neurobiology standpoint,

but what seems to, for whatever reason,

kind of alleviate that are these substances,

some new, like MDMA,

some that have been around for thousands of years,

like psilocybin, and used in kind of sacramental,

and as a sacrament in traditions,

seem to have a therapeutic effect

that seems to be pretty long-lasting for these phenomenon,

and so it’s just curious, right?

It’s curious that in the absence of that,

these things will keep going on and on,

but in the presence of that exposure,

then all of a sudden you see a resolution of the problem,

and we have some work now,

we’re treating folks with Navy SEALs,

and the data’s still being analyzed,

but the anecdotes that we’re getting, right,

are folks are coming back,

and they’re saying it’s finally gone, right?

These set of PTSD symptoms are finally gone,

and so this idea that, for whatever reason,

going into what’s probably a highly plastic state,

like we were talking about earlier,

upregulation of brain-derived neurotrophic factor,

in the case of ibogaine,

glial-derived neurotrophic factor,

this highly plastic state,

and the ability to kind of re-experience memories,

and then, as you know, we always re-consolidate a memory

when we bring it back up.

But re-consolidating it in that state,

for whatever reason, may drive a therapeutic effect.

And, you know, the jury’s still out.

I would say that I’m kind of agnostic

to what tool I’m using kind of guy.

My business is to find treatments that help people,

and so I’m much more pragmatic about it.

If this sort of thing,

which has a lot of cultural baggage,

but if this sort of thing

ultimately ends up being therapeutic,

if we can design trials that convince me and others

that it is, then we should absolutely use it.

And if it doesn’t, then we clearly shouldn’t use it, right?

And I think that’s a big question

the field’s gonna have to work out.

We have a hard time blinding these trials

because the placebo condition

is not easy to pull off, obviously.

A placebo for a psilocybin journey is hard to imagine.

We’ve been thinking about this,

and maybe that ketamine study

that I was talking about earlier,

if we could give people naltrexone and ketamine,

maybe that’s a good sort of placebo condition, right?

Because we know that we can block

any of the actual antidepressant effects of ketamine,

but they still have an experience, you know?

And so that’s one way of doing it,

but thinking about ways to do that

and really kind of proving this out.

And that’s been, yeah, I think that’s been kind of central

to the way I’ve been thinking about this.

But yeah, I think there’s the work that’s been done so far,

the first psilocybin trial,

the first MDMA trial

that was published in Nature Medicine recently.

And what do those generally say?

I mean, that they are effective for a number of people

after one session, two sessions?

What’s sort of the general contour?

Let’s start with psilocybin and MDMA.

Yeah, so MDMA appears to, in one to a few MDMA sessions,

have an anti-PTSD effect that seems to be, you know,

outside of the kind of standard assumed levels

of PTSD improvement that you can observe in individuals

with this level of PTSD, right?

So what we call the effect size,

which is essentially like a measure,

a Cohen’s d effect size is a measure

that allows for you to compare different treatments

to each other for different conditions

that are, you know, agnostic to what the actual illness is.

You know, the effect size is there,

you know, approach effect size is the things

that are pretty effective,

like antacids for heartburn, right?

And you see that with MDMA treatment.

So does that mean that for people that have trauma,

who do a, and again, we’re talking about

in a clinical setting, they take one or two doses of MDMA,

I think the standard MAPS dose is 150 to 775 milligrams,

again, doing this with a physician, et cetera,

control clinical trial, legal.

Yeah, exactly.

They do it once or twice.

And broadly speaking, what percentage of people

who had trauma report feeling significant relief

from their trauma afterward?

It’s about two thirds of people

had a clinically significant change in their PTSD.

That’s impressive.

Which is impressive, right?

And how long lasting was that?

I mean, these trials were ended pretty recently, so.

It appears to last for a while.

In the earlier trials where they followed people out,

it seemed to last for kind of in the year’s range

for some people.

And so it’s, you know, it’s pretty compelling.

Psilocybin, you know, in contrast that with ketamine,

which only on average lasts about a week and a half

for a single infusion.

So it’s a much shorter.

So they have to get repeated infusions of ketamine

every 10 days or so?


For some people, or they end up getting like a bunch of doses

for a couple of weeks.

And then for some people that seems to last a while.

You know, that’s where I think the psilocybin story

for depression and the MDMA story for PTSD

seem more interesting to me.

So for psilocybin, what is the rough percentages on,

and this would be relief not from trauma,

but from depression, correct?

Yeah, exactly.

So it’s, you know, in open label studies,

it’s closer to like half to two thirds of people

end up getting better depending upon their level

of treatment resistance.

In the blinded trials, it was more like a third or so

of people, you know, experienced relief.

And this is, you know, this is a press release of the data,

you know, and so it hasn’t, to my knowledge,

it hasn’t been published yet.

And so I’m looking forward to seeing the full paper

on that one.

But it, you know, separated from placebo

and looks, you know, looks pretty good as well.

It looks like it’s, you know, the first of two trials

that need to be done to get this thing approved

for treatment resistant depression.

And so that stuff looks good.

In terms of MDMA, for many years,

it was reported in the popular press

and there was a paper published in Science

that MDMA was neurotoxic,

that it would kill serotonin neurons.

This was what was always said.

Then I saw another paper published in Science

that wasn’t a retraction of the previous paper,

but rather was a second paper in the same group

that essentially admitted that the first time around

they had injected these monkeys,

because with not MDMA, but with methamphetamine,

which is known to be neurotoxic.

So it was kind of a public admittance of oops,

or big, like really big screw up, so oops,

but never a retraction

and then never really a publicly acknowledged correction

in the popular press.

So it seems that in the appropriate dosage range

and with these one or two sessions,

my assumption, and this again is an assumption,

tell me if I’m right or wrong here,

is that MDMA is not neurotoxic for serotonergic neurons

at appropriate doses

and with appropriate sourcing, et cetera.

So it was an interesting study that,

I think the guy’s name is Halpern, last name’s Halpern.

Not Casey Halpern.

Not Casey, different now.

I think Joshua Halpern,

I’m blanking on his first name, but-

Casey Halpern was a guest on this podcast

and is a former colleague of ours at Stanford

who unfortunately we lost to University of Pennsylvania

and maybe someday we’ll bring him back.

Yeah, that’s right.

So this individual received some NIH funding to actually,

NIDA, National Institute for Drug Abuse funding

to explore individuals of the Mormon faith in Utah

of the Mormon faith in Utah who partake in only MDMA.

So the way this works is that MDMA happened

kind of after a lot of the religious documents

were developed and so MDMA isn’t on the prohibited drug list.

The banned substance list.

The banned substance list.

I have some good friends who are LDS.

Yeah, great people.

I do as well.

Just to kind of set of facts, you know?

And so these folks only use MDMA,

but they don’t, they’re not, you know,

the problem with some people using drugs

is they’re polysubstance users, right?

So you can’t say it’s the MDMA

if they’ve also taken other psychedelics

and they’ve taken opiates and they’ve taken cocaine

and you have this picture

where you can’t really tease out that problem.

But with this, right, it was just individuals

that were part of the Mormon faith

and so they were kind of purists

in the sense they only used MDMA

and he confirmed all of that

and it was a brilliant study, right?

Because then he was able to go in

and look at their cognitive profiles

versus individuals of the same geography,

the same faith, all of that,

that happened to not take MDMA

and found there were no neurocognitive differences.

So does that mean that it was not damaging?

It was not damaging.

It’s hard to know because to really do this study well,

you’d have to track these folks down

before they ever took MDMA

and do a pre-post and compare to people that didn’t,

but you know, this is about as good of a study

as you can do given the situation

to be able to check this out.

Additionally, when I was back in Charleston

and working at the Medical University of South Carolina,

one of my mentors there, Dr. Wagner,

was a neuropsychologist at MUSC

and he was also the neuropsychologist

for the early MDMA trials

and so he did all the neurocognitive batteries

for individuals pre-post

and similarly did not see any changes

in neurocognitive profiles in a negative way

and so, you know, there’s data

from experimental patients receiving this,

there’s data from people that are chronic users,

who only take MDMA

and that combination of data suggests

that there’s certainly no apparent risk

in the kind of one to two to three dose range.

It’s probably unlikely that at least, you know,

modest dose exposure over a lifetime

doesn’t appear to have a profound

neurocognitive damaging effect.

Interesting, yeah, I know that sourcing is key

and we’re here, we’re talking about clinical trials

where purity is assured

and, you know, years ago when so-called raves

were really popular, maybe they’re still popular,

never been to one, so I wouldn’t know

if they’re happening or not,

that’s how in the know I am,

but it was clear that, you know,

testing for purity was important

because sometimes the drugs

are made such that there are contaminants

like methamphetamine,

which we know is highly neurotoxic.

