Yale Psychiatry Grand Rounds: December 18, 2020

December 18, 2020

Information

"Psilocybin: History, Neuropharmacology, and Implications for Therapeutics."

Roland R. Griffiths, PhD, Oliver Lee McCabe, III Professor in the Neuropsychopharmacology of Consciousness; Professor of Psychiatry and Behavioral Sciences, Johns Hopkins Medicine.

ID6021

To CiteDCA Citation Guide

00:00Leave, you're introducing our speaker
00:02today. Yes, my pleasure.
00:03Do we have any announcements before?
00:06Yeah, I just I just wanted to
00:08to everybody on the call.
00:10I just wanted to say that this
00:13has been just an incredible year.
00:17Where we faced many,
00:20many terrible challenges and losses.
00:23With particularly Randumb Ann
00:26and Bob Malesan. Close friends
00:30and colleagues teachers mentors.
00:33People have played an important
00:35life in the Department. We've lost
00:38other important alumni and friends.
00:40Other apartment as well.
00:43Um? On top of that,
00:46we've had to completely adapt
00:48and change nearly everything
00:49that we do the way we treat the
00:52way that we conduct research.
00:55The way that we take care of patients
00:57and the Department has shown remarkable
01:00flexibility and resilience and
01:02adapting to the changing context.
01:04I also wanted to note that
01:07whenever our Department was
01:09asked to step up and to do more.
01:11That we had volunteers from our
01:14residents who volunteered to serve
01:16taking care of medical patients,
01:19going back to to volunteer and
01:22medical units to volunteers on our
01:25voluntary and full-time faculty
01:27who have provided support to
01:30people in our healthcare community
01:33without any compensation.
01:35Trainees participated
01:36in that program as well.
01:39That that that the actions of
01:43our Department have provided.
01:45You know,
01:46one source of inspiration after
01:49another and and that's been really
01:52good because as a Department we've
01:55also faced the terrible burden of
01:58the murder of of black Indigenous
02:01people of color by police that
02:04reverberated through our Department
02:07and resonated with the health care
02:10disparities in the impact of Covid.
02:13They have been such a painful
02:16part of this year as well.
02:18And and the hopeful actions
02:21of many in the Department.
02:23And now the Anti Racism Taskforce,
02:26hopefully will will make something
02:29good and positive out of the adversity
02:33that that we've seen around us.
02:36So I come away thinking that I'm
02:40very glad to put 2020 behind us.
02:43Looking forward to 2021 with
02:46great anticipation.
02:47I hope those of you who have
02:51the opportunity to do so.
02:54Take advantage of the opportunity to
02:57get an early injection of the vaccine.
03:00This is really going to be another
03:02way that we in our community can
03:05take care of ourselves and to prevent
03:08being part of the spread of this
03:11terrible pandemic to our families,
03:13to our patients, to our colleagues.
03:15So I hope you will take advantage
03:18of this vaccine that has been
03:21so well tested and developed.
03:23Um? So thank you again.
03:27I think we have a wonderful lecture to
03:32celebrate the end of 2020 and Chris,
03:36would you introduce our
03:39distinguished speaker today?
03:41Thank you John.
03:42Yeah my pleasure in my honor to to do so.
03:46Our speaker today is Roland
03:49Griffiths from Johns Hopkins.
03:51Roland is let me get the
03:53full title right here.
03:54The Oliver Lee McCabe,
03:55the third professor in the
03:57Neuropsychopharmacology of consciousness
03:58as well as professor of Psychiatry
03:59and Behavioral Sciences in Hopkins.
04:01And he's the director of the
04:03Hopkins Center for Psychedelic
04:05and Consciousness Research.
04:07And Roland was already added
04:09extraordinarily impactful and and
04:10productive figure in pharmacology prior
04:12to getting involved in psychedelics.
04:14But since 1999,
04:16when he began his work with psilocybin
04:18and other psychedelic drugs,
04:20it's it's really difficult to
04:22overstate the impact he's had as a
04:25central figure in the resurgence of
04:27interest in psychedelics as potential
04:29therapeutic agents as well as agents
04:32that give us some window into the
04:35nature of human consciousness.
04:37This is,
04:38as I'm sure many in this audience knows,
04:41something that's that's really
04:42burst onto the the the the
04:44mainstream public imagination,
04:45and as well as academic
04:47medical seen in the last.
04:49I'll say five or six years.
04:51But it was been.
04:52But that is due to the pioneering
04:54efforts of Roland and a small
04:56handful of other colleagues
04:58who's kept interest in these
05:00substances alive over the decades.
05:02The work of the Hopkins Group has
05:04been truly seminal in doing the
05:06first modern controlled studies.
05:08Of psilocybin and other drugs as.
05:11Therapeutic agents across
05:12a number of indications,
05:14particularly impactful or 2016,
05:15study on the use of psilocybin in late life,
05:18existential despair.
05:19So in the hospital setting and
05:21then the study that just came out
05:23in depression and I trust we'll
05:25hear something about those today.
05:27So this is an area that we're
05:29beginning to do some work on it.
05:32Yale and with work in a number
05:34of different agents.
05:35Of course,
05:36this has been the Home Academy
05:38in research for some time,
05:40but more recently with Serial
05:42Diseuse is work.
05:43Looking at salvinorin A as well as
05:45ongoing studies with DMT and and psilocybin,
05:48Ben Kelmendi has spearheaded work
05:50in both PTSD and USI Dee Ann.
05:52We have some work in depression coming
05:54along as well as some mechanistic work.
05:57Alex Kwan and others,
05:58and Alan anticipating this group have
06:00been doing some mechanistic work.
06:02So this is an area that we're excited
06:05about and so to bring one of The
06:08Pioneers of this field in to speak
06:10to us today is really a great way to.
06:13Map upper Ground round series for 2020,
06:15so Roland it's really a pleasure to
06:16have you here today and we're very much
06:18looking forward to your presentation.
06:22Thank you, Chris is delightful to be here,
06:25so I'm going to talk about psilocybin
06:29little bit of history neuro.
06:31Pharmacology and then implications
06:33for treatment user might disclosures.
06:36In a nutshell, a variety of.
06:40Private sector and philanthropic
06:42support has been important to this.
06:46A little bit of NIH support as well.
06:51But I'm going to talk about is our research
06:55at Johns Hopkins over the last 20 years.
06:58Ancilla Simon and that started off with.
07:03As a labor of love with a very little bit
07:07of philanthropic support and blossom,
07:10this last year with the founding
07:12of our Center for psychedelic
07:15and Conscious Research.
07:17The work I'm going to present is is that on
07:21behalf of a team of very talented colleagues,
07:25a member of whom I've worked
07:28with for some time, like Matt.
07:31Johnson and then Bill Richards.
