So with my technology, I can create the
zombie apocalypse. I can eliminate the
desire for sleep. I can make you
voraciously aggressive. I can increase
your appetite for brains. And I can turn
off the circuits that are responsible
for the sensation of pain. Basically,
whatever you can imagine, we can do. We
can turn that on and off with a pill.
And it's already being used in China in
clinical trials. Of course, the Chinese
are beating us at everything literally.
Okay,
>> I literally have the technology to
create the zombie apocalypse. Okay, you
have to be an optimistic person that
Western civilization is going to be
around in 30 years.
>> David Nichols and Brian Roth have
carried the field of psychedelics on
their backs for decades. David Nichols
made the molecules by hand for the
earliest and most important experiments
in the field. The MDMA for the first
PTSD trials, 1.4 kg, 99.97%
pure, sold to Rick Doblin for only
$4,000. The DMT for Rick Strawman's
famous spirit molecule studies and the
psilocybin for John Hopkins experiments
where a third of healthy volunteers
called it the single most spiritually
significant experience of their life. He
published nearly 400 papers, coined the
term intacten in 1986, and founded the
Heft Institute in 1993, which has since
funded over 156 studies, including the
John Hopkins and NYU cancer trials that
dragged psychedelics back into
mainstream medicine. Brian Roth cracked
how they work under the hood. The first
atomicresolution image of LSD locked
inside a human serotonin receptor. In
2017, he founded a completely different
receptor that Salvia hijacks. He
invented Dreads, a remote control for
neurons, now running pioneer and frankly
terrifying work in over a thousand labs.
He's directed America's drug screening
program for 25 years and he holds a
$26.9 million grant from DARPA to build
the next generation of non-h
hallucinogenic psychedelics. One made
the keys, the other mapped the locks.
The universe owes these two a great
debt. And if you want to thank me for
getting them in one room, the completely
free way to do so is to subscribe to the
giant shoulder. We're only getting
started. There are no limits to what we
can do if we imagine what we want to
happen. I mean, neuroscience is really
advanced, pharmarmacology is advanced,
computer technology is really advanced.
My my son has got a home computer. He's
running molecular dynamics on it. Um, I
mean, these are things, you know, that I
you couldn't have done just a few years
ago.
>> If you have a problem in science, it's
because you lack imagination. Basically,
I tell people, dream bigger. Yeah.
Literally anything almost anything you
can imagine in my area of science we we
can do basically. Okay. I I don't have
any doubt. Let me just give you a sense
Evan of where some technologies are that
you don't know about. Okay.
>> Please.
>> So
>> David Nichols, Brian Roth, a huge
welcome back. I'm so so excited and it's
an honor and pleasure to be able to have
you together. It's going to be great.
I'm really excited.
>> I hope it's as good as the uh as the
buildup.
>> For the for the listeners who may have
missed our first conversations firstly,
I would I would fully recommend that
they go watch them after this. But would
you each mind giving some of the most
important context toward your scientific
contributions, your scientific mission,
what you've accomplished throughout your
career? Maybe we can start with David.
>> You want me to summarize that? Um well I
was a distinguished professor uh at
Purdue University for 38 years. A named
professor a distinguished professor in
both medicinal chemistry and also
professor of uh pharmarmacology and I
supervised students in both chemistry
and pharmarmacology.
Um I was continu continuously funded by
an nimh grants for my years at Purdue. I
had grants to study dopamine agonists
and also psychedelics and also for a
while ecstasy
published around close to 400 papers and
some book chapters. Um I started the
Heafter Research Institute to uh recruit
um a philanthropist to fund clinical
studies of psychedelics. It started at
93. We raised about $10 million. So the
earliest clinical studies of
psychedelics that most people would be
aware of in 2011 2016 were funded by the
Heftter Research Institute and also um
there were no chemists who were willing
to make controlled substances for
psychedelic studies. So I made the uh
more than a kilogram of highly pureed
MDMA for Rick Dalin's maps for their
phase one and two clinical studies. uh
made uh DMT, a couple batches of DMT for
Rick Stman and he published a book and v
video called DMT the spirit molecule and
also made a couple of batches of
psilocybin for research at Johns Hopkins
University and also that psilocybin was
used in their 2016 study of uh dying
patients in existential distress. So
basically um I had a fairly large
research group not as large as what
Brian's got but large enough and we did
a lot of interesting work and really
pushed especially pushed the field of
psychedelics forward a lot. Um there
were very few people who could give a
seminar on psychedelics and I was one of
the few. So I often gave seminars in the
early years about psychedelics and I
would go to medical schools and the
audience would just be packed and the
host would come up and say, "Wow, I've
never seen so many people at this
seminar." Because there were a lot of
people who are just dying to know
information about psychedelics. It was
all mostly underground. So to have a
professor from Purdue come in and talk
about it and have funding from a
government agency was somewhat unusual
in those days.
That's probably I go somewhere I can
give in a short time.
>> It's a remarkable contribution. Amazing.
>> Well, let me add that when I retired in
2012, Brian Roth, we were at a meeting
and he says, "You're retiring. How can
you retire? Why don't you come and do a
sobatic on my lab and I wasn't had no
plans I was going to retire?" And so
when I retired, I moved to Chapel Hill.
indeed accepted a sbatical visiting
professor position in Brian's lab and
continued my work for a couple years. So
I was very grateful to be able to do
that instead of having to fully retire.
So I should add that as as an end note.
>> Brian, you want to kick off?
>> Oh yeah. Yeah. Are you in a hotel room
or is that a background a fake
background there?
This is this is my this is my hotel room
in Malaysia at the moment where I'm
staying. This is just my this is my full
apartment. You can see right now.
>> Okay.
>> All right.
>> Um so I'm Brian Roth. Uh I've been so um
you know as I mentioned before uh I was
you know interested in psychedelics and
psychoactive drugs
uh since my misspent youth. and um sort
of fell into the field of serotonin
receptors completely by accident
um in
I guess 1983
uh when I was doing a posttock with
Armeniocasta
and um at the time there was just this
there was this unusual serotonin
receptor it's called the 5HT2 receptor
When I started studying it, there wasn't
really a whole hell of a lot known about
it, but it was um it had it had some
unusual properties as a as a receptor
that that Costa thought was interesting.
Um and I didn't I didn't mention this
before, but um
it's sort of funny. uh my my project
when I entered his lab at the NIH was to
identify the endogenous peptide for the
5HT2A receptor, what what's now known as
the 5HT2A, what was then the 5HT2
receptor
because he didn't believe that serotonin
was the ligan for that receptor.
Um the there I won't get into any of the
details of it, but but Dave will
appreciate this. So uh SSRIs which
elevate level of serotonin does not
downregulate the receptor if you leion
serotonin neurons you don't upregulate
the receptor but if you give you know a
mouse or a rat either LSD or cloopene
socloine is a is an atypical
antiscychotic drug that um basically
blocks the effects of LSD in humans if
you give either of those drugs you
downregulate the receptor. So you had
this very bizarre thing where uh this
receptor, you know, has these uh really
paradoxical
um actions of pharmacologic
agents. And so he said study that
basically. And uh so I spent uh a couple
years in the cold room trying to isolate
the endogenous peptide for the 5HT2A
receptor. And uh at the end of two
years, I told him it was serotonin.
There was no peptide. And then he
started yelling at me, screaming. And uh
Dave will appreciate this. He he was
Italian, had a very thick Italian
accent, and he would start
justiciculating, and then Spittle would
come out, and my whole forehead and face
was sort of spattered with his
So in uh in trying to find the quote
unquote peptide for this receptor,
I developed uh bioassays and biochemical
assays because there you know there
wasn't nothing really nothing known
about it. And so uh I sort of
co-discovered how it uh uh mediates a
signal and you know published a lot of
stuff on that. Um and uh around that
time basically Richard Lennon
uh discovered you know provided the
first data uh real good pharmacologic
data that the uh effects of psychedelics
at least the ones he tested
uh were correlated very well with their
ability to bind to the 5HT2 receptor
5H22A.
Um and then uh work by Herb Meltzer
uh really implicated uh blocking the
5HT2A for treating schizophrenia.
So um as I mentioned my my interest in
going into all of this was for
schizophrenia
and along the way you know maybe to
understand how psychoactive drugs work.
Um so so basically by a complete cosmic
accident I ended up studying the
receptor that was you know is
responsible for both
um and uh you know that's what I've been
studying you know I when I when I
entered Costa's lab
uh his uh he had uh a humongous lab he
had 50 postocs he had two floors of a
building at the NIH and he had a number
of lieutenants and his chief lieutenant
was this guy Darwin Cheney. And I
remember Darwin told me he said, "If you
spend a year in Costa's lab, you'll have
enough to study for the next 20 years."
And that was that was basically true. I
mean, he told me to study this receptor.
We didn't know anything about it. We
still don't know a lot about it, but we
know more. Uh, and it turns out it's
it's, you know, key for psychedelic drug
action. And so, um, that's what I study
basically. So, and I has published, you
know, a lot of papers on it, some of
which I I think have stood the test of
time. We'll see.