I think that one reason why people

think that MDMA might be neurotoxic

is the reported drop in energy

or sort of feeling fatigued for a few days afterward.

I spoke to a physician colleague of ours

who said that that very likely has something to do

with the surge in prolactin

that arrives subsequent to the big dopamine surge

that occurs in MDMA.

And I mentioned that because I know a number of people

talk about serotonin depletion after taking MDMA.

He has in mind that while that could be true,

it’s likely that anytime somebody takes something

or does something where there’s a huge lift in dopamine,

that there’s very likely a huge compensatory increase

in prolactin that follows,

and prolactin has a kind of sedative effect,

numbing effect on mood and libido, et cetera,

that eventually also wears off.

Does that make sense to you as a physician?

Yeah, it makes sense.

I mean, you know, the difference between say MDMA

and psilocybin is that MDMA

is kind of an amphetamine of sorts, right?

So it has effects in dopamine,

and psilocybin’s pretty neutral

and maybe a little bit of dopamine effects,

but kind of much more of a serotonergic-focused drug.

And so, yeah, I think you’re going to see

kind of a different profile after,

and I haven’t heard that story,

but that makes sense to me too.

Since you mentioned psilocybin,

let’s talk a little bit about

the neurochemistry of psilocybin.

As a serotonergic agent,

my understanding is it operates on these,

is it the 5-HT serotonin 2C receptor?


2A, excuse me, 2A and receptors,

and that I’ve seen a bunch of different reports

in terms of what it’s actually doing to the brain

while people are under the effects of the drug.

And this is important for us to segment out

because there are the effects that happen

while people are under the influence,

and then the more long-lasting effects.

But some of the effects I’ve heard about are, for instance,

and tell me again if these are right or wrong,

that there is increased activation of lateral connections,

sort of broader areas of the brain being co-active

than would normally occur.

Maybe that explains some of the synesthesias,

seeing sounds and hearing colors as the trivial example,

but rule-breaking within the mind.

But then I’ve also heard that perhaps

it’s lack of gating of sensory input.

So normally if I’m looking at something,

I’m not thinking about the sensation in my right toe

unless it’s relevant.

But if I’m thinking about the sensation in my right toe,

I’m generally not thinking about the truck

around the corner.

So we have these attentional spotlights,

but that somehow it creates a more, it adds spotlights.

Yeah, it de-gates the thalamus.

De-gates the thalamus, right,

through the reticular thalamic structure.

So what is the evidence that any of that is true?

And are there other phenomena?

Is there involvement of dorsolateral prefrontal cortex

that we are aware of?

And where I’m really headed here in a few minutes is,

is there a place for combining directed stimulation

of the brain with psychedelics

so that the effects of serotonin could be primarily

within the structures that you know from your work

to be relevant to depression?

But to simplify it first,

what’s going on when one takes psilocybin

and why is it interesting in light of depression?

Yeah, definitely.

So David Nutt and Robin Carhart-Harris’s work

around neuroimaging psychedelics

are kind of some of the first folks to do that work.

And to their great surprise,

they thought there was gonna be an increase

in activity on psychedelics.

And what they found is the opposite, right?

There’s kind of an overall decrease in the level

of activity in the brain with psychedelics.

But they have also looked at connectivity

and there’s this kind of small world,

large world connectivity that you think about.

And so small world meaning there’s a lot,

there’s kind of a much more kind of focused

kind of cortical function or subcortical function

or whatever it is.

And what you see is a difference in that level of engagement

and of brain regions.

So the connectivity, kind of global connectivity

to your point kind of increases.

And so it’s interesting.

I think to kind of have a convergent theory on this,

it’s still to be determined.

There’s still a lot of work I think that needs to be done.

But it’s certainly suggestive

that there’s pretty profound changes in brain activity

and brain connectivity after.

And what we found to be really interesting

is the antidepressant effects of psilocybin

have a particular connectivity change

that we also see with our TMS approaches, right?

And it’s this connectivity

between the subgenual anterior cingulate

and the default mode network.

And so when we do this effective

Stanford neuromodulation therapy stimulation,

we see a down regulation,

the connectivity between the negatively valenced mood state

in the case of depressed individuals

and the self-representation of the brain.

And you see that same connectivity change

occur post psilocybin,

suggesting there’s a convergent mechanism.

And it makes sense, right?

You’ve kind of got an over-connected,

negatively valenced system, conflict system

that’s kind of attached onto the self-representation

and people feel stuck, right?

And then when you do whatever you do that’s effective,

it unpairs those two systems.

I want to ask you about this phenomenon

I’ve heard about during psilocybin journeys.

I heard about this from Dr. Matthew Johnson,

who’s running a lot of the clinical trials at Johns Hopkins

and has been a guest on this podcast.

He said that there’s something seems to be important

about the patient who’s depressed

or who’s and is under the influence of psilocybin

or the patient who’s trying to get over smoking

or an eating disorder,

who’s taking psilocybin and is in the clinic,

that there’s something important to this notion

of letting go,

that people will feel as if their thoughts

and their feelings and maybe even their body

aren’t under their control

and that the clinician’s job under those circumstances

is of course to make sure that they’re physically safe,

that they don’t jump out a window

or try to actually give an example of a patient

who thought that, I think it was a she,

could move into the painting in the wall.

And obviously that wasn’t true in the real world,

although it was true in her mind.

So they prevented her from doing that.

But that letting go,

that somehow untethering from the autonomic arousal

that’s occurring is important,

which brings us back to this idea

or me back to this idea of like a seesaw

where you’re sort of letting go of the hinge

and just sort of your heart rate’s going up,

like just go with it and trust.

Your heart rate’s going down, just go with it and trust.

You’re thinking about something very powerful

and depressing related to your childhood.

You’re just supposed to go there without fear.

You’re thinking about what’s possible

in terms of what could happen.

So anyway, you get the picture.

Can we think of that as just the willingness

to do a million different variations

on the emotional stroop task?

You will entertain the full array of rules within your head

and consider them.

Or is there something more to it?

And again, we’re in the outer margins

of understanding here,

but what are your thoughts on this notion of letting go

as such a key variable for relief from depression

during the psychedelic journey?

Yeah, so I’ll talk a little bit about something

called exposure and response prevention therapy

that’s a typical kind of gold standard treatment for OCD.

And I’ll help this a little bit conceptually.

And so what that really is, is it’s a letting go therapy.

And so exposure response prevention,

the idea is that you have to expose the individual

to something that triggers an obsession

that they then want to do whatever the compulsion is.

And so I’ll give you my first exposure

and response prevention patient when I was a resident.

He was very concerned about leaving the lights on his car.

And so what we did is we went out

and we turned the lights on in his car

and locked his door so his lights were on.

And he was super worried this is gonna kill his battery.

And we went and we spent an hour talking about things.

And we went back out to his car and his battery was fine

and his lights were on and he cranked the car

and we did it maybe one other time.

And then all of a sudden that was gone, right?

And that’s the idea, is that you’re essentially exposing

and you want to do it at levels that are,

from an anxiety standpoint, tolerable.

But exposing the person to something

and then letting them see that that exposure

ends up being fine, right?

It ends up not causing the thing

that they end up being worried about.

And so in some sense, being in the psychedelic state,

and we’re all taught at a level

to retain some level of control.

People have more or less of that,

but we’re all effectively retaining some level of control.

We all wake up in the morning

and put clothes on to go into society.

We all try to say, most people try to say the right things.

They don’t try to do things that are outside

of cultural norms when they’re in conversation.

And so we’re constantly at some level

controlling the situation that we’re in.

And so it’s not, it makes a lot of sense

that in that state, part of the therapeutic effect

that may be linked to the neural circuitry

is this idea of letting go

and essentially letting the system,

the network configuration maybe, whatever it is,

assume a state that you’ve essentially

been fighting the whole time.

It’s the same way that my OCD patient

was fighting this need to click the off button

on the lights of his car 50 times

before he would go and do whatever he needed to do.

And at some level, letting go there,

meaning letting us just turn the lights on

and him not do anything, or letting go,

meaning in the psychedelic state,

you’re just letting go of whatever it is

you’re holding onto, negatively valenced thoughts

about yourself in the setting of having depression

or re-experiencing a trauma, memory,

and allowing that to just happen

and re-seeing it again through a different light.

It feels the same in the sense that

that’s allowing for whatever’s going on

with these psychedelic states to do whatever they do.

It’s fascinating.

You said it’s exposure response therapy

is the traditional name?

Exposure response prevention therapy.

Done outside of the psychedelic journey.

It’s done outside the psychedelic journey,

but that idea of letting go is present in both of those.