07:36So just by way of background,
07:38psilocybin is a naturally
07:40occurring tryptamine alkaloid.
07:42It's the principal psychoactive
07:43component of Sloss Pea,
07:45genus of mushrooms and psilocybin,
07:47in the form of mushrooms,
07:49have been used for hundreds or perhaps
07:53thousands of years in various cultures.
07:56In terms of background,
07:58these classic.
07:59Psychedelics are structurally diverse
08:02group of compounds that bind serotonin
08:052A receptors and then of course,
08:07they produced this unique profile
08:10in changes of perceptions,
08:12emotions and thoughts.
08:13And so, structurally,
08:15they are the classic tryptamines
08:18and then the phenethylamines.
08:20Historically,
08:21a lot of research was conducted
08:23back in the 50s and 60s and then
08:26research with this whole set of
08:28compounds went dormant for almost
08:30three decades because of the safety
08:33concerns that were raised in response
08:36to the widespread non medical use of
08:39these compounds in the in the 60s.
08:42Just a brief statement about abuse and risk,
08:47of course.
08:48Psilocybin is a schedule.
08:50One compound is not considered to
08:53be a drug of addiction sabinada
08:56because it doesn't produce compulsive
08:59drug seeking behavior.
09:02Medical emergency from psilocybin
09:04use are very rare.
09:06Nonetheless,
09:07there is concern about potential
09:10adverse effects,
09:11including panic reactions and
09:13possible precipitation.
09:15Of enduring psychiatric conditions and and,
09:18we documented the validity of these
09:20concerns in a large Internet survey.
09:24We did have almost 2000 people
09:26who described and reported the
09:29effects of challenging experiences.
09:31After taking psilocybin and 11%
09:34of this group describing their
09:36very worst experience,
09:38put themselves at risk or others at
09:42risk for physical harm an I think.
09:45Most most notably to me is 10% reported
09:50in during adverse psychological
09:52symptoms lasting over a year that they
09:56attributed to this difficult experience.
09:59So such.
10:00Experiences are very uncommon
10:03in laboratory environments.
10:05With respect to molecular
10:07mechanisms of action,
10:09I mentioned serotonin 2A receptors is
10:11is the target in which they function as
10:15agonist Saint Agnes just as last year,
10:19Kim at L and Incel looked and
10:22determine the active state structure
10:24of the serotonin 2A receptor as it's
10:28bound to a prototypic hallucinogen,
10:31and so I think we can expect
10:34with this kind of development.
10:37In the understanding of the
10:39receptor pocket and the active
10:42sites that this is going to accelerate the
10:46discovery of even more selective compounds.
10:50Again, in terms of mechanisms
10:53and serotonin 2A receptors are
10:56expressed in key cortical areas,
10:59particularly cortex in apical dendrites,
11:02in layer five of paramel cells,
11:06thalamus, claustrum, locus Aurelius.
11:10And with respect to biological mechanisms.
11:13The current thinking is that there's
11:16really a small subset of serotonin 2A
11:19excitatory trigger neurons that are
11:22responsible for initiating cascade of
11:25cellular events that result ultimately
11:28in destabilization of brain networks.
11:31And then the emergence of novel
11:34patterns of connectivity that of course
11:37resolved when the drug is illuminated
11:40and it's been hypothesize, d'oh.
11:43He said metaphor, if you will,
11:47that in the case of psychiatric disorders,
11:51malfunctioning networks can
11:52subsequently reconnect in more
11:54adaptive and healthier ways.
11:57So the metaphor given is to that
12:00of resetting the computer system.
12:05This is a now classic depiction of
12:09brain network communication patterns.
12:12This was out.
12:13This is MRI data out of Imperial and
12:18what's shown here is this connected gram.
12:24And the left shows placebo.
12:26The different colors are different
12:28networks and most of the connectivity
12:31is within network connectivity.
12:34Some across network connectivity and
12:36then on the right they connectivity
12:39pattern acutely under psilocybin.
12:42So there's this large breakout
12:44of intercommunication.
12:45This isn't just random.
12:47The width of those lines are indicating that.
12:54Systematic organization
12:55of that communication,
12:57and then that resolves as psilocybin is.
13:03Illuminated so another snapshot at.
13:07You know what are these
13:10mechanisms of action you know,
13:12takes us to the different
13:14network functions and.
13:16And one very popular and metaphorically
13:20compelling observation has been
13:23that there are deactivations in the
13:27default mode network under psilocybin,
13:30and the default mode network is very
13:34often thought to under write a sense of
13:40self or self preferential processing.
13:44It's increased in depression.
13:46Decreased acutely with Silla Simon
13:49and it fits with this story that
13:52these compounds may result in,
13:54you know, dissolution of self,
13:57if you will,
13:58or ego if you dissolve this
14:00self preferential processing.
14:02It also fits with the fact that long
14:06term meditators showed decreases
14:07in default mode network processing,
14:10but this is just going to be one
14:13of many levels of explanation.
14:19Barrett Fred Barrett from our lab
14:22has just recently published some work
14:25showing that psilocybin alters colostrum
14:28connectivity to classic brain networks,
14:30and that's a big interest because.
14:36Crick, among others,
14:38hypothesize that the Claustrum might
14:40be intricately involved in the nature
14:43of consciousness and classroom is,
14:46you know, a structure that is
14:48highly enervated in serotonin.
14:502A receptors in a lot of connectivity
14:54in cortical brain structures,
14:56so that's that's going to be an
14:59interesting piece to the puzzle
15:01and then buried in a separate study
15:05showed psilocybin transcendent.
15:07Transiently reduces amygdala response
15:09to emotional and neutral faces.
15:12This is a week post psilocybin,
15:16so we're what we're looking for.
15:19Here is what?
15:21What elements of neuronal functioning might
15:25account for enduring effects of psilocybin?
15:29The Olsen lab at UC.
15:34Davis has, let's see.
15:39Well, let me start with the
15:42anti inflammatory effects.
15:44So Chuck Nichols has shown that
15:47psychedelics have very potent
15:48anti inflammatory effects,
15:50so that may be among the potential
15:53mechanisms and then the Olson
15:56lab has shown that psychedelics
15:58produce structural and functional.
16:01Neuroplasticity narrated Genesis,
16:02Spina Genesis of Napa Genesis immediately
16:05through various signaling pathways.
16:07So, so,
16:08the idea that.
16:10Enduring neuroplastic changes might
16:12account for what's going on with
16:15psychedelics is certainly compelling
16:17and interesting biological mechanism.
16:22Overall, this neuropharmacology is
16:23just a very active area of research,
16:27and there's a lot of progress being made,
16:30so it's a hugely exciting area to jump into.
