Dr. Nolan Williams: Psychedelics & Neurostimulation for Brain Rewiring | Huberman Lab Podcast #93

- 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 anti trauma 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 bsl.stanford.edu,

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.

I'm pleased to announce

that the Huberman Lab Podcast has now launched

a premium channel.

I want to be very clear

that the Huberman Lab Podcast will continue

to be released every Monday at zero cost to consumer

and there will be no change in the format of these podcasts.

The premium channel is a response

to the many questions we get about specific topics,

and it will allow me to really drill deep

into specific answers related to those topics.

So once a month,

I'm going to host an ask me anything, so called AMA,

where you can ask me anything about specific topics covered

on the Huberman Lab Podcast,

and I will answer those questions.

Those of course will be recorded.

There will also be other premium content available

to premium subscribers,

such as transcripts and short videos of new tools

and unique tools for mental health, physical health,

and performance.

If you want to check out the premium channel,

you can go to hubermanlab.com/premium.

There is a $10 a month charge or $100 per year,

and I should mention that a large portion of the proceeds

from the Huberman Lab premium channel will go

to support scientific research

that develops the very sorts of tools

that we talk about on the Huberman Lab Podcast.

The rest of the support

for the Huberman Lab Podcast premium channel will go

to supporting the regular Huberman Lab Podcast.

Again, that's hubermanlab.com/premium.

Before we begin,

I'd like to emphasize that this podcast is separate

from my teaching and research roles at Stanford.

It is, however, part of my desire and effort

to bring zero cost to consumer information about science

and science related tools to the general public.

In keeping with that theme,

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

Our first sponsor is InsideTracker.

InsideTracker is a personalized nutrition platform

that analyzes data from your blood and DNA

to help you better understand your body

and help you reach your health goals.

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

for the simple reason that many of the factors

that impact your immediate and long-term health

can only be analyzed with a quality blood test.

One problem with a lot of DNA tests

and blood tests, however,

is you get data back about levels of metabolic factors,

levels of hormones, et cetera,

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

InsideTracker makes interpreting your data

and knowing what to do about it exceedingly easy.

They have a personalized platform where you can go

and you can see those levels of hormones, metabolic factors,

lipids, et cetera,

and they point to specific nutritional tools,

behavioral tools, supplement based tools, et cetera,

that can help you bring those numbers

into the ranges that are optimal for you.

If you'd like to try InsideTracker,

you can go to InsideTracker.com/Huberman

to get 20% off any of InsideTracker's plans.

Again, that's InsideTracker.com/Huberman to get 20% off.

Today's episode is also brought to us by Eight Sleep.

Eight Sleep makes smart mattress covers

with cooling, heating, and sleep tracking capacity.

I started sleeping on an Eight Sleep mattress cover

a few months ago, and it is simply incredible.

In fact, I don't even like traveling anymore

because they don't have Eight Sleep mattress covers

in hotels and Airbnbs.

One of the reasons

I love my Eight Sleep mattress cover so much is that,

as you may have heard before on this podcast or elsewhere,

in order to fall and stay deeply asleep,

you need your body temperature to drop

by about one to three degrees.

And I tend to run warm at night,

which makes it hard to sleep

and sometimes wakes me up in the middle of the night.

When you sleep on an Eight Sleep mattress cover,

you can program the temperature of that mattress cover

for specific times in the early, middle,

and late part of your night so that the mattress stays cool.

And as a consequence, you sleep very, very deeply.

It also tracks your sleep,

so it's paying attention to how many times you're moving,

how deep your sleep is.

It gives you a sleep score,

all wonderful data to help you enhance your sleep.

And of course, sleep is the foundation of mental health,

physical health, and performance,

which makes an Eight Sleep a terrific tool

for enhancing not just your sleep,

but all aspects of your life really.

If you're interested in trying a Eight Sleep mattress cover,

you can go to EightSleep.com/Huberman

to check out the Pod 3 cover,

and you can save $150 at checkout.

Eight Sleep currently ships to the USA, to Canada, the UK,

and select countries in the EU and Australia.

Again, that's EightSleep.com/Huberman

to save $150 at checkout.

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

ROKA makes eyeglasses and sunglasses

that are the absolute highest quality.