Psychotherapy, straight up, totally sober,

non-psychedelic, non-anything,

manualized psychotherapy that we know works really well

for OCD and then in that psychedelic state.

And so people have done studies with psilocybin

and now there’s some studies with MDMA

trying to look at treating OCD

with the same sort of idea of letting go, right?

And how do you have an OCD patient kind of let go,

maybe even letting go of not washing their hands anymore,

kind of accepting the idea

they’re not going to get germs on their hands

or whatever it is.

And so it’s kind of part and parcel

of that same sort of thinking.

When I was in college,

I developed a compulsive superstition.

I’m not afraid to admit this.

I somehow developed a knock on wood superstition

and I was actually kind of ashamed of it

because it rationally made no sense.

I don’t consider myself a superstitious person,

never was a superstitious kid.

I’d step on the sidewalk cracks,

I’d walk under ladders,

I’d probably even try to walk under a ladder,

even though I don’t suggest it.

But somehow I picked this thing up

and I used to sneak it at times.

I told my girlfriend at the time that I had it

in hopes that that would prevent me from doing it.

And it’s tricky.

Sometimes it actually comes back where I think,

gosh, I didn’t say knock on wood,

I didn’t knock on wood,

I hope that doesn’t actually happen.

And it’s quote unquote crazy, right?

But crazy in the sense that it makes no sense rationally

why the events would be linked.

And yet I think a lot of people out there

do have internal superstitions.

Maybe by talking about it now, it’ll go away.

Clearly I just need to challenge it.

You know, it’s a, anyway,

I mentioned it because I consider myself,

you know, generally rational person,

but it’s interesting how these motor patterns

get activated and this notion of letting go,

because I don’t actually know what consequence I fear.

And the fear, as I was hearing the example you gave,

you know, the fear of the car battery running down,

I was about to say,

well, what if the battery actually did run out,

then the therapy would be undermined.

And yet that could also be interesting too,

because it’s not that big of a deal.

You jump the car.

But in my case,

I need to think about what the ultimate fear is.

Yeah, and you know, I think a lot of people,

so there’s, it’s interesting if you look at,

say the OCD scale or the depression scale or whatever,

we don’t define normal as zero.

We define normal as some number range above,

so zero to, in the case of the Montgomery Asperg

depression rating scale,

one of the depression scales we use, 10, right?

That’s the normal range.

And so people can have some sadness

and still be considered normal.

In the case of the OCD scale,

it’s about the same 10, right?

Where we say it’s kind of starts to be,

you know, mildly abnormal or something.

And I always, you know,

I’d always tell the medical students,

look, my friends that are surf instructors,

they’re more like a zero on the YBOC.

People that are professionals, you know,

they’re non-zero, but it’s still within the normal range.

And especially, you know,

in the case that you’re talking about,

it doesn’t sound like it got in your way.

You’re obviously highly successful,

tenured professor at Stanford

and do all the great things that you do.

And so it’s very much kind of within the normal range.

And I think totally assumed that a lot of people

have these sorts of things.

And as long, I think something as a psychiatric diagnosis,

when it severely impairs your ability to function,

and that’s when we kind of cross that threshold.

But, you know, I think that a lot of people,

and it’s great that you’re bringing this up.

I mean, it’s very anti-stigmatizing

that you’re bringing it up, right?

Because I think a lot of people hold that stuff in

and they don’t want to talk about it

because they’re worried

that somebody else may think something.

But the reality is, as a psychiatrist,

I talk to a lot of patients,

a lot of people that are, you know, family members,

you know, folks that are just going through

a death in the family, whatever it is.

And what you figure out is like,

everybody’s got a little something here and there.

Everybody has the knock in some way, if that makes sense.

And it’s just, and we’re just all,

we’re all just kind of more predisposed

not to talk about it.

But I think it’s important to talk about it

because I think that when we start all talking about it,

then we realize that we’re all

kind of in this together in a way.

And that we’re, and then some folks that, you know,

have to knock 100 times, we call that OCD.

When, you know, and they have all, you know, germ,

they’re worried about germs and all these other things,

we call that OCD.

And then in that circumstance, you know,

they need treatment, right?

But it is really on, just like blood sugar,

just like blood pressure, it’s on a range, you know,

and it’s not just these discrete diagnoses.

You have them or you don’t.

And it’s good to know.

I actually feel some relief just hearing this

because I am slightly, I wouldn’t say ashamed,

I was sort of embarrassed by it,

but I offer it as a, you know,

it is what it is, as they say.

And it certainly doesn’t seem to hinder my life

as much, knock on wood.

So if we could talk a bit about Ibogaine.

I don’t know much about Ibogaine,

although anytime I hear the, you know, A-I-N-E,

you know, lidocaine, Ibogaine, I think of an anesthetic

and going to the dentist,

which is an unpleasant experience for me, generally.

What’s, what is Ibogaine?

Does this have anything to do with the so-called toad?

You know, people talk about smoking frog skin, toad skin.

What is it used for clinically?

Is it legal in the U.S. as a clinical tool?

Who’s using it and for what purposes?

If you could educate me on Ibogaine,

I truly know nothing about it,

except I think I know how to spell it correctly.

Yeah, that’s fair.

So Ibogaine is one of the alkaloids

that you can extract from a Iboga tree root bark

that’s typically growing in the country of Gabon, Africa.

So Gabon is one of the West African countries,

kind of middle of Africa on the West Coast.

And Gabon is, has a group of ferns

or folks, you know, called the Bwiti.

It’s a religious kind of sacramental group

that sacramentally uses Iboga root bark

as part of that, the sacrament.

And they, they’ve been using Iboga root bark

for a very long time.

And it’s, it’s, you know, part of the tradition.

There’s a whole, there’s a whole set of,

of kind of ceremony around it.

If you’re interested in this,

there’s a book called Breaking Open the Head

by Daniel Pinchbeck that goes,

goes through and talks about this, this whole process.

But essentially, the Gabonese have been using this

for a long time.

And it’s a, it’s a kind of an atypical psychedelic.

It’s not, it’s not a psychedelic

that we normally think about with psilocybin and LSD,

where there are visual perceptual changes, right?

So if you, if you take psilocybin or LSD,

what you, what you experience is you experience

these kind of visual perceptual differences

in the external world, right?

And on enough LSD or psilocybin,

an individual can actually perceive something visually

in the external world that isn’t there,

as we talked about earlier.

Ibogaine doesn’t do that.

Ibogaine does something different.

It’s kind of like, have you ever seen Minority Report

with, you know, the movie with Tom Cruise?

I think 15 or 20 years ago or something,

so it dates us a little bit.

But it was this, it was this movie

where he would be able to go and see these kind of pre-crimes

and he had this big, you know, this big screen

where he could look at scenes from, from time

and like kind of go through that scene and see it.

And so what, what individuals taking Ibogaine will say

is that open eyes, they don’t see anything,

but closed eyes, they’ll go back through

and re-experience earlier life memories

and they will be able to experience it

from a place of empathy, not only for themselves,

but from others and kind of a detached empathy

and being able to see this as almost a third party,

even though they were there,

but they’re able to see it, you know, as a third party.

So Claudio Naranjo, a psychiatrist from Argentina,

you know, described this in a lot of books that he wrote

in I think the 80s and 90s around this.

And so, you know, Ibogaine’s been around for a long time.

Howard Lotsoff, American guy that brought it over

from Africa, he was a polysubstance user,

used every drug, you know, that he had his hands on,

took Ibogaine, including a lot of other psychedelics,

by the way, took Ibogaine

and then never did another drug again, supposedly,

because he had such a profound Ibogaine experience.

Ibogaine is in no way a recreational substance.

It’s not a recreational substance

if you want it to be a recreational substance,

because you’re essentially having this,

what they call a life review.

They also call it 10 years of psychotherapy in a night.

So these are the terminology that people talk about.

The issue-

How long does it last?

Is it truly one night?

It’s usually, you know, it can go,

depending upon if you get re-dosed or anything,

go sometimes, depending upon how fast you metabolize it,

sometimes 24, sometimes 36 hours.

Sometimes it can be shorter, but it is a long time.

It’s a very long time.

So it’s definitely the longest acting

psychedelic substance I know of.

And so people will take this,

and they’ll have this re-evaluation of a given memory,

and then, as we were talking earlier,

re-consolidate that memory again,

and then it seems to have an effect

of that re-consolidation process.

And so about four or five years ago,

I was tapped by Robert Malenko,

one of the senior neuroscientists we both know

in the university.

He says, well, there’s an unnamed donor

that’s very interested in funding a group,

you know, a scientific kind of open-label study

of these Navy SEALs that have been going down to Mexico

and taking Ibogaine, and also a 5-MeO-DMT,

which I’ll talk about in a second,

to treat PTSD, you know,

they claim to have traumatic brain injury,

depression, you know, that whole constellation of symptoms.