16:36However, to me when we first started this
16:39among the most interesting features of
16:41the psychedelics were that they produce
16:44these profound acute and sometimes
16:47enduring alterations of consciousness.
16:49And just I just need to say how
16:53deeply ignorant we are about the
16:56very nature of consciousness.
16:58So I think we need to go into
17:01this with some humility.
17:04There's this hard problem of consciousness,
17:06which is indeed a hard and
17:09perhaps unsolved soluble problem.
17:11And it strikes me as a mystical
17:15puzzle in and of itself.
17:18And then just last week we published
17:20a pair of viewpoint articles.
17:23This is in pharmacology and
17:25translational Sciences.
17:26Olson taking the position,
17:28that subject subjective effects are
17:30not necessary for therapeutic effects,
17:33and we took the contrarian
17:35position that they are.
17:37And of course it's going
17:40to be some interaction.
17:41Well, I would submit it's going to
17:45be some interaction between the two.
17:48Um?
17:50So to tell you a little bit about what we
17:54have done over the last 20 years we've done.
17:59A number of studies in healthy participants,
18:03both psychedelic,
18:04naive and experienced.
18:06We've looked at novice
18:08and long-term meditators,
18:10religious professionals.
18:13Depressed and anxious cancer patients,
18:15people with major depressive disorders,
18:18cigarette smoking.
18:19We're doing studies now with anorexia
18:21nervosa and depressed patients
18:24with early Alzheimer's disease.
18:26And So what I'm going to do is tell you
18:30a little bit about the healthy volunteer.
18:34Participants were search and then
18:36quickly go over the work with the
18:40cancer and depressed patients and.
18:43And smokers.
18:44Today we have treated over 375
18:47participants and over 700 sessions,
18:50so we've accumulated a good bit of
18:53experience with still assignment.
18:57So I want to start off with the studies
19:01in healthy participants because it's a
19:04model for administration of high doses
19:08an it's that model that we have used
19:12in our our treatment studies to date.
19:15So these I'm going to just summarize some
19:18results across several different studies,
19:21but these are all double blind studies.
19:25Participants were medically and
19:27psychiatrically healthy and most.
19:29In these studies were without any
19:32histories of psychedelic use because
19:35we didn't want to skew the population
19:38toward people who were proponents or
19:41had had positive experiences that our
19:45participants meet with our session
19:47monitors to develop repor and trust,
19:50thought to minimize adverse reactions.
19:53An experimental conditions are
19:55designed to minimize expectancy bias,
19:58but this is a.
20:00Incredibly complex thing to do with
20:04approach to different ways.
20:07Studies are conducted in a comfortable
20:09living room like environment.
20:11I participant comes in in the morning,
20:14takes a capsule containing cell assignment,
20:17is asked to lay on a couch.
20:20We used this structured situation
20:22developed back in the 60s.
20:24We ask people to have eye shades and
20:27headphones through which they listen
20:29to a program of music throughout
20:32the period of drug action there,
20:34in the presence of two.
20:37Monitor facilitators guides if you will,
20:39but the invitation is to go inward and
20:42explore their own inner experience,
20:44so this isn't a guided session.
20:46We don't. We don't think of it as a.
20:50Certainly not a classic
20:52psychotherapeutic session.
20:53We're not inviting them to talk.
20:55We're inviting them just to going inward.
21:00This shows time course of monitor
21:02ratings across the six Hours session period.
21:05This is from a dose effect study
21:08showing very nice orderly dose
21:10and time related effects of.
21:13Up still assignment with effects.
21:15As you can see coming on in about
21:1730 minutes reaching peak effects at
21:19two to three hours and then tapering
21:22off by the end of the session day.
21:25People are very close to back to normal.
21:28We release them in the company
21:29of a friend or family member who
21:32accompanied them home.
21:35So what happens will,
21:37not surprisingly,
21:38you give a high dose of psilocybin,
21:42and you produce these
21:43classic psychedelic effects,
21:45including the perceptual changes,
21:47greater emotionality,
21:48both positive and negative,
21:49and cognitive changes.
21:51Sense of meaning,
21:53sometimes suspiciousness but what was
21:55stood out and was so intriguing to me
21:59initially was that in most participants
22:02under these kinds of conditions.
22:06Psilocybin produces large increases
22:07in self rated questionnaires.
22:09To designed that were initially
22:12designed to measure naturally occur
22:14in mystical or insightful type
22:16experiences and this shows post session
22:19ratings of mystical experience on
22:22our Mystical Experience questionnaire
22:24that we've developed and validated.
22:26Just showing this is nice dose
22:29related effects high scores.
22:31What in the world is a
22:34mystical experience you?
22:36Might very well ask,
22:37and in retrospect we have a.
22:40We made a series branding error here.
22:43Calling this questionnaire and
22:45mystical experience Questionnaire
22:47'cause if the funnels people but.
22:50But in any case,
22:52this questionnaire is really comprised
22:55of questions that probe different
22:58phenomenological factors and the.
23:00The first three questions,
23:03or three sets of questions you know,
23:07probe the phenomenological.
23:08Our concept of unity as a core feature.
23:12This interconnectedness of all people
23:14and things all is 1 pure consciousness.
23:18And that's accompanied by
23:19this sense of sacredness,
23:21reference or press ishness.
23:23There's something valuable
23:24about this experience,
23:26and it has this noetic quality of.
23:31Having encountered ultimate
23:32reality or the truth value of it,
23:35it seems more real and more true
23:38than everyday waking consciousness.
23:41And then the other factors are
23:44this deeply felt positive move
23:46transcendence of time and space and the
23:49ineffability difficulty put into words.
23:52Well, here's that.
23:54Thorn in our side,
23:56having used mystical and so so I just
23:58need to state mystical experience
24:00is defined by respondent endorsing
24:03a constellation of empirically
24:05measured phenomenological dimensions,
24:07and these this measure need
24:10not imply supernational or non
24:12rational levels of explanation.
24:14And and if you think about it,
24:18it's just been this kind of phenomena
24:21has been described by very many
24:24different names across the decades,
24:27like conversion experience with what
24:30William James initially described this.
24:32But also mystical religious peak.
24:35Transcendental experiences,
24:36transforming moment epiphanies.
24:39So when I initiated this work at Hopkins,
24:43Paul McHugh was our chair.
24:45Anne and Paul was insistent that
24:48we were just looking at delirium.
24:51And so we did a study in which
24:55we administered his scale,
24:57which is a gold standard measure
25:00now for delirium than many mental
25:03status examination to people
25:05who had psilocybin and what we
25:09were able to show is that.
25:11Um,
25:12that many metal isn't affected
25:14across the same range of doses
25:17of psilocybin that produced
25:20full on mystical experiences.
