Welcome to Huberman Lab Essentials,

where we revisit past episodes for the

most potent and actionable science-based

tools for mental health, physical

health, and performance.

I'm Andrew Huberman and I'm a professor

of neurobiology and opthalmology at

Stanford School of Medicine. And now for

my discussion with Dr. Nolan Williams.

Thanks for joining today. I'm really

excited to have this conversation. 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.

>> Sure.

>> I heard you say in a wonderful talk that

you gave that depression perhaps the

most debilitating condition worldwide.

Yet in contrast to other medical

conditions like cancer, we actually have

a fairly limited number of tools to

approach depression. And yet the number

of tools and the potency of those tools

is growing.

>> Depression is u the most disabling

condition worldwide. Um what's

interesting about depression is it's

both a risk factor um for other

illnesses and it makes other medical and

psychiatric illnesses worse. Right? So

recently the American Heart Association

added depression as the fourth uh major

risk factor for coronary artery disease.

Right? So alongside the the risk factors

that we know hypertension, high blood

pressure, hyper lipidmia, high

cholesterol and diabetes, you know, high

blood sugar, those three have been on

the list for a long time and depression

end up, you know, being added to the

list as the fourth one. A lot of what

we're doing in the lab actually is um 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 we can capture

that heart rate deceleration um over the

mood regulatory regions and so actually

a direct probe of that connection. We've

been very interested in a very

particular um clinical set of problems

around the 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. the field

really hasn't developed a way of um you

know consistently being able to treat

that problem and folks end up getting

the same standard oral anti-depressants

that they've been getting outpatient and

and I came to this because I've 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 brainbased problems and

really wanted to emulate that in

psychiatry and find ways to develop and

engineer new, you know, brainbased

solutions.

>> Many people out there probably think of

the relationship between the the heart

and the mind as kind of woo or kind of a

a soft biology. But here you're talking

about an actual physical connection.

>> Y what area of the brain is it?

>> You know, the first place where the

stimulation goes is called the

dorsalateral prefrontal cortex. It's

kind of the sense of control kind of

governor of the brain. And then it'll

and then what we know is that when you

use a magnet kind of what we call

Faraday's law this idea of um using a

magnetic pulse to induce uh an

electrical current in electrically

conducting substances. So in this case

brain tissue but not skull or sk sc

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 dorsal

prefrontal. And if you do that in the

actual scanner, which we can do, you can

see that that distributes down into the

anterior singulate in the insula and the

amydala and ultimately the tract goes

into something called the nucleus tract

of solitarius and ultimately into the

vagus nerve into the heart. So the the

heart uh very consistently seems to be

the end organ of the uh dorsal

prefrontal cortex 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 other folks work Martin ARS

in um in in Europe uh the Netherlands

work showing the same connections I

think it's been replicated like four or

five times where I think TMS is really

interesting. Actually, we had a lot of

patients who've told me like my my

therapist told me that I wasn't trying

hard enough in therapy. These are, you

know, moderate to pretty severe

depressed patients. And as soon as we

get them well with with the TMS

approaches, you know, kind of rapid, you

know, 5day 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. In one case, it's like the coach

telling the player what to do and in the

other case it's like a player telling

the coach what to do and you you restore

order to the game.

>> You restore order to the game and what

it looks like is depression is a bunch

of kind of spontaneous content that's

semi valitional that's being kind of

generated out of this conflict um

detection system. the singulate. In

depression, it looks like the left

dorsal lateral 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 dorsal lateral

over the singulate area and that is

correlated with treatment improvement.

So the degree in which you can re- time

or reeregulate in time the left dorsal

lateral over the singulate, the more of

an anti-depressant effect you have. 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 for this show is, you know,

we had a couple of folks um 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 5day block. By Wednesday,

they're like totally zero down on the

depression scales, you know, even better

than most people walking around, like

really no anxiety, no no depression or

anything. By Thursday, the first guy

that 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, "hm, that's

interesting, but kind of wasn't sure."