You know, and as it was described to me

by various people that had done this,

by their spouses and whatnot, you know,

John, we’ll just say John,

John couldn’t screw a light bulb into a light fixture,

right, they were just so debilitated,

they couldn’t do simple tasks,

what we call activities of daily living.

And they were coming back

and having these really dramatic improvements

in, you know, all aspects of life.

And so, you know, we have over the last couple of years

been able to do this first in human

kind of full neurobiological,

clinical neurocognitive evaluation

of what Ibogaine is doing.

In this case, in special operations,

special forces individuals, former Navy SEALs,

former Army Rangers, that kind of crew of folks,

and look at the pre-post changes that we,

that they’re experienced to be able

to totally quantitate all of that.

And so we’ve been able to capture

all the clinical scales, you know,

depression scales, PTSD scales,

all that standard stuff.

Neurocognitive batteries,

so how does your executive function work specifically,

how does your verbal memory, all of that.

And then neuroimaging and EEG.

So this will be the first human study of Ibogaine for those.

And the reason why is because Ibogaine’s kind of the,

both seemingly the most potent and most,

seemingly to me at least, most powerful psychedelic,

but the one that has the most risk too,

because it has a cardiac effect.

It seems to be that you can screen people out

that have risk off of their electrocardiogram

and reduce the risk quite a bit,

and that’s what we all did.

But that’s why people haven’t really studied it as much.

And it isn’t as, in addition,

there’s no, nobody goes to a rave on Ibogaine.

There’s no recreation at all with it.

It’s not fun.

It’s, people say that it’s relieving,

but it’s hard work, right?

Because, yeah, you’re reexamining things.

And, you know, and so then,

so then we see these folks after,

and I’ll tell you, you know,

we haven’t fully analyzed the data yet,

but I’ll tell you that, you know,

from what my folks are telling me,

it’s pretty dramatic.

You know, people come back and they’re doing,

they’re doing a lot better.

They’re doing a lot better,

and nobody, I’ll knock on wood,

nobody’s had any sort of cardiac issue at all,

you know, in the cohort that we’ve studied.

And they look a lot better,

and they feel a lot better too.

And they describe these experiences

of being able to go back through,

and, you know, soldiers experience

something called moral injury, right?

Where they, maybe they accidentally blew something up

and it had a kid in it, or something like that.

You know, if they’re in Afghanistan or Iraq,

maybe a child died on accident,

or maybe, you know, a civilian died,

or whatever it was, right?

And then they suffer these moral injuries

as part of the job,

and it’s almost one of the kind of, you know,

vocational risks.

They come back and say that they’ve forgiven themselves,

which is huge, right?

And part of that is being able to see themself

in a different light,

and having empathy, finally, for themself,

and being able to kind of have that experience of forgiving.

And so, very cool.

The study, you know, what was happening

was they were taking Ibogaine,

and then taking something called 5-MeO-DMT,

people call it TOAD.

It’s the Sonoran River TOAD, I think.

It’s like, you can find these in Mexico,

find them in Arizona.

And in the back of the TOAD,

produces something called 5-MeO-DMT,

which is a flavor of DMT

that produces a particular psychedelic effect,

also used as a sacrament.

Is it a dimethyltryptamine, is that?

It is a 5-MeO-dimethyltryptamine.

So it’s a kind of dimethyltryptamine

with a kind of addition to it.

The deal there is that it lasts longer

than traditional DMT.

You know, it’s like 20 minutes instead of five,

three or whatever kind of thing.

And so then, so these guys were taking Ibogaine,

and then they would take the 5-MeO-DMT

after we had to kind of divorce those two things,

be able to do the study

and just understand what Ibogaine was doing.

And they go back down a month later,

and they’ll do the 5-MeO-DMT.

So two completely separate sessions.

Two completely separate sessions.

And then one quick question about Ibogaine

before a bit more on 5-MeO-DMT.

Is the Ibogaine journey guided,

or the person just closes their eyes

and they just start falling

into the back catalog of memories?

They have a bunch of preparatory sessions,

and then they have a bunch of sessions after

that they kind of, they’re able to kind of rehash things.

During, there’s a sitter that sits there

and kind of sits with them and helps them out.

But it’s not, it’s pretty,

the phenomenon of the drug seems to drive a lot of this.


And so a lot of it ends up being

what we call supportive psychotherapy,

or just kind of being there.

And you know, maybe you’re holding the person’s hand,

maybe you’re just saying, I’m here,

or maybe whatever it is,

but you’re making sure they know you’re around.

But you’re not really,

there’s not really an interaction per se.

And then the whole kind of goal there

is just to get folks to kind of go back through

and re-examine these memories

and ultimately look like they re-consolidate them.

And you know, it’s very interesting.

I mean, there’s this kind of, as you said earlier,

Timothy Leary kind of sociocultural construct

that ends up being overlaid over psychedelics.

And what I think is that if you rid yourself

of all of those preconceived notions

of what it is and isn’t and the counterculture movement,

all that stuff that neither of us were ever involved in,

neither of us were ever partaken,

it’s kind of straight scientists looking at this, right?

If you can kind of rid yourself

of all those sociocultural constructions

and then re-examine this,

these, if we just discovered these today,

we would say that these sorts of drugs

are a huge breakthrough in psychiatry

because they allow for us to do

a lot of the sorts of things we’ve been thinking about

with SSRIs, with psychotherapy,

but kind of combined, right?

Psychotherapy plus drugs in a substance

that kind of allows you to re-examine these things.

And so it’s interesting, there’s a lot to do

to try to figure out if that’s true, you know?

And I can say that as it stands right now,

we don’t know if that statement is true, right?

There’s a lot more work that needs to happen

for that statement to be proven to be true.

But the hypothesis is if it is true,

then it’s very likely that this will be seen

as a breakthrough because it allows you

to do these sorts of things that you can’t do

with normal waking consciousness.

But also why we have to really think about this

and you know, these drugs can’t be recreational drugs.

They really shouldn’t be recreational drugs, right?

They’re really too powerful to be used

in the context of recreation

because they can put you into these states.

And this generation of psychedelic researchers

are really clear about that.

You know, I think the 60s folks were not clear about that

and they felt like there was this whole kind of cultural

thing that was going on there.

But I think this cohort of individuals really understands

that in order to really make this happen,

we have to understand that if you need a prescription

for an SSRI, which doesn’t change your consciousness

a whole lot, and we’re very worried about that

and the doctor has to evaluate you for that every week,

that the idea that some of these substances

would go outside of very strict medical supervision

is kind of preposterous, actually.

It’s kind of a dumb moment, I think,

for all of medicine to say, look,

if we’re gonna do this right, we’ve gotta do it

in such a way that’s so protected, that’s so safe,

that we make sure people know

these things are not recreational

and they’re really for the pure purposes

of really powerfully changing cognition for a while

and letting people have these, what seem to be,

you know, relatively therapeutic states.

I think it’s great that you’re doing this study

and along the lines of the sort of early iterations

of psychedelics and the counterculture of the 60s and 70s,

some of which took place, like One Flew Over the Cuckoo’s

Nest, I think, is actually based on the Menlo Park VA,

which is, you know, in our neighborhood of Stanford.

And things are quite a bit different now.

I know you and I have spent some time

with the operators and former operators

at an event on Last Veterans Day, in fact,

the so-called Veterans Solutions Group

that’s pioneering a lot of these psychedelic treatments

for former special operators and current special operators.

And what’s interesting to me about that

is in contrast to the counterculture movement

of the 60s and 70s, that room was filled with people

that are very much of a structure, the military, right?

So it’s no longer considered left-wing, right-wing,

anti-military, pro-military.

Here, this is just about one group of people

who’s exploring psychedelics as a treatment

for trauma and PTSD and other things.

And of course, you also have other domains of society

looking at this.

And in fact, it was really interesting

because there were both far left and far right politicians

at that event, up on stage together,

talking about, in kind of lighter terms, heart medicine,

but also talking about neurobiology.

And it was just fascinating from the perspective

of somebody who’s trying to learn about this stuff

that psychedelic therapies no longer sit

within the anti-establishment realm.

It’s independent of all that.

Certainly when people in the military

are adopting it as a potential treatment.

Again, still under exploration,

but also under exploration at universities

like Stanford and Johns Hopkins and UCSF

and University College London and on and on.

Along the lines of tree barks and toad skins,

tell me about ayahuasca and as a plant, it’s intriguing.

And is it a pro-serotonergic drug like psilocybin?

And is it useful for the same sorts of conditions

that we’ve talked about thus far?

And if you could perhaps tell me a little bit also

about the Brazilian prisoner study.

Yeah, yeah, definitely.

