The need for research on psychedelics, chronic pain and opioid use disorder

Transcript

• 00:00Okay.
• 00:07We'll get started
• 00:09probably in about two minutes.
• 00:10Just wanna give folks a
• 00:11couple
• 00:12minutes to join in.
• 00:16Really excited to have
• 00:18doctor Pittenger and doctor De Aquino
• 00:21here.
• 00:31Okay. Why don't we go
• 00:32ahead and get started?
• 00:35Well, welcome to
• 00:37the need for research on
• 00:38psychedelics,
• 00:39chronic pain,
• 00:41and,
• 00:42opioid use disorder.
• 00:44This is a teaching seminar
• 00:46for early stage investigators and
• 00:48individuals who may be
• 00:50transitioning towards
• 00:51the area of opioid use
• 00:53disorder or pain.
• 00:57We're really lucky to have
• 00:58two experts in this area.
• 01:01The first is doctor Christopher
• 01:03Pettinger,
• 01:04who's the Elizabeth Meers and
• 01:06House Jamieson professor of psychiatry
• 01:09at Yale School of Medicine.
• 01:11He's the deputy chair for
• 01:13translational
• 01:13research,
• 01:15director of clinical neuroscience
• 01:16research,
• 01:17and director of the Yale
• 01:19program for psychedelic
• 01:20science, as well as the
• 01:22co director of the Yale
• 01:23setup for brain and mind
• 01:24health at the Yale School
• 01:25of Medicine.
• 01:26We will also be joined
• 01:27by doctor De Aquino
• 01:29who's an assistant professor of
• 01:31psychiatry here at Yale, and
• 01:33he will he is also
• 01:34the assistant chief of the
• 01:35inpatient psychiatry
• 01:37clinical neuroscience research unit, and
• 01:40the assistant director of the
• 01:41research affairs of of the
• 01:42clinical neurosurge unit here at
• 01:44Yale.
• 01:45So very excited to have
• 01:47our two speakers.
• 01:49And without further ado, we'll
• 01:51we'll let you guys take
• 01:52it away. Thank you, Chris
• 01:53and JP.
• 01:55Great.
• 01:57Thank you, everyone. It's really
• 01:58a pleasure to be here
• 01:59with you today. We'll jump
• 02:00right in.
• 02:02I'm not an expert either
• 02:03in substance use or pain,
• 02:05but I have done some
• 02:06work in psychedelics, and I'm
• 02:08gonna,
• 02:09start with maybe about twenty
• 02:10minutes, a broad overview of,
• 02:13what psychedelics are and an
• 02:15introduction to some of the
• 02:15current research that's been done
• 02:17over the last fifteen years
• 02:18or so and what's been
• 02:19called by some of the
• 02:20psychedelic renaissance. And then I'll
• 02:22pass it off to Joao
• 02:23who's going to talk, in
• 02:24a more focused manner. He
• 02:25he is an expert in
• 02:27both, addictions and pain, and
• 02:28he'll talk a little bit
• 02:29more about what we know,
• 02:30which isn't a lot to
• 02:31date, but what we know
• 02:33about use in these conditions.
• 02:35And then what we're hoping
• 02:36to do twenty minutes each
• 02:37and then have some time
• 02:38for discussion at the end.
• 02:39That's the plan.
• 02:40And I will try to
• 02:41keep an eye on the
• 02:42time to keep to that.
• 02:46Okay. I have disclosures. I
• 02:47do do do some consulting
• 02:49in this space. It's not
• 02:49relevant anything I'll be talking
• 02:50about today. So what is
• 02:52a psychedelic? Psychedelic is a
• 02:53is a fairly complicated word
• 02:55and is used in different
• 02:55ways in different contexts, and
• 02:57that can breed confusion.
• 02:58And so I wanna spend
• 02:59a moment unpacking it. There
• 03:01are really three ways that
• 03:02the word is used. The
• 03:04first is as a class
• 03:06of drug or pharmacological, which
• 03:08is what's illustrated on this
• 03:09slide.
• 03:10The second is it's a
• 03:11type of psychological
• 03:12experience, a psychedelic trip, a
• 03:14psychedelic experience, psychedelic art, psychedelic
• 03:16music, sort of a a
• 03:18somewhat
• 03:19vague but evocative description of
• 03:21a class of experience,
• 03:23or aesthetic.
• 03:24And the third is as
• 03:25an approach to treatment, the
• 03:27psychedelic medicine
• 03:28paradigm, which is the idea
• 03:30of using a mind or
• 03:32consciousness altering substance in conjunction
• 03:35with a psychotherapeutic
• 03:36manipulation
• 03:37to produce
• 03:38a a net effect that
• 03:39is at least intended to
• 03:40be greater than the sum
• 03:41of its parts. So that
• 03:43necessary synergy as opposed to
• 03:44just the additive effect of
• 03:46pharmacological
• 03:47and psychological effects that we,
• 03:49more commonly deploy
• 03:50in psychiatry. So these are
• 03:52the three senses in which
• 03:53the term is used. And,
• 03:54again, I think it's useful
• 03:55to parse that out just
• 03:56because often disagreements or confusions
• 03:58come from the fact that
• 03:59people are using the same
• 04:01words in different ways,
• 04:02and can be avoided if
• 04:04we're more clear.
• 04:05Focusing on the first sense
• 04:06of the word, which, would
• 04:07what it what is a
• 04:08psychedelic in terms of a
• 04:09kind of drug or a
• 04:10kind of molecule,
• 04:12Many of the common drugs
• 04:13that are called psychedelics are
• 04:14illustrated on this slide. Over
• 04:16on the left side, the
• 04:17tryptamines and the ergolines, these
• 04:19are drugs like psilocybin, five
• 04:20methoxy, DMT, DMT, Ibogaine,
• 04:23as well as LSD
• 04:25that have psychedelic effects
• 04:27through the consciousness altering effects
• 04:29through their activities in the
• 04:31serotonin
• 04:32two a receptor. And these
• 04:33are sometimes called the classic
• 04:34psychedelics, and that's the narrowest,
• 04:36cleanest definition of what a
• 04:38psychedelic is.
• 04:39There are other drugs that
• 04:41cause similar or adjacent alterations
• 04:43in consciousness,
• 04:44but through somewhat different mechanisms,
• 04:46often through the flooding of
• 04:47the synapse with lots of
• 04:48serotonin, which is what MDMA
• 04:50does,
• 04:51and other drugs in this
• 04:53in this group, mescaline and
• 04:54these less less well known
• 04:55synthetic drugs. And then there's
• 04:57a large so these are
• 04:58these are called, atypical psychedelics,
• 05:00I think is a useful
• 05:01term for these. There's a
• 05:02little bit less everyone means
• 05:03basically the same thing by
• 05:04classic psychedelics.
• 05:06A little bit more more
• 05:07heterogeneity in how people describe
• 05:08these terms. But I think
• 05:09atypical psychedelics is a pretty
• 05:11good,
• 05:12term for these.
• 05:14And then there's a wide
• 05:15selection of heterogeneous, mechanistically and
• 05:18structurally heterogeneous drugs that are
• 05:20sometimes used by psychedelics. I
• 05:22actually don't like using the
• 05:23term psychedelic for these because
• 05:25it just the term becomes
• 05:26so broad that it's useless.
• 05:28But things like salvinorin a,
• 05:29which acts on the kappa
• 05:30opioid receptor, ketamine, which acts
• 05:32on the NMDA receptor as
• 05:33well as others, PCP, also
• 05:35NMDA receptor, Musimol, which is
• 05:37a muscarinic
• 05:38agent. All of these have
• 05:40some,
• 05:41consciousness altering effect. But if
• 05:43we start calling everything with
• 05:44a consciousness altering effect a
• 05:46psychedelic, then why not cocaine?
• 05:47Why not cannabinoids? So I
• 05:49think the term uses loses
• 05:50its specificity to a point
• 05:52that it makes it unhelpful.
• 05:53So I prefer not to
• 05:54call these drugs psychedelics, but
• 05:56sometimes people will.
• 05:58So just just to be
• 05:59aware of this heterogeneity and
• 06:00usage in the literature. We're
• 06:02gonna be talking primarily about
• 06:04the classic psychedelics today.
• 06:08And the research in classic
• 06:11psychedelics is exploding.
• 06:13This is illustrated in a
• 06:14couple slides here.
• 06:16There's a history. I'm I'm
• 06:17not taking time because we
• 06:19wanna keep things focused today
• 06:20to describe the history of
• 06:22psychedelic research, but you probably
• 06:24know that psychedelics would be
• 06:26appreciated by western medicine going
• 06:27back a couple hundred years,
• 06:28but really since the nineteen
• 06:29fifties. They've been appreciated by
• 06:31humanity and used, you know,
• 06:33for thousands of years and
• 06:34used by various indigenous groups.
• 06:36There was a lot of
• 06:37research as well as a
• 06:38lot of recreational use and
• 06:39cultural conversation,
• 06:41from the fifties through the
• 06:42sixties, but then that was
• 06:43largely shut down in the
• 06:44nineteen seventies
• 06:45by because of the,
• 06:47the,
• 06:48Controlled Substances Act.
• 06:50And then it's over the
• 06:51last fifteen years or so
• 06:52that there's been this enormous
• 06:53resurgence in interest in research,
• 06:55and that's what's illustrated in
• 06:56these next couple slides. This
• 06:58is an older slide, twenty
• 06:59twenty one, but showing the
• 07:00number of trials in clinicaltrials
• 07:02dot gov
• 07:03investigating the therapeutic use of
• 07:05psychedelics, including the atypical psych
• 07:07psychedelic MDMA.