I want to share a really embarrassing
story. So, I was working with this
company to build a really awesome
science product and we were using AI to
summarize the entirety of the available
literature and a hallucination crept its
way into the work. It was presented to
me confidently. It sort of fit the
narrative and everything just seemed
right about it. But of course, as you
might guess, it was a complete
fabrication. It actually cost me
thousands of dollars, completely blew up
in my face, and has made me terrified of
hallucinations. And honestly, it's
changed the way I think about AI and
science. That is why for every Giant
Shoulder episode, I use long-term
sponsor of the channel Consensus.
Consensus searches 220 million
peer-reviewed papers. first, then uses
AI to synthesize the results. Every
claim links to a real verifiable study.
It's the difference between asking an AI
to remember science from memory, which
is where hallucinations creep in, and
actually get it to verify from first
principles that that is actually what
was said. I'm personally obsessed with
the deep search function because it
presents consensus across the whole
literature, not just one confidently
stated perspective. Where studies agree,
where they conflict, where the gaps are,
even how the research has evolved over
time. It flags studies for this episode
that I just simply would not have found
without it. Lately, they introduced an
MCP integration with Claude, and this
has exploded my research workflow. It
basically means the two systems can talk
to each other. I put my podcast
transcripts into Claude and it contacts
Consensus and pulls a full list of
verified citations and papers from the
conversation. The way that I've started
thinking about it is that Consensus is
like Claude's direct supervisor. It
makes sure it actually does its damn job
and isn't just slacking off and being
lazy. The two working together is where
you unlock insane research capabilities.
The link is in the description. You can
access a full month completely free. It
supports the channel. consensus are
awesome. Again, that is link in the
description completely free for a month.
So, you have really no reason not to try
it out. Now, back to the episode. It is
very hard to overstate how much impact
you two have had on the psychedelic
field in the last few decades. It is
>> Let me let me just tell you Dave Dave
has had even more impact than he he's
mentioning. Okay.
So Dave was also a grant reviewer
and uh I run this thing called the
psychoactive drug screening program uh
which I run now for more than 25 years
and uh
you know it may be that that it's Dave
is responsible for me having that and uh
uh if I didn't have that there would be
a lot of knowledge that we wouldn't know
basically you know it's it's been
Uh so Dave has had you know as a
reviewer and of grants and papers
really a huge impact on the field. Uh my
sense of Dave as a person is he's not
you know a lot of scientists are sort of
vindictive and petty. Dave is not that
way.
Um he's always encouraging and kind. Um
so he his influence goes way beyond
what what you're what you're imagining.
Um the only thing you know Dave Dave let
me just say a couple words about Dave.
Dave mentioned that he would give talks
on psychedelics.
So what Dave didn't mention is nobody
else gave talks on psychedelics because
if you use the word psychedelic
in a grant you would not get funded.
It was like it was like DEI is now you
know it was a forbidden word and uh I I
use the word hallucinogen all the time.
Um
and it's only recently that you know in
the last 5 years that I sort of come out
of a closet said yeah I actually study
psychedelics I don't study hallucin
>> only in the last five years really.
>> Yeah
>> yeah you know it's
>> Abe can say probably more about that. We
we tried to rehabilitate the word when
we started the heft institute in 1993
and this is a while back. Um we were
going to call we were going to say we're
going to study the effects clinical
effects etc of psychedelics and we had
some pretty big names in the field who
said no you don't you don't use that
word it's a it's a bad word don't call
them psychedelics call them psychotamics
call them lucian and I insisted no we're
going to call them psychedelics and we
always have and all the work that we've
supported we supported a lot of
publications if you go to our website
www.f ftra.org we got a list of all the
publications we've supported and there
are tens and tens of them and they all
deal with psychedelics. So we really I
think got to the point well I wrote a
review on a subject in 2004 was called
hallucinogens
and then um this one of the associate
editors uh wrote me and asked me to
write a review on psychedelics. He even
spell you spelled it wrong. He said
psychedelics. I thought yes I can write
a review in a mainstream science article
in a journal mainstream journal about
psychedelics.
So that article has been cited thousands
of times. So I think the word
psychedelic has been pretty much
rehabilitated. Nobody's afraid. Brian's
not afraid to talk about it anymore. I
don't think I'm certainly not afraid to
talk about it. But you couldn't even use
that word. It was like, "Oh, you're
hippies. You're hanging out with the
tie-dyed,
you know, Lery folks and all." So we
made a special effort to kind of
rehabilitate even the terminology.
That's just completely wild to me, you
know? Like, of course, I've never
studied the substances, but I've just
never used any other word. That's the
only word there ever has been in my
lexicon for it. Um, so to hear that
there is such a taboo and it was
actually such a practical restriction
and blocker towards great scientists get
money getting money on a label seems so
silly.
>> I am. The problem the problem is the
funding agencies like NAIDA they didn't
want to give any impression that
psychedelics had any value. So
psychotamimetic says oh that implies
they produce a psychosis. Hallucinogen
implies that they produce
hallucinations. They do neither of those
things. Psychedelic the meaning as you
know is mind manifesting. That's a
positive term. So government agencies
who have tried to control these didn't
want people to call them psychedelics
because they indicated they had some
positive value and now of course we know
they have tremendous positive value. All
these clinical studies been done in
depression and substance use. I mean
they basically have validated the ideas
that they they really have value.
>> I'd love to talk about your recent
collaboration paper. It seems like you
published almost a master analysis of
psychedelics and its receptors.
318 receptors, 41 psychedelics. First
off, I didn't know that there were 41
psychedelics or 318 receptors. Just to
start off,
>> talk about that analysis. What motivated
it? What were the big findings?
>> Yeah, go ahead, brain. Dave was the uh
uh
sort of person who chose all the all the
compounds. Uh
so I'll let him talk about that first.
Um but but the goal it
it basically uh
was uh I would say my goal to understand
the pharmacology of these compounds. you
know we knew that they had this very
complex uh polypharmacologic uh activity
and uh it's clear uh when you talk to
people who have taken some of these more
exotic substances the bioxy DMP or DMT
itself
that the experience quite a bit
different from
the experience with psilocybin LSD
measculine or iawasa
Um and uh so the question is you know
does this is this because of the route
of administration some people make that
argument that
um by oxygen and BNT have this effect
because they're injected or insflated
or uh there's something about
the targets that they interact with in
the brain the molecular target
And um
and there was a previous uh sort of
attempt at this by Tom Ray
uh in the '9s. I don't know what the
exact date this was. I think in the 90s
uh where uh he had he had actually
worked with Dave and I to collect a a
group of psychedelics
and then to screen them against uh this
panel of receptors that I had through
the PDSP
and uh he published this work. goes
published at POS one fairly highly
excited but what I told him is I told
him not to not to publish it because the
data wasn't it was just screening data
we had never actually replicated any of
the findings
and and in fact I knew a lot of the data
was wrong in the paper that was that was
the big thing
uh
and but despite that he published it and
I think he even wrote a book about it
and has a company now or something. Um,
and so a lot actually a lot of my
motivation was just sort of cleaning up
the literature because there are all
these you know there was there's this
literature that DMT is selective for the
sigma receptor. You know that's complete
nonsense. Uh it it has the same affinity
for the sigma receptors all the
psychedelics and is low. It there's
nothing particularly astounding about
that. So there were a lot of these
things that I basically knew were
incorrect. Um and you know my my goal
was just to you know do the best job
possible
so that people could rely on the data
and just publish it. Um
so it was just a simple you know a
simple idea. Uh but Dave, you know, the
key was actually Dave
because I some of these more exotic
exotic things, you know, that we tested.
I, you know, I I had I'd read the name
before, but I didn't really know
anything about them. So, so he was
really the key person who were choosing
uh the drugs. And in terms of the the
318 receptors
and other things, those were just
technologies my lab developed
uh which are very useful for basically
screening uh small molecules. Um so we
just use technology that was in the lab.
Um
so what what's your sense of that?
Yeah,
Brian minimizes the importance of what
he's doing, I think. But u it's true
that we we really don't know how
psychedelics work. Yeah, they activate
the serotonin 2A receptor,
but some of them hit other receptors,
alpha receptors and so forth. We don't
know for each one. So when you have all
these labs doing little studies where
they measure the affinity or activity of
one molecule or two molecules, then
somebody else measures them in a
different essay and somebody else
measures them in a different essay. you
don't really have a consistent database.
And so what Brian did was say, let's
take all the ones, they're mostly
psychedelics, but there's some that are
non-csychedelic because they had some
minor structural change. Put them all
in, generate this big database of data.
And I'm still convinced that that will
be useful for many people, especially
now that they're starting to look at
other drugs that could be used other
than the classic psychedelics. So we
have a whole database of what these
molecules which inter which which
receptors they interact with which
signaling pathways they activate. So
it's a database that should be useful
for many people and when it's all done
in one laboratory like that you can
trust the comparisons because they're
all done by the same people in the same
way and the same assays. So that was
important to to actually get a database
of really the standard data for all the
molecules that we know of that are
psychedelic and some non-csychedelic in
an attempt to figure out you know if
this psychedelic has a different effect
than this other psychedelic is it
because it's also activating say alpha
receptors or dopamine receptors. So
that's a very useful database and that's
one of the things that we emphasized I
think at the end of that article and now
there's this big database that should be
useful for the whole community of
researchers who are working in this
field.
So I know uh
>> that you know all the pharmaceut well
the pharmaceutical companies I know
about have all download data basically
um and are using it um
but it's you know it's it can be really
helpful for things like uh you know
there's this speculation that fivethoxy
DMT has this unusual effect because of
some special activity at the 5HT1A
receptor.