Ayahuasca is another psychedelic.

It’s used as a sacrament in Brazil

and in Peru and Ecuador and Colombia.

So a lot of the South American countries.

And what they do is they combine two plants together

where one plant of the two plant combination

would effectively do nothing.

But the two plant combination together

is capable of producing this very profound

psychedelic effect.

And what’s really kind of curious

is that there are, as I understand it,

10 to 20,000 plant species in the Amazon.

And somehow, somebody.

Someone tried them all.

Combined these two plants together

in certain proportionality and cooked this

for five, 10 hours to the point where you cook out

the dimethyltryptamine out of one of the plants

and cook out the reversible monoamine oxidase inhibitor

out of the other plant in such a way

that the reversible monoamine oxidase inhibitor

prevents the GI breakdown of the dimethyltryptamine

in such a way that it’s then allowed

to cross the blood-brain barrier and get into the brain.

And if you didn’t add the reversible

monoamine oxidase inhibitor plant-derived

into this combination, then it would never cross the brain.

If you put people on a standard psychiatry-prescribed

monoamine oxidase inhibitor that wasn’t reversible,

you’d throw them into serotonin syndrome, right?

So this kind of sweet spot that somehow

ayahuasca practitioners have found

being able to get DMT into the brain

from an oral source with this combination

of a monoamine oxidase inhibitor is curious.

And so that substance has been explored

as an antidepressant agent,

and some studies have looked at that.

It also seems to be very safe.

There was a psychiatrist down at UCLA Harbor

who’s done a lot of work with this

where he’s looked at children, even,

that have been exposed to small doses of ayahuasca

as kind of a sacrament within Amazonian tribes

and found no neurocognitive effects,

no neurocognitive effects in adults.

And so it appears to be safe.

It’s kind of part and brought into various religions,

including kind of merged with Catholicism in South America,

which is kind of very interesting.

And so in some sects of Catholicism in Brazil,

it’s used as a sacrament during religious ceremonies.

And so it became interesting to Brazilian researchers

as to whether or not they could affect recidivism rates

for prisoners in Brazilian prisons, right?

So they gave half of the prisoners

some sort of inert substance

and half of the prisoners an ayahuasca session.

And the recidivism rate or the return to prison rate

in the ayahuasca-exposed individuals

was statistically significantly lower

than the recidivism rate in the control group,

suggesting that whatever’s going on there

seems to have an effect on whatever drives

criminal behavior, whatever criminal behavior

that happened to be.

And I don’t have the details

on the exact nature of the crime.

I am also in no way saying that we should just be giving

psychedelics to folks in prison and all of that.

I think that that is a very edgy thing to do

and probably not something that anybody should try.

But it does kind of bring up this curious question

of what is it about that that would drive people

to change those behaviors?

And why do people make those behavioral decisions?

And a lot of times, if you look at prisons

in the United States, people say this,

what’s the biggest mental health facility

in the United States?

It’s a prison.

Yeah, there’s a lot to unpack there, for sure.

The homeless issue, the prison issue.

It does lead to something that I heard recently,

which is related to all this, which is cannabis.

We hear a lot nowadays about,

people will say, well, it’s safer than alcohol.

And we did an episode on alcohol

that at least by my read of the literature,

indeed, alcohol does seem to be quite bad

for our health beyond.

I think it’s pretty clear that not drinking

is better for your health than drinking at all.

And here, I’m not trying to tell people what to do,

but those are what the data say.

And forget the studies on red wine.

You’d have to drink so much red wine

to get enough resveratrol.

It’s not even clear resveratrol does anything useful

in any way, et cetera, et cetera.

Nonetheless, cannabis is now available

in a lot of very high potency forms.

People are vaping cannabis.

People are smoking cannabis.

I certainly am not saying that cannabis is bad

for people necessarily, although I think children,

I would hope that their brain development

would be completed first, get to age 25.

I know that sounds late for a lot of people,

but the THC obviously taps into some endogenous systems

of endocannabinoid systems and is powerful.

And I’ve seen this report that was in Lancet Psychiatry

this last year that said that early use of potent cannabis,

meaning age 14 to 20 or so,

can potentially lead to an exacerbation

of psychosis later in life.

And I actually put this out on social media

and it sort of exploded.

I didn’t expect it to.

And people were saying, well, that’s not causal.

And obviously it’s not causal because people say,

well, maybe people with psychotic tendencies

are seeking out cannabis.

Although that’s sort of a weak argument

in the sense that there’s at least a four times,

a 4X increase in these psychotic episodes

for people later in life.

But what are your thoughts about cannabis?

Because I do want to acknowledge

that it does have medical benefits for certain things,

a pain, chemotherapy.

So by no means trying to knock on cannabis

and its appropriate medicinal use,

but what should we think about cannabis

in terms of this finding that can exacerbate a psychosis

in certain individuals?

Yeah, so I think there’s a couple of things, right?

So cannabis is multiple cannabinoids, right?

THC, CBD, CBN, sativas, and indicas.

It gets, yeah, there’s a lot there to unpack.

Yeah, there’s a lot of,

but there are two main kind of chemicals you think about

and kind of how things are essentially bred, right?

And so there’s a lot of cannabis

that’s really bred to be very high, very potent THC,

and there’s cannabis where the THC’s bred completely out.

So there’s stories from Colorado, right?

This strain of cannabis that’s THC-free.

There’s no THC at all, and it’s all CBD,

and it’s called Charlotte’s Web.

And a bunch of kids’ parents,

one kid and then kind of a string of parents

after that moved to Colorado when cannabis was legalized

because CBD is anti-epileptic.

So CBD is also anti-psychotic.

And so there have been a number of studies

that if you give CBD at high doses,

it’s anti-psychotic in schizophrenic,

established schizophrenic patients.

The issue is that we’ve bred CBD out of marijuana

selectively over time.

And we’ve gotten very good

at figuring out how to do that, right?

Conversely, THC is pro-psychotic and pro-epileptic, right?

And so when you talk about does cannabis cause psychosis

or does cannabis treat psychosis,

it appears to be more related to the proportions of CBD

to THC than it does to the kind of idea of cannabis.

So for me, there’s a, and I have no stock on this

or anything like that,

but there’s a company called GW Pharmaceuticals

and I haven’t looked into them in a while,

but they have a lot of clinical trials

for something called Dravet’s syndrome,

which is a seizure disorder where kids seize a whole lot.

Lennox-Gastaut syndrome, which is a seizure disorder

where kids are seizing 300 times a day.

Both of these are like kids are seizing so much

they’re basically in a seizure

or in the post-ictal phase constantly.

And they’ve failed everything.

They’ve failed barbiturates, they’ve failed bromides,

which we just don’t use anymore,

except in these cases because of the side effects,

and they’ll give kids CBD.

And I think CBD is a pretty safe drug

compared to bromide, right?

And so this idea that CBD in a kid is actually safe.

It’s a cannabinoid, but it’s CBD and it’s safe, right?

And so that to me is totally fine.

Also giving CBD as an adjunctive treatment for schizophrenia

there’ve been some positive trials

and negative trials in that,

but there seems to be no negative side effects.

It seems to reduce some of the metabolic syndrome issues

in folks with schizophrenia who are having side effects

from the primary antipsychotic.

The converse is there’s clearly cases

where people that are taking very high doses of THC

become psychotic, they get put into the psychiatric unit,

nothing happens other than they kind of get the THC

out of their system,

and then they resolve their psychosis, right?

And so that, and a handful of people

who’ve had seizures related to high doses of THC,

and syncope, and all sorts of things.

And so this idea that THC, high doses of THC

can be pro-psychotic is also not taking a shot

at people that think that cannabis overall is a good thing.

It’s just, it just is what it is.

And the kind of pure, if you,

I think if you zoom back and you say,

you’re a true naturalist,

you’re thinking about natural medicines in the world,

you should think, well, probably marijuana

was balanced THC, CBD at some point,

and then we just, we humans messed with it, right?

And that most likely that was probably okay at some level,

and then we pushed it one way or another.

And what I mean by okay is in a 45-year-old,

it’s okay kind of thing.

Now, what I think is going on with the kids,

with the teenagers is you’ve got prefrontal maturation,

right, and then you’re exposing them

to a whole lot of high THC load.

And while it’s unclear if it’s cause or effect,

it’s certainly in the picture.

And if I were a parent,

I wouldn’t want my 16-year-old smoking marijuana.

If I were a parent and my 30-year-old

otherwise healthy, totally fine, whatever,

banker, lawyer, kid, decided to try marijuana

for the first time, I wouldn’t scold them about it, right?

So I think it’s kind of a different thing, right?

I would never want my up to 25-year-old,

just like you’re saying, before prefrontal maturation,

I would never want my kid to be exposed at all.