• 07:09And you can see this
• 07:09dramatic increase. There were a
• 07:11couple of big papers published
• 07:12in twenty sixteen, and that's
• 07:13when it really entered the
• 07:14mainstream of research. So you
• 07:15see this big increase here.
• 07:16On the right, you know,
• 07:17through the same time frame,
• 07:19you see the total number
• 07:20of patients
• 07:21I'm sorry, of individuals and
• 07:22participants
• 07:23who have been engaged in
• 07:24psychedelic research trials. Green is
• 07:26healthy controls and blue is
• 07:27people with a diagnosis
• 07:29in a therapeutic trial. Again,
• 07:30you see this dramatic increase
• 07:32over the same time frame.
• 07:34This is the number of
• 07:35publications going back decades.
• 07:37You see the early era
• 07:38of psychedelic research, but then
• 07:39this explosion in the last
• 07:41fifteen years in publications.
• 07:43And this is an, once
• 07:45a consulting group's estimate of
• 07:47the size of the psychedelic
• 07:48drug market,
• 07:50and the projection that this
• 07:51will be a many billion
• 07:52of dollar billions of dollar
• 07:53market subject to a bunch
• 07:55of assumptions about legalization and
• 07:56access
• 07:57to these drugs.
• 07:58But this is so there's
• 07:59been a lot of industry
• 08:00excitement,
• 08:02because of this this projection
• 08:04of a burgeoning value in
• 08:06this space. And, obviously, that
• 08:07is all the usual, the
• 08:08benefits, which is new research
• 08:09coming into the space, and
• 08:11the risks,
• 08:12which is, you know, financial
• 08:13incentives,
• 08:15perverting the the conversation and
• 08:17and influencing how how the
• 08:18research is done. Something for
• 08:20us to be aware of
• 08:21and alert to.
• 08:22Okay. I'm now gonna review
• 08:24some of the classic psychedelics,
• 08:25some of the and and,
• 08:27just to again, with a
• 08:28sort of a thirty thousand
• 08:29foot overview.
• 08:31The the earliest
• 08:32psychedelic in which there was
• 08:33a lot of clinical research
• 08:35back in the fifties and
• 08:36sixties was LSD or lysergic
• 08:38acid diethylamide.
• 08:40This is a semi synthetic,
• 08:42derivative of, molecule that comes
• 08:44from the ergot fungus, and
• 08:46it was produced in nineteen
• 08:47thirty seven. And its psychedelic
• 08:49pro properties were were discovered
• 08:51in nineteen forty three after
• 08:52an accidental,
• 08:54not ingestion, but absorption through
• 08:56the skin by this guy,
• 08:57Albert Hoffman, who's a legend
• 08:59in psychedelic science and is
• 09:00revered by a lot of
• 09:01people in this space.
• 09:03Especially, like and I I
• 09:05I use the word revered
• 09:07knowingly. There's a lot there's
• 09:08a sort of a a
• 09:09great deal of enthusiasm
• 09:11and, and an almost
• 09:13religious,
• 09:14component to to to some
• 09:16some people working in this
• 09:17space. And and Albert Hoffman
• 09:18decided has been called a
• 09:19patron saint.
• 09:21He was a Swiss chemist.
• 09:22He worked for Sandoz, and
• 09:23there's an interesting history behind
• 09:24the production of LSD that
• 09:26I'm not gonna take the
• 09:27time to go into. I'll
• 09:29just say that in the
• 09:30fifties and sixties, there were
• 09:31quite a few trials,
• 09:32and I know that,
• 09:33Joao was gonna come back
• 09:34to some of these. But
• 09:36most research was on alcohol
• 09:37use disorder. This was summarized
• 09:39in a meta analysis by
• 09:40Krebs and Johansson in twenty
• 09:41twenty twelve.
• 09:44This should be LSD. That's
• 09:45a typo.
• 09:46But there were six trials
• 09:47done that were pretty good
• 09:48by the standards of the
• 09:49day, not by modern standards,
• 09:50but pretty good controlled trials
• 09:52by the standards of the
• 09:53day, mostly in male inpatients.
• 09:55And they suggested a significant
• 09:57benefit,
• 09:58in the treatment when LSD
• 09:59was used as an adjunct
• 10:01to other forms of treatment
• 10:03in people with alcohol use
• 10:04disorder. And this is from
• 10:06that meta analysis. So, again,
• 10:08not diving into the details.
• 10:09Joao will will give us
• 10:10a little more. But, but
• 10:11just there there was a
• 10:13pretty decent literature by the
• 10:14standards of the day back
• 10:16in the sixties and the
• 10:17work done in the sixties
• 10:18publication to nineteen seventy,
• 10:21suggesting there's benefit for the
• 10:22treatment of alcohol use disorder.
• 10:26And there was a single
• 10:26trial that I know of
• 10:27in the treatment of opiate
• 10:28use disorder, which I, again,
• 10:29I know trial is gonna
• 10:30come back to. So not
• 10:32not gold standard research by
• 10:34today's, you know, but it
• 10:35wouldn't wouldn't wouldn't, be up
• 10:36to snuff by today's standards.
• 10:37But there is data from
• 10:39what was the mainstream of
• 10:40psychiatric
• 10:41research at that time.
• 10:44I'll say in in wrapping
• 10:45up about LSD, I don't
• 10:46know of any modern trials
• 10:49looking at LSD and substance
• 10:50use disorder,
• 10:52Joao Mei.
• 10:53But there is an active
• 10:55development program by MindMed Pharmaceuticals
• 10:57trying to develop it for
• 10:59use in generalized anxiety disorder,
• 11:01And they're now they have
• 11:02very promising phase two b
• 11:03data. Phase three is underway,
• 11:05and they're branching out to
• 11:06other indications. So there does
• 11:08continue to be interest in
• 11:09the therapeutic use of LSD.
• 11:12Psilocybin
• 11:13is really where more,
• 11:15research is being done, more
• 11:17in in the broader field
• 11:18as well as in,
• 11:20the treatment of substance use
• 11:21disorder. Psilocybin is a naturally
• 11:23occurring molecule. It was actually
• 11:24synthesized, purified,
• 11:26by Arthur Hefter in the
• 11:28early twentieth century and then
• 11:30synthesized by the same guy,
• 11:31Albert Hoffman,
• 11:33in the nineteen fifties.
• 11:34This is the chemical structure.
• 11:36It looks very similar to
• 11:37serotonin. It's a classic psychedelic.
• 11:38It binds to serotonin receptors.
• 11:40It's been used for centuries
• 11:41by people of the Sierra
• 11:42Mazteca region in Mexico here
• 11:45as well as other regions,
• 11:46but this is where it
• 11:46was most famously used. And
• 11:48it was from, contact with
• 11:50the people of this area
• 11:51of this region that, the
• 11:53western science came into contact
• 11:55with, this drug.
• 11:57And there's been more more
• 11:59modern day research in psilocybin
• 12:01than in any of the
• 12:02other classic psychedelics.
• 12:06There were studies in the
• 12:07nineteen seventies nineteen fifties and
• 12:09nineteen sixties suggesting benefit for
• 12:11both addiction and mood. There
• 12:13isn't as much careful work
• 12:14in addiction as there was
• 12:15for LSD,
• 12:17in the fifties and sixties,
• 12:18but definitely enough to suggest
• 12:19that there's a benefit,
• 12:21and to motivate modern research.
• 12:24And recreational use, as I've
• 12:26mentioned, triggered a backlash, which
• 12:27triggered led to the Controlled
• 12:29Substances Act in the nineteen
• 12:31early nineteen seventies, leading to
• 12:33an almost complete shutdown of
• 12:34research for about thirty years.
• 12:37I wanna take this opportunity.
• 12:38I could have shown similar
• 12:40slides for LSD because we
• 12:41think they work in in
• 12:42similar ways in the brain,
• 12:44but I wanna dip just
• 12:45a little bit into the
• 12:46some of the neurobiology
• 12:47about how these substances work.
• 12:50They bind to several serotonin
• 12:52receptors, prominently two a, two
• 12:54c, and one a.
• 12:57Nonserotonin
• 12:58serotonergic effects appear to be
• 12:59much lower affinity. So it's
• 13:01probably these receptors that have
• 13:02most of the benefit. This
• 13:04is the crystal structure of
• 13:05the two a receptor. I
• 13:06just like to put it
• 13:07up there because it's pretty.
• 13:08But of more relevance, if
• 13:09you look on the right,
• 13:10this is a PET imaging
• 13:11study showing the distribution of
• 13:13the two a receptor
• 13:14over the surface of the
• 13:15brain. And you can see
• 13:16it's found all over,
• 13:17but particularly in regions of
• 13:19the, multimodal or or, association
• 13:22cortex, the default mode network
• 13:23and the posterior cingulate
• 13:25and then, medial prefrontal cortex,
• 13:28lateral temporal cortex shown here
• 13:30and here. So there's,
• 13:32there's a lot of expression
• 13:33in association
• 13:35cortex,
• 13:36in the brain.
• 13:37And so it's not terribly
• 13:39surprising that that's where you
• 13:40see a lot of effects
• 13:42when you treat with psilocybin.
• 13:44This is an analysis that
• 13:45was done on data collected
• 13:46in Switzerland where the moratorium
• 13:48on research was never as
• 13:49severe as it was in
• 13:51other western countries,
• 13:52but analyzed by Alan Antisevich
• 13:54and his colleagues,
• 13:55here at Yale. What's shown
• 13:57here, the I'm not gonna
• 13:58dig and dive into all
• 13:59the details, but this is
• 14:00an fMRI study looking at
• 14:01changes in degree connectivity,
• 14:04which is a measure of
• 14:05functional connectivity, sort of how
• 14:07how much is one piece
• 14:09of brain correlated or connected
• 14:11with all the rest on
• 14:12psilocybin
• 14:13compared to within subject control.