And then and then I didn't tell any, you

know, obviously any more patients about

that. And then about five over the last

couple of years when they get they were

mid early in the week by the end of the

week they're like going to the beach and

they're like totally having a 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 it's

just it's a it's an interesting

anecdote, right, that that folks when

you push them through this point of of

feeling kind of clinically well that

some people end up reporting this

additional set of features. So,

>> I want to make sure that before we dive

into ketamine and psilocybin that we do

touch on SSRI, selective serotonin

reuptake inhibitors, because we can't

really have a discussion about

depression without talking about SSRIs.

My understanding is that the SSRIs are

powerfully effective for certain forms

of obsessive obsessivempulsive disorder

and may also be effective for treatment

of depression. Is that right? And how

should we think about SSRIs? Are they

useful? Are they not useful? SSRIs

clearly work. Um, you know, many many

metaanalyses kind of proving that out,

right? That that in a subopul of

individuals, they achieve great benefit

for depression, for obsessivempulsive

disorder, for generalized anxiety

disorder, panic, you know, all these

things, you can see an improvement in

those symptoms um with what we call

SSRIs or selective serotonin reuptake

inhibitors. 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 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 brain plasticity effects,

right? There's not a deficit of

serotonin. You're not born with uh what

people call a chemical imbalance. And

psychiatry has known this. This is not

actually new information anybody, you

know, 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 to grab attention um 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 what I'll

call psychiatry 1.0, right? this kind of

idea of Freud and and psychotherapy and

its and its origins. Um, it was a lot

around, you know, the your family and

those experiences and psychotherapy kind

of going in and correcting or helping

you to figure out or, you know, show 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? 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 to the 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. The

trouble there for a patient right is

that it's telling it's sending a message

of there's something missing with me.

Whether it be my experiences I had no

control of over when I was a child or um

a chemical in my brain. What I think's

really powerful with with TMS,

um, you know, really powerful with TMS

and a level even powerful with the

psychedelic story is it's saying

something different. You know, TMS works

and there's no serotonin coming in or

out of the brain, right? And we're doing

a rapid form of TMS that works in 1 to 5

days. So, there's no there's 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 neurom modulation. Neurom

modulation is a really nice you know use

case for psychiatry 3.0 because it's a a

way to focally and directly perturb

brain regions in in whatever modality

you're using. But you know there are a

lot of a lot of groups that are actually

doing neuroiming 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 subgenial

default mode network connection that we

see is changing with our our our stand

um Stanford neurom modulation therapy

technique. It's that same set of brain

regions that that ketamine and uh

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 it's basically

electrphysiology

and it's basically kind of recalibrating

a circuit that is re-calibratable

instead of I have something missing or I

have some set of experiences early in

life that are um that are going to

forever trap me in these these

psychiatric diagnoses. And so it kind of

challenges that idea. And I think that's

what's so powerful about psychiatry 3.0.

Um this idea of focusing on the circuit

because it gets us gets us into thinking

about psychiatry and psychiatric

illnesses is something that are

recoverable. People can get better.

People, you know, we've seen with our

TMS techniques, we've seen it with 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 5 days

>> within five or less days. And in the

case of of the psychedelics within a few

days, right? So we can get people out of

these states, they're totally well.

There's no drug in their system at that

point. In the case of the psychedelics,

it was never a drug in their system in

the case of of TMS. And it and it just

tells us that that it's it's it's

fixable. It's just like an arrhythmia in

the heart. It's like a broken leg. We

can go in and do something and we can

get somebody better. Then I think what's

what's empowering and what a lot of

patients have told me is they say you

know I've gotten dep you know some

people will relapse and need more

stimulation or need more psychedelics or

whatever it is but they'll tell me 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 that's what's so

powerful about this.

>> And that brings me to this uh question

about psychedelics and and the frankly

the altered thinking and perception that

occurs in in highdose psilocybin

clinical uh sessions. Many people do

report improvements in uh 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. They will

report, for instance, a new way of

seeing the old problem. That's right.

>> And the old problem could be the voice

that they're no good. They'll never

nothing will ever work out or could be

even more subtle than that. Why do you

think the brain would ever hold on to

rules that um uh don't serve us well?

>> I think it's an it's an it's an evol

evolutionary neurobiology answer, right?