The company was founded by two all American swimmers

from Stanford, and everything about ROKA eyeglasses

and sunglasses were designed with performance in mind.

I've spent a lifetime working on the visual system,

and I can tell you that your visual system has to contend

with some pretty significant challenges

in order to be able to see clearly

as you move from one area to the next.

For instance,

when you go from a shady area to a bright area.

ROKA understands this and have designed their sunglasses

and eyeglasses accordingly

so you always see with crystal clarity.

In addition,

because they were initially designed for performance,

things like running and biking,

they're extremely lightweight,

but they have a terrific aesthetic.

So unlike a lot of eyeglasses and sunglasses

that were designed for sports

and make you look like a cyborg,

they have styles that make you look like a cyborg

if you like those, but they also have styles

that you'd be perfectly comfortable wearing to work

or out to dinner, et cetera.

They're really terrific glasses.

I love mine because I can wear them anywhere

and I also use them when running and going out hiking,

et cetera.

If you'd like to try ROKA eyeglasses or sunglasses,

you can go to ROKA, that's ROKA.com,

and enter the code Huberman

to save 20% off your first order.

Again, that's ROKA, ROKA.com,

and enter the code Huberman at checkout.

On many episodes of the Huberman Lab Podcast,

we talk about supplements.

While supplements aren't necessary for everybody,

many people derive tremendous benefit from them.

Things like enhancing sleep and the depth of sleep,

or for enhancing focus and cognitive ability,

or for enhancing energy or adjusting hormone levels

to optimal range for you.

The Huberman Lab Podcast is now partnered

with Momentous supplements.

To find the supplements we discussed

on the Huberman Lab Podcast,

you can go to livemomentous, spelled O-U-S,

livemomentous.com/huberman.

And I should just mention that the library

of those supplements is constantly expanding.

Again, that's livemomentous.com/huberman.

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.

- Yeah.

- 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 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, you know.

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.

You know, 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, you know, 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 you know, 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 the risk of having a heart attack in the future?

And, you know, there's 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, you know, as you said a second ago, you know,

it's a very disabling condition.

Moderate depression's about as disabling

as having a heart attack, acutely having a heart attack.

Severe depression is disabling,

is having cancer without treatment, you know,

and dying from a cancer without treatment.

And so, you know, 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 illnesses,

then the idea that we can start really putting more funding

and putting more focus at the federal level, you know,

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, you know, emergency settings

where they go into inpatient units.

And you know, 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 going to have a certain number of tests

and treatments, right?

But very limited cuz 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, you know,

fairly okay with a pretty moderate depression

and then 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 outpatient.

And I came to this because I, you know, 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, you know, brain based solutions.

- There's a lot to unpack there.

One thing that you said is,

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.

- [Nolan] Yes.

- 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.

- [Nolan] Yep.

- 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

and 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 anterior cingulate and the insula and the amygdala.

And ultimately the tract goes into something called

the nucleus tractus solitarius

and ultimately into the vagus nerve into 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.

Drifts back up and the stimulation goes back in

and then the heart rate goes back down.

And so you see the heart rate just do this,

10 beats per minute every train.

And so we know, and 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.

And so, yeah, it seems to, you know,

it's our work, other folks' work.

Martin Arens 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, you know, rare exceptions to this,

like the pineal and things of that sort

that there is 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 demonstrated

that if you have strokes in the brain that cause depression

and you put them on the human connectome,

a hundred, you know, thousand 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 on the human connectome map

and ask what the one common area they're all connected to,

it's the right dorsolateral.

And so there seems to be a hemispheric, you know,

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 is 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 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 you know, it hasn't been worked out,

which your original question was around,

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 unfortunately that study still hasn't been done

at the level, 'cause that would be probably pretty helpful

for teasing some of this out.

But, you know, 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 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, you know, 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.

- Interesting.

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?

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 bradycardia

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 this,

the afferent parts of the vagus project ultimately up

to the DLPFC through the cingulate

through these anterior insula, so that same,

that 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 on 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 a kind of a whole track 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 by 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, you know, 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, right?

Where people in a very severe form of depression get

kind of stuck motorically, right?