25:22In addition to mystical experiences,
25:25there's this other quality
25:27of these experiences,
25:29and that's those would be labeled experiences
25:32of significant psychological insight,
25:35and so those are increased
25:37in a dose related manner.
25:40We've actually now just developed and.
25:45I think it's in press or maybe
25:48just recently published.
25:49Our Psychological Insight questionnaire
25:52that pairs with our Mystical experience
25:55questionnaire and gets at a different
25:57facet of these experiences that may
26:00be quite important. We think too.
26:03And during therapeutic effects.
26:06So what I've described to this point
26:08has been the session experience.
26:11You know, these are all post session ratings,
26:15but the interesting piece of this
26:18work is the attributions that
26:20people make to these experiences.
26:23Going further out in time.
26:25And so here's one month after high dose
26:29sessions and healthy volunteers in which
26:32we have about 80% of people staying.
26:35Reflecting back on that experience
26:38a month ago and rating,
26:40it is among the five most personally
26:43meaningful or spiritually significant
26:45experiences of their entire lifetimes.
26:48And that it wouldn't even occur to
26:51me to ask a question of this sort.
26:54People rate these things about
26:5730% say it's the single most
26:59spiritually significant experience
27:00of their entire lifetime,
27:02but it was only after we start
27:05bringing people back in to do follow
27:09up interviews and we're realizing this.
27:11This is really unusual and certainly
27:14unprecedented in my working with a
27:17variety of psychoactive. Substances.
27:21And here we have about 90%.
27:25Attributing increased sense of
27:27well being life satisfaction
27:29or positive behavior change.
27:32So I'm just going to run down the kinds
27:36of things that people are endorsing.
27:39This is either one month after Sessions
27:42or in the right hand side from a
27:46different studies were six months after
27:49sessions and just the large effect sizes,
27:53Cohen D's of greater than one.
27:56But this is classically people attribute
27:59to these experiences, positive changes,
28:01positive attitudes about self, so.
28:04Increase self confidence in authority,
28:07authenticity, playfulness etc.
28:09Positive attitudes about life
28:11like increased life appreciation,
28:15gratitude, enthusiasm, meaning,
28:17etc.
28:18Positive mood changes increased love,
28:21inner peace,
28:23positive emotions decreased anger.
28:27Positive social effects.
28:28Positive relationships,
28:29greater tolerance start.
28:31Others love towards others.
28:33Empathy towards others compassion.
28:38Broadly speaking, increased
28:40spirituality, increased sense,
28:42of reverence, preciousness of life,
28:45profound sacred experiences.
28:50And people will also endorse
28:52behavior changes now these are in
28:55the healthy volunteer so we didn't
28:57have a single behavior target which
29:00we do in the addictions of course.
29:03But people report all kinds of things,
29:06such as increased improved
29:08social relationships or increased
29:10physical self care activities,
29:12spiritual practices, creative activities.
29:15So that's out to six months.
29:17Here is 14 months and this
29:19is just endorsement of.
29:21Increases in well being or life satisfaction.
29:24The red bar shows five weeks after a
29:28high dose of psilocybin and the blue
29:31bar shows 14 months in that same group.
29:35So these are these are sustained
29:37and anecdotally years later people
29:40will still make attributions of
29:42this type and and it's not just the
29:45volunteer that's reporting this,
29:47we have done, we've added.
29:51Measures of Community observer ratings.
29:53These would be family members,
29:55friends, colleagues at work.
29:59Providing ratings.
30:00Volunteers across a range of measures
30:04similar to those that they report and
30:08those are showing similar kinds of effects.
30:12And then just as a placeholder,
30:15'cause I'm going to return to
30:18it at the very end,
30:20mystical experiences scores predict
30:22meaningfulness and spiritual significance
30:24and openness in personality.
30:26At 14 months of there's something about
30:29these mystical experiences that are
30:31predictive of long-term enduring effects,
30:33and I'd just be remiss not
30:36to acknowledge that,
30:37in spite of all the screening
30:40we do in the preparation,
30:42the support during and after.
30:45About 1/3 of volunteers in
30:48one of our studies and I think
30:51that figure is roughly right.
30:54Experienced stronger extreme feelings
30:57of fear sometime during the session.
31:02Figure as unpredictable time course,
31:04but Despite that,
31:06most of these volunteers rated
31:08these experiences overall having
31:10meaning and spiritual significance.
31:13Then no volunteer rated the
31:15experiences to decrease their sense
31:18of well being or life satisfaction.
31:23OK, so now I'm going to move on to
31:26talk about our therapeutic trials and
31:29I'll start with our cancer study.
31:31These are people. With.
31:36With the. And a significant life
31:41threatening diagnosis of cancer.
31:45And as as you might imagine,
31:48people with such a diagnosis often develop
31:51chronic and debilitating syndromes
31:53of either anxiety or depression.
31:55There were several studies back
31:57in the 60s or 70s that suggested
32:01that psychedelics might be an
32:03interesting intervention here.
32:05In this case, we have 51 participants,
32:09mean age, 56 have female.
32:12Most of the studies that we have
32:15done to date, you know are skewed
32:19toward educated white individuals.
32:21In this case, about 45% had some
32:25lifetime use of a psychedelic,
32:28but on average 31 years ago.
32:31So these weren't current users.
32:35This is the prognosis.
32:39About 65% had recurrent or
32:43metastatic disease.
32:4435% possibility of recurrence,
32:47and there are various types of cancers.
32:52Terms of skin diagnosis.
32:55About 40% had depressed mood,
32:5930% anxiety 3030% mixed
33:02anxiety or depression.
33:0451% had used medications previously
33:08for treatment of anxiety or depression.
33:15This is the study design.
33:17It was randomized double
33:18blind crossover design.
33:20Looking at the acute and sustained
33:22effects of a very low dose placebo like
33:25dose of still 7 one milligram for 70
33:29kilogram versus a moderately high dose.
33:31And and we administered that
33:34very minimal dose, partly blind,
33:36for blinding reasons.
33:37I can go into that in more detail,
33:40but people were told that they
33:43were going to receive psilocybin.
33:45The dose might vary.
33:46They were not told that there
33:49were simply 22 conditions,
33:51and that instruction set was similar
33:54for both the guides and the volunteers.
33:57So we're bending over backwards to.
34:01To blind the study as best as we
34:04could with respect to expectancies.
34:07Some people were randomized
34:09to just two session orders.
34:11They either received the high
34:13dose first on session one,
34:15and then there's a five week follow up,
34:18followed by the low dose or or the
34:21inverse sequence of dough sing,
34:24and then we did a six month follow up.
34:28Not surprisingly,
34:30under these conditions.
34:32People are reporting mystical
34:34type experiences.
34:35You can see our low dose session actually
34:38produces a not inconsequential elevation
34:41of this and that's as it should be.
34:44People are told they're
34:46going to get psilocybin.