But it looks like, except in susceptible individuals

or susceptible to drug-induced psychosis,

it looks like it’s a relatively safe thing

past prefrontal maturation.

Again, I’m not gonna comment of cause and effect,

but I would say that if you’re a parent,

it doesn’t make much sense, right?

You never know what’s ultimately gonna hurt your kid.

I mean, we were talking about this earlier,

my wife’s pregnant now, she kind of avoids everything,

right, and rightfully so, right?

This idea that we just, we wanna be careful

when our children’s brains are developing,

and I think that’s really what you were saying,

and I think actually important.

The bigger question that you asked,

which is relative risks of drugs, is an interesting one.

So David Nutt published in, I think it was in The Lancet,

I’ll have to look it up, but I think in The Lancet,

an article about relative drug risks

for the person and for society, and this was like,

he was on the UK’s British drug policy group,

where essentially what he showed was,

if you look at societal risk plus personal risk,

and you combine those two, you know what drug

is the most dangerous drug in the world?

I’m gonna guess it’s alcohol.

It’s alcohol, right behind heroin and cocaine,

and da-da-da-da-da, and somewhere in the middle

is marijuana, and right on the tail end,

on the other, on the exact other end of this, psilocybin.

Is caffeine, usually doesn’t make the list.

It may have been on the list.

If it was, it was probably pretty close to psilocybin,

but somewhere in the middle was ketamine,

somewhere in the middle was amphetamine,

somewhere in the, you know, a little closer to psilocybin,

I think it was MDMA, you know, but it’s this combined

personal, you know, kind of world risk of these things,

and so alcohol makes it, because there’s a huge amount

of personal risk, and there’s a huge amount

of societal risk, right?

Drunk drivers kill X amount of people in the world.

Fight, sexual assault, all that.

Yeah, and then all the cancer and all that stuff,

and so it beats out cocaine, it beats out heroin,

it beats out all of these things, and yet we don’t,

we don’t as a culture, for whatever reason,

we don’t as a culture see it as a drug,

and that’s the part that really baffles me, you know?

And I’m not-

I mean, they serve it, I mean, this is no knock

on Stanford at all, of course I wouldn’t do that.

This is, at every institution I’ve been to,

they serve alcohol at the graduate student events.

That’s right.

You know, they serve alcohol, they do a happy hour.

I’ve never been a drinker, I can take it or leave it,

so, and I realize that some people,

they really enjoy alcohol, you know, my former partner,

I mean, she just was in that, you know, 10% or so

of people who have a glass of wine and just feel great,

and the second one feel great.

I just want to take a nap after I have a bit of alcohol,

so it never does much for me.

I always feel poisoned, I feel lucky in that sense,

but it’s unbelievable that it is so prevalent,

and it’s just, it’s baked into the medical,

even medical institutions, they’ll pop a bottle of champagne

to celebrate the opening of a hospital.

That’s right, that’s right.

You know, it’s pretty crazy.

Yeah, no, you’re absolutely right.

You know, I think what’s going to happen,

but this is me, you know, looking at a crystal ball

a little bit, but I think what’s going to happen

is what happened with doctors and smoking.

So if you look at the 50s and 60s, right,

there are all these pictures of doctors smoking cigarettes,

you know, with patients or, you know,

psychiatrists doing psychotherapy and smoking a cigarette

with the patient sitting on the couch, you know,

surgeons smoking a cigarette in between cases.

There are all these pictures of that, right,

and now all of a sudden, smoking’s totally banned.

I think it’s totally banned for most of Stanford campus.

My suspicion is, as you’re suggesting, right,

you know, this is everywhere and it’s all kind of ubiquitous.

At some critical point, some tipping point,

everybody’s going to realize that just like with smoking,

we’ve got to rid hospital systems

and universities of alcohol.

And at some point in 50 years, it’s my view that

we’ll look back at these scenarios that you’re talking about

and be like, you know what, we were foolish about this.

We can’t believe that we gave people alcohol

when they graduated from whatever, you know,

and I think we’ll have a different take on it.

But it’s going to take a longer time.

I think people did a really good job

tying smoking to lung cancer,

and it’s like a very simplistic story,

smoking, lung cancer, you know?

Now, as you know, alcohol increases the risk

of a lot of different cancers,

but it’s not so clear which one.

I mean, there’s like, you know, the kind of oral,

like the throat, tongue cancer, that’s one of them.

Breast cancer.

Yeah, breast cancer, you know,

and so it’s kind of, it’s a harder story to tell,

you know, and I think that’s why, and everybody,

you know, and then there’s this whole,

my mom says this, it’s like,

I drink my glass of wine because my doctor told me

it was heart healthy, and we were talking about this,

and I try to, no, no, no, but Dr. So-and-so

said it’s heart healthy, and so it ends up being this thing

where, like, she’s drinking alcohol

because she thinks that it’s good for her heart,

and, you know, and it’s hard.

I’ve had those conversations with her.

It’s hard to untie that, and I think that, yeah,

at some point, we’re going to hit some threshold moment,

and it’ll be interesting if we really look at the data,

and we really look at what’s safe and not safe

from purely from this analysis.

It kind of points to the right direction.

It’s really interesting, and also,

just saying nothing of poor judgment

under the influence of alcohol.

I mean, I would venture that if we were to remove alcohol

from university campuses, watch the students

are going to lobby against me if I say this,

but if you were to remove alcohol from campuses,

I mean, just think about the,

what I suspect would be the improvement

in good decision-making, and that would occur,

or, you know, I’ve got stories from graduate school,

and it was very different, you know, 10 years ago.

There was a lot more alcohol consumption.

Again, that was never my thing,

but I know people who make really bad decisions.

In any case, there’s a whole landscape there emerging.

I think you’ve got your finger right on the pulse of it.

I want to touch on something slightly different

than what we’ve been talking about,

but definitely related to depression,

and this, again, is one of these intriguing

but perplexing things, which is that sleep deprivation

can improve symptoms of depression,

and yet I’m personally very familiar with the fact

that if I don’t sleep well for one night,

or don’t sleep at all, in fact,

I do have an ability to function pretty well the next day.

I’ll do this non-sleep deep rest practice

that I blab a lot about on the Huberman Lab podcast,

which for me is tremendously restorative,

but I like a good night’s sleep.

I think everybody understands now,

thanks to the great work of Matthew Walker and others,

they’ve really gotten out into the world saying,

look, the foundation of mental health, physical health,

and high performance, if that’s your thing,

being a functional human being,

is to try and get enough quality deep sleep

at least 80% of the nights of your life, if you can.

That’s something to focus on, just like good nutrition,

just like exercise and social connection, et cetera.

So sleep deprivation, we know, can, in particular,

I think rapid eye movement components of sleep deprivation

can improve the symptoms of depression,

and yet being sleep deprived

can also really dysregulate our control

of the autonomic system.

I notice on night two or night three of poor sleep,

if I’m going through a stressful phase and that’s happening,

all of a sudden my heart rate is chronically elevated.

My thought patterns become really disrupted.

I can’t then exercise.

My decision-making is thrown off.

My emotionality is more labile.

The hinge, as we were referring to it earlier,

feels less in control, under my control,

and maybe I wonder sometimes if I enter that state

that you referred to earlier

where the dorsolateral prefrontal cortex

is no longer leading the cingulate,

but the cingulate is now in charge.

The players are in charge of the coach.

Not a good situation.

So I know you’ve done some work on sleep deprivation

and light and effects.

Please tell us about that,

and please tell us about this triple therapy.

Is that-

Yeah, yeah, so friend of mine, Greg Salem,

another one of the professors at Stanford,

was very interested in sleep.

He did a bunch of training in sleep

before he went to medical school

and got very interested in this idea that,

as you’re saying, if you sleep deprive somebody one night

in just kind of an isolated single night,

at the end of that sleep deprivation,

they will have an antidepressant effect,

but as soon as they fall asleep, they lose it.

So if it’s a depressed individual,

you can get them to be less depressed acutely

as soon as they fall asleep.

They wake up eight hours later,

then they come back into the same level of depression.

And so the idea was that you needed to do

some sort of circadian reset,

and that part of what depression is

is that it’s a dysregulated circadian system.

And so mentors of mine say,

if you can just get the sleep better,

that’s half the battle of dealing with depression

because so many people have insomnia around depression

and have a whole host of types of insomnia,

having a hard time falling asleep,

waking up in the middle of the night

and waking up earlier, all symptoms of depression.

And so what this does is it sleep deprives the individual

and then there’s a certain calculation

of shifting their phase

and simultaneously exposing them to bright light.

So that’s the triple, the phase shift,

the sleep deprivation and the bright light

to try to get their circadian rhythm.

Essentially, the theory is re-entrained.