And they obviously can't, they have no control

or very limited control.

And so, you know, 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, you know,

athletes hold a lower resting heart rate

than folks that aren't, you know, 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

in kind of lowering of, say,

heart rate with mood improvements.

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

and depression and, you know,

studies kind of point towards it.

Not every study is positive for this,

but quite a few studies say basically

that lower heart rate variability is associated

with, you know, 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 you know, 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?

- Yeah, that's right.

- 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, you know,

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 you know, 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, you know, 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's going to

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, you know, it's independent of mood.

You can take a normal healthy individual and you can do this

and they're going to decelerate their heart rate.

- I'm so glad you mentioned

the parasympathetic nervous system,

which of course is the,

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, you know, 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 to the...

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 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 be 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?

- [Nolan] Yeah, absolutely, absolutely.

- Okay, I just want to make sure

that I'm framing this correctly in my mind.

- Yeah, yeah, absolutely.

And in some studies,

if you do the same identical stimulation

on the right dorsolateral, you can get an acceleration.

You know, just kind of further confirming this idea

of lateralization, right?

That it appears that even the prefrontal cortex, you know,

cortical areas seem to be lateralized in this way.

And, 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,

'cause 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 of 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

or are we talking about dreamlike thoughts?

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

And here I spend 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, you know, to...

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 you know, 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 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,

you 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 on 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.

You know, with the part of the dorsolateral

that seems to be lower in the, you know,

kind of more lateral and inferior on the DLPFC

and connected with this subgenual anterior cingulate,

so the part of the anterior cingulate

that processes emotion.

- I'd like to take a quick break

and acknowledge one of our sponsors, Athletic Greens.

Athletic Greens, now called AG1,

is a vitamin mineral probiotic drink

that covers all of your foundational nutritional needs.

I've been taking Athletic Greens since 2012,

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

The reason I started taking Athletic Greens,

and the reason I still take Athletic Greens once

or usually twice a day is that it gets to me the probiotics

that I need for gut health.

Our gut is very important.

It's populated by gut microbiota

that communicate with the brain, the immune system,

and basically all the biological systems of our body

to strongly impact our immediate and long-term health.

And those probiotics in Athletic Greens are optimal

and vital for microbiotic health.

In addition, Athletic Greens contains a number

of adaptogens, vitamins, and minerals that make sure

that all of my foundational nutritional needs are met

and it tastes great.

If you'd like to try Athletic Greens,

you can go to AthleticGreens.com/huberman

and they'll give you five free travel packs

that make it really easy to mix up Athletic Greens

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

on the plane, et cetera.

And they'll give you a year supply of vitamin D3K2.

Again, that's AthleticGreens.com/huberman

to get the five free travel packs

and the year supply of vitamin D3K2.

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?

- [Nolan] That's right.

- Okay, a rule in some sense is, 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 they would 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 saying that, you know,

whatever we heard in middle school

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

'Cause I can remember things that people said

about a jacket I wore one day

or something in the fourth grade, 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 to 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 dorsolateral 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 the Stroop task.

So given its connectivity,

can we assume that the talk therapy that occurs

in the psychiatrist 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 rescripting that,

that somehow it allows us to do a sort of Stroop 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.

- [Nolan] Yeah, totally.

- 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 you know, kind of determine how fixed they are,

you know, 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 had a lot of patients who've told me,

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

in therapy, and you know, and I really am trying hard,

but these are, you know, 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.

And we've got some data in review now

where we're seeing that in depressed individuals

that are responsive to our rapid TMS approach,

what we call

Stanford Accelerated Intelligent Neuromodulation Therapy,

or SNT, 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 the other is like a 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 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, right?

So you can experimentally manipulate the system,

and so kind of buffing it up,

it's like 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.

And we can't, 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 zeroed out 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 obviously any more patients

about that, and then about five

over the last couple of years,

when they remit 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 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.

- 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 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 neuroscientist 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 Stroop 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 neural imaging 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?

'Cause that area seems to be overactive in people

who are experiencing obsessive compulsive disorder.

You can kind of walk, the cingulate wraps around, you know,

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 Stroop 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, you know, heart rate kind of components to it

and autonomic components in there too.