34:48These are conditions are optimized
34:50to produce these kinds of effects,
34:53but a much bigger effects
34:55with still assignment.
34:57And here's the Attribution of meaning
34:59spiritual significance and well,
35:01being.
35:01Orange bars showing five
35:03weeks after the high dose.
35:06And blue bars now are showing that these
35:09effects are sustained out to six months.
35:13OK, So what about our clinical measures?
35:17So this is Hamdy Gold standard
35:20clinician rated measure of depression.
35:24The left panel shows clinically
35:27significant improvement.
35:28That's 50% drop in Ham D scores.
35:32So you're seeing about 92% of participants
35:36showing clinically significant
35:38improvement five weeks after the high dose,
35:42and that's sustained.
35:44It's six months.
35:47And then in the right panel,
35:49remission to the normal range.
35:52That's a handy score of seven or less
35:55considered to be in the normal range,
35:5960% at the end of five weeks
36:02and 70% at six months.
36:04Hamdy is showing very
36:07similar kinds of results.
36:09So we concluded from this study
36:12single moderate dose of psilocybin,
36:14when administered under supported
36:16conditions to these carefully
36:18screen and prepared participants can
36:20produce substantial and enduring
36:22decreases in depressed mood.
36:24In these people would like threading,
36:27cancer diagnosis and and the NYU
36:30Group ran a very similar study,
36:33slightly smaller in and got
36:36very similar conclusions.
36:38OK,
36:39moving on to the treatment
36:42of major depressive disorder.
36:45Don't need to tell your Department,
36:49but depressions of serious
36:51concern and I leave it at that.
36:55This study we reported JAMA
36:58Psychiatry just last month.
37:01And it was a randomized delayed
37:03treatment or or wait list control
37:06trial examining the efficacy
37:08of two psilocybin sessions,
37:10either 20 or 30 milligrams, for 70 kilogram.
37:14Sequentially 1st 20,
37:17then 30 under psychologically
37:20supported conditions.
37:21This is the study design,
37:24so there was a screening baseline.
37:27People randomized to immediate
37:29treatment or delayed treatment.
37:31They after preparation they receive
37:34two psilocybin sessions and then
37:36they followed up with handy.
37:39So the delayed treatment you
37:41literally just was delayed.
37:43They got timing of their hamdis
37:46were at similar time points and
37:49then they were crossed over.
37:52To the active condition.
37:5524 subjects mean age, 40 years,
37:58females overrepresented again.
38:01Educated white mean duration of illness.
38:0522 years duration of current episode
38:0824 months 58% had failed one or more
38:13medical trials in the current episode,
38:17baseline Hamdis were 23%.
38:19About 25% had some lifetime
38:23use of psychedelics.
38:25Hi, mystical experience scores.
38:28Not much of a difference
38:31between the two doses.
38:33And here's blinded handy ratings in
38:36the delay treatment and the immediate
38:40treatment at 5 weeks and eight weeks.
38:44So we're seeing huge effects.
38:47Major consti SUV.
38:50Well over 2.
38:53And this is showing data combined
38:56across the groups just showing that.
38:59The delay group decreased just
39:02in the very same way that the
39:05immediate group did post treatment.
39:09This is clinically significant response
39:12in the upper panel showing that one
39:15week for week and 12 weeks we have about 70%.
39:20And remission.
39:21At the same time,
39:24points is about 50 minutes better than 50%,
39:28which is very good.
39:30Here's quids.
39:31This is a patient rated depression
39:34inventory showing rather similar effects.
39:36I can't account for why that increased
39:40in the late treatment group at 5 weeks,
39:44but nonetheless big effect sizes,
39:47and this is interesting because we
39:50gave the quids post session days.
39:53And so what's shown here?
39:56This is collapsed across both
39:59groups is changing.
40:00Score from Baseline today day one
40:04post session one is that first
40:07point suggesting that we're getting
40:11full on therapeutic effects even
40:14the day after the first session.
40:20This is Beck depression inventory.
40:22Then this is just showing
40:25the same kinds of effects.
40:27Here's Patient health questionnaire,
40:30patient rated depression,
40:32large effect sizes. Here's hammeh.
40:37State trade inventory patient rated.
40:41And suicidal ideations with
40:44not significantly different,
40:45intended to decrease, and in both groups.
40:50Sport conclusions here are the
40:52modern high dose of psilocybin when
40:55administered under supportive conditions,
40:57can produce substantial in and
40:59during decreases and depressed mood.
41:02Depression was subsequently deep
41:03was substantially decreased the day
41:06after the first monitor dose session,
41:08suggesting that a single dose may be
41:12adequate for therapeutic response.
41:14Treatment did not exacerbate
41:16depression in any participant.
41:18I didn't didn't show you that,
41:21but there was no indication that
41:24treatment exacerbated depression.
41:26Two of the 24 participants had little or
41:29no therapeutic response, and and were.
41:34Working up our follow up data now but these.
41:38These attacks are impressively
41:41sustained out to our one year followup,
41:45with some some recurrence,
41:48but nonetheless it's it's interesting.
41:51Um?
41:52Big limitation of this study is
41:54that didn't include a placebo or
41:57pharmacologically active control condition.
41:59But as I said, that's a it's a.
42:03Very difficult to figure out.
42:06Well,
42:06I don't think there's any single
42:09comparison condition that actually
42:12results in an adequate control.
42:15And in terms of status,
42:17FDA is given breakthrough therapy
42:20status designation to two companies
42:23that are working now with psilocybin
42:26for indications of either treatment
42:28resistant depression or MDD.
42:31And so if those trials are positive,
42:34that's a big.
42:36If you know the FDA approval processes.
42:41Incredibly involved,
42:42but it could result in approval
42:46of psilocybin for medical use
42:49and I would guess it will take.
42:52Four to six years for that to occur.
42:55OK, turning now to treatment of addiction.
42:59Why would we have even thought of addiction?
43:03Well,
43:04you know there's anthropological evidence
43:07from Native Americans suggesting that
43:09addictions of reasonable thing to do,
43:12and also again look reflecting
43:14back on earlier studies in the
43:181950s and meta analysis and recent
43:20study in Alcoholics suggests that
43:23addictions are reasonable target.
43:26In this case,
43:28this study was led by Matt Johnson
43:31from our group and our first study
43:34was a simple pilot study looking at
43:39psilocybin facilitation of treatment
43:41cessation with cognitive behavioral
43:44therapy for smoking integrated
43:46into our standard preparation
43:49and support for psilocybin.
43:51We offered up to three psilocybin sessions,
43:55first one being 20.
43:57Milligrams for 70 kilograms that
44:00corresponded to the target quit date
44:03for smoking and then two subsequent
44:06sessions so it's open label.