Well, you can easily go in and compare
it to all the others and yeah, it's it's
a little more potent, but it it it's
it's like doesn't really jump out at you
that that that that is the key to the
whole, you know, human phenomenology of
it. Um, so, you know, when you dig into
it there there are a lot of, you know, a
lot of very interesting things. Um, and
uh, you know, it's been it's being
highly cited. So, uh,
you know, it's going to get probably a
hundred citations of or more than that,
which is, you know, the typical paper
doesn't ever get cited. So,
so this is this is going to have, you
know, it's going to be very highly
cited. So, hopefully people read it. Uh,
I know they're citing it. I don't I
don't even know if they read it.
>> Their their claw or chat GBT is
definitely reading it.
>> Yeah.
>> Yeah.
>> Talk about because could when you say
something like 5 Mod DMT, it activates
the 5HT
2A receptor. It activates all of its
other receptors. What does the analysis
actually look like when you're trying to
figure out, okay, how much of the
experience, the physiological effect,
the behavioral change, how much of that
effect is responsible or caused by each
of the receptors? How is that sort of
analysis done? And are you able to do
that kind of analysis in an accurate
way? You can get a breakdown of the
receptor and its influence on the
overall effect that a drug is having.
So it's basically the database is a
hypothesis generator and a hypothesis
tester.
So if you have let's say your hypothesis
is that DMT is different from all other
psychedelics
because of its preferentially high uh
potency for the 5HT1A receptor. Okay.
So one thing you can do very easily is
you can compare its ability to activate
the 1A versus the 2A
and do that comparison for all
psychedelics.
And you know what you'll find actually
is
you know LSD is a pretty good one
agonist
compared to 2A.
So yeah, it's, you know, if you compare
it to psilocybin, that's true. DMT, it's
less true.
Uh, when you get into some of the other
compounds, not so much. Um, but then
there are other targets that it hits.
Okay.
So, there are these, you know, these
really
unusual serotonin receptors that nobody
really knows anything about. the 5HT1E,
the 5HT5A, the 5HT6, the 5HT7,
etc. Uh, and then, you know, some of
these psychedelics activate what we call
orphan receptors, which are receptors we
don't even know what they do.
And so when you see this profile
basically of all these receptors that it
activates then if you're a systematic
scientist what you can do is you can say
well let's go in and test these one by
one
and uh you know you can test them in
animals uh if you have some readout of
fibroxybt activity
or since there you know it turns out
that there are approved drugs for many
of these receptors
uh you know you could design a clinical
study and just test test the hypothesis.
So it basically lays the groundwork for
sort of a more systematic and informed
study of these compounds
uh is the way I look at it.
>> Do you know what percentage of receptors
are orphan receptors?
>> About 50%.
>> Wow. Interesting.
>> Yeah,
>> that's worth restating. We don't know
what 50% of is that is that brainwide or
this is this is psychedelic targets. So
50% of the psychedelic targets we just
simply do not know what they do. Well,
it's less it's less than 50% of the
psychedelic targets, but uh 50% at least
50% of the gene protein coupled
receptors in the human genome are or
orphan receptors and even the ones that
are not orphaned uh you know if you do
and I've done this before sort of uh an
analysis of the scientific knowledge
about every receptor uh what you'll find
is there are some receptors like the
5HT2A for example, thousands of papers
published on them. And then there are
other receptors like the 5HT1E that I
mentioned and you know maybe a dozen
papers basically nobody studies it. We
don't really know what it does. Uh but
it you know same with the 5HG5 and six
and seven you know these unusual
receptors.
Um and then you know when you when you
dig into even a receptor that we know
about or that we think we know about the
5HT2C receptor
uh probably important for attenuate so I
think it's probably important for
attenuating the activity of psychedelics
um sort of makes the psychedelic
experience more tolerable uh than than
complete 2A activity. Um, the 5HT2C
receptor has 24 different
uh variants,
protein variants,
and there's very little information on
these. We don't we don't really know
how they're expressed in the brain as
pro in terms of protein. We don't know
anything about their protein expression,
where they're where they're located,
uh, and so on. So
it's it's basically a black box with
respect to psychedelics. You know, we
know that they activate the 5HT2A
receptor. That's clear. We know the
pathways they activate. They cause
plasticity, but that's just, you know,
that's just the very
the dust on the surface basically,
>> right?
>> Fast. It's like the first snowflakes
on the top of Mount Everest. Okay.
That's what we know. So, we know
something, but we don't really know that
much. Um, and you know, I play, you
know, I place the blame for this, the
federal government, because they
disallowed, you know, they wouldn't let
us study it basically, of course. And
so, now we have this situation where
these drugs are going to be approved. We
should have, you know, thousands of
papers published on their basic biology.
And you know it's like this handful of
papers from people like me and Dave and
then you know over the past few years
there have been more but it's it's it's
a terrible situation
>> right
>> um you know uh
you know just just our paper you know
the pharmarmacology this is something
that if this was a cancer drug for
instance
uh so it's been routine for drugs that
are being tested for cancer to screen a
very early stage against every kynise in
the human kynote. Okay.
And
you know for CNS drugs it's just we have
the capacity basically to do the same
thing for receptors but it's just not
done. Uh and it's you know it's even
worse for psychedelics.
uh you know and you know so
this is a societal problem. I'm not
going to preach anymore though.
>> No, I think you're right.
>> Please Dave the
Nixon's drug war was a terrible tragedy
and nobody really realized it. There was
no so there was no funding for research
in this field. I was lucky. I had a
grant from NAIDA for most of my time at
Purdue, but uh no one else was working
in the field. And NIDA was only
interested in find out why people use
them. There was no no indication. You
couldn't write a grant and talk about
therapeutic indication because it
wouldn't go anywhere or they're not good
for anything. Only the hippies are using
them, whatever. It's terrible tragedy in
in psychopharmarmacology. And it's only
recently when we start to see that you
can really in people who are having
existential distress facing death, you
can really give them quality of life
back. People who have been addicted to
substances and haven't been able to get
off. These drugs can be useful in
getting them off. Uh and a whole variety
of other things, obsessivecompulsive
disorder, eating disorders, things we
haven't really had. You know, psychiatry
is probably the most conservative branch
of medicine. Haven't had new drugs. And
here's this whole pallet of new
potential therapeutics that was stifled
because Nixon didn't want the hippies to
vote, you know, and uh I mean, basically
that's the reason.
>> Yeah, it's wild.
>> You know, his uh his administrative
assistant said, you know, we knew, what
was his name? Bill something. He said,
we knew we we knew we couldn't take away
their right to vote. I mean, to keep
from voting. They were protesting the
Vietnam War. He said if we if we could
catch them with drugs that were illegal
and then put them in jail, they would
lose their right to vote. So that was a
strategy to keep them from voting
because of their protest against this
the illegal Vietnam War.
>> Fortunately, I was
fortunately I was an iconoclast so I
wasn't deterred by my father had been
kind of anti he was a real prick as far
as he's gone now. I can say that but uh
I rebelled against him and then any form
of control like psychedelics were the
perfect thing for me to work on because
you weren't supposed to work on them and
I was convinced they had value and of
course they do have value we know that
now and of course Brian spent
significant resources in figuring out
how they work and looking at the
receptors and that was all valuable too
that would been very difficult to do 20
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interviewed top scientists who study
psychedelics, sensory deprivation, lucid
dreaming, and they all say a similar
thing that these kinds of states of
consciousness can be achieved by trained
meditation. Now, while I've always been
skeptical of this claim, it's just been
repeated again and again by the top
scientists, people who I really trust.
So, I had to try this myself. But the
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Now, the device is definitely not for
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>> Yeah. Um, you know, it's interesting
thinking back on this. Um, as I as I
think I may have mentioned to Evan, I I
mention this typically when I when I get
interviewed, but I, you know, I forget
each interview. Um, I didn't really
think they'd be therapeutic for anything
to be quite honest with you. Um, so
there were, you know, Dave Dave and I
have known each other for a long time
and I I consider him a real close
personal friend. And let me just say at
this stage, I'm sorry I missed your
party last week, Dave. Um, but I have a
really I have a really good excuse.
And then let me tell you the excuse now
in front of, you know, how many
thousands of people are going to
>> I really wasn't expecting this.
>> So there was this big party for Dave
last week and
>> my invite must have been must have been
lost in the mail, Dave. I guess it's
probably still on the way to Malaysia.
Is it probably still? So Dave can tell
you about this, but I want to give give
my apology first. Um, so I didn't get my
I didn't find out about it until
literally two days beforehand. Okay. So
if there was an invite sent to me,
it was never sent. And so the guy,
whoever the guy is, I forget his name,
contacted me and said, you know, a bunch
of luminaries are going to be there,
etc. And I said, you know, it turns out
that I I was scheduled to give a talk at
UCSF the exact same day on psychedelics.
So I gave a talk on the psychedelic
synapse, Dave. Uh and uh I mentioned you
the acknowledgements,
but I I really wanted to go to that, but
I didn't find out about it until
literally two days beforehand. So,
>> well, the theater was sold out. They
sold every ticket.
>> Oh, really? Wow. Wow. Wow. Wow.
>> At the Aluminina Theater.
>> Yeah.
>> They sold 140 tickets.