• 14:15And what you see here
• 14:16is reduced
• 14:18degree connectivity,
• 14:19decoupling
• 14:20with the rest of the
• 14:21brain in some of these
• 14:22association areas where there are
• 14:23high amounts of receptor,
• 14:25expression. And interestingly,
• 14:27increased coupling with the rest
• 14:29of the brain, increased synchronous
• 14:31activity
• 14:31in primary sensory cortices, the,
• 14:34occipital lobe and the primary
• 14:35visual cortex here, as well
• 14:36as subtle. You see this
• 14:38a little bit less subtly
• 14:39in some other cortices, but
• 14:40this is the, primary somatosensory
• 14:42cortex, and here would be
• 14:44some audit primary auditory cortex.
• 14:46So it looks like an
• 14:47increased synchrony or coupling in
• 14:49primary sensory
• 14:50areas and a decreased synchronicity
• 14:52or coupling in association areas.
• 14:54And this has been used
• 14:55to explain some of the
• 14:56subjective effects that this drug
• 14:58has where there's sensory alterations,
• 15:01not not frank hallucinations usually,
• 15:03but alterations in the sensorium
• 15:05and the dissolving of the
• 15:07coherent sense of self, which
• 15:08is thought to be mediated
• 15:09by the default mode network.
• 15:10So I can make up
• 15:11a story about how the
• 15:12psychological effects map onto these
• 15:14brain effects, although, of course,
• 15:15causal relationships,
• 15:17are difficult to prove.
• 15:19Other things we know about
• 15:20the effects of psilocybin, this
• 15:22is animal work done here
• 15:23at Yale.
• 15:25This was work by, Alex
• 15:26Kwan, who has since left.
• 15:28Similar work has been is
• 15:29being done by Al Kaye,
• 15:31in our department. And what's
• 15:32shown here is how the
• 15:33how psilocybin affects single neurons.
• 15:37This what you're seeing here
• 15:38is a visualization of the
• 15:39apical dendrite of a single
• 15:41neuron in the frontal cortex
• 15:44visualized in vivo in a
• 15:45mouse. So this is a
• 15:46living mouse. We're visualizing a
• 15:47single neuron that's fluorescently labeled.
• 15:49And you zoom in on
• 15:50this dendrite, and you see
• 15:52all these little protuberances. These
• 15:53are dendritic spines, and they're
• 15:54thought to be the site
• 15:56of synaptic contacts.
• 15:57And they can they're able
• 15:58to visualize. The technology here
• 16:00is actually quite remarkable. They're
• 16:01able to visualize the same
• 16:02dendrite over time for over
• 16:04a month
• 16:05and look at these dendritic
• 16:07spines and look at the
• 16:08growth and retraction of synaptic
• 16:10contact. And what you see
• 16:11is that psilocybin increases
• 16:14stable synaptic contacts,
• 16:16not by a huge amount,
• 16:17but but with a clear
• 16:18statistical significance,
• 16:20going out for a month.
• 16:21This is striking because ketamine
• 16:24does something similar, and, actually,
• 16:25so do classical antidepressants like
• 16:27like fluoxetine.
• 16:29But in the case of
• 16:30ketamine, they don't last nearly
• 16:32as long. So psilocybin appears
• 16:34to be having proplasticity,
• 16:35prosynaptic growth effects
• 16:37that last out for over
• 16:39a month.
• 16:40This is hypothesized
• 16:41to be related to its,
• 16:43therapeutic effects, although exactly how
• 16:45that connection works isn't entirely
• 16:48clear.
• 16:49Alright. So psilocybin has been
• 16:50used extensively in clinical studies.
• 16:52It's a slightly cleaner drug
• 16:53than LSD. It has a
• 16:54shorter half life of about
• 16:56four hours, four to six
• 16:57hours, whereas LSD has a
• 16:59half life of, like, fifteen
• 17:00hours, which makes it more
• 17:01difficult to manage in the
• 17:01clinical setting. Also, psilocybin, I
• 17:03think, is a little less
• 17:04scary. I think it was
• 17:05a little easier to get
• 17:06IRBs to sign on to
• 17:07it ten years ago when
• 17:08this was all new, to
• 17:09many people, because it didn't
• 17:11have the the as much
• 17:12cultural baggage as LSD. So
• 17:13for all of these reasons,
• 17:15it's been the focus of
• 17:16most clinical studies in the
• 17:17modern era.
• 17:18I mentioned the psychedelic,
• 17:21medicine
• 17:22paradigm, and that's the idea
• 17:23that you give a drug
• 17:24that has mind operating mind
• 17:26altering or consciousness altering properties,
• 17:28and you couple it with
• 17:30a psychotherapy. And that's how
• 17:31most studies in this space
• 17:32have been done. And what's
• 17:34shown here is the kind
• 17:35of environment in which we
• 17:36do this kind of treatment.
• 17:38This is actually my office.
• 17:39It's where I'm seated right
• 17:40now. And this was from
• 17:42when we were doing a
• 17:42study here on the clinical
• 17:43neuroscience research unit. But the
• 17:45unit a few years ago,
• 17:46the unit was closed because
• 17:47of a pandemic quarantine.
• 17:49And so we had to
• 17:50scramble to, to create a
• 17:52dosing space, and we retrofitted
• 17:54my office. But what you
• 17:55can see, and this is
• 17:56pretty typical of many, though
• 17:57not all studies, is we've
• 17:59tried to make it less
• 18:00clinical appearing. There is a
• 18:01blood pressure machine, but we've
• 18:02tried to sort of mask
• 18:03some of the clinical,
• 18:05clinical office like,
• 18:07characteristics
• 18:08and and make it, make
• 18:09it a little bit more
• 18:10of a of a natural
• 18:11you know, space that evokes
• 18:13nature. This is often done
• 18:15for, these dosing studies.
• 18:18I'm not gonna go through
• 18:19data on the pie. That
• 18:20would be a longer lecture,
• 18:21but I would I'll just
• 18:22say that there's
• 18:23good small single site, but
• 18:25high quality controlled studies
• 18:27in treatments of the anxiety,
• 18:29depression, and existential
• 18:30despair that attends the end
• 18:32of life in patients with
• 18:33advanced cancer. This is where
• 18:35the first clinical trials of
• 18:36the modern era were done
• 18:37published in twenty sixteen. And,
• 18:39again, I think that the
• 18:40invest I was not part
• 18:41of this work, but I
• 18:42think that the investigators who
• 18:43started this work may have
• 18:44started in in, this population
• 18:46because it was easier to
• 18:47get,
• 18:48to get IRB approval in,
• 18:50in an advanced cancer population
• 18:52than it might have been
• 18:53in a young physically healthy
• 18:55population.
• 18:56There've been a lot of
• 18:56studies in major depression, including,
• 18:59two phase three research pair,
• 19:02programs that are being forced
• 19:04and I think are reasonably
• 19:05likely to lead to FDA
• 19:07approval of psilocybin within the
• 19:09next couple years for depression.
• 19:11There's a bunch of complexity
• 19:12there that we don't have
• 19:13time to get into. But
• 19:14my prediction is that we
• 19:15will see approval of psilocybin
• 19:17within two to three years,
• 19:19for major depression.
• 19:21There's some studies in alcoholism.
• 19:23I told you about the
• 19:24work from the fifties, but
• 19:25more recently,
• 19:27Michael Bogenschips and his colleagues
• 19:28at NYU have picked up
• 19:29this baton
• 19:30and, did a a first
• 19:32study in twenty fifteen. This
• 19:33was sort of an open
• 19:34label proof of concept
• 19:35study where you see group
• 19:37of people, treated for alcohol
• 19:38use disorder with psilocybin
• 19:40together with a CBT based,
• 19:43treatment paradigm that in in
• 19:44included both motivational enhancement,
• 19:47and and CBT components.
• 19:50So not a controlled study.
• 19:51But they treated with psilocybin
• 19:53twice, and they saw a
• 19:54dramatic reduction in both percent
• 19:56drinking days in blue and
• 19:57percent heavy drinking days in
• 19:58red.
• 19:59And and it's it's quite
• 20:00a dramatic drop off though,
• 20:01again, without a control group.
• 20:03This was followed up with
• 20:04a large well controlled study.
• 20:05I think this is an
• 20:06n of ninety six. It's
• 20:07a very robust study. Again,
• 20:09coupling psilocybin
• 20:10administration
• 20:11with CBT based treatment.
• 20:13And what you can see
• 20:14is that everyone got better,
• 20:15so their CBT based treatment
• 20:16worked.
• 20:17The people in gray received
• 20:19no psilocybin. They received a
• 20:20placebo.
• 20:21People in blue did receive
• 20:23psilocybin and had a markedly
• 20:25better they everyone got better,
• 20:26but they had a markedly
• 20:28larger effect,
• 20:29and it lasted out for
• 20:30many weeks.
• 20:32So this is very promising.
• 20:33This is the best single
• 20:35study, in the treatment of
• 20:36substance use disorders, this this
• 20:38controlled study for depression. There
• 20:40are some studies in nicotine
• 20:41addiction.
• 20:42They're smaller. Here's a list
• 20:43of some of the, some
• 20:45of the reported studies. There's
• 20:46a couple open label studies.
• 20:48I don't there's a there's
• 20:49a controlled study that's not
• 20:51yet published that I'm aware
• 20:52of that shows promising results,
• 20:53and there are also,
• 20:55some naturalistic survey data that
• 20:56support benefit for nicotine
• 20:58use disorder. This is data
• 21:00from that from a controlled
• 21:01study by Johnson and colleagues
• 21:02twenty fourteen. That was the
• 21:04second controlled study in twenty
• 21:05fifteen showed similar results.