44:09It's very weak in that respect.
44:1215 participants mean age 50 years.
44:15Males over represented 19
44:17cigarettes per day on average.
44:20Mean year.
44:21Smoking 31 mean previous quitus attempt 6
44:24so these are chronic long-term smokers.
44:28But the results are astonishingly
44:31clear when you look at them like this.
44:34This is urinary code, Nina,
44:36major metabolite,
44:37for for nicotine.
44:39And you can see in the left there
44:41prior to the target quit date when
44:44people are learning the cognitive
44:46behavior therapy approaches,
44:49code mean is maintained at
44:51relatively stable levels.
44:52They hit the target quit date
44:56corresponding to that first.
44:58Session and these are median
45:01levels dropped to 0,
45:03so there's some. Some variation,
45:08but they are sustained at.
45:13At very low levels and
45:15at six months follow up,
45:18we had 80% abstinence, which.
45:21In the smoking cessation business
45:23is just an absurdly high number
45:27and and so really calls on us
45:30to continue to look at that.
45:33This is some follow up data with Johnson.
45:37He has published this that's incorrectly
45:40labeled looking at 7 point prevalence
45:43abstinence rates out to 30 months,
45:46which is still up to 60%.
45:51So this whole area I should also say
45:55Matt now has moved onto an is a good way
46:00through a comparative efficacy trial.
46:04Comparing psilocybin to nicotine replacement
46:07therapy in the results of that look,
46:10very look very promising.
46:14So that works that works going on and
46:17and we're looking for opportunities to
46:19expand the cigarette smoking research,
46:22but I just wanted to point out
46:24with respect to addiction,
46:26Michael Bogen shoots at NYU, you has some.
46:31Very promising data with alcohol dependence
46:34that we expect should be published.
46:37Certainly in the next several months.
46:40Um? Peter Hendricks has a small study in
46:44cocaine use disorder down in Birmingham,
46:48AL, which looks quite promising and
46:51we did a cross sectional survey study
46:55documenting naturalistic psychedelic use
46:59associated with reductions in cessation
47:02of opiate cannabis and stimulant use,
47:06with substantial decreases and
47:08substance use criteria so so.
47:12The concept here is that there really could
47:17be significant transdiagnostic applicability.
47:22So earlier I spoke about the
47:24biological mechanism of action.
47:26I just now want to kind of pick up on.
47:31Psychological or cognitive mechanisms
47:32of action and just throw out some
47:35ideas floating around about those.
47:37So one is mystical experience
47:39as as an important component,
47:41and I'm going to show you a little bit
47:46more data on that in just a second.
47:49And these are.
47:51These aren't independent,
47:53but another of label ontological
47:55shock resulting in profound shift
47:58and sense of self and worldview
48:01that may result in a reconstruction
48:03of life story and hallucinate,
48:06loosening himself focused narrative.
48:08Another is this insight about self
48:11or relationships could be experienced
48:14as memory or catharsis.
48:16I mentioned that we've developed a
48:20Psychological insight questionnaire.
48:21Another domain,
48:22just this sense of increased
48:25self efficacy or agency.
48:27Openness to.
48:30Seeing the world differently
48:32to trying alternative things,
48:35curiosity about the nature of
48:38mind or consciousness, that's.
48:41Akin to increased mindfulness.
48:43And that may be at play and then
48:47this interesting one kind of varied
48:50or tolerance for an interest
48:53in benefiting from discomfort.
48:55Um?
48:57Turning to mystical experience,
48:59now I just want to show you the.
49:03The correlations that have.
49:06I that have been demonstrated across a
49:09range of studies showing that mystical
49:12experience predicts positive outcomes,
49:14so this was in healthy volunteers
49:17and I already said this.
49:19Mystical experience scores predict.
49:22The meaningfulness,
49:23spiritual significance and
49:24openness in personality.
49:2614 months later and that's shown
49:28in the left panel there there's
49:30a mysticism SCORM immediately
49:32after psilocybin is correlated
49:35significantly and positively with.
49:37In this case its rating of
49:40spiritual significance.
49:41Set at one year or 14 months and
49:45that correlation does not hold
49:47true in the right hand panel.
49:50For the intensity of the psilocybin effect.
49:53And so we've seen variations of
49:55that across a range of studies,
49:57so this is our mystical.
49:59This is the can.
50:01Search study where mystical experience
50:03scores predicting decreases in
50:05depression and anxiety at 5 weeks.
50:08This is the major depressive disorder study.
50:13Again,
50:13mystical experience predicting
50:15decreases in depression.
50:18This is mystical experience scores
50:20predicting decreased smoking,
50:22craving and smoking is biologically
50:25measured at 6 and 12 months.
50:30This is the model that we have actually.
50:34Currently favoring and thinking about
50:36this fell out of a large survey study,
50:40but I think there's some value in this Ann.
50:45What's showing here is this is a
50:49path model looking at survey data,
50:52but when it's showing is that.
50:56Their their tune fact interactive factors
50:59that is this acute miskell if it affects
51:03in this acute insightful effects,
51:06and they seem to feed into this
51:08mediating construct of increases
51:11in psychological flexibility.
51:13And that's a there solid measures of
51:16that that have come out of the Act,
51:20psychotherapy, literature,
51:21and that accounts for decreases
51:24and depression and anxiety.
51:28So the overall conclusion and implication
51:32of this work is under these conditions.
51:36Psilocybin occasions, discrete experiences,
51:38having marked similarities to classic
51:41mystical insightful experiences.
51:43These experiences are associated
51:45with enduring positive trait
51:47changes and attitudes,
51:49moods and behaviors in both
51:52healthy and patient populations.
51:55And then when I find most intriguing,
51:59is that the finding that psilocybin can,
52:02in most people studied occasion these
52:05mystical and insightful experiences
52:07that are so similar to those that
52:10occur naturally suggests that such
52:13experiences are biologically normal.
52:15That is where we're wired to have such
52:19experiences and the exciting piece of this
52:22is that these experiences their consequences.
52:26And the basic neuropharmacology
52:29are now amenable to systematic
52:31prospective cyantific study,
52:33and they have alluded this to
52:37this to this point in time.
52:41And I often feel like.
52:45And they met.
52:46That thought is kind of Rip Van Winkle.
52:49This is an opportunity for us all
52:52within the scientific community
52:54to explore these compounds.
52:56The psychedelics that have been put
52:58in the deep freeze for a couple
53:02of decades and think about think
53:04of all the science and all of our
53:07the methods that have developed,
53:09you know, over over the last 20 years.
53:13And so there are so many really
53:16interesting questions at.
53:17Any different level that can be
53:20addressed about these compounds that
53:23really could be quite consequential,
53:25so biological psychiatry how factors
53:28such as personality, genetics,
53:29intention affect likelihood,
53:31neuroscience, ton of stuff.