It turns out there's this organization
in Asheville, North Carolina called the
Pearl Institute, and they plan to use
psychedelics in therapy. The guy that's
in charge is a doctoral degree in
clinical psychology. and they're used in
ketamine right now, but they were
planned to use MDMA until it was
torpedoed by this group called Symposia.
And now um when psilocybin is approved
and MDMA is ultimately approved, he will
probably use them. Well, he found out
through local connections that I was
here and I I was planning on spending my
retirement making Native American
flutes, which I play as a hobby. and all
of a sudden, you know, oh, I started
working in Brian's lab that kept me in
the lab for a while until I had a heart
attack heart attack in 2019. And then uh
giving seminars, I'm still writing some
papers. I'm still doing a little bit of
that work. But um I just I was caught
off guard and then they they found out
about me. I went to Ashel. They had a
big celebration there. had me get I was
the plenary speaker and then they had
this movie theater they rented and there
was a tribute to Dr. Nichols and they
had this video interview of me that they
showed on the screen. It was a Q&A
afterward. So I mean I'm just kind of
>> I think I think they invited Rick
Doblin. Right. So tell
>> Dublin came there. Right.
>> Yeah. Rick Doblin and Bob Jesse came out
from California. Yeah. I'm just I'm I'm
not really much of a self agrandizing
person. I feel kind of strange when
people were honoring me for stuff. I
mean, I know I did all this. I kept the
field kind of alive for a while, but uh
it still feels kind of strange.
>> Well, it's been an honor to tell both of
your stories and we've got and both both
episodes are getting tens of thousands
of views. Brian's up to up to over 60
now. David, you're well on the way. Like
the stories are incredible and that's
why I had to have you together. To be
honest, when I when I invited you
together, I actually didn't know that
you were close friends or even at the
time that you had collaborated. That
came up in research and I was like, "Oh,
that's that's convenient. That's
interesting." And I didn't know that
we'd be talk we'd be talking about
missing each other's parties a week ago
in the different social situations. But
let me I'm curious about this. to show
you. So the Heft Research Foundation, I
got an award from the Heft Foundation uh
in the in the 1990s for outstanding uh
basic science research and then I used
the reward money to purchase the first
computer that is the database that we
run. Um and so we have this we have this
database uh which gets you know a mill
couple million hits a year. So, um, the
Heft Foundation, you know, initially
paid for that, too. So, it's, you know,
the long reach, uh, when the when the
history of the psychedelic, uh, so I
I've told Dave and, um, Mark Guyire,
uh, that they both need to write
personal histories.
>> Yes. Um because this is
this is one of those uh things in human
history that's going to have a huge
effect
uh going forward. For better or worse,
you know, I don't know. I'm not going
to, you know, time will tell.
Um but the Heafter Research Foundation
actually was key. I mean, Dave is really
minimizing that, but they were way ahead
of the curve.
And you know, as Ding said, there would
not have been compound for the clinical
trials if somebody hadn't synthesized it
under, you know, appropriate conditions.
And actually, the the LSD that we use
for our structural studies, Dave made uh
because it's better than commercial LSD.
It just sounded better physical chemical
properties.
when I retired from Purdue um and I was
at a meeting with Brian and he said how
can you retire he said why don't you
come and do an it's like a sobatical in
my lab and so when I was retiring from
Purdue I had this bottle of lysurgic
acid and I didn't want to throw it away
if it's a controlled subst you're
supposed to dispose or transfer so I
transferred it to Brian's lab I'd kind
of forgotten about for a while he came
in one day and he said we want to do a
structure on LSD can you make LSD D for
us. I said, um, let's see, my screen's
super hit. Okay. He said, can you make
LSD? And I says, well, you remember that
bottled lysurgic acid I transferred
down? He said, yeah. I says, we can make
it. So, I made LSD and we had a thing
called a chromaticron that we used to
purify, got super pure stuff, made the
tart trade salt. So, that was that was a
great pleasure for me to be able to make
LSD for the Brian Roth. That was
>> Yeah, those those are that's that's
Dave's LSB and those structures.
>> What do you think makes you such a good
chemist, Dave? What do you think it is
about your unique skill sets that make
you so good at at at these pure
concentrations, these big batches?
>> Well, chemistry was always my Bailey
Wick. Um, I had a chemistry lab when I
was a kid. I had a really complete
chemistry lab. I I mo mostly made
explosives and pyro techniques.
So I told people
>> there's got to be a story there.
>> I told pe I tell people that
psychedelics are pyrochnics for the
mind. So I've always made pyro
techniques.
>> So one of the one of the I'll just tell
you a little bit about Dave as a
chemist. One of the
all good chemists are obsessivempulsive.
>> Sounds about right. [ __ ] you, Brian.
[ __ ] you.
No, in a good way. In a good way.
>> I'm obsessed with saying
>> it helps actually a lot.
Um so you know Dave as I say
there there were you know when we were
when I was sort of growing up in the
field there were other people in the
field uh uh most of whom have retired by
now um but they weren't all kind like
Dave let me just put it that way. Okay.
And there was a period back then, I mean
Dave will remember this when Steve
Grudka
and uh Milt Titler were arguing about
whether there were subtypes of the 5HT2A
receptor.
And you know it got they were going for
blood basically. They were both trying
to destroy each other's career. You know
it was
it could get it could get pretty hot and
heavy. And um
you know I I've seen reviewer you know I
I won't say who it is but
um
uh somebody who is who now is in
pharmaceuticals at Gilgamesh
who used to be a famous
electrphysiologist who knows this person
I'm not going to say his name but you
know I saw his grants destroyed
by
competitors.
Okay.
So to have somebody at Dave's level that
is at least supportive of of others
getting in the field was extremely
important actually and I I wouldn't
minimize that day. It it played a huge
you know as I say without you I there
would be no Roth lab basically um and a
lot of other labs as well uh you know so
uh it
those other things have actually had a
huge effect
>> tend to be somewhat negative viewer um
sadly but uh Dave you know Dave's
positive
>> yeah I I always tried to move especially
well I helped anybody but especially
with psychedelics I tried to move the
field forward you know after I made the
MDMA for Rick Dobin I still he only
needed 250 grand so I still had 3/4 of a
kilo in my safe and people would find
out you know that I had it and send me
their DEA forms and I'd send to them I
donated I said just send me the form and
I'll ship it to you. So a lot of the
research with MDMA was done with MDMA
that I made um psilocybin I mean I had I
spent a lot of time with the drug
compounds for you.
>> Yeah and
>> Yep.
>> So I was pretty open about you know if
you need it yeah send me a form I'll get
it back to you. I just always wanted to
help people. People would call and say
you know how do you think you know can I
get this compound for this clinical
study? What do you think about it? and I
would tell him everything that I that I
knew that could help him. So, a lot of
people along the way, you know, I really
tried because I wanted the field to move
forward and I was convinced it was an
important it was important subject that
had been, you know, overlooked and in
fact just abused. So, I did everything I
could, you know, the Heft Institute that
was 1993. is because nobody was funding
clinical studies and I thought we
thought we could go to the Silicon
Valley Bros and get money because they'd
all taken psychedelics.
They want to keep their money. We tried
really hard. We got one guy early on who
was one of the one of the early founders
of Microsoft, Bob Wallace. He ultimately
he died unfortunately but he gave us
about a hundred thousand a year for
several years and we used a lot of that
for doing you know basic stuff given
awards to people in the field like Brian
who had made significant contributions
and you know things like that. So yeah,
I tried to do any anything I could to
move this field forward. And I never
thought a woman asked me some years ago,
probably back in 2010, something like
that. She says, "Where do you see the
field of psychedelics going?" And that
was before any of this was big now. I
says, 'Well, in my opinion, someday,
probably long after I'm dead, you'll be
having a midlife crisis and your uh
personal physician will send you down
the corner to see a psychiatrist/shaman.
He'll give you a session with a
psychedelic, and you'll get your
perspective and your life back. She do
you think he'll be dead by then? I said,
probably, but the vector will be
pointing, it's pointing in the right
direction.
This has really surprised me how fast
this has taken off now. Yeah, you can go
to you can go to Oregon right now, Dave,
and and get your, you know, existential
crisis fixed right now.
>> Yeah.
>> No, I'll if you want to go, I'll I'll
chip in.
>> I'm ready.
>> We can make this happen on on a
recording. Let's Let's do it. I I think
that would be enormously educational and
great for everyone. I'm ready to have an
existential breakthrough with you, Dave.
>> I'm almost hit again.
>> If I get a terminal diagnosis, Brian,
I'll be getting in touch with you. Okay.
All right.
>> You even helped me last week. You
introduced me to Rick himself and I had
a great conversation with Rick Doblin
last week and that was through your
intro introduction. So, you're still
helping people and you just helped me
last week. Um, Rick is fascinating. like
what a wild story he has and his impact
on on psychedelics and trying to push
through phase three clinical trials and
the the heartbreak with the FDA um you
know decision and everything like going
back to Harvard at 40 to get like he's
he is some he has some wild story as
well you know he's he's certainly up
>> I'm interested in listening to that
because I've never I've actually never
heard his story he tells about little
bits of bits of it so that that'd be
very interesting. Yeah. You know, I I
met Rick Doblin at Esland. They had a
big conference there for everyone
involved in psychedelics, and I was kind
of the only academic they could find.
The rest of them were all related to Tim
Liry and people like that. But Rick
Goblin was there. He was still a student
at New College.