I think that we end up being a result of

of probably a lot of biology that's not

that useful in the modern era. And I

think in the brain for for say let's say

PTSD, right? A lot of a lot of veterans

come back and they experience these PTSD

symptoms and they're not at all useful

back home, right? They hear some loud

noise and all of a sudden they're behind

a car or they're behind a you know I've

heard of folks you jump and run behind a

trash can or whatever in the middle of

San Francisco when they hear a loud

noise. But if you put them back in the

battlefield,

>> highly adaptive.

>> That's highly adaptive, right? We hold

on to those things from I think an

evolutionary neurobiology standpoint.

But what seems to for whatever reason

kind of alleviate that are these um are

these substances some new like MDMA,

some that have been around for thousands

of years like psilocybin seem to have a

therapeutic effect that seems to be

pretty longlasting for these phenomenon.

And so it's 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 the anecdotes that we're

getting right are folks are coming back

and they're saying 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

and reexperienced memories and then as

you you know, you know, we we

reconsolidating it in that state for

whatever reason um may drive um drive a

therapeutic effect. My business is to

find treatments that help people. And so

I'm much more like pragmatic about it.

You know, if if this sort of thing,

which um has a lot of cultural baggage,

um but if this sort of thing ultimately

ends up being therapeutic, if we can

design trials that convince me and

others that it is, then we should

absolutely use it. And if it doesn't,

then we clearly shouldn't use it, right?

The work that's been done so far, the

first psilocybin trial, um the first

MDMA trial that's published in nature

medicine recently. Um

>> and what do those generally say? Let's

let's uh start with psilocybin and MDMA.

So MDMA appears to in in um you know one

to a few MDMA sessions have an anti-PTSD

effect that seems to be you know um

outside of the kind of um standard

assumed levels of PTSD improvement that

you can observe in individuals um with

this level of PTSD. Right? So,

>> so does that mean that um for people

that have trauma who do a and again

we're talking about in a clinical

setting they they take a one or two

doses of of MDM I think the standard

MAPS dose is 150 to 175 milligrams again

doing this with a physician etc control

clinical trial legal

>> exactly

>> they do it once or twice and broadly

speaking what percentage of people who

had trauma report feeling significant

relief from their tra trauma afterward

>> it's about twothirds of people had a had

um a clinically significant uh change in

their PTSD.

>> That's impressive. And how how

longasting was that?

>> 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 it's

pretty compelling. In contrast that with

ketamine, which only on average lasts

about a week and a half for a single

infusion. So it's a much shorter.

>> So they have to get repeated infusions

of ketamine every 10 days or so

>> for some people. or they end up getting

like like like a bunch of doses for a

couple of weeks and then for some people

that seems to last a while. Um you know

that's where I think I think the the

psilocybin story for depression and the

um in the MDMA story for PTSD seem more

interesting to me.

>> So for psilocybin what is the um rough

percentages on and this would be relief

not from trauma but from depression.

>> 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 in the

blinded trials, it was more like a third

or so of people.

>> Since you mentioned psilocybin, let's

talk a little bit about the

neurochemistry of psilocybin. What's

going on when one takes psilocybin and

um why is it interesting in light of

depression?

>> Yeah, definitely. So David Nut and Robin

Card Harris's work around neuroiming

psychedelics were kind of the some of

the first folks to do that work and um

you know 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 a an overall decrease in

the level of activity in the brain um

with psychedelics but they they've also

looked at connectivity and there's this

kind of small world you know large world

connectivity that you you think about

and So you know small world meaning

there's a lot there's kind of a much

more kind of focused kind of cortical

function or you know subcortical

function or whatever it is and uh and

what you see is a difference in that um

in that level of engagement of of brain

regions the connectivity kind of global

connectivity kind of increases and so

it's interesting you know I think to to

kind of have a convergent 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 um but it's

certainly um suggestive that there's

pretty profound changes in um in brain

activity and brain connectivity after.

And what we found to be really

interesting is the the anti-depressant

effects of psilocybin

have a particular um connectivity change

that we also see with our our TMS

approaches, right? And it's this

connectivity between the subgenial

anterior singulate and the default mode

network. And so when we do this

effective Stanford neurom modulation

therapy stimulation, we see a down

reggulation the connectivity between the

negatively valanced mood state in the

case of depressed individuals and the

self-representation of the brain. And

you see that same connectivity change

occur posts 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,

you know, kind of attached on to the

self-representation and people feel

stuck, right? And then when you when you

do whatever you do that's effective, it

it unpairs those two systems.