53:33They're wondering,
53:34the structural functional changes
53:36in brain that account from this
53:38behavioral Sciences.
53:40What behaviors are changed with
53:43behavioral mechanisms can account
53:45for such experiences.
53:47Then of course we have the whole
53:49area of therapeutics and the
53:51exciting prospect that there might
53:54be cross diagnostic generality to the
53:56efficacy of these of these drugs,
53:59but yet is yet to be proven.
54:02And then and then a piece that I can't
54:05help but feel is deeply important,
54:09but we don't have.
54:10We don't have funding agencies
54:13to allow us to pursue it.
54:15Is this the fact that these drugs can?
54:19Increase these tendencies towards
54:21altruism and pro social behavior.
54:23It really couple into ethical systems
54:27that have been promulgated by major
54:30religious traditions and are are
54:32so integral to the survival of our
54:35culture and ultimately to our species.
54:38And I think with these compounds,
54:41among others,
54:42will allow us to get purchase
54:46an unstudied such effects.
54:48Song, I think that I think that's it.
54:51Thank you very much.
54:55Thank you Roland for a
54:57wonderful talking edit.
54:57It's an overview of this
55:00extraordinary body of work.
55:02Really exciting to see and
55:03to see you synthesize it.
55:06We have a good bit of time for
55:09questions now and I guess let's see.
55:11If I can see if people can raise their hands.
55:16And I can call on you, or you're
55:18welcome to put questions in the chat.
55:21As well. And I want to ask a quick
55:25one if I made to get things started,
55:28which is you shared at the beginning.
55:31This model,
55:31which is intuitively quite compelling,
55:33especially in light of the default
55:35mode network effects of the drugs.
55:37That perhaps what's happening is
55:39the drugs are acute psilocybin
55:40and perhaps other drugs.
55:42Other psychedelics are acutely
55:43dissociating the mechanisms of
55:45sense of self and then they are
55:47being reconfigured or reassembling
55:48in a more adaptive or positive way.
55:50My question is that in the context
55:53of psychopathology.
55:54If you are turning,
55:55if you're rebooting the computer,
55:56you know if you're if you're disrupting
55:58the sense of the integrative sense
56:00of self and then reassembling it.
56:02Why should it reassemble in
56:03a more adaptive way?
56:06But why is that good?
56:12I haven't I have. I have no idea.
56:17I mean, it's yeah, it's it's,
56:20it's highly. Curious that the even
56:24that these effects seem to be skewed
56:29toward this positive beneficial.
56:34You know outcome?
56:36I mean it wouldn't.
56:38Ah, Priora, you wouldn't think
56:40that would need to be true.
56:42Yet it is. Yeah, yeah.
56:47I don't know, you know,
56:49you know other than the thought is
56:52that it's it's pretty clear in the
56:54context in which we now find ourselves,
56:58and in these cultures that that
57:00we get entangled in, you know,
57:03a web of narrative structures
57:06of you know that sets out our.
57:10Our our moment to moment
57:12priorities in terms of the kind
57:14of a narrative context of what
57:17of how we're viewing the world,
57:19and if you pull back from
57:22that very substantially,
57:23there can be this shift
57:26that occurs that that.
57:28Wakes people up to the idea
57:31that there's those narrative.
57:33Trues are only one aspect of what
57:36it is to be aware in a in a in in
57:40the fully functioning amazement
57:42that we are actually these.
57:45Highly evolved.
57:47Creatures that have developed
57:51this capacity for language and
57:55to to change our environment.
57:59We've invented mathematics and.
58:03And and yet the most astonishing
58:06piece of that mystery is that we're
58:08aware that we're aware that we had,
58:11that that we're in this this awareness,
58:14and that needn't necessarily be the case.
58:16And so if someone is ripped out of
58:19that narrative structure and kind
58:21of blinks at the astonishment of
58:24what we don't understand but is so
58:27compellingly true about the human condition,
58:29that we're all in this together.
58:31In this mystery of not knowing what
58:34the hell is actually going on here.
58:37Uh, you know, perhaps there's.
58:42Deep potential therapeutic value to that.
58:48As you say it empirically, true,
58:49yes, so we have. We have a number of
58:51hand raised in quite a lot in the chat,
58:53so I'm going to call and fill Corlett.
58:56Thanks so much for a brilliant talk and
58:59beautiful work. I have a question
59:02about a potential experiment that you
59:04might do to resolve this debate about
59:08the necessity of mystical experiences.
59:11Are you considered or do you know of
59:13anyone who's trying to administer
59:15these substances to people who are
59:17unconscious under other anesthetics?
59:18Because of course,
59:19that would be one way of showing that you
59:22get these therapeutic improvements in
59:24the absence of the mystical experiences.
59:26Full disclosure,
59:27I'm betting on the mystical experience
59:29is actually being a mediator,
59:31but but I'm interested in your
59:33thoughts there.
59:35Yeah, well, thanks for asking that.
59:38So this viewpoint article we
59:41actually proposed that as the as the
59:46critical question to disprove the
59:49importance of psychedelic experience.
59:52It might be an impossibly
59:55difficult experiment to run
59:57to come to any final conclude.
01:00:01But yeah, the idea is yeah,
01:00:03if you fully anesthetize someone.
01:00:05And then give them a full on psychedelic.
01:00:08Maintain the anesthesia past the point
01:00:11that the psychedelic is no longer active
01:00:14and then allow people to come out.
01:00:17They have no memory of
01:00:19having gotten psilocybin.
01:00:20And then the question is, are they?
01:00:23Are they therapeutically?
01:00:24You know benefited from that
01:00:27and if this is all. Uh.
01:00:30If this is all neurogenesis, and then,
01:00:34then you're going to have full on
01:00:37therapeutic effects, and we think that's.
01:00:41Incredibly unlikely.
01:00:44But you know the problem with that
01:00:47is that even if you didn't show the.
01:00:51Uh.
01:00:54The. That in during effects of.
01:01:01The the psychedelic.
01:01:03It could be argued that whatever
01:01:07anesthetic you gave interrupted that
01:01:10you know whatever narrow genic.
01:01:15Neural processes underlying
01:01:17neural processes and would have
01:01:19under undermine those, and so you
01:01:23wouldn't have a final Test of that.
01:01:27But it does. It seems to me
01:01:30that there's there's something.
01:01:32Profoundly important.
01:01:35About this shift in narrative structure,
01:01:38'cause if you if you think of it,
01:01:42you know for for our cigarette smokers,
01:01:45for instance,
01:01:46they come in and they identify
01:01:48as being addicted to cigarette
01:01:50smoking and they and for good
01:01:53reason they've they've quit numerous
01:01:55times and an failed and relapse,
01:01:58they know that they concede to craving.