• 21:07Impressive,
• 21:08results in a small uncontrolled
• 21:10study. So this work is
• 21:11ongoing.
• 21:13And there's ongoing ongoing work
• 21:14in a bunch of other,
• 21:16conditions. And Joao will will
• 21:17give you give us more
• 21:18details about opiate use disorder
• 21:19in particular.
• 21:21We've just completed the first
• 21:22controlled study in obsessive compulsive
• 21:24disorder. So there's evidence of
• 21:25benefit in many of these,
• 21:27contexts.
• 21:27The one interesting exception is
• 21:29anorexia nervosa,
• 21:31where the early studies have
• 21:32not been as promising,
• 21:34and work there is ongoing.
• 21:36I'm gonna wrap up. I'll
• 21:37just say there's, you know,
• 21:38another another classic psychedelic is
• 21:40dimethyltryptamine,
• 21:42which is found in the
• 21:43t iahaska,
• 21:44which is, used by indigenous
• 21:46groups in the Amazon and
• 21:47Brazil, but has it used
• 21:48to spread worldwide
• 21:50in a sort of syncretic,
• 21:51quasi religious context.
• 21:53There is some research about
• 21:54Ayahuasca. It's used actively used
• 21:57in, substance abuse treatment
• 21:59centers in South America,
• 22:01but the research base at
• 22:02this point is quite thin.
• 22:04There was a survey study
• 22:05shown here a couple years
• 22:07ago suggesting that it helped
• 22:08with smoking cessation, but this
• 22:09is naturalistic survey data. There
• 22:11are no controlled studies that
• 22:12I'm aware of with Ayahuasca.
• 22:14Cyril D'Souza and our VA
• 22:15is beginning to and some
• 22:16of his colleagues are beginning
• 22:17to use synthetic DMT. They're
• 22:19starting with depression.
• 22:20But, Anahita Basurnia has a
• 22:22study that's just getting off
• 22:23the ground using DMT for
• 22:25alcohol use disorder. So we're
• 22:26just seeing the beginnings of
• 22:27investigations
• 22:28of DMT,
• 22:29which is the active ingredient,
• 22:32for substance abuse.
• 22:34Ibogaine has gotten a lot
• 22:35of press recently. It's a
• 22:36complicated drug with complicated pharmacology
• 22:39that, honestly, I don't understand
• 22:40particularly well. Does have some
• 22:42effects on, the serotonin two
• 22:44a receptor.
• 22:45It's found naturally in in
• 22:47the bark of trees in
• 22:48West Africa, which is shown
• 22:49here, the aboga tree.
• 22:52And there have begun to
• 22:53be some some studies of
• 22:55Ibogaine. It's again being used
• 22:56actively in substance abuse clinics
• 22:58in South America and in
• 22:59Mexico
• 23:00for substance abuse as well
• 23:01as for trauma.
• 23:03But there isn't a lot
• 23:04of,
• 23:05control really no control data.
• 23:08It it also has, potential
• 23:10cardiotoxic
• 23:11effects. It is a tricky
• 23:12substance to work with. So
• 23:14lots of work to be
• 23:14done here to see if
• 23:15there's any anything.
• 23:17I'm gonna wrap up by
• 23:19by raising this question, are
• 23:20psychedelics addictive?
• 23:22When,
• 23:23psilocybin,
• 23:23LSD, and other psychedelics were
• 23:25classified
• 23:26as schedule one drugs back
• 23:28in the early nineteen seventies.
• 23:30That implies that there is
• 23:31no therapeutic use, and I've
• 23:32shown you there actually was
• 23:33some evidence of therapeutic use,
• 23:35though nothing approved,
• 23:37and that they are highly
• 23:38addictive. And so question, are
• 23:39they addictive?
• 23:41This is data from a
• 23:42survey study done by David
• 23:44Nutt a few years ago.
• 23:46David Nutt is an advocate
• 23:47for psychedelic use, and so
• 23:48I think there's a little
• 23:49bit I think this is
• 23:50a a motivated survey study
• 23:52to to try to make
• 23:53a point. But it did
• 23:54make the point. This is
• 23:55a survey of,
• 23:57of specialists in substance abuse
• 23:59to asking them to rate
• 24:00for a variety of drugs
• 24:01how harmful they are to
• 24:02their users and how harmful
• 24:03they are to others.
• 24:05And you see alcohol, heroin,
• 24:06crack, methamphetamine over here at
• 24:08the left rated as very
• 24:09harmful.
• 24:10And you see mushrooms, the
• 24:11natural occurring psilocybin
• 24:13way over here at the
• 24:13right, LSD,
• 24:15ecstasy, also MDMA.
• 24:17So the point of this
• 24:17is that these were not
• 24:19but not seen as particularly
• 24:20harmful by experts. It's a
• 24:21survey study of experts for
• 24:23what it's worth. But they're
• 24:24clearly in a different category
• 24:26from these very harmful addictive
• 24:27drugs here.
• 24:29Bunch of points to suggest
• 24:30that psychedelics aren't addictive or
• 24:32shouldn't be considered
• 24:33addictive, certainly not to the
• 24:35same
• 24:36point, to the same degree
• 24:37as nicotine or cocaine or
• 24:39methamphetamine or heroin. They have
• 24:40limited reinforcing effects.
• 24:42They often exhibit tachyphylaxis.
• 24:45There's little evidence for dependence
• 24:46or withdrawal. So these classic
• 24:48markers of adaptivity,
• 24:50they really don't meet the
• 24:51bar. There are, however, potential
• 24:53harms, and it's important to
• 24:54take these into account when,
• 24:57when counseling patients who might
• 24:58be considering
• 24:59using these drugs in the
• 25:00underground,
• 25:01who are actively using them
• 25:02or when considering,
• 25:04research. And I know Joao
• 25:05will come back, to some
• 25:06of that. There are potential
• 25:07harms, dysregulated
• 25:08behavior. They produce psychological distress.
• 25:11They can exacerbate psychotic symptoms,
• 25:13and people with any risk
• 25:14for psychosis
• 25:15are carefully ruled out of
• 25:16most studies in the modern
• 25:17era.
• 25:19You have to worry about
• 25:20interactions, cardiovascular
• 25:21effects, etcetera.
• 25:22The potential for lasting perceptual
• 25:24disturbances, although this is quite
• 25:25rare with therapeutic use as
• 25:27opposed to unregulated high dose
• 25:29recreational use. I'll stop there
• 25:31and hand over to Joao
• 25:32acknowledgments, especially Ben Calmendi,
• 25:34close colleague who sort of
• 25:35pulled me into the work
• 25:36in this space and has
• 25:37led our work in OCD
• 25:38and a variety of other
• 25:39colleagues who've who've supported our
• 25:41work in this space. Funding,
• 25:42thank you all for your
• 25:44attention.
• 25:45I think that was about
• 25:46twenty minutes given our late
• 25:47start. Joel, over to you.
• 25:49Thank you. Thank you, Chris.
• 25:51Just a quick thank you,
• 25:52Chris. That was a wonderful
• 25:53overview.
• 25:55Yep.
• 25:56My pleasure.
• 25:59Let me share.
• 26:02You guys see my slides?
• 26:05Yes.
• 26:07Okay. On the on the
• 26:08theme of, David Nutso,
• 26:11they had a campaign in
• 26:12the UK,
• 26:14quite provocative campaign,
• 26:16that said horse riding kills
• 26:17more than in MDMA.
• 26:20And the reason why,
• 26:22MDMA
• 26:23killed,
• 26:24if you ask him, is
• 26:25because of the hyperthermia. People
• 26:26end up drinking a lot
• 26:27of water and have electrolyte
• 26:28imbalances.
• 26:30So,
• 26:31yeah, quite quite provocative, interesting,
• 26:34interesting guy.
• 26:36So,
• 26:37again, thank you, David, for
• 26:38your invitation.
• 26:40Joel De Aquinos is the
• 26:41professor of psychiatry, and my
• 26:42research sits at the inter
• 26:43intersection of chronic pain and
• 26:44substance use disorders.
• 26:46Here are my disclosures.
• 26:48Chris has just set the
• 26:50stage,
• 26:50with the broader,
• 26:52psychedelic landscape,
• 26:53what these drugs are, why
• 26:55there's renewed interest, and what
• 26:57the conversation looks like right
• 26:58now. My role for the
• 26:59next twenty minutes or so
• 27:01is more pragmatic. So is
• 27:03it I'm gonna describe what
• 27:04we actually know so far
• 27:06in pain and OUD,
• 27:07what we should be measuring
• 27:09if we want this area
• 27:10to mature into responsible
• 27:12clinical science. And I hope
• 27:14that by the end of
• 27:15the talk, I'll I'll have
• 27:16made the case for why
• 27:17we need more rigorous research
• 27:19because access is expanding in
• 27:21ways that may out may
• 27:22outpace evidence.
• 27:29So this is what computers
• 27:30look like when methadone and
• 27:32buprenorphine were synthesized.
• 27:34About,
• 27:34a third of people with
• 27:35OUD continue to live with
• 27:37chronic pain despite, being treated
• 27:39with these medications.
• 27:41And I'm sure this is
• 27:42a patient you all recognize,
• 27:43someone on buprenorphine or methadone
• 27:45who's back pain or neuropathic
• 27:47pain or fibromyalgia
• 27:49really dominates their daily experience.
• 27:51They're not just uncomfortable. They're
• 27:53not sleeping. They're not functioning.
• 27:55They're isolated.