There's something called akinetic mutism,

you know, I'm a board certified neuropsychiatrist,

behavioral neurologist, and I've seen, you know,

a lot of these what we call zebra cases in neurology

where people have, you know,

these unusual neurological presentations

and one of them is akinetic 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 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 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?

And 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.

There's, so you see catatonia as an extreme outcome

of depression and sometimes schizophrenia

and other illnesses.

Dissociation is an extreme outcome,

or even in some cases, a less extreme outcome

of PTSD and trauma.

And you know,

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, you know,

some of the work that he's been working on is

around posterior cingulate in the capacity to disassociate.

But yeah, you know, 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 know,

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 Live clips channel.

I've always, well, always.

Starting at 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? - Yep.

- 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, you know,

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,

mu and kappa opiate receptor antagonist.

And we gave folk, 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?

- [Nolan] 50 milligrams, so it's pretty high dose.

- Okay.

- 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 'em 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,

you know, completely worked in,

which is the glutamate system,

then you would have no effect of naltrexone.

'Cause naltrexone just interacts with the opioid system.

It doesn't do anything with any other systems.

Ketamine has a lot of effects over, you know,

it has clear opioid effects in mice

in various ways of looking at that,

and an MDA 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 is

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.

Yeah, 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 a 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,

very painful operation, right?

You know, total knee replacement and you age, sex, you know,

everything match 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, right?

- That's required.

- That's required to cover the pain

but what may be happening is

it's not just treating physical pain,

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, you know, 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, you know,

we think we pretty clearly debunked that idea

that the underlying pharmacology and the state, you know,

seem to be important.

We don't know for sure if you can,

a lot of people are working on this,

if you can take out, you know,

essentially the psychological effect

and still have a drug that works to treat the illness

that you're trying to target.

And 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, you know, 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,

you know, if somebody takes a multi gram 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 be shown to be useful for

in certain contexts, clinically supported, et cetera.

There's this like 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 this is a chemistry lab essentially,

modifying psychedelics

to remove the hallucinogenic properties,

the mood altering properties,

and actually seeing some pretty impressive effects

and shifts in mood after the drug wears off.

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

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 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 they're, 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 really important topic

that has been in the press a lot lately,

which is SSRI, selective serotonin reuptake inhibitors.

'Cause 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 the experiment that I described a bit ago

around the naltrexone and ketamine was the first time

I'm aware of where we were able to essentially eliminate

an antidepressant's effect by using a second drug

as a 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 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.

You know, many, many meta analyses

kind of proving that out, right?

That in a subpopulation of individuals,

they achieve great benefit from depression, you know,

for depression, for obsessive compulsive disorder,

for generalized anxiety disorder, panic, you know,

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

and leaving the serotonin, you know,

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 with the authors of this paper,

this 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's known this.

This is not actually new information, anybody, you know,

and 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,

you know, for a while, I think psychiatry,

you know, what I'll call psychiatry 1.0, right?

This kind of idea of Freud and psychotherapy

and its origins.

It was a lot around, you know, your family

and those experiences and psychotherapy kind of going in

and correcting or helping you to figure out,

and you know, 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, you know,

things like the schizophrenogenic mother and all of that,

you know, that was a concept at some point, right?

And so we've transitioned from that to, you know,

for a long time the chemical imbalance,

which I'll call psychiatry 2.0.

You know,

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, you know, 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 is really powerful with TMS,

you know, really powerful with TMS,

and 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.

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.

Neuromodulations are really nice, you know,

use case for psychiatry 3.0

'cause it's a way to focally

and directly perturb brain regions

in whatever modality you're using.

But you know, 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, right?

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 recalibrate-able instead of I have something missing

or I have some set of experiences early in life

that are going to 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.

People, you know, we've seen with our TMS techniques,

we've seen with some of the psychedelic work that we've done

where people are actually in normal levels of mood

for sustained periods of time or-

- 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 in that point,

in the case of the psychedelics.

It 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, you know, 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,

you know, 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 reachieve it and I can't.

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, you know,

are going to be there and drive this problem forever.

And I think that's what's so powerful about this.

- [Andrew] 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.

And 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.