And so in the trials that we’ve done

and other trials prior to ours and after,

it looked like there was a pretty profound

antidepressant effect from this triple therapy

that seemed to be durable,

meaning durability is this term we use

to say that not only can you get point relief,

but that the relief ends up lasting.

What’s important to know about this

is you shouldn’t do this at home for sure.

You would need to do this with a professional

because it’s complicated, it’s not just one thing.

And in sleep deprivation,

while it seems to be antidepressant, it’s pro-anxiety.

So if you take a highly anxious person

that’s not depressed and you sleep deprive them,

they get profoundly anxious.

And so that’s the other thing

that you have to really realize

is that this is like everything else

that I’ve talked about today,

all things that you have to do under medical supervision,

but curious, right?

And I think the question that always comes up

is why isn’t this used more?

And I think the reason is that

there’s not really a mechanism for,

ultimately in medicine, as sad as it is,

you have to have a code to do a thing.

There has to be a code associated with a treatment

and it’s hard to figure out how to make a code for this.

And so I think that’s part of it.

And so if there’s a way

and somebody’s got to kind of take that baton on that,

but if there’s a way to make a code for this,

I think you could actually turn it into something

that was more widely utilized.

And probably dream up ways of how to integrate AI,

passive sensing, all that stuff to really make that work.

But I think that would be the idea,

that would be the trajectory I’d see.

Yeah, having a billable to insurance code is fundamental.

And a lot of listeners to this podcast,

I think have a background in engineering science

and we will put a link to that manuscript

that talks about the triple therapy,

because here we’re talking about

one night sleep deprivation,

some time to light exposure to the eyes

and then shifting in the circadian clock,

things central to the themes of this podcast

that come up often.

I think for the typical person,

can we say that trying to get a regular light dark cycle

and sleep rhythm would be beneficial

for overall mood regulation?

Yeah, I think for the typical person,

really kind of re-regulating your sleep

and trying to get a good night’s sleep

in which you fall asleep, stay asleep,

wake up at a set time every morning

is going to be pretty crucial.

In mild depression, I think that one has a lot of control

over that as we were talking about earlier.

I think when you hit some threshold in depression

where things become kind of semi-volitional,

it’s harder to kind of will yourself into that.

There are therapies like,

there’s a CBT for insomnia, for instance,

where you can do cognitive behavioral therapy

to help with insomnia.

Sometimes people, and I’m no sleep expert,

I’d kind of pass this to Greg to fully talk about this,

but some of what goes on that people

with kind of milder insomnia experience

is like blue light out of their computer

and things like that that they,

so you can use like blue light blockers

and it tricks your brain, as you know better than me,

it tricks your brain to think that it’s still light outside

and so people will, they’ll have insomnia

because their brain still thinks that it’s light outside

and then people will, the kind of strict CBT for sleep,

therapists will say there are only two things

that you should do in your bed

and if you’re under a certain age and whatnot,

it’s really one thing that you should do in your bed,

which is to sleep and be with your partner, right?

And so those are kind of the two things

that you should do in a bedroom

and that’s really the only things

that you should do in a bedroom

if you’re having sleep problems.

You shouldn’t watch TV in a bedroom,

shouldn’t eat in a bedroom, shouldn’t hang out.

Keep the phone out of the bedroom.

Keep the phone out of the bedroom, yeah.

Yeah, we should get Greg Salem on the podcast.

I’ll just mention for people

that want to regulate their sleep,

we have a sleep toolkit that’s available

as a downloadable PDF at

Just go to the menu

and a lot of the things in that toolkit

are based on work from Stanford Sleep Laboratories,

including Jamie Zeitzer’s and others’ lab,

not aimed at depression specifically.

Listen, Nolan, Dr. Williams,

this has been an amazing voyage

through the circuitry of autonomic control.

This landscape of the prefrontal cortex

is I find incredibly fascinating

and I just want to start off by saying,

please do come back again

and teach us more about that and your TMS work.

Before we wrap, however,

I do want to give you the opportunity

to talk about the SAINT study.

Is it SAINT or saints, plural?

Yeah, it’s SAINT.

So SAINT or what we’re calling it S-A-I-N-T now,

SAINT has, you know, the intent was not

to kind of connect it to religion,

but we may have accidentally done so.

We abbreviated it to S-A-I-N-T for the subsequent trials,

which was initially

Stanford Accelerated Intelligent Neuromodulation Therapy,

or now we’re calling Stanford Neuromodulation Therapy,

but the idea there, which is a cool idea,

is that TMS is a device that delivers a treatment

and the treatment is the protocol

and the protocol is the stimulation parameter set

in a specific brain region for a specific condition.

And so what’s cool about neuromodulation,

whether it be transcranial magnetic stimulation

or transcranial direct current stimulation

or deep brain stimulation,

like what Casey Halpern talked about on another podcast,

is this idea that in all of those cases,

the device itself is a physical layer conduit

of a stimulation protocol that’s therapeutic

for a given condition in a given brain region.

And so in the case of depression,

which we know the most about with TMS,

we’ve been doing TMS studies for depression since 1995,

right, and a clearance in 2008, 2009.

And in that timeframe, we were able to go

from really knowing very little at all

about how to do something like this

to getting an FDA clearance.

And the way that it went down was that

there were two groups studying different components at NIH.

The first group was studying mood neuroanatomy

on functional imaging that was kind of the first generation

of functional imaging back then, so PET scans,

which are kind of metabolic scans, and then SPECT scans.

And the idea there was looking at activity

and metabolism in prefrontal cortex.

And what they found in these kind of more crude scans

is a just general hypoactivity, hypometabolism.

The other group right upstairs at the National Institute

for Neurological Diseases and Stroke, NINDS,

they were looking at using TMS,

which had been around for 10 years,

and repetitively stimulating in motor cortex.

What they found was, gosh, we can get a readout

in thumb muscle movement amplitude

that’s really reproducible across people.

It’s universally reproducible.

And if we do certain stimulation approaches,

they are biologically active to either increase excitability,

i.e. the thumb motion on a set intensity goes up,

the amount of amplitude goes up,

or inhibitory, depotentiating,

it goes down with other biological stimulation approaches.

And then a third outcome, which is important,

that it’s inert, it doesn’t do either.

So you can have stimulation approaches that do one,

increase activity, decrease activity, or are inert.

And so what they found was,

oh, we can excite certain brain regions.

And my mentor, Mark George, had this kind of aha moment

where he said, wow, there’s underactivity

in prefrontal cortex in depression,

and we can increase activity using this thing

that we know we can increase activity in motor cortex,

we just need to put it

in the left dorsolateral prefrontal cortex,

and then they combined the two and started stimulating

once a day in this kind of very abbreviated fashion,

and lo and behold, some of those depression patients

resolved their depression, and back then, and still today,

you can go, and as a psychiatric patient,

stay at the National Institute of Mental Health

and go through clinical trials to try to get treated,

and there were patients who’d been there for months,

and they were able to be discharged

because their mood was better.

Yeah, and so it was this very crude approach

where they were using ruler measurements

where DLPFC was, and they were stimulating with devices

that you needed to physically dunk the coil in an ice bath,

and with that, they still were able to,

the kind of genius of this, Mark and others,

they would still be able to create

a purely engineered stimulation approach.

What’s cool about that is that

they kind of found two things, right?

They found this one stimulation protocol

that does have some antidepressant effect.

It’s limited.

It doesn’t treat everybody.

It does have some antidepressant effect,

and this bigger concept that a neuromodulation device

is kind of like a pharmaceutical company for you, right,

that in a given individual, a TMS device

or whatever neuromodulation device is able to generate,

you can create a stimulation approach

that is specific to a given condition

and specific to an individual,

and so the physical layer is just how you exert that,

similarly to how we make pharmaceutical drugs

in a pharmaceutical company,

but the actual therapy itself is what you do

where you do it, and so what we learned from

another 20, 30 years of this

is that you can modify the stimulation protocol

in such a way where you can create a whole new treatment

and put it through the same TMS device,

or thank God, an evolved version of it

where you don’t have to dunk it in ice baths

and they can actually really handle

much more aggressive stimulation approaches,

and so in 2005, a group published in Neuron,

a paper demonstrating that if you stimulate

with the hippocampal rhythms through a TMS coil,

you can excite the brain with memory rhythms,

and it’ll last an hour,

so you can change cortical excitability

in this thumb twitch for an hour,

sending three minutes of excitatory,

or 40 seconds in the case of inhibitory stimulation

that mimics the hippocampal rhythms,

so much more efficient than the original TMS approaches,

and so after that, group tried to do it

in this kind of six-week schedule,

and after that, and while they were doing that,

we decided, gosh, this problem I talked about

at the beginning of the show where you have this problem

that we don’t have a treatment for people

who are in these high-acuity psychiatric emergency states,

this idea that we’re gonna engineer a treatment

where we can reorganize the stimulation approach in time

to be much more efficient by utilizing

something called space learning theory,

and so you probably know about the space learning theory,

so the idea for the viewers is

it’s a simple psychological thing,

but we’ve also seen it in hippocampal slice

sort of physiology too,

where if I’m cramming for a test,

what I do is I write out 60 note cards,

and I read each one for a minute

until I get to the first note card again,

and that’s about an hour later, right,

and we just intuitively do this.