• 27:56And over time,
• 27:57pain becomes
• 27:59a persistent stressor that wears
• 28:00down coping
• 28:02and and eventually leads to
• 28:03return to using opioids,
• 28:05non medically.
• 28:07And the reality is that
• 28:08we have not had new
• 28:09approaches to treat o u
• 28:10d in half a century
• 28:11other than new formulations of
• 28:13existing drugs and alpha two
• 28:14agonist to to treat opioid
• 28:16withdrawal.
• 28:17And the hypothesis
• 28:19isn't that psychedelics are a
• 28:20new pain killer.
• 28:21The hypothesis is more specific,
• 28:24is that these drugs might
• 28:26engage shared mechanisms,
• 28:27biological and psychological
• 28:29that reduce suffering and improve
• 28:31function. And in some cases
• 28:32may reduce,
• 28:34opioid burden.
• 28:36I like this slide because
• 28:37it forces a reset in
• 28:38how we talk about pain.
• 28:40Pain is a sensory experience,
• 28:42yes, but it's also effective
• 28:44and cognitive. It's threat,
• 28:46it's attention, mood.
• 28:48It it's really a story
• 28:49that someone tells themselves about
• 28:51their body and their future.
• 28:53And now look at opioid
• 28:54phenomena through the same lens,
• 28:56craving, withdrawal,
• 28:57negative affect.
• 28:59These aren't separate from pain.
• 29:00They overlap.
• 29:01And over time, both pain
• 29:03and opioid exposure can be
• 29:04associated with changes in a
• 29:06nervous system
• 29:07that amplify the pain experience,
• 29:10what we often summarize as
• 29:11central sensitization,
• 29:13or in some context,
• 29:15opioid induced hyperalgesia.
• 29:17This is really the somatosensory
• 29:19systems volume knob getting turned
• 29:21up.
• 29:22So so the question becomes,
• 29:25can one intervention
• 29:26interrupt this loop,
• 29:27not just lower a pain
• 29:29score for the day, but
• 29:30improve sleep,
• 29:31reduce avoidance,
• 29:33reduce negative affect,
• 29:35and reduce pain, related craving
• 29:37in a way that helps
• 29:38people stay engaged with medications
• 29:41for OUD
• 29:42and and and and with
• 29:43life.
• 29:46And and Chris already described
• 29:48some of this, but, the
• 29:49goal here is really to
• 29:50highlight the systems level neurobiology
• 29:52that makes these drugs interesting
• 29:53for pain and OID. So
• 29:55these circular graphs,
• 29:57visualize whole brain functional connectivity.
• 30:00So each dot is a
• 30:01node and each line is
• 30:02a connection.
• 30:03On the left, under placebo,
• 30:05connectivity is more segregated. It's
• 30:07more modular. The networks talk
• 30:09mostly within themselves.
• 30:11On the right, under psilocybin,
• 30:12you see a much denser
• 30:14web of cross network links,
• 30:16more global integration.
• 30:17And the takeaway is that,
• 30:19in this case, psilocybin
• 30:21may transiently
• 30:22induce
• 30:23network flexibility
• 30:25or it it may
• 30:26increase the brain the brain's
• 30:28communication bandwidth, if you will,
• 30:30expanding the dynamic or repertoire
• 30:32of these, brain networks.
• 30:34And and why does it
• 30:35matter for pain and and
• 30:37and OUD?
• 30:38Well, both of these conditions
• 30:40involve very rigid, overlearned,
• 30:42threat reward predictions.
• 30:45Pain is a danger. Craving
• 30:47is a need. So So
• 30:48a temporary shift toward flexibility
• 30:51may create a window for
• 30:52new learning,
• 30:53especially if paired with psychotherapy
• 30:55or behavior change.
• 30:56And this is not a
• 30:57proof of efficacy,
• 30:59but it is a mechanistic
• 31:00rationale for plasticity enabled,
• 31:03intervention.
• 31:05And again,
• 31:06it turn if it turns
• 31:07out the psychedelics help,
• 31:10with pain,
• 31:11their benefit may not look
• 31:12like a classic kind of
• 31:13music. It may look like
• 31:15changes in how pain is
• 31:17processed and how a person
• 31:18relates to pain.
• 31:20I described this hypothesis in
• 31:22in three lanes, and this
• 31:23is a figure from a
• 31:23paper we wrote about a
• 31:24year ago.
• 31:25First, from ecological,
• 31:27biological lane, there are receptor
• 31:29level effects. So five h
• 31:31two a receptors are very
• 31:32present in somatosensory
• 31:35cortical areas in the dorsal
• 31:36horn.
• 31:38There are potential anti inflammatory,
• 31:40effects
• 31:41and neuroplastic effects, which Chris
• 31:43highlighted. All these mechanisms could
• 31:45plausibly change pain processing.
• 31:48Second, there is a psychological
• 31:49lane,
• 31:51decreases in pain catastrophizing
• 31:52and avoidance and increases in
• 31:54cognitive flexibility,
• 31:56less,
• 31:57attentional capture by pain.
• 31:59And catastrophizing
• 32:00is basically the mind or
• 32:02the habit of pain means
• 32:04damage and it will never
• 32:05end, and it predicts disability
• 32:08as strongly as many biomedical
• 32:09variables.
• 32:10And third, a social blame,
• 32:12isolation versus connection,
• 32:14meaning, support. And in chronic
• 32:16pain, as people get disabled,
• 32:18social disconnection becomes often part
• 32:21of the disorder.
• 32:23And we know that addiction
• 32:24circuitry intersects with pain circuitry,
• 32:26particularly in domains like threat
• 32:28processing,
• 32:29negative
• 32:30affect,
• 32:31learning, and and reactivity to
• 32:33drug cues.
• 32:34So so the plausible pathways
• 32:36for benefit aren't just less
• 32:38pain or craving isolation.
• 32:40These drugs may act to
• 32:41be overlapping mechanisms,
• 32:43And the hope is that
• 32:44they can help change the
• 32:46relationship to both pain and
• 32:47opioids so people can reengage
• 32:49with valued activities.
• 32:51But the gap and and
• 32:52the opportunity is studies that
• 32:54intentionally target both pain and
• 32:56OUD are scarce
• 32:58in general, let alone,
• 33:00if they're administering psychedelics,
• 33:02despite this comorbidity being everywhere.
• 33:06This figures from the same
• 33:07review paper, and it organizes
• 33:09mechanisms across the three phases
• 33:11of the addiction cycle. Intoxication,
• 33:14craving and negative affect,
• 33:16and anticipation of opioid use.
• 33:19And the take home here
• 33:21is,
• 33:22the effects could range from,
• 33:24like I said, the regulation
• 33:25of receptors in the dorsal
• 33:26horn to,
• 33:28reduce fear and avoidance
• 33:30to enhanced social connection serving
• 33:32as a buffer or an
• 33:34external inhibitor
• 33:35against relapse later. So,
• 33:38defects are fundamentally by psychosocial.
• 33:40So the outcomes
• 33:41in the safety monitoring should
• 33:43match, that complexity.
• 33:46Okay. But what do we
• 33:47know, clinically?
• 33:49For
• 33:50pain, we mostly have early
• 33:51signals, so not conclusive data.
• 33:54There are older studies,
• 33:56administering LSD in cancer pain,
• 33:59that Chris already highlighted in
• 34:00case series like phantom limb
• 34:02pain. These are interesting historically,
• 34:05but most of them are
• 34:06not modern trial design.
• 34:08More recently,
• 34:10there's there have been low
• 34:11dose LSD
• 34:13studies testing pain in lab
• 34:14in the laboratory.
• 34:17For psilocybin, there's there are
• 34:18there is data from a
• 34:19crossover
• 34:20randomized control trial that provided
• 34:22a signal in migraine,
• 34:24and also some, headache cluster
• 34:26reports done at Yale by,
• 34:27Emanuel Schindler.
• 34:29And microneursing,
• 34:30patients ask about this all
• 34:32the time. This is one
• 34:33of the messiest areas. There's
• 34:35a lot of self selection,
• 34:36expectancy effects, and mixed outcomes.
• 34:39So as clinicians,
• 34:40I think the tone we
• 34:41should carry back to the
• 34:42clinic
• 34:43if asked about this is,
• 34:44you know, don't dismiss the
• 34:46signals, but don't let the
• 34:47signals become conclusions.
• 34:49I think the better responses,
• 34:51better trials, better endpoints,
• 34:53better safety measurement.
• 34:58So these are the human
• 34:59data.
• 35:00As you as you can
• 35:01see, the evidence base is
• 35:02early and heterogeneous.
• 35:04The strongest signal show up
• 35:06in cancer, palliative context,
• 35:08headache, and then a couple
• 35:10of examples in nociplastic
• 35:12pain or, fibromyalgia.
• 35:14And I'll show you some
• 35:15of those examples,
• 35:17starting with, migraine headaches. So
• 35:19this was an exploratory
• 35:20double blind placebo controlled crossover
• 35:22study. At two sessions separated
• 35:24by fourteen days.
• 35:26Placebo was given first
• 35:28to avoid long term carryover.
• 35:30Contaminating placebo, we just heard
• 35:32from Chris. These drugs may
• 35:33have protracted effects.
• 35:35The dose was
• 35:37around ten milligrams,
• 35:39orally,
• 35:40and there were ten, participants
• 35:42in this study. They were
• 35:44given,
• 35:45diaries to keep track of
• 35:46the frequency and intensity of
• 35:48their migraine,
• 35:49attacks.
• 35:50In the left,
• 35:52this graph shows a reduction
• 35:53in weekly migraine days,
• 35:55and it was significantly greater
• 35:56after psilocybin than placebo.