>> I want to ask you about Ibagane. Is it

legal in the US in terms as a clinical

tool? Who's using it and for what

purposes? Ibugane is a um is one of the

alkaloids that you can extract from a um

an ibogga tree root bark that's um

typically growing in the country of

Gabon Africa. So what uh individuals

taking ibeame will say is that open eyes

they don't see anything but closed eyes

they'll go back through and reexperience

earlier life memories and they will be

able to experience it from a place of

empathy not only for themselves but from

others and kind of a detached empathy

and being able to see this as almost a

third party even though they were there.

Ibegan is in no way a recreational

substance. You're essentially having

this what they call a life review. They

also call it 10 years of psychotherapy

in a night. So these are the terminology

that people talk about the issue.

>> How long does it last? Is it truly one

night

>> depending upon how fast you metabolize

it? Sometimes 24, sometimes 36 hours,

sometimes it can be shorter. But it is a

long time.

>> Wow.

>> It's a very long time. So it's it's

definitely the longest acting

psychedelic substance I know of. And so,

you know, we have over the last couple

of years been able to um to do this

first in human kind of full

neurobiological clinical neurocognitive

evaluation of what I is doing in this

case in in uh special operations,

special forces individuals, former Navy

Seals, former Army Rangers, that that

kind of crew of folks and look at the

pre-post changes that we um that they're

experiencing and 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 neurokcognitive

batteries so how does your executive

function work specifically how does your

verbal memory all of that and then neuro

imaging and EEG so this will be the

first human study of ibugane for those

and the reason why is because I gain

kind of the both seemingly the most

potent and most um

in and mo seemingly to me at least most

powerful um psychedelic, but the 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 electroc cardiogram

and and reduce the risk quite a bit and

that's what we we all did. But um but

but that's why people haven't really

studied it as much. Um and it's it isn't

as uh in addition there's nobody goes to

rave on ibain. There's no recreation at

all with it.

>> It's not fun. People say that it's

relieving, but it's hard work, right?

Because yeah, you're re you're

re-examining things. So then we see

these folks after and I I'll tell you,

you know, we haven't fully analyze the

data yet, but I'll tell you that from

what my folks are telling me, it's

pretty dramatic. You know, people come

back and they're doing a lot better.

Soldiers experience something called

moral injury, right? Where they maybe

they accidentally blew something up and

it had a kid in it or something like

that. you know, you know, if they're in

Afghanistan or Iraq, maybe, you know, a

child died on accident or maybe maybe,

you know, a civilian died or whatever it

was, right? And they and they suffer

these moral injuries as part of the job.

And it's almost one of the kind of, you

know, vocational risks. They come back

and say that they've they've they've um

forgiven themselves, you know, which is

which is huge, right? And and part of

that is being able to see themsel in a

different light and having empathy

finally for themsel and being able to

kind of have that experience of

forgiving. And so there's this kind of

Timothy Liry kind of socioultural

construct that ends up being overlaid

over psychedelics. And what I think is

that if you rid yourself of all of those

preconceived notions of what it is and

isn't and the counterculture movement,

all that stuff that neither of us were

ever involved in, neither of us are ever

partake in, you know, as is kind of

straight scientists looking at this,

right? If you can kind of rid yourself

of all those socioultural constructions

and then re-examine this, these if we

just discovered these today, we would

say that these sorts of drugs are a huge

breakthrough in psychiatry because they

allow for us to do a lot of the sorts of

things we've been thinking about with

with SSRIs, with psychotherapy, but kind

of combined, right? psychotherapy plus

plus plus drugs in a in a substance that

kind of allows you to reexamine these

things. And so it's it's interesting.

It'll you know there's a lot to do to

try to figure out if that's true, you

know, and and I can say that as it

stands right now, we don't know if it's

that statement is true, right? There's a

lot more work that needs to happen for

that statement to be proven to be true.

But the hypothesis is if it is true then

it's very likely that

this will be seen as a breakthrough

because it allows you to do these sorts

of things that you can't do with normal

waking consciousness.