You know, New College has been destroyed
by the Trump administration. Um, it was
an it was a college where you could go
and basically create your own degree.
And I think he has a degree in
psychedelic studies. Anyway, I met him
at Esin and he was a ble young guy full
of, you know, full of piss and vinegar.
And I said, Rick, nobody's going to take
you seriously if you don't go back to
school and get a PhD or an MD or
something. I don't know whether it was
my encouragement for him to go back and
get a degree or not, but I did counsel
him. And then when he was trying to
start MAPS, I thought he's never going
to be able to do this. and he was
telling me the story, you know, we want
to make it couple's therapy and da da da
because he' taken a lot of MDMA and and
I've taken that's an interesting
molecule. So he he uh we kind of
connected and then um I thought he was
okay guy a little you know kind of full
of I don't know what but anyway um so
then he wanted to start MAPS and he
found out he needed to get pre-clinical
toxicology and he needed MDMA and he
checked with all the people that he knew
that were connected to manufacturers etc
custom synthesis and nobody would do it
for less than $100,000.
and he didn't have quite that much
money. You can imagine he was a young
college student. So he called me at
Purdue and he says, "Can you make MTMA?"
I said, "Sure, I can make it." And uh I
said, "How much do you need?" He says,
"I think probably a kilogram." And so I
added up the price of everything. I
charged him $4,000, which was the price
of the chemicals that we actually had to
buy. And I didn't Purdue didn't know I
did, so they didn't get any overhead or
anything like that. And all my grad
students helped. We cleaned off this one
bench, scrubbed it down with ethyl
alcohol, cleaned all the equipment, made
it real nice and clean and made the
stuff, made the free base and it was had
a slight impurity, vacuum distilled it,
had a slight impurity, vacuum distilled
it again until it was like super pure
and everything. We used all these USB
solvents, put it in USP ethanol and USP
ethylacetate and everything was done
with the, you know, certified solvents
and chemicals. We made 1.4 4 kg and it
cost Rick $4,000.
And you can't buy 1.4 kg of ecstasy for
$4,000.
>> Not in Dublin city anyway where I went.
That's the only place I know the rates.
Not in a chance.
>> Even black market chemists won't sell it
to you for that price. So yeah, so that
got he used all he used that for his
phase one and two studies. When he gets
to phase three, you have to use it made
from a GMP facility. So he had to get I
I can't remember how much but it was
like $500,000 he ended up having to pay
for it something like that. So but
without that you know the initial MDMMA
he wouldn't have been able to start his
whole procedure. So, and you know the
the psilocybin that I made for John's
Hopkins. The first batch I made was for
normals, it was published in 2006. I
think they gave normal people psilocybin
and Bob uh Jesse funded that and Rowan
Griffith supervised it and these were
just normal individuals and they after
the experience they said it was among
the five most spiritually significant
events in their entire lives. So that
was like wow. And that surprised Roland
Griffith because he had no idea that a
psychedelic experience could have such a
profound effect. And so then he got
ready to do the bigger study that he
published in 2016 and I made 20 grand
with psilocybin for him then. So we
figured out some of the best ways to
make psilocybin. Now you can make it.
There's a better way to make it now uh
that's more direct but you know no one
was willing to make it back then. You
couldn't buy it from any custom chemical
supplier without paying a whole lot of
money.
>> Yeah. Were a lot of these your chemical
procedures like you had figured out the
step by step the exact solvents
>> the were for the psilocybin. We had to
figure that out when they got ready to
make the MDMA. I was a good friend of
Sasha Shogun's and it turns out that um
he made MDMA for a lot of people as you
probably know. Um and he had a method uh
using a dissolving aluminum reduction.
If you mix this starting ketone with
methylamine hydrochloride I think and
you just cut up squares of aluminum foil
it leeches the aluminum foil and
generates hydrogen and does it reductive
amination. We actually used that worked
really well. We got good yields. So that
step Sasha gave me because he'd been
making it for his friends and colleagues
in the Bay Area. So we actually used
that procedure because we used aluminum
foil. The FDA made us analyze for
residual aluminum contamination. But
after we vacuum distilled it twice,
there was no aluminum in there. But we
had to do all the we have benchmarks to
show that it didn't have any, you know,
unexpected contaminants. But it was
99.97%
pure. I think something like
unbelievable.
We made the chemicals we made in my lab
that we donated to people. We there we
said their purity was UFP. And everybody
go UFP? What's that mean? Ultra [ __ ]
pure. So
that was that was that was that was a
saying in my group, you know, they made
something and I I said, "Is it pure?"
And they said, "Yeah, it's UFP grade."
So it was kind of a joke in the lab.
Surely people have called you the real
life Walter White, have they?
>> Uh, once. Once. I'm shocked you didn't
get that more cuz that's like most
people's idea of like a drug dealer now
is is him and being a great chemist, 99%
purity, washing down all of his things,
really strict with procedure. I mean, it
seems perfect.
>> Yeah. Well, Walter Wise is just he's
just a chemist basically.
>> Yeah. doesn't. He follows standard
chemical procedure.
>> Yeah. I I would never have made
methamphetamine that had a blue color.
That was a copper contaminant in his
MDMA or in his whatever it was he was
making. I saw that. I'm watching going,
"Oh, hell. That was his trademark making
a blue compound. That means it was
contaminated with copper."
You're probably one of like three people
in the entire world that would think
that maybe even or maybe the one.
>> So guys, where does the field need to
go? Like we beautiful I think retellings
of of the story there and I love hearing
about about the past and everything. I
find it so fascinating. But in your view
like where is it heading now? What needs
to happen? I if both of you were put in
charge of a research institute with
basically bottomless funding and I mean
like bottomless funding like where are
you distributing those funds tomorrow?
>> Yeah. So um we're sort of headed to the
wild west right now.
Um,
so you know, with the current
administration,
uh, you know, it's likely that
methylone, I think methylone and
psilocybin are probably going to be the
first to be approved.
Uh, my guess is late this year or next
year probably.
Um,
>> what's methylone? Sorry, I haven't heard
>> methylone is just it's an MDMA. It's an
MDMA analog. Uh it it has so if you go
to our paper,
we profile it in our paper. Um so it's
it has some differences from MDMA. It's
a little more dopamineergic,
a little more dopamine uh releasing
activity. Uh and it lacks uh 5HT2B.
So 5HT2B is sort of this uh bad
receptor. uh so drugs that bind to it
can cause valvular heart disease if
they're taken for long long periods of
time. So methylone doesn't hit the 2B
but it's it's a little more dopamineeric
but
basically
uh you know it's like MDMA and uh so it
was it was given priority along with two
psilocybin studies. Uh so I I suspect
those are the first two that will be
approved. Um here here's my concern.
Okay. I I you know I'm convinced based
on the clinical trials and
uh my discussion with with people who I
know who have
you know who have had severe depression
or PTSD whose life have you know been
transformed with psychedelics
although not usually with a single dose.
I'll just put put that out there. Um
particularly for PTSD.
Um,
so you know, I I'm convinced they have,
you know, this this therapeutic
activity.
I'm not I'm not entirely convinced that
it's going to be lifelong miraculous
recovery. I mean, we'll see.
Um, but the problem is we don't have
enough data in normal humans that has
been uh done under appropriate
circumstances.
So we know for instance that the
classical psychedelics can cause this
thing called a lucen persisting
perceptual disorder or HPPPD
and and I you know because of my work
day they probably as well I've been
contacted with people that have this and
it's you know it's maddening to them uh
to have these visual distortions
continuously
after they took LSD once basically.
Um, and it's probably pretty rare, but
you know, we don't because we don't have
any baseline data on, you know, tens of
thousands of humans like they normally
would for a drug that's going to be
approved.
You know, we don't know what the
instance of of that side effect. We
don't know, you know, if you have a
family history of mania or
schizophrenia, we know you shouldn't we
we encourage people not to take
psychedelics.
But we don't know under what
circumstances they might be safe.
Co- administration with SSRIs
probably safe, but you know, that's
information we should already have. We
just don't know.
Um, you know, sex uh differences based
on sex and ethnicity, all those things
that we would have normally for a drug
which is, you know, ready to be
approved. and
millions or billions of people may be
taking it. We just, you know, because
the federal government refused to allow
us to study these compounds,
we simply we don't know how they work
and we really don't know when they're
out there in clinical practice how safe
they're going to be. I mean, this is
this is to me is a big concern.
Uh so that that's that's how I see it. I
mean we're going to get more of these
you know uh there are companies now that
are trying to make designer psychoactive
compounds based on the you know specific
pharmacologies to have you know induce
specific therapeutic effects or
different mind states. So all that is
going to happen at some time in the
future.
Um but we really need to study these
compounds in normal people.
Uh which we don't we don't have that
data and it's going to cause us problems
uh going forward.
>> Dave,
>> we also I think don't know the
fundamental mechanism of action. We can
say they activate the serotone 2A
receptor. We still don't know where it
is. We know some of the things it does.
But what's the difference between a drug
that's very similar? Two drugs are very
similar. one of which produces
psychedelic effects and the other which
doesn't. Normally you could compare
those two and you could see what are
they doing in the neurons in terms of
signaling and we really don't know what
the key signaling events are for a
psychedelic you know
>> and I'll just I'll disagree with Dave
there
>> okay
>> and say actually I know
and um
it turns out in a slice Dave
um that drugs that are not psychedelic
do not activate the human serotonin
receptor in the slice. Uh so Brmo LSD
liceride don't do it.