- Yeah, I have a good friend, I won't out him

for reasons that'll 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 what 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, you know,

once somebody understands they can do it

because they've been there before,

this idea again of considering new rules, that there's...

And that brings me to this question about psychedelics

and 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 area.

Also, you know, 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 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, you know,

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

'cause it's like,

that's not particularly that good for my health

in the long term.

But if you think about it, like, you know,

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, say, 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?

You know, they hear some loud noise

and all of a sudden they're behind a car

or they're behind a, you know, I've heard of folks,

you know, jump and run behind a trashcan

or whatever in the middle of San Francisco

when they hear a loud noise.

But if you put them back in the battlefield.

- [Andrew] Highly adaptive.

- That's highly adaptive, right?

And so I think what's interesting is that we,

in the absence of using substances like psychedelics,

end up having these very persistent memories

that are attached to negatively balanced emotion,

predominantly, as you were saying earlier,

the jacket in elementary school, you know,

I 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 as a sacrament in traditions,

seem to have a therapeutic effect.

It 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 reconsolidate a memory when we bring it back up,

we always reconsolidate it.

But reconsolidating 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 an agnostic

to what tool I'm using kind of guy.

Like my business is to find treatments that help people.

And so I'm much more like pragmatic about it, you know.

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.

You know?

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

And I think that's a big question

the field's going to 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 got, you know, 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?

'Cause we know that we can block any

of the actual antidepressant effects of ketamine,

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 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 of?

And 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 effect size,

the 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,

and again, we're talking about in a clinical setting,

they take a one or two doses of MDMA.

I think the standard maps dose is 150 to 175 milligrams.

Again, doing this with a physician, et cetera,

control clinical trial, legal.

- [Nolan] Yep, 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 2/3 of people had

a clinically significant change in their PTSD.

- That's impressive.

- [Nolan] Which is impressive, right?

- And how long lasting was that?

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

- Yeah, 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 years range

for some people.

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

Psilocybin, you know, and 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?

Forever?

- 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 seemed

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, yeah, exactly.

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

it's closer to like half to 2/3 of people end up

getting better depending upon their level

of treatment resistance.

In the blinded trials it was more like 1/3 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 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 with not MDMA,

but with methamphetamine, which is known to be neurotoxic.

So it was kind of a public admittance of oops

or 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.

- [Andrew] Not Casey Halpern.

- Not, different Halpern.

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, you know,

received some NIH funding to actually, NIDA, you know,

National Institute for Drug Abuse funding

to explore individuals 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.

- [Nolan] The banned substance list.

- I have some good friends who are LDS.

- Yeah, great people.

I do as well, you know,

just a 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,

they're poly substance 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 purist

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 in 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,

you know, 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.

And 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, yeah.

- 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 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 mention that because I know a number of people talk

about serotonin depletion after taking MDMA.

He has it 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, you know, pretty neutral,

and you know, 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 that makes, 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 5HT serotonin 2C receptor?

- 2A. - 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 connection,

sort of broader areas of the brain being coactive

than would normally occur.

Maybe that explains some of the synesthesias, you know,

seeing sounds and hearing colors

and that 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, degates the thalamus.

- Degates the thalamus, right,

through the particular 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 what I'm really headed here in a few minutes is,

you know, 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.

So, 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' 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 going to 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've also looked at connectivity

and there's this kind of small world, you know,

large world connectivity that you think about.

And so, you know, small world meaning

there's kind of a much more kind of focused

kind of cortical function

or, you know, sub-cortical function or whatever it is.

And what you see is a difference

in that level of engagement of brain regions,

the connectivity, kind of global connectivity,

to your point, kind of increases.

And so, you know, it's interesting, you know,

I think to kind of have a conversion theory on this.

It's still, you know, 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've found to be really interesting is

that the anti-depressant 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 them,

negatively balanced 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, you know,

suggesting there's a convergent mechanism

and it makes sense, right?

You've kind of got

an overconnected, negatively balanced 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 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 clinicians' job under those circumstances is

of course to make sure that they're physically safe

so they don't jump out a window or try...

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, you know?

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 know, you'll entertain the full array of rules

within your head and consider them.

Or is there something more to it?

You know, 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, it's a letting go therapy.