But also why we have to really think

about this and you know these drugs

can't be recreational drugs. They really

shouldn't be recreational drugs, right?

they're really too powerful to be used

in the context of recreation because

they can put you into these states and

and the this generation of psychedelic

researchers are really clear about that.

You know, I think the ' 60s folks were

not clear about that and they they felt

like there was this whole kind of

cultural thing that was going on there.

But I think this cohort of individuals

really understands that in order to

really make this happen, we have to

understand that if you need a

prescription for an SSRI, which doesn't

change your consciousness a whole lot,

and we we're very worried about that and

the doctor has to evaluate you for that

every week, that the idea that some of

these substances would would go outside

of of very strict medical supervision is

uh is kind of preposterous, actually.

It's kind of it's kind of a a dumb

moment, I think, for for all of medicine

to say, "Look, we've, you know, if we're

going to do this right, we've got to do

it in such a way that's so protected,

that's so safe that we make sure people

know these things are not recreational,

and they're really for the pure purposes

of of really powerfully changing um

cognition for a while and letting people

have these what seem to be, you know,

relatively therapeutic states. Tell me

about Iawaska um and as a plant. Is it

useful for the same sorts of conditions

that we've talked about um thus far? And

if you could um perhaps tell me a little

bit also about the um Brazilian prisoner

study.

>> Yeah,

>> definitely. IA is another psychedelic.

It's used as a sacrament um in um in

Brazil and um in Peru and Ecuador and

Colombia. So a lot of the South American

countries and um and what they do is

they combine two plants together where

one plant of the two plant combination

would effectively do nothing but the two

plant combination together is capable of

producing this very profound psychedelic

effect. And what's really kind of

curious is that there are, as I

understand it, 10 to 20,000 plant

species in the Amazon. And somehow

somebody

>> someone tried them all

>> combined these two plants together in

certain proportionality

and cooked this for five 10 hours to the

point where you cook out the

dimethylryptamine out of one of the

plants and cook out the reversible

monoamine oxidase inhibitor out of the

other plant. It's such a way that the

reversible monoamine oxidase inhibitor

prevents the the GI breakdown of the

dimethylrypamine in such a way that it's

then allowed to cross the bloodb brain

barrier and get into the brain. And if

you didn't add the reversible monomine

oxidase inhibitor plantder derived into

this combination then it would never

cross the brain. If you put people on a

standard psychiatry prescribed

monoimmune oxidase inhibitor that wasn't

reversible, you'd throw them into

serotonin syndrome. Right? So this kind

of like sweet spot that somehow I

practitioners have found of being able

to get DMT into the brain from an oral

source with this combination of a

monomine oxidase inhibitor. It's

curious. Um and so that that substance

has been explored as an anti-depressant

agent and some studies have looked at

that. It also seems to be very safe

there. Um there was a there's a

psychiatrist down at um UCLA Harbor

who's done a lot of work with this where

um where he's looked at children even

that have been exposed to to kind of

small doses of Iawaska as is kind of a

sacrament within Amazonian tribes and

found no neurocognitive effects, no

neurocognitive effects in adults. And so

it appears to be safe. It's kind of part

and brought into various religions

including kind of merged with

Catholicism in South America which is

kind of very interesting. And so you

know in some

sects of Catholicism in Brazil it's used

as a sacrament during religious um

ceremonies. And so it became interesting

to Brazilian researchers as to whether

or not they could affect recidivism

rates for prisoners in Brazilian

prisons, right? So they gave half of the

prisoners

um you know some sort of inert substance

and half of the prisoners a um an

Iawaska session. And the the uh

recidivism rate or the return to prison

rate in the Iawaska exposed individuals

was statistically significantly lower

than the recidivism rate in the uh in

the control group. suggesting that um

you know whatever is going on there

seems to have an effect on whatever

drives criminal behavior whatever

criminal behavior that happened to be

and I don't have the the details on the

exact nature of the crime. Um you know

no I am also in no way saying that we

should just be giving psychedelics to to

to folks in prison and all of that. I

think that that that that is a very edgy

thing to do and probably not something

that anybody should try. But but it does

it does kind of bring up this this

curious question of of what is it about

that that would drive people to um to

change those behaviors and and why why

do people make those behavioral

decisions?