Yes.
Um, and
this is sort of a technical thing, but
um,
people that are running their assays,
there's too much receptor reserve there
in virtually every assay by every group.
Um, even people with this is only
something that we discovered very
recently.
Um
so uh the reason that in our hands the
reason that drugs like bromo LSD leride
etc are not psychedelic they just don't
activate the receptor enough that that's
basically it. Um it seems like a simple
explanation to me. I mean we'll see if
that turns out to be the truth but
that's that's my sense of the way things
are happening. The ancillary
pharmarmacology
may have some role but not not so much.
I mean that's that's what we're seeing.
>> What's the receptor signal in your
opinion? Just
>> GQ.
>> It's just GQ.
>> Yeah, that's it. That's that's basic. So
you should come to lab meeting
uh if you can
uh the next time we're we're going to
have it in I think
Thursday of this week or something. And
I can show you the data. I mean, we just
have we have a ton of unpublished
convergent data from multiple sources.
Um, and it seems like that's basically
it. You know, one of the one of the
problems with this field uh which is
what you see a lot in in fields that are
emerging and becoming uh popular is
there's a lot of stuff that's published
that is just completely wrong.
>> Oh yeah.
>> Uh it's just 100% wrong.
uh it gets published in a high impact
journal and then uh people feel like and
it it basically contradicts what's been
out there for 20 years and uh and then
people say well there's this controversy
in the field and it turns out that the
the paper's just wrong. is just
completely wrong. And you know, I could
you chapter and verse on so many of
these that are out there, but there
right now we're in we're in an area
we're in a part a history of the field
where a lot of people are trying to make
names for themselves and become famous.
uh I'll ascribe I'll ascribe ulterior
motives to them rather than they want to
get to the truth which is what
scientists do. We want to find the
truth. they want to become famous and so
it's a it's an area in which you can
become famous if you publish something
outlandish
um like co you know
uh back in the co era you know people
were were saying you know you can cure
covid with ivormectin of course it's
complete malarkey
but um you know people became famous and
there still is you know there there is
quote unquote controversy
about this, right? So, we're in this
it's the same sort of thing where
they're we're getting these
these reports by people
who
are not very careful at what they do.
And so, I don't think a lot of these are
going to uh pass the test of time. But
but my sense is things are actually in
some ways more simple than than people
are letting on. But what we're finding
is underneath this there's this huge
universe of other signaling proteins.
So I'll just give you a hint at this.
It's what I talked about at UCSF.
So we we've uh we've developed this
technology uh where we can identify uh
basically all the proteins
uh at the syninnapse in the brain. So
the synapses where uh chemical
communication takes place where
psychedelics have their action.
So, we've identified hundreds of
proteins that are in close proximity to
the 5HT2A receptor
uh including dozens that are responsible
for synaptic plasticity and things like
this. Um the other thing we found is I
had a genetics uh colleague of mine uh
go over the data
and uh more than a third of the proteins
that are in proximity to the 5HT2A
receptor you know the site of action of
LSD and antiscychotic drug
are bonafide genetic risk factors for
psychiatric disease.
>> Okay. So you have this
now we're having converging signals. So
now this this explains how how it can be
that a drug like LSD may be effective
for all these neuroscychiatric diseases.
It turns out it's talking to all the
proteins that are responsible for the
diseases. Okay, they're in proximities
and a lot of them have to do with
synaptic plasticity and uh synaptic
transmission.
Uh and it also can explain how it is
that uh uh you know some people don't
have a particularly good outcome when
they take psych
you know they might go psychotic it's
rare but it goes down.
So so that's my sense Dave uh it's you
know the signaling is it's simple it's
just magnitude of signaling that's it we
can
pretty much classify everything
correctly. Um, and then it's just, you
know, uh, if it's too much EQ
signalings, any psychedelic experience,
and they're fool, you don't and you may
still get it. And it's just it's sort of
like um the D2 agonist schizophrenia,
you know, Eric Piperol and those. So
Dave knows um uh years ago Arvin
Carlson, the guy who got the Nobel Prize
for dopamine, uh believed you could make
dopamine agonist to treat schizophrenia.
And he made one, but it made people work
because it was too too effective of a
dopamine agonist.
And then Otuka Pharmaceuticals uh you
know eventually made a drug called
Aeraprizol which essentially
revolutionized how we treat
schizophrenia basically partial agonist
and since then uh you know there have
been maybe a dozen of these D2 partial
agonists that have been approved for
treatia very effective and it's all
because they hit this sweet spot of of
partial agonism
and you know my sense is probably going
to be the exact same thing with psycho.
We don't we don't know where that is.
You know, you need the right assay
system because uh receptor reserve
really screws things up and use the
right right readout. But once you have
that, it's fairly clear. Just mic.
Could you explain GQ signaling really
quick for the listener because I think
this this is quite fundamental to
understanding psychedelics. Maybe it's
it's worth explaining this a bit.
>> Yeah. Oh, D2 D2 is is this refers to
dopamine receptors.
So, dopamine is another neurotransmitter
in the brain. Um, drugs like amphetamine
increase the amount of dopamine.
Uh, drugs that are antiscychotic block
the effects of dopamine. basically
um and you know it's been known since
the 70s that that if you have a drug
that blocks dopamine receptors it it it
will be effective antiscychotic drug
and and the idea that Arvin Carlson had
was um you know maybe we can activate
them to a certain extent
and uh if we use a partial agonist this
this is sort of like giving an antake
you a third level of antagonism.
And uh
and so so the idea was rather than
making dopamine antagonists which have
lots and lots of side effects
uh we can make dopamine agonists and the
initial ones didn't work because they're
too much too a too much agonist
activity. um and now they all work. And
so what I'm saying is it might be the
same thing with the psychedelics that
um there's sort of a threshold of
activity uh that we need uh for the
therapeutic action
and a thresh threshold that we need for
the psychedelic action. Okay. And what
I'm suggesting is those two thresholds
may be distinct
uh and and that we can target a drug to
that lower threshold or attenuate uh you
know attenuate that activity. That's
that's my sense. I mean we'll see you
know we'll see if if if
uh if things go. But what I was saying
to Dave is that um most people and I,
you know, I consult regularly for
biotech and pharma, so I have a pretty
good idea of what's going on. Uh most
people, most people, most labs,
companies, etc., uh express the receptor
at way too high of a level and they
don't use the fight.
uh and because of this not getting a
good sense of the relative activity of
their compound
and and so what we that if we use the
most physiologic relevant one which
would be looking at your ponal firing
in the brain okay
so we use a brain slice
um drugs that are not psychedelic will
not activate that nerve at all in our
Whereas every drug which in our hands is
psychedelic does
and um so you need you need to basically
be measuring that pathway
and you have to know what that pathway
is and it's it's a complicated pathway.
It deals with uh you know oscorrelation
of ion channels and depletion of pip 2
and
uncy
of gasing channels and so on it's it's
fairly
but but once you know and then you have
an idea of how how to throw compound
um and
you know it looks like
you know that's as true as any right
now.
>> Right.
>> So, so what I'm saying is it's it's
really not that clearly. It just depends
on how how how good they are at
activating the receptor. They're really
good. You're going to have a psychedelic
experience. If they're not, you're not
in the story. It seems simple to me. So,
we'll see. That's my guess. We'll see if
it turns out true.
I think didn't John McCory co-publish a
paper where they talked about you need a
certain level of GQ activation.
>> Yeah. Yeah. Yeah. It's just they get the
wrong assays, but the idea is is
correct.
Uh and there's a little backstory to
that. I saw the initial draft of his
paper and told him that we were
convinced it's a threshold and he should
By then I was convinced it was a
threshold and I I basically told people
who were reviewing his paper to have him
emphasize that aspect.
Dave, I'm very curious to hear your
perspective on Brian's research program
to develop these non-h hallucinogenic
psychedelics. We discussed it in our in
our call. I know you're you're somewhat
agnostic about if you think they'll
work, you think it's a it's a worthy
research venture regardless. But I'm
curious, Dave, what's your what's your
opinion next?
So, this idea of a non- psychedelic
psychedelic, um, what I've told people
is if you have a non-sych a quote
non-csyched psychedelic and someone's
got a major depressive disorder that's
been intractable, you can give them
that. They don't need to experience it.
Just like an SSRI except it's more
efficacious.
But my opinion is if you're approaching
death
or if you have a substance use disorder,
um especially if you're approaching
death and you're in an existential
crisis, just giving that person a pill,
they can give them any anxiety drugs now
and it it's not it doesn't take care of
it. Um, if you give them a psychedelic,
they basically have a life review and
they look at their relationships with
their family, with other people, and you
know, I've seen videos of these people
that have been given a psychedelic that
were terminal cancer patients, and it
gave them a quality of life that just
was so much better than what they had.
One fellow who I saw, he had been
estranged from his younger brother for
10 years and under the effect of the
psychedelic, he realized he was dying.
He says, "I realized recon connections
with my family were really important
emotionally." And he called his brother
and said, you know, please, we need to
get together. You've been apart too
long. So these kinds of um cognitive
awakenings if you will for people
especially people that are approaching
deaf is you can't give them a pill to
give that and I think the same thing is
true for many types of substance abuse.