We all automatically do that,

and we intuit that because we know

that what doesn’t work is writing out one note card

and looking at it over and over again.

Nobody ever does that, right?

We’ve all been in graduate school, medical school,

and we have these big stacks of note cards.

That’s space learning theory.

It’s this idea that you need to see it

about every hour to an hour and a half,

and that optimizes learning.

If you take the same stimulation approach

that I’m talking about,

this theta-burst stimulation approach,

and you take a hippocampal slice of a mouse

and you stimulate,

you enlarge some dendritic spines and you prime some,

and then if you stimulate right after that,

you don’t get any change.

It’s called in-mass stimulation,

but if you wait about an hour to an hour and a half,

you get more dendritic spines enlarged and more primed,

which, by the way, also is what ketamine does.

It causes this dendritic spine enlargement,

and so what we found was that the old way of doing TMS,

this idea of just doing it once a day,

every day, five days a week for six weeks,

didn’t utilize the space learning theory.

It’s like studying for a month or two,

just a little bit once a day.

You remember some of that stuff,

but it’s not as potent as that week

where you’re kind of cramming, right?

And what we realized is that if we could

reorganize the stimulation in time

so that we took the whole six-week course,

we actually figured out a way to do it in a day.

And then what we also figured out

is that people were underdosing TMS

because if you just keep going after six weeks

out to month three, four, five,

more and more people got better,

so we figured out it’s not just one day.

We’re gonna give five times the normal dose.

We have seven and a half months worth in five days

using space learning theory.

So every hour?

Every hour for 10 hours.

For five days.

For five days, so it’s a 50-hour block.

It’s 90 minutes of actual stimulation,

but spread out through the day in the same way of learning,

which is perfect for an inpatient psychiatric unit, right?

Five days is manageable.

Yeah, you can get stimulation.

Nobody’s ever dropped out by the schedule.

Folks that want to do this want to do it,

so they’ll do their nine minutes.

They’ll go get breakfast.

They’ll do their nine minutes.

They’ll go see their therapist or whatever it is,

and so what we found with this reorganization

in time of the stimulation, dose,

and then the third component is we do

resting state functional connectivity scans on everybody,

and we have ways now in the last five to 10 years

of picking out that specific subgenual DLPFC subcircuit

that I was talking about earlier, that cingulate DLPFC.

We can pick that out in every single one.

If you want to come to the lab,

we can find your DLPFC subgenual.

It’s even more robust than non-depressed.

Maybe we can stimulate too just while we’re in there.

Yeah, if you want to, we can move around

your hypnotizability, and we can find that spot

in each person, and instead of finding the same spot

on the skull, we find the same spot on the brain,

and we can stimulate, and we do that every hour on the hour,

and what we’ve found is that folks will,

within one to five days, in more cases than not,

depending upon if you’re looking at this open label

or in trials, somewhere between 60 and 90% of the time,

they will go into full-on remission in the sense

they’re totally normal from a mood standpoint

at the end of this, and like I said,

with variable durability, so that’s the part

we have to figure out now about dosing

and how to keep people well, but for some people,

we’ve had four years of remission, a year of remission,

and it’s really that cramming of the test.

It’s really that idea that you’re laying

in that information to the exact right spot,

and the signal’s a simple signal, but it’s a profound one,

which is turn on, stay on, remember to stay on.

You know, that idea that you’re sending this memory signal

into the brain, and you’re doing it in such a way

that you’re telling the system, you’re kind of taking it

out of the hippocampus’ hand, your own hippocampus’ hand,

and you’re sending the same signal

the hippocampus normally signals out.

Now you’re sending that signal

into the prefrontal cortex, and kind of utilizing

the brain’s own communication style

to get it to get out of the state,

and what’s very cool about this is that people,

when they kind of exit out of that,

they end up saying they don’t have any side effects from it,

and they feel back to normal.

Like some people, you know, not everybody,

but there’s a subsection of people with SSRIs

where they’ll say, I kind of feel numb,

or I have GI side effects, or I can’t, you know,

I don’t have the sexual interest that I used to have,

and that sort of thing.

You know, not anything against SSRIs,

as I said earlier, life-saving, you know,

for a subsection of people, these things really work,

but with this, what you see is that people

don’t talk about any of that stuff,

and I think it’s likely because you’re tapping

into that core circuitry, and you’re reversing it,

and you’re doing it with a magnet,

that because it’s a very profound electromagnet,

it’s the same field strength as an MRI scanner,

it’s able to induce a current in the brain

in this focal, targeted way,

without getting into the rest of the brain,

without getting into the rest of the body at all,

and just really kind of acting only

on that circuitry that’s involved.


Is the SAINT study still ongoing,

and if people are interested in potentially being

patients or subjects in the study,

can we provide them a portal link?

Absolutely, yeah.

So we have, now the treatment,

some of my students went over to a company

called Magnus Medical, and they’ve been working on this,

they’ve got an FDA clearance now,

and now folks can get it through trials

over the next couple of years,

because it’s going to take some time for that company

to kind of get up and running and get a device

and get the whole thing set up nationally,

but while that’s all going on,

there’s still about 1,000 patients

that need to be recruited across a bunch

of different trials all over the country.

We’ll take people from anywhere in the country.

We also have partners in New York and San Diego

and soon to be South Carolina and other places

where we can actually, my lab can help

to kind of let people know where to go,

based off of where they’re at in the US,

and get them access to being able to be in a trial,

and what we’ve tried to do is make it so that

even if you get the 50-50 chance

you’re going to get the real deal,

or you’re going to get the non-real deal,

but what we have figured out is a way

to let everyone have access.

If they got the not real deal version,

the kind of sham version or the fake version

for the first part of the trial,

there are other trials where they can have access

to the real version, so essentially everybody

eventually gets access to having the real version,

and so that’s been a big thing for me

is I want everybody that comes through one of our trials

to be able to have access.

I think it’s important while the company’s doing

what they’re doing and what the lab’s doing

and kind of nationally what other partner labs are doing.

Well, I can assure you, you’re going to get some interest.

Happy to have it, yeah.

Thank you.

And listen, thank you so much for taking us

on this incredible voyage through the neurocircuitry

underlying certain aspects of depression,

the coverage of the different types of depression,

the various therapeutic compounds, how they work.

We’ve talked about a lot of things today,

and you’ve shared so much knowledge,

and even as I say that, I very much want to have you back

to talk about many other things as well

that we didn’t have time to cover,

but also just really want to thank you

for the work that you do.

I know we are colleagues,

but you run an enormous laboratory,

enormous in my book, 40 people is a big group,

very big group, plus you’re in the clinic.

You also have a life of your own outside of work,

and to take the time to sit down with us

and share all this knowledge

that really is in service to mental health

and humans feeling better,

and in fact, avoiding often suicidal depression.

It’s just incredible work and an incredible generosity,

and just thank you so much.

Oh, thank you, man.

I mean, similarly, I want to thank you for what you’re doing.

I mean, I think that what you,

I’ve got a lot of friends,

folks that are not in the medical profession,

friends of mine, one of my buddies

who’s a real estate agent who works with us,

who’s a big fan of your show,

and I told a couple people like that I was coming on,

and they were super stoked.

They’re like, we watch every show,

and super excited to watch mine,

and they said something very important to me

that you make this complicated neuroscience

and brain-body science accessible

in a way that few have a gift to do,

and I think that that’s so important,

and this show is doing so much

to help with science literacy,

and yeah, appreciate you.

Well, thank you.

I’m gratified and honored by your statement,

and I look forward to more.

Thank you.

Absolutely, thank you.

Thank you for joining me today

for my discussion with Dr. Nolan Williams.

I hope you found our discussion

about psychedelics and other compounds,

about transcranial magnetic stimulation,

and about the treatments for depression in general

to be as stimulating as I did.

If you’d like to learn more

about the work being done in Dr. Williams’ laboratory,

you can go to the Brain Stimulation Laboratory website,

which is,

and there you have the opportunity to apply

to be in one of the clinical trials for depression

or other studies,

as well, if you’d like to support the work being done

in Dr. Williams’ laboratory

for the treatment of depression

and other psychiatric disorders.

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♪ Yeah ♪

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