>> Before we wrap, I do want to give you

the opportunity to talk about the Saint

study.

>> Yeah. Saint or what we're we're calling

it S&T now. Um Stanford accelerated

intelligent neurom modulation therapy or

now what we're calling Stanford neurom

modulation therapy. The idea there is

that TMS um is a device that delivers um

that delivers a treatment and the

treatment is the protocol and the

protocol is the stimulation parameter

set in a specific brain region for a

specific condition. Whether it be

transcranial magnetic stimulation or

transcranial direct current stimulation

or deep brain stimulation like what

Casey Halpern talked about. In all of

those cases, the device itself is a

physical layer conduit of a stimulation

protocol that's therapeutic for a given

condition in a given brain region. We

decided gosh, you know, this problem I

talked about at the beginning of the

show where you have these, you know,

this problem that we we don't have a

treatment for people who are in these

high acuity psychiatric emergency

states, right? this idea that we're

going to engineer a treatment where we

can reorganize the stimulation approach

in time to be much more efficient by

utilizing something called space

learning theory. And so you you probably

know about the space learning theory. So

the idea for the for the viewers is if

I'm cramming for a test, what I do is I

write out 60 note cards and I read each

one for a minute until I get to the

first note card and again and that's

about an hour later, right? That's space

learning theory. It's this idea that you

need to see it about every hour to an

hour and a half and that optimizes

learning. What we found was is that the

old way of doing TMS, this idea of just

doing it once a day, every day, 5 days a

week for 6 weeks, didn't utilize the

space learning theory. It's like

studying for a month or two, just a

little bit once a day. Like you remember

some of that stuff, but it's like not as

potent as that week where you're kind of

cramming, right? And what we realized is

that if we could reorganize the

stimulation in times that we took the

whole six week course, we actually

figured out a way to do it in a day. And

then what we also figured out is that

people were underdosing TMS because if

you just keep going after 6 weeks out to

month three, four, five, more and more

people got better. So we figured out

it's not just one day. We're going to

give five times the normal dose. We're

going to give 7 and 1/2 months worth in

5 days using space learning theory. So

every hour

>> every hour for 10 hours

>> for 5 days

>> for 5 days. So it's a 50-hour block.

It's 90 minutes of actual stimulation

but spread out through the day in the

same way of learning. What we've found

is that folks will um will within one to

five days, you know, in in more cases

than not, depending upon if you're

looking at this open label or in trials,

somewhere between 60 and 90% of the

time, they will go into full-on

remission in the sense they're totally

normal from a mood standpoint at the end

of this. And like I said, with variable

dur durability. So that's the part we

have to figure out now about dosing and

how to keep people well. But for some

people, you know, we've had four years

of remission, you know, a year of

remission. And it's it's really that

cramming of the test. It's really that

idea that you're laying in that

information to the exact right spot. And

the the signal is a simple signal, but

it's a profound one, which is turn on,

stay on, remember to stay on. You know

that idea that you're si you're sending

this memory signal into the brain and

you're doing it in such a way that

you're telling the system you're kind of

taking it out of the hippocampus's hand

your own hippocampus' hand and you're

sending the same signal the hippocampus

normally signals out. Now you're sending

that signal into the prefrontal cortex

and kind of utilizing the brain's own

communication style to get it to get out

of this state. And what's very cool

about this is that um is that people

when they when they kind of exit out of

that, they end up um they end up saying

they don't have any any side effects

from it and they feel back to normal.

>> Thank you so much uh for taking us on

this incredible voyage through the

neurosircuitry underlying certain

aspects of depression, the coverage of

the different types of depression, the

various uh therapeutic compounds, how

they work. We've um talked about a lot

of things today and you you've shared so

much knowledge and even as I say that I

um I very much want to have you back to

talk about many other things as well

that we didn't have time to cover. But

to take the time to sit down with us and

share all this knowledge that really is

in service to mental health and and

human feeling better and in fact

avoiding often suicidal depression. It's

just incredible work and an incredible

generosity and just thank you so much.

>> Absolutely. Thank you.