I heard the talk by a guy who was
alcohol use disorder. He lived with his
parents. He was the late 20s and uh
didn't have a job and he gave he was
treated with m by moaches in New York
University and he said you know under
the effect of the drug and the therapy I
realized that my life was I was just
wasting my life basically and he said I
quit drinking he said it used to be
every time I went someplace I'd go to a
new city and I'd walk around the block
to see where the bars were because I had
to have drinks pretty much whenever I
wanted a drink. He says, "And after this
treatment and my parents said like,
what's happened to you? You're not
drinking anymore. You're looking for a
job." So, it really changed his
perspective. And I think for some
conditions, you need that maybe eating
disorders as well. You know, people
don't know what causes how to treat it.
There's no good treat eating disorders.
It's mostly strikes young women. But a
pill may not may not solve that. but
something that gives them insight into
why they have this, why they're eating,
and look at themselves, look at their
body image. I think there's a cognitive
component for many of these conditions
that you won't get just with a
non-csychedelic pill.
That's just my opinion.
>> Would you agree or disagree with any of
that, Brian?
>> Oh, I agree 100% uh uh with Dave. Uh let
let me just tell you uh my motivation
for this for the project.
Um and Dave was actually involved with
this. I think Dave sat on most of the
meetings
uh and may have actually had some ideas
on chemical design for some of the
compounds.
>> Well, hasn't Dave impacted? That's one
thing I'm taking away from this. There's
pretty much nothing that David hasn't
impacted. So,
>> Dave was Dave was involved with that
project. Um, so
you know the project came to me from
DARPA basically. So DARPA contacted me
uh because they had seen me give a talk
and I had mentioned basically that there
were these you know signaling pathways
and you know maybe we could make a drug
for one versus the other and it might be
therapeutic. That was it. It was
basically a throwaway line in a talk I
gave and so they contacted me and um you
know they were keen to study it for you
know obvious reasons.
And uh you know what I basically told
everybody is I'm basically agnostic. You
know I you know it's what I say is it's
a hypothesis worth testing. Uh we need
to test the hypothesis and we need to do
it right.
And I think you know we strove to do
that and hopefully our compounds will
soon be in humans and we'll find out. Um
but so that was my main motivation.
Basically DARPA said you know they're
interested. They promised a lot of money
which they followed through on and we
were able to do you know just a ton of
really interesting science and
um but the other the other motivation
was this uh so I'm a psychiatrist uh by
training uh although I don't practice
anymore but um you know in the course of
of of seeing psychiat of seeing patients
I used to tell my wife it was like an
unending stream of human suffering
coming through my door every day. Okay?
I would see at least 20 patients a day.
Uh most of whom,
you know,
I would prescribe medication for and it
might help a little bit. Um
but the problem is that we have uh you
know what how many billion people in the
world? Let's say four billion just or
number uh one billion of those people
are going to have depression at some
point in their life.
And uh you know they're not they're not
all going to be eligible for
psychedelics. They're not going to have
psychedelics uh etc.
But if we had a medication that worked
50% as well as psilocyum
that was safe and effective, I would
take that as a win. Okay? So, I'm very
practical-minded. If I can, you know,
I'm not out out there to cure every
human being in the universe, but if I
can help 20% of the depressed patients,
you know, that's that's a big number.
And you know that would be a huge huge
benefit. Uh
>> yes.
>> So that's you know that's my motivation
and um I think there's some promise
there. you know, we'll see.
Honestly, you don't know till we do the
studies which are going to be very
expensive to do, right?
But um you know it is a hypo we need to
multiple groups need to test this
hypothesis once and for all uh with the
right molecule see if we can you know if
there's any therapeutic benefit from a
non-csychedelic 5HT2A agonist and then
we'll know basically
uh and we can move on. But right now,
you know, I mean, you could you could
fill a whole hour with two people
arguing, right, about the benefit of the
trip, right?
And they would give you chapter and
verse on both sides. But with the fact
is we don't know. And and actually it's
it's a test it's a testable hypothesis.
So I say just do the experiment and then
we'll find out.
>> Yeah.
100% I agree fully. There seemed to be a
nuance that was lacking in so many
people commenting on that video being
like the trip is required. The trip is
needed. The trip is needed. Like I
needed the trip, but they couldn't
really hold it in mind that maybe they
did need the trip, but it still would
help somebody else that didn't want the
trip. I know people in my life, as you
say, that don't that just don't want the
trip. They don't want they're they're
they're worried about it
psychologically. They don't want it, but
they might try the non-trip version. So
absolutely we should do the science if
it's funded by the government. Hell
yeah.
>> Or what if they're bipolar? If they're
>> right
>> if susceptible to mania, you don't want
to give them a psychedelic under any
circumstance.
>> Yeah, for sure.
>> Yeah.
>> So what are the what's the timeline on
something like that look like? Do you
have big are there trials lined up? How
do you plan this? What what are the
pre-experiments that need to be ran?
>> Yeah. So Dellex Pharmaceuticals I think
is in the US is probably the farthest
along.
Um and they had some
sort of somebody asked me about the
results the other day. They had some
phase one results or phase two results
and I said me
m
apostrophe eh me was my comment on their
on their results. Not so encouraging.
Um, but they're going to probably go on
to phase two and you know we the thing
is we're not going to know until phase
three. Okay. And the phase three trials
are going to cost at least 150 million
bucks as a minimum. And whether you know
whether Delix was ever going to raise
that kind of money, I you know I don't
know. Um but you know and then we have
compounds there are other other
compounds percolating up.
they're going to go. But the ones that
are probably farthest along are in
China.
So I have a former posttock that you
might want to interview. He has an
amazing story to tell uh and some
amazing videos actually. Uh his name is
Shang Wang WG
and he's published extensively on this.
One of one of my most brilliant postocs
I've ever had. Just astounding.
But uh I heard that he has positive
phase 2 results in China on his
compounds.
They're called IHC.
So they're are non-csychedelic 5HT2A
agonists.
And um
that that's what I heard. But but I
don't know for sure. I know they they at
least have been in phase two. Um,
I've looked at those compounds, Dave,
and they're so weak, partial agonist,
they're basically antagonists
if you use the right assay. Um, and and
so they will have some anti-depressant
activity because 5HT2A antagonists are
anti-depressant. We already know that,
but they're not going to be very good
anti-depressants,
uh, is my guess.
Um but but his are are pretty far along
and um you know if you wanted to do
something about that probably probably
he'd be the guy to talk to. Um
and I I don't know of any else. Do you
know of any else Dave? I mean there are
other other company. I don't know if
anybody has any No, I I'm
work for 2A biosciences and we have a 2
agonist that doesn't appear to produce
any animal behavioral effects like a
psychedelic. It is a two agonist and
we're using it we're developing it for
neurotropic keratitis. It's for an eye
diseases if people that are diabetic
they lose their retinal cells and uh the
pre-clinical trials are promising. So
we're getting ready the dose is very low
though we're getting ready to go to a
phase 2a uh sometime in the near future.
So that's a non-csychedelic as far as we
know, at least in the animal models, but
it does activate the 2A receptor, but
it's extremely potent in treating this
eye condition. The doses are 0.00003%
topically.
>> So that's another possibility. These
things do have anti-inflammatory effects
at very low concentrations that are
subbehavioral.
At what point are they kind of just not
psychedelics anymore?
Like what what does it what does it
still need to maintain in its
pharmacological profile
for it to still fit in that label
appropriately or is it just a new drug
at that point?
>> Well, the structure we have activates
the serotonin 2a receptor. Um it's not
particularly potent, but it does
activate it and doesn't activate any
others. and uh the the proximity we
proxim uh the proxy we've used is a
mouse head twitch and it doesn't produce
that. So that's kind of the basis but
the concentrations that would be applied
topically are so low that you wouldn't
even if it was a psychedelic it wouldn't
give you enough concentration to produce
a psychedelic effect.
>> Yeah. I think I think from a a legal
perspective, from the DEA's perspective,
uh they make that decision at phase one.
So at phase one, you'll be giving doses
to normal humans typically.
And if the drug has a psychedelic action
in humans, if they report a psychedelic
effect, then then they will be
interested in it as a psychedelic.
So it's it's from a regulatory
perspective and a legal perspective,
it's not until you get that phase one
data
that it is considered potentially a
psychedelic. Okay?
You need to have the human data.
So even Dave's compound
um
you know in mice it's not psychedelic
but we really don't know until we give
it to a person.
>> Yeah.
>> Then we'll know.
>> Yeah. This head twitch model has always
seemed a little strange to me. I mean
you guys are obviously the experts here.
Mice models in general for these things
have always just seemed quite dubious.
like is that really a good proxy for
having a psychedelic trip that the
mouse's head is is is is twitching? I
mean, is that a reliable model?
>> Well, so I let me give you my
perspective and then Dave, so I've
actually thought about this a lot
recently. So, um, it's a it's a test for
it's an assay for testing drugs. Okay,
first off, it is not I don't consider
assay of psychedelic drug action. It
turns out uh there are no false
positives as far as I know for this
assay. Okay. Or or no false ne I'm
sorry, no false negatives. So there's no
drug as far as I know there is no drug
that causes an LSD like experience in
humans
that does not cause a head twitch
response in a mouse. Okay?