• 35:59And on the right,
• 36:00you see the time to
• 36:01the second migraine attack was
• 36:02longer after psilocybin.
• 36:05The first attack there there
• 36:06was a trend for the
• 36:06first attack as well.
• 36:09And interestingly, this is a
• 36:10this is a what's conventionally
• 36:12called
• 36:14it it used to be
• 36:14called a sub hallucinogenic
• 36:16dose,
• 36:17or minimally hallucinogenic dose. People
• 36:19don't use that terminology anymore,
• 36:20so instead, we just call
• 36:21it low dose,
• 36:23meaning it's not a dose
• 36:24that will produce a trip.
• 36:27The interesting part is,
• 36:29the migraine improvement did not
• 36:31correlate with the intensity of
• 36:33the the psychedelic effects. So
• 36:35the
• 36:36the benefit was
• 36:37dissociable from,
• 36:39whatever minimally,
• 36:41psychedelic experience they had with
• 36:43this ten milligram dose. And
• 36:44while while migraine is a
• 36:46specific,
• 36:47headache disorder with limited general
• 36:49generalizability
• 36:50for other types of chronic
• 36:51pain, This is a good
• 36:52example of a control signal
• 36:54after limited dosing for a
• 36:55merit debilitating disorder.
• 36:58This other study emphasizes feasibility
• 37:00and safety, and functional outcomes.
• 37:03This is the this is
• 37:04fibromyalgia, the prototypical,
• 37:06nociplastic,
• 37:08chronic pain condition.
• 37:10So it it's often framed
• 37:11as the as the prototypical
• 37:13nociplastic condition because it's associated
• 37:15with pain,
• 37:16sleep, mood, cognition dysfunction, and
• 37:18there are limited effective treatments.
• 37:20The design was open label.
• 37:22There were five people in
• 37:23this study, and they first
• 37:24got fifteen milligrams of psilocybin,
• 37:26then they got twenty five.
• 37:28So twenty five, it it
• 37:29is considered a psychedelic dose.
• 37:31This is separated by two
• 37:32weeks. The primary outcomes were
• 37:34safety related.
• 37:36There were transient changes in
• 37:38blood pressure to heart rate,
• 37:40during the dosing session that
• 37:41were normalized by the end
• 37:42of the session. There were
• 37:44no series AEs.
• 37:46Four out of five people
• 37:47reported,
• 37:48post dosing headaches.
• 37:50At one month post the
• 37:51second dose,
• 37:53there were clinically meaningful improvements
• 37:54in pain severity, interference,
• 37:56sleep disturbance, and they report
• 37:58a larger effect size of
• 37:59going to the f two
• 37:59and above.
• 38:01Obviously, limitations include a tiny
• 38:03sample, all the label, highly
• 38:05selected.
• 38:06So this is best for
• 38:07this feasibility study.
• 38:08And, you know, together with
• 38:10the migraine model, this supports
• 38:11moving toward larger control trials
• 38:14that prioritize
• 38:15function and and, risk monitoring.
• 38:18And finally, for the pain
• 38:19part of the talk, I'd
• 38:21like to highlight a controlled
• 38:22human evidence of an analgesic
• 38:24signal. This is closer to
• 38:25my heart because it's a
• 38:26human lab study.
• 38:28And this was a randomized,
• 38:29double blind, placebo controlled,
• 38:31within subject crossover study. There
• 38:33were twenty five, in this
• 38:34case, healthy people.
• 38:35They received a low doses
• 38:37of LSD
• 38:38of five, ten, and twenty,
• 38:40micrograms
• 38:41per day versus placebo,
• 38:44each separate session.
• 38:45They did the cold pressor
• 38:46test, which is a pretty
• 38:47reliable,
• 38:49model for evoking the experience
• 38:51of pain using,
• 38:53a rapid onset and rapid
• 38:54offset, type of stimulation because
• 38:56you're you're looking at primarily
• 38:58unmelanated fibers.
• 39:00And the the key result
• 39:01is that the highest dose
• 39:02of twenty micrograms
• 39:03was associated with increase in
• 39:04pain tolerance so people could
• 39:06stick their hand in this
• 39:07bath water for much longer.
• 39:09They also,
• 39:11reported,
• 39:12lower, ratings of painfulness and
• 39:14unpleasantness.
• 39:15There there were modest increases
• 39:17in blood pressure,
• 39:18but heart rate was not
• 39:19affected.
• 39:21And it it this supports
• 39:23biological plausibility for analgesic and
• 39:26hyprogesic
• 39:27effects,
• 39:28given that this model is
• 39:29believed to have predictive validity,
• 39:32for this clinical phenomenon. But,
• 39:34again, this is experimental pain
• 39:35in in healthy volunteers, not
• 39:37chronic pain, and not comorbid
• 39:39with OUD.
• 39:41Okay. But,
• 39:42what about OUD?
• 39:45What has this has this
• 39:46any of this been tested
• 39:47in OUD? And the candid
• 39:48answer is not enough. Not
• 39:49enough yet,
• 39:51but the data is emerging.
• 39:53Historically, there's LSD psychotherapy work,
• 39:57in chronic heroin use from
• 39:58the seventies. Chris had his
• 40:00line about that. That is
• 40:01import important proof of concept,
• 40:03but it is not modern
• 40:04MOUD era care.
• 40:07In more in modern work,
• 40:08we have early safety data,
• 40:10which is small but reassuring.
• 40:12And now we have registered
• 40:13trials underway that explicitly
• 40:16ask safety and efficacy questions
• 40:18in people with MOUD,
• 40:20primarily in phase two.
• 40:22Now do the side effects
• 40:23look different in people with
• 40:24the o u d?
• 40:26Probably, yes.
• 40:28But we don't have enough
• 40:29data to say.
• 40:30And I say probably, yes,
• 40:31because what we do know
• 40:33is that the baseline vulnerability
• 40:34is often higher.
• 40:36Both psychiatric and and medical
• 40:38comorbidity,
• 40:39trauma exposure, polysubstance
• 40:41use.
• 40:42So our safety approach must
• 40:43be more intentional,
• 40:45and our follow-up needs to
• 40:46to be real.
• 40:49This table summarizes the human
• 40:51OUD evidence and highlights why
• 40:53safety and real world risk
• 40:55must be accounted for in
• 40:57in in the study design.
• 40:59The big picture is OUD
• 41:00evidence is thinner
• 41:02than the pain evidence,
• 41:03and and the studies vary
• 41:05widely by setting,
• 41:07dosing, and and outcomes.
• 41:10There is enough signal to
• 41:11justify modern trials in OUD
• 41:13and pain, in my opinion,
• 41:15but the risks we actually
• 41:16care about overdose
• 41:18risk of polysubstance use,
• 41:21in some cases,
• 41:22cardiac arrhythmia,
• 41:24and,
• 41:26pain interference function
• 41:28have to be built into,
• 41:30design and and measurement.
• 41:33This slide shows some of
• 41:34the historical control OUD signal.
• 41:37So this was a randomized
• 41:38incarcerated,
• 41:40randomized trial in which they
• 41:41people were incarcerated
• 41:43in, they they had a
• 41:44residential psychedelic therapy program versus
• 41:46an outpatient
• 41:48abstinence program without MOUD.
• 41:51Both had intense monitoring.
• 41:53In the psychedelic arm,
• 41:55people received five weeks of
• 41:56preparatory
• 41:58psychotherapy
• 41:59that culminated
• 42:00in one very high dose,
• 42:02of LSD,
• 42:04administered in one session. The
• 42:05dose was three hundred to
• 42:06four fifty. So just to
• 42:08compare, this is over ten
• 42:09times higher than the human
• 42:11lab study I just showed,
• 42:13but what people call heroic
• 42:14dose of LSD.
• 42:17Twenty five percent what the
• 42:18graph shows is that twenty
• 42:19five percent maintained verified
• 42:21abstinence
• 42:22for a year
• 42:24versus in in the, LSD
• 42:26group as opposed to five
• 42:27percent in the control group.
• 42:28And you see some of
• 42:29the patient quotes on the
• 42:31right.
• 42:34This patient describes,
• 42:35heroin as an escape.
• 42:38The overall theme is the
• 42:39LSD as a confrontation
• 42:41or reorientation.
• 42:43So, again, this is not
• 42:45a modern,
• 42:46clinical trial. People were not
• 42:47getting m o u d.
• 42:49This is not blinded.
• 42:50Still, it's durable behavior change
• 42:52signal,
• 42:53that is motivating
• 42:55modern
• 42:56and safer trials in people
• 42:58with, people receiving m o
• 42:59u d.
• 43:01And here I'd like to
• 43:02make the safety point. I
• 43:04Ibogaine
• 43:04illustrates this well. This was
• 43:06an open label observational study
• 43:09in four people receiving m
• 43:10o u d. On the
• 43:11left,
• 43:12you see,
• 43:14the figure show shows prolongation
• 43:16prolongation
• 43:17proportion of subjects with a
• 43:19QTC
• 43:20time exceeding four fifty milliseconds
• 43:22or five hundred milliseconds
• 43:25in the first twenty four
• 43:26hours period after Ibogaine.
• 43:28And and there's a clear
• 43:29signal there. The in on
• 43:31average, the QPC was prolonged
• 43:33by around a hundred ninety
• 43:34five to a hundred milliseconds.
• 43:36And,
• 43:37Ibogaine, especially the metabolite of
• 43:39Ibogaine or Ibogaine
• 43:41blocks,
• 43:42potassium channels.
• 43:44So it delays ventricular
• 43:45repolarization.
• 43:47It's it's a very promiscuous
• 43:49drug.