And so, you know, exposure response prevention,

the idea is that you have to expose the individual

to something that, you know,

something that triggers an obsession

that they then want to do whatever the compulsion is, right?

And so I'll give you, you know,

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 going to 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 know,

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, you know, in some sense,

being in the psychedelic state,

and we are all taught at a level

to retain some level of control.

You know, 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, you know,

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, you know, 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, you know,

the network configuration maybe, whatever it is,

assume a state

that you've essentially been fighting the whole time.

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 in 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 balanced thoughts about yourself

in the setting of having depression

or, you know, re-experiencing a trauma memory

and allowing that to just happen

and seeing it again through a different light.

You know, 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?

- [Nolan] Exposure response prevention therapy.

- 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.

You know, psychotherapy kind of straight up,

totally sober, non psychedelic,

non anything psycho manualized,

that psychotherapy that we know works really well for OCD.

And then, you know, 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, you know,

with this 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,

you know, kind of accepting the idea

they're not going to get germs in their hands

or whatever it is, you know?

And so it's kind of part and parcel,

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.

You know, I'd step on the sidewalk cracks,

I'd walk under ladders, you know,

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, you know, 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, anyway, I mention 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 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-Asberg Depression Rating Scale,

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

That's the normal range.

And so people could 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'd always tell the medical students,

"Look, my friends that are surf instructors,

they're more like a zero on the Y bar.

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.

It doesn't sound, I mean,

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 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 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 then some folks that have to knock 100 times,

we call that OCD, you know,

and 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 discreet diagnoses.

You have them or you don't.

- It's good to know.

I actually feel some relief just hearing this,

because I am slightly...

I wouldn't say ashamed as 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 much,

knock on wood.

- [Nolan] [laughs] Nice.

- 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 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 US 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, yeah.

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 and on the west coast.

And Gabon has a group of folks, you know,

called the Bwiti.

It's a religious kind of sacramental group

that sacramentally uses iboga root bark

as part of the sacrament.

And they've been using iboga root bark for a very long time.

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

There's a whole set 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 through

and talks about this whole process.

But essentially the Gabonese have been using this

for a long time and it's a kind of an atypical psychedelic.

It's not a psychedelic that we normally think about

with psilocybin and LSD

where there are visual perceptual changes, right?

So if you take psilocybin or LSD,

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,"

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 movie where he would be able to go

and see these kind of pre crimes.

And he had this big screen where he could look at scenes

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

And so 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 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 Claudia Naranjo, a psychiatrist from Argentina,

described this for 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 Lotsof,

American guy that brought it over from Africa.

He was a polysubstance user,

used every drug that he could get his hands on,

took ibogaine,

and 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 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, you will take this,

and they'll have this reevaluation of a given memory.

And then as we were talking about earlier,

reconsolidate that memory again,

and then it seems to have, you know, an effect

of that reconsolidation process.

And so, you know, about five, four, five years ago,

I was tapped by Robert Malenka,

one of the senior neuroscientists we both know

in the university.

And he says, "Well, there's an unnamed donor

that's very interested in funding a scientific,

kind of open label study of these Navy SEALs

that have been going down to Mexico

and taking ibogaine and also 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 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 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 their experience 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 is 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,

nobody goes to a rave on ibogaine.

There's no recreation at all with this.

- 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 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 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

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 experienced something called moral injury, right?

Where maybe they accidentally blew something up

and had a kid in it or something like that.

You know, if they're in Afghanistan, Iraq,

maybe, you know, a child died on accident

or maybe a civilian died or whatever it was, right?

And they suffer these moral injuries as part of the job.

And it's almost one of the kind of vocational risks.

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

you know, which is huge, right?

And part of that is being able to see themselves

in a different light and having empathy finally

for themselves 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 the Toad,

it's the Sonoran River Toad.

I think it's like you can find these in Mexico,

find 'em in Arizona.

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 dimethyltryptamine?

- It is a 5-MeO dimethyltryptamine.

So it's a kind of a 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 to five, three,

or whatever kind of thing.

And 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

to be able to do the study

and just understand what the ibogaine was doing.

And they'd go back down a month later

and they'll do the 5-MeO-DMT.

- So two completely separate sessions.

- [Nolan] 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