So if your drug does not cause a head
twitch response,
it will as far as we know will not be
psychedelic in a human. So I use it for
that purpose. That's the only reason I
use it basically is to predict. It's
it's actually very good at predicting as
far as we know. As I said, there are no
no exceptions to that.
And the way I look at it is um
so this may be something that your
listeners can uh resonate with.
Artificial intelligence
relies on what are called neural
networks. Neural network computing.
Okay.
And uh the problem with neural networks
is they give you the answer which is
correct but you don't know how the
answer was derived. Okay. And so the
mouse literally the mouse head twitch
response is a neural network. Okay. That
is giving us a response this drug is
psychedelic. We don't know why that is
at all,
but is it it is actually an extremely
reliable predictor. Okay.
So, um that's what I use it for. Uh you
know, it will predict if your drug is
positive or I'm sorry, if your drug is
negative, as far as we know, it's not
going to be a psychedelic in humans. End
of story. If it's positive, it may or
may not be psychedelic. you still have
to test it, but if it's negative, as far
as we know, it's not going to be
psychedelic to humans.
>> Okay.
>> So, that that that makes it a useful
test.
>> It's more reliable than I would have
guessed.
>> Yeah. It makes it useful for drug
discovery.
It does not make it useful for
understanding how psychedelic drugs
work.
>> Yes.
>> Okay.
>> Dave, do you have any finishing thoughts
on that? Yeah, we've we've used as as a
proxy for human activity. We have a big
library of compounds and we've screened
most of them and the ones that produce
this mouse head twitch, we set them off
to the side say they're probably going
to be psychedelic in man. So,
we'll see with this one we're
developing. Um, of course, the
concentrations are so low that we will
use topically. It probably wouldn't give
enough exposure in the CNS to produce an
effect in any case. But anyway,
at least by that measure, it's not
psychedelic.
>> Do you envision a world where people get
their own unique receptor distribution
scanned and then that kind of goes into
the the LLM, goes into the DAI, drug
discovery machine, and bam, output, is
my perfect psychedelic for my perfect
receptor distribution. Is is this
science fiction or is this something
that that is is very feasible?
>> I think it I think it's probably science
fiction at the present day.
>> Talking about designing a personalized
psychedelic. I mean, we have to know a
whole lot more about how psychedelics
work and their offtarget effects and
everything to be able to design a drug
like that.
>> Yeah. It's I know I was asked this. So I
was interviewed
last week by somebody from the Atlantic
monthly and they basically had the same
question
uh sort of couched a different way
and uh you know what I said is yeah
we're you know I said right now we can
design compounds that ostensibly will
have different psychological effects
basically
and because we know we're understanding
the pharmarmacology in in greater
detail. We have more gran we know we
have more granularity on how how we
might go about designing compounds. So I
said you know it's no stretch of the
imagination that in 30 years we will
have compounds that are tuned for either
a specific experience or a specific
aspect of a therapeutic utility. I said,
you know, assuming there's a world in 30
years,
that's a big caveat. Assuming Western
civilization still exists and science,
>> how dare I how dare I assume such a
thing?
>> Then I said, "Yes, you know, we can do
it. You know, if you have money, we
could start now." basically. Um, and
there are some companies that are that
are trying to do this. Uh, but the the
the thing you you brought up um
the reason Dave said no is uh designing
a drug just for you that would be a new
chemical entity. Okay.
And there's all sorts of safety
pharmarmacology
uh we need to have before we could have
you take that drug.
Okay? Unless you know the possibility is
that in 30 years uh and I don't think
this is too much of a stretch
that uh you know we would have enough uh
information
where we could you know predict with a
high degree of certainty what the
physical chemical properties of the drug
are going to be the distribution the on
and offtarget pharmacology and so we
might be able to do that like they do on
Star Trek you know I I you know I
measured your brain
uh using my fancy machine and my other
fancy machine is going to spit out a
pill. Yeah. Uh you know, if the world
exists in 30 years and we're progressing
at the rate we are now, yes, it is
certainly doable. Okay. I have I have a
a close friend of mine who was just
hired by Sam Alman.
You know who Sam Alultman is? Yeah, he's
been in the news a bit in the in the
last Yeah.
>> So, this guy is a really really smart,
super smart guy from Caltech
and he's basically been given an
unlimited budget to make the mind
machine interface.
Okay? And he will do it. Okay? It's
going to happen.
uh provided we don't you know provided
we live for five provided there's the
world in five years you know I would say
that's that's a bigger
gamble
>> greater uncertainty
>> there's other stuff we're talking about
you know my sense is if civilization
continues then yes all this stuff is
I see as as certainly uh not science
fiction but with within the realm of
possibility.
But you know, you have to be an
optimistic person that Western
civilization is going to be around in 30
years.
>> You haven't been sounding very confident
of that in the last 10 minutes. I'm not
remotely sure that you believe that.
>> I don't I am very worried actually.
Do you want to I'd love to hear one
finishing prediction from either of you.
This has been such a fun conversation.
Really is. I I'd love to hear about
anything that you think about the future
of psychedelics, the future of drug
discovery, how AI will interact. You
know, I'm speaking to the president of
Isomorphic Labs next week. They just a2
billion dollar spin out out of Deep
Mind. I am I don't know if they have the
most money in the world right now for
drug discovery, but if they're not the
most, it's probably
>> Here's the thing. Two billion is lot not
a lot of money in drug discovery.
>> They'll they're going to find that out
really soon.
>> Wild.
>> Um but
uh you know, I'll make I'll make
predictions first. Uh
you know, basically whatever you can
imagine we can do. What I tell people is
you know if you have a problem in
science it's because you lack
imagination basically. I tell people
dream bigger. Um
and I mean yeah literally anything
almost anything you can imagine
in in my area of science we we can do
basically. Okay. I I don't have any
doubt. It's just a it's just a matter of
money and time. Okay. With sufficient
resources, yes, any anything you can
imagine, you know, other than going
through a wormhole, you know, things
that that that
violate basic laws of physics as we
understand it.
Um, so I don't I don't really see any
limits. I I see limits in imagination.
Okay,
Dave.
Yeah, I mean the way things have been
speeding up and going if you look at you
know AI was nowhere what a few years ago
um even in receptor structure you know
when Brian started doing receptor
structures he was using X-ray
crystalallography and now cryeleron
microscopy is much faster and is
improving every day and getting better
resolution I don't know the technology
there are no limits to what we can do if
we imagine what we want to happen. I
mean, neuroscience is really advanced,
pharmarmacology is advanced, computer
technology is really advanced. Man, my
son has got a home computer. He's
running molecular dynamics on it. Um, I
mean, these are things, you know, that I
you couldn't have done just a few years
ago.
>> Let me Yeah, let me let me just give you
a sense, Evan, of where some
technologies are that you don't know
about.
>> Okay.
>> Please. So there's a technology I
invented called chemogenetics. And
basically what it allows you to do
ultimately
is if you understand the neural
circuitry that's responsible for a
particular
um condition,
we now have the technology where we can
turn that on and off with a pill. Okay?
And uh uh it's already being used in
China in clinical trials. Of course, the
Chinese are beating us at everything.
Um but it allow you know so basically
one of the areas that we're headed for
is uh circuitrybased therapeutics. So
not a pill anymore.
Um and there are a lot of these
technologies that are moving along and
when we have the mind machine interface
it'll make things a lot easier.
So, um
there there's a lot more out there
that that you don't know about.
Basically,
>> um that the the applications are truly
mindblowing.
Um one of the
when I talk about this technology, one
of the things that I warn people about,
so we have the technology I'll just I'll
just give you an example. So uh I can
eliminate the desire for sleep.
I can I can make you voraciously
uh aggressive.
I can uh increase your appetite for
brains
and I can uh turn off the circuits that
are responsible for the sensation of
pain. Okay.
So with my technology, I can create the
zombie apocalypse literally.
>> Okay,
>> I literally have the technology to
create the zombie apocalypse. Okay, it
exists. Okay,
or I could create uh
saintly people like Dave. Everybody
could be like Dave.
They could have a smile.
Uh they could be kind.
Okay. So, we have technology actually to
do that now. Okay.
Um or or I can induce a false memory in
you. Okay. I can create memories and
then turn them on and turn them off at
will.
I can create sensations and turn them on
and turn them off at will. Okay. So,
this is where the technology is going.
Um, so pills, you know, in 30 years
there may not be pills anymore.
Uh, you might, you know, the the AI will
have figured everything out and have um
interfered or uh made made an adjustment
in neural firing so that nothing
happens.
That that's my guess of where we're
headed.
>> Have you seen the new horror movie
Colony? Korean horror movie.
>> Which one is it?
>> Colony.
>> Colony. What is it about? Is it about
the zombie apocalypse?
>> Yeah, pretty much. A mad biotech sort of
um leader
created this virus that creates like
this. They were trying to make links
with like slime collective intelligences
where he infects the zombies and then
the zombies are all a collective
intelligence so they can communicate via
like electrochemical signaling in the
air or something. and they don't really
fully explain it. It's quite good, but
it's sort of it's interesting. It sort
of does lay out what you what you
described. And now I'm kind of picturing
you as the evil man in that movie. Gent,
it's been so much fun. Thank you so
much. This has been an awesome
conversation. Truly an honor to host you
both. Brian, we need to have another
two-hour conversation on all the ways
you're going to end the world. I am I'm
curious to dive into more of the science
of that. Thank you so much, guys. Such a
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