• 43:51On on on the right,
• 43:53you see, another consequence of
• 43:55this receptor promastridium
• 43:57of, Ibogaine,
• 43:59which is ataxia. It's a
• 44:00spaghetti block with individual
• 44:02level data, and you see
• 44:03that
• 44:04people experience attack ataxia primarily
• 44:06in the first two to
• 44:07six hours
• 44:09after getting Ibogaine.
• 44:11And and, you know, it
• 44:12has a lot of cerebellar
• 44:13and vestibular effects. It's an
• 44:15NDMA antagonist.
• 44:16Also, it has some effect
• 44:17on sodium channels.
• 44:19So the the message here
• 44:20is that,
• 44:21especially for people getting methadone,
• 44:23the arrhythmia risk is real
• 44:25with Ibogaine.
• 44:26So,
• 44:27strict medical monitoring is required.
• 44:30And and we have to
• 44:30be cautious to, generalize. Most
• 44:33of these studies are done
• 44:34in Central America or South
• 44:35America, and they're observational.
• 44:38There are companies working in,
• 44:40tweaking the ibogaine molecule to
• 44:41avoid some of these effects,
• 44:42but we we have yet
• 44:44to see,
• 44:45high quality data with those
• 44:46compounds.
• 44:48And here's
• 44:50one of the few modern
• 44:51data points on psychedelics in
• 44:53an,
• 44:54NYUD context.
• 44:56The question here was, can
• 44:58salsalvin be given safely to
• 44:59people who are getting buprenorphine?
• 45:01And this was an open
• 45:02label case series.
• 45:06People were getting buprenorphine naloxone.
• 45:08They completed two psilocybin sessions
• 45:10in a supportive setting. There
• 45:11were no serious AEs,
• 45:13and and no evidence of
• 45:14psilocybin compromising,
• 45:17the effectiveness of buprenorphine in
• 45:19any way.
• 45:20The n is very small.
• 45:21There's only two people, so
• 45:22take that with a grain
• 45:23of salt.
• 45:25The figure shows subjective effects,
• 45:28looking broadly consistent
• 45:29consistent with previous psilocybin
• 45:32studies.
• 45:33And, you know, supporting
• 45:34feasibility without
• 45:36over claiming out outcomes, which
• 45:38the paper doesn't,
• 45:39given the tiny sample.
• 45:42And here we see epidemiology
• 45:44epidemiology as
• 45:46additional early signal. This is
• 45:48an SDOH data from forty
• 45:50five thousand adults.
• 45:52The authors here examine the
• 45:53relationship between history of nonmedical
• 45:55opioid use
• 45:57and lifetime classic psychedelic use.
• 45:59So,
• 46:00think about the first quadrant,
• 46:02think about on the first
• 46:02slides Chris shows.
• 46:05Those are the classic psychedelics.
• 46:07And and the results show
• 46:08that psychedelic use was associated
• 46:10with reduced risk of past
• 46:11year, opioid dependence, and opioid
• 46:13abuse. This is DSM four
• 46:15criteria.
• 46:15The paper came out around
• 46:17three years ago, but the
• 46:18data itself is from twenty
• 46:20thirteen, I believe. So it's,
• 46:22the DSM,
• 46:23four.
• 46:24And a couple caveats, it's
• 46:26cross sectional, so we cannot
• 46:27infer causality.
• 46:28There's unmeasured confounding, very likely.
• 46:31The point here is that
• 46:32the signal doesn't come it's
• 46:34not confined, just the small
• 46:36clinical cohorts.
• 46:38You know, these large scale
• 46:39epidemiological studies also lend support
• 46:42to hypothesis driven,
• 46:44clinical trials.
• 46:46Now let me also give
• 46:47you a preclinical
• 46:49snapshot
• 46:50as plausibility for what we
• 46:51should test and what we
• 46:52should measure.
• 46:53On the left, you have,
• 46:55paper that came out last
• 46:56year, Nature Neuroscience paper.
• 46:58They looked at two standard
• 47:00chronic pain models. One of
• 47:02neuropathic pain, called spare nerve
• 47:04injury and another of inflammatory
• 47:06pain called the CFA model.
• 47:08And the the key point
• 47:09is that once these animals
• 47:11have chronic pain, they have,
• 47:12mechanical hypersensitivity.
• 47:15And a single dose of
• 47:16psilocybin
• 47:17produces a rapid improvement by
• 47:19the next day. So you
• 47:20see the psilocybin administered here
• 47:22here in a normalization
• 47:24of, mechanical
• 47:26hypersensitivity,
• 47:28across the follow-up window
• 47:31on the order of weeks.
• 47:32And I'm showing this animal
• 47:33data because
• 47:35it supports,
• 47:36I believe, an an important
• 47:37clinical idea,
• 47:38which we may be looking
• 47:40at a time limited window
• 47:41of change rather than daily
• 47:43symptomatic
• 47:44dosing.
• 47:45So human trials should prioritize
• 47:47durability and function and not
• 47:49just same day pain ratings.
• 47:52And on the right, we,
• 47:53there's a a molecular psychiatry
• 47:55paper also from last year.
• 47:57Actually, it's twenty twenty four.
• 48:00And this was a heroin,
• 48:02self administration study.
• 48:04And and and here, psilocybin
• 48:05blunted
• 48:06cue induced heroin seeking, which
• 48:08is believed
• 48:10to model relapse.
• 48:12And in this pattern of
• 48:14effects on relapse vulnerability
• 48:16maps onto what we care
• 48:17about clinically.
• 48:19So I I think explanations,
• 48:20we should treat these as
• 48:21directional signs.
• 48:23In pain, measure interference and
• 48:25function
• 48:26over a longer period than
• 48:27you normally would with the
• 48:28traditional analgesic.
• 48:29In OUD, measure cue, stress,
• 48:31pain, provoke, craving, and relapse
• 48:33risk along with safety.
• 48:36And there's also momentum in
• 48:38clinical research. So these are
• 48:39the registered studies. There are
• 48:41studies looking psilocybin assisted therapy,
• 48:44to help taper long term
• 48:46opioid therapy for for pain.
• 48:48Also,
• 48:51safety interaction work with buprenorphine
• 48:53expanding on the preliminary data
• 48:55I showed earlier. And also
• 48:57plan studies in people on
• 48:58methadone,
• 49:00where medication and and cardiac
• 49:02monitoring matter matters the most.
• 49:04So the the science is
• 49:06finally moving from idea to
• 49:07to program.
• 49:10And, you know, the patients
• 49:12are already living in this
• 49:13reality. I don't know if
• 49:14you have patients who ask
• 49:15about this, but,
• 49:17I I have patients who
• 49:18have asked about states like
• 49:19Oregon.
• 49:21And, you know, sometimes people
• 49:23assume that,
• 49:25states that have programs
• 49:27that facilitate facilitate access to
• 49:29psychedelics,
• 49:30such as psilocybin,
• 49:33It is the same phenomenon
• 49:35we saw with cannabinoids, right?
• 49:36State level indication
• 49:38is different than an FDA
• 49:40approved indication.
• 49:41The states have regulated access
• 49:44frameworks.
• 49:45A clinical trial on the
• 49:46other hand which is how
• 49:47you obtain a date approval
• 49:49you have diagnosis based enrollment,
• 49:51medical monitoring,
• 49:53you have defined endpoints,
• 49:54you have systematic adverse event
• 49:56tracking,
• 49:57And and here's why that
• 49:59gap matters.
• 50:00If psilocybin
• 50:01were to receive FDA approval
• 50:03for any indication, which is
• 50:05likely to happen
• 50:06in the next several months
• 50:07to a year for depression,
• 50:10it would become,
• 50:11you you know, legally prescribable
• 50:13off label,
• 50:14including for people with OUD
• 50:17or even pain well before
• 50:19we have mature
• 50:20efficacy and safety data in
• 50:22those populations.
• 50:23So if if access expands
• 50:25faster than evidence,
• 50:27the earliest adopters may be
• 50:29the the people who are
• 50:30most vulnerable. And those people
• 50:32are often those with pain,
• 50:33OED, trauma histories, and polysubstance
• 50:35exposure. So we really need
• 50:37high quality data in in
• 50:38the populations that we actually
• 50:40treat.
• 50:43So what should we measure
• 50:44to mitigate OUD risk? Because
• 50:46this population has
• 50:47higher baseline rates of trauma,
• 50:49anxiety, mood disorders,
• 50:51including both depression and bipolar
• 50:53disorder, suicidality and polysubstance use,
• 50:57We need to assess those
• 50:58medically. We need to look
• 50:59at cardiac arrhythmia risk,
• 51:01sleep deprivation,
• 51:03autonomic instability,
• 51:05medication lists, DDI, drug drug
• 51:07interactions.
• 51:08And there's also general a
• 51:09gender analyzability
• 51:11issue.
• 51:12Many psychedelic studies,
• 51:14exclude the very patients we're
• 51:16talking about.
• 51:17So that doesn't mean we
• 51:19shouldn't study them.
• 51:20We can study this safely,
• 51:22but only if we measure
• 51:23risk as rigorously as we
• 51:25measure benefit.
• 51:29This slide is basically the
• 51:30approach or should I say
• 51:32the philosophy of our lab.
• 51:35If we want to understand
• 51:36pain, especially pain in people
• 51:37with SUD,
• 51:39we have to bridge two
• 51:40worlds.
• 51:41On the left is what
• 51:42we can do in the
• 51:43lab, controlled pain testing. So
• 51:45we use,
• 51:46quantitation sort of testing or
• 51:48QST
• 51:48to probe mechanisms like central
• 51:50sensitization.
• 51:52We pair that with pharma
• 51:53PKPD,
• 51:54pharmacokinetics,
• 51:55and pharmacodynamics
• 51:57modeling when drugs are involved
• 51:59so that we're not just
• 52:00asking did pain change, but
• 52:01also how did the system
• 52:03respond to this drug and
• 52:04at what level of exposure.
• 52:06And on the right,
• 52:08in the real world, this
• 52:09is where pain actually drives
• 52:10disability and relapse risk. That's
• 52:12why we use,
• 52:14experience sampling or EMA.
• 52:16So smartphone based assessments, accelerometers
• 52:18to capture pain intensity, interference,
• 52:21mood function,
• 52:22in real time, not just
• 52:24as a monthly clinic visit.
• 52:27And and the reason we
• 52:27do both is lab measures
• 52:29give mechanistic precision,
• 52:30but they miss the lived
• 52:31experience. And the real world
• 52:33measures,
• 52:35they capture what matters to
• 52:36patients, but they can be
• 52:37very noisy.
• 52:38When you combine them, we
• 52:39can test a stronger question,
• 52:42which is does an intervention
• 52:43move the mechanisms that we
• 52:44care about as scientists,
• 52:46and does that translate into
• 52:47better function and less the
• 52:49day less day to day
• 52:50suffering?
• 52:51And this is the bridge
• 52:52that we're trying to build.
• 52:55And I'll end with one
• 52:55concrete example of that approach,
• 52:57which is,
• 52:58we're going through the JIT
• 52:59process right now for this.
• 53:00So this is, an NIH
• 53:02grant, the National Center of
• 53:03Culinary Integrator Health.
• 53:05And we're going to test
• 53:06psilocybin as a nudge on
• 53:08the treatment of physical therapy
• 53:09to chronic low back pain.
• 53:11The reason to test
• 53:13to pair psilocybin with PT
• 53:15is that PT is an
• 53:16evidence based, intervention for chronic
• 53:18low back pain, but many
• 53:19patients can't fully
• 53:21engage with it because pain,
• 53:23fear of movement, and avoidance
• 53:24get in the way.
• 53:26And the hypothesis here isn't
• 53:27that psilocybin,
• 53:29will have a a a
• 53:30traditional ad hoc effect is
• 53:32that it will create a
• 53:33time limited window where people
• 53:35are more able to engage
• 53:36with movement,
• 53:37update their threat beliefs.
• 53:40So pain you know, motion
• 53:41is lotion, like physical therapist
• 53:43say, rather than pain is
• 53:44a threat,
• 53:45and, and do the work
• 53:46of of, of recovery. And,
• 53:49and, you know, this might
• 53:50be a if it does
• 53:51work, it could be a
• 53:52scalable concept,
• 53:54because it will work by
• 53:55strengthening,
• 53:57an existing clinical
• 53:58intervention,
• 54:00backbone of PT rather than
• 54:02building a stand alone psychedelic
• 54:04intervention.
• 54:05And this is the direction
• 54:06that I'm I'm looking for,
• 54:08a psychedelic science that's embedded
• 54:10in standard care,
• 54:12with measurable mechanisms
• 54:14and outcomes that
• 54:15clinicians,
• 54:17already trust.
• 54:19So I'll close with this
• 54:20mindset of responsible acceleration.
• 54:23That means that we take,
• 54:25risk seriously.
• 54:27We plan follow-up
• 54:28because benefit and risk don't
• 54:30end when the drug administration
• 54:32ends.
• 54:33It also means that we
• 54:34designed,
• 54:35clinical trials that include patients
• 54:37we actually
• 54:38treat,
• 54:39in both mechanistic studies and
• 54:40pragmatic,
• 54:41studies. So we can answer
• 54:43not just does it work,
• 54:44but
• 54:45for whom and wonder what
• 54:47conditions, and if so, at
• 54:48what cost,
• 54:49and and what risk. So
• 54:51so that we can replace
• 54:53the uncertainty with data and
• 54:54patients are enforced to choose
• 54:56between unrelieved pain and OUD
• 54:58or hype and speculation.
• 55:01Thanks again for the invitation,
• 55:03and the CNRU for being
• 55:04the home of our cannabinoids
• 55:06and now psychedelic studies and
• 55:07all the funders of this
• 55:08work. I'm happy to answer
• 55:10any questions.
• 55:12Thank you, JP. Wonderful overview.
• 55:14Thank you again, Chris, for
• 55:16your overview of psychedelics.
• 55:18I wanted to open it
• 55:19up for questions if anybody
• 55:21as we've got a couple
• 55:22of minutes.
• 55:24There's a question in the
• 55:25chat.
• 55:26Many for doctor,
• 55:28Dakino, many studies suggest that
• 55:30the psychedelic experience is important
• 55:32for therapeutic outcomes in depression
• 55:35and other psychiatric
• 55:37conditions.
• 55:38What do you make of
• 55:38one of the study finding
• 55:40that psychedelic intensity
• 55:42did not correlate with migraine
• 55:43improvement?
• 55:44Is this a signal that
• 55:45psychedelics work differently for pain
• 55:47than for psychiatric conditions?
• 55:51There's a pretty question.
• 55:52And this is,
• 55:53along with, you know, all
• 55:55the, all the methodological questions
• 55:57around blindness is probably one
• 55:59of the top two, top
• 56:00three questions in the field
• 56:02to what degree the psychedelic
• 56:04experiences matter.
• 56:07You know, many people think
• 56:08that,
• 56:09if you want to change
• 56:10the relationship,
• 56:12with pain or with,
• 56:14opioid use and if you
• 56:16have these entrenched
• 56:17beliefs
• 56:19that the experience itself and
• 56:20going through it,
• 56:22might be important to,
• 56:24dissociate them. But I I
• 56:26I I have not seen
• 56:27convincing data yet. I think
• 56:28it I think we have
• 56:29to extrapolate thoughtfully.
• 56:32Like I said, migraine headaches
• 56:33are, a specific ideology.
• 56:35It's unclear. I mean, they
• 56:37have central citizenization
• 56:38does happen in migraine headaches,
• 56:41but,
• 56:42it's hard to extrapolate that
• 56:43to chronic low back pain,
• 56:45which is a heterogeneous condition
• 56:46in itself.
• 56:48So so the the honest
• 56:49answer is, I don't know,
• 56:50as as more data becomes
• 56:51available, hopefully, we can, you
• 56:53know, harmonize those datasets and
• 56:55and see where it matters
• 56:56and where where it it
• 56:58doesn't.
• 56:59If if it doesn't matter
• 57:00as much from a clinical
• 57:02monitoring standpoint,
• 57:04that could be interesting because
• 57:06one of the main reasons
• 57:07why, you know, the you
• 57:08have to have two people
• 57:10when you when you administer
• 57:11these medications, the very intestinal
• 57:12abnormalities precisely because of phenomenological
• 57:14effects.
• 57:15So if it turns out
• 57:16we can have some of
• 57:17the benefit
• 57:18without having to go through
• 57:19that experience,
• 57:22From building a service that's
• 57:24able to administer these drugs,
• 57:25that would be advantageous.
• 57:29I'll just throw in that
• 57:30I think it's premature
• 57:31to conclude that the specific
• 57:34characteristics of the of the
• 57:35of the phenom the phenomenological
• 57:37experience during the psychedelic dosing
• 57:38are necessary,
• 57:40but the therapeutic benefit there
• 57:41are these correlations. They're not
• 57:43seen in every study, but
• 57:44more often than not, there's
• 57:45a correlation between certain
• 57:47aspects of the experience, especially
• 57:49the religious mystical oceanic boundlessness
• 57:51ego dissolving aspects, which are
• 57:54operationalized in self report scales
• 57:55in a veranda in a
• 57:56variety of different ways, but
• 57:57very hard to grapple with.
• 57:59There are often these correlations.
• 58:01However, this is a classic
• 58:02example of correlation does not
• 58:03equal causation. The simplest explanation
• 58:05to that is just that
• 58:06it's a surrogate marker of
• 58:07the effect effective dose amount
• 58:08of drug that's in the
• 58:09brain.
• 58:10Right? You get the drug
• 58:11into the brain, you get
• 58:12therapeutic effect, and you get
• 58:13the psychological effects. And so
• 58:14it simply may be a
• 58:15marker that you got the
• 58:16drug there at an adequate
• 58:18dose.
• 58:19And it could be a
• 58:20marker of activity in in
• 58:22certain brain circuits that are
• 58:24are,
• 58:24you know, relevant to therapy
• 58:26and related to these,
• 58:28experiences. So
• 58:30might be necessary.
• 58:32What that means is an
• 58:34interesting question when you talk
• 58:35about causality happening at the
• 58:36psychological level and at the
• 58:37neural level simultaneously. That gets
• 58:39into deep waters. But it
• 58:40might might be it. I'm
• 58:41totally open to the possibility.
• 58:43I think it's pre premature
• 58:44from the existence of these
• 58:45correlations
• 58:47to use that as a
• 58:48to assume that or to
• 58:49conclude that.
• 58:53Preston, JP, doctor Pittenger, and
• 58:55doctor Dakino,
• 58:56thank you so much.
• 58:58Fascinating. It's clear there's a
• 59:00lot of opportunity here. If
• 59:02I were an early stage
• 59:04investigator, I'd certainly be thinking
• 59:06about
• 59:07including research on,
• 59:09psychedelics and the potential impact
• 59:11in both acute and chronic
• 59:12pain and then not to
• 59:13mention opioid use disorder.
• 59:16So thank you very much,
• 59:17and, thanks everybody for joining,
• 59:20and we look forward to
• 59:21seeing you next time. Take
• 59:22care.
• 59:23It's been a pleasure to
• 59:24be with you today. Thank
• 59:25you. Yep. Thanks.