01:02:03And if they hold themselves as addicted,
01:02:06then that's that's exactly what they are.
01:02:09I mean, they're never going
01:02:11to get out of that,
01:02:13but you change that narrative
01:02:15structure and make it plausible to
01:02:18them that they they have a sense
01:02:20of freedom and efficacy that they
01:02:23didn't imagine they had before.
01:02:25And then everything ships here.
01:02:27You really,
01:02:28it's almost like you're rewriting
01:02:30the operating system.
01:02:31If you can change that.
01:02:34Narrative structure because the self
01:02:36instructions that they're going to
01:02:38be giving themselves going forward
01:02:40are going to be very different,
01:02:42and my guess is that that's at play in,
01:02:46you know,
01:02:46in a lot of the therapeutic kinds
01:02:49of effects that we're going to see.
01:02:55Jerry, I think your sister next and
01:02:57I saw. Yep, can you hear
01:02:58Chris so role in great.
01:03:00Great job and just sorry you couldn't
01:03:01be there in person to to be with you.
01:03:06Just a very quick comment on.
01:03:07Yeah, I think anesthetize Ng
01:03:09somebody in doing it could be a
01:03:10real problem even with cada mean.
01:03:12We can see if.
01:03:14If we give high enough dose even we
01:03:16don't get these physiologic changes,
01:03:18so I think that's a problem,
01:03:20but that wasn't the main point.
01:03:22The big point I have is I don't
01:03:25see maybe the discrepancy or seems
01:03:27like a false dichotomy between
01:03:29all sending you in terms of.
01:03:32Yeah, what?
01:03:34Is going on in terms of the
01:03:36psychological and biological.
01:03:37If you look at it in terms of.
01:03:40Just these drugs, including you know
01:03:42all the psilocybin and keta mean
01:03:44actually having this
01:03:45ability to induce cognitive
01:03:46flexibility. Then there's
01:03:47this huge component of expectation
01:03:49and how you build this up.
01:03:51And I'm not sure I.
01:03:53I guess what my question to you
01:03:55is how sure are we that it's the
01:03:58mystical experience part of it?
01:04:00'cause all these people are prepped
01:04:02for it to have this mystical experience
01:04:04in the prep sessions usually correct?
01:04:06Where in Europe they usually
01:04:08don't prep them so much and they
01:04:10don't. Report so much of the mystical
01:04:12experience. Could you
01:04:13just comment on, you know,
01:04:15is that the critical thing? Or is it
01:04:18the fact that you're getting
01:04:19a drug that induces cognitive
01:04:21flexibility and you're doing
01:04:22something to reinforce that?
01:04:25Yeah, let's see. So I mean,
01:04:28there's no question that the seven
01:04:30setting conditions are primary
01:04:32determinants of of what people
01:04:34come out of these experiences.
01:04:36And it is the case that our.
01:04:41Set and setting conditions and preparation
01:04:44conditions are optimized to provide support.
01:04:48You know for this deeply introspective
01:04:52introvertive kind of experience.
01:04:54Our initial studies.
01:04:56We actually bent over backwards not to.
01:05:01Matt to provide.
01:05:05The suggestion that people are going
01:05:07to have mystical experiences. Um?
01:05:10But nonetheless they did, and that was,
01:05:13I think, what was so compelling
01:05:16to me about that initial work is
01:05:19how that really was falling out.
01:05:22Now, however, it's totally unavoidable.
01:05:24I mean, the word is out.
01:05:26It's in their culture, and we and we can't.
01:05:30We can't, possibly, you know,
01:05:32pull back that expectancy.
01:05:34And so that's you.
01:05:36Know that that is a real challenge in
01:05:39terms of how you know what controls you
01:05:43want and how you tease out the role of that.
01:05:48But I do think you know,
01:05:51with mystical experiences,
01:05:53still that there's something about this.
01:05:56Dissolving of a worldview.
01:06:02As a sense of worldview and a sense of self.
01:06:06And getting a different
01:06:08perceptual set on that.
01:06:10That is as I described as ontological shock.
01:06:13It's like wait a second.
01:06:16What I thought to be true.
01:06:19I no longer no.
01:06:21To be true, you know everything's
01:06:24on the on the table here,
01:06:26and for whatever reason.
01:06:28People feel empowered by that it's it's.
01:06:32It's not scary.
01:06:34It's it's an opening to change.
01:06:37How we move forward to tease those
01:06:40you know kinds of things apart.
01:06:42You know for that matter I mean yeah.
01:06:47What does FDA do in terms?
01:06:49Yeah, exactly.
01:06:50That's where it really comes down to
01:06:53is when you go to implementation.
01:06:55This this is.
01:06:57To do it the way it's currently
01:07:00done would be incredibly expensive.
01:07:02We see how difficult
01:07:03it is to implement esketamine
01:07:05treatment because of the cost and
01:07:07the Accessibility limitations.
01:07:08This you know, until we can really figure
01:07:11out what the critical component is,
01:07:13it's going to be a major
01:07:16problem in implementing this.
01:07:17Yeah, I mean that I can imagine
01:07:20there may be group that there's.
01:07:23Could be elements of group preparation
01:07:27and certainly subtracting out some of the.
01:07:32Incredible support that we're providing
01:07:34with two, you know, folded full-time.
01:07:37Essentially therapists there
01:07:38you know for duration.
01:07:40I mean, that's just that's not going
01:07:43to be workable in the long run,
01:07:45but you know, I'm imagining there,
01:07:48you know there there could be
01:07:50changes of that sort and we have yet
01:07:54to investigate the shorter acting
01:07:56psychedelics and whether they are going
01:07:59to have some of these same affects.
01:08:01That's that's all open.
01:08:03Uh, so there's I mean there's so much
01:08:06to tease apart that's but that's why
01:08:09this is so astonishingly interesting,
01:08:11I, I think.
01:08:14Well,
01:08:14it's great to have stuff to tease apart.
01:08:18And that's what we that's what we've
01:08:21been bred to do right? As scientists,
01:08:23that's you know, this is fun.
01:08:28Congratulations. There's a lot of
01:08:31questions in the chat too that I'm
01:08:34going to lump together.
01:08:36Here are about predictors of non response.
01:08:38Have you any factors associated with
01:08:40people who experience fear or have
01:08:42negative experiences during psilocybin?
01:08:44And are there any predictors or
01:08:46characteristics of those who have a
01:08:49relatively poor clinical response?
01:08:51Not during but
01:08:52after. Yeah, you know in our hands,
01:08:56sadly no, we don't have predictors of
01:09:00difficult experiences or non response.
01:09:03We need to look for that.
01:09:07Um? You know, but.
01:09:09You know all of our subject groups have been
01:09:14highly selected and and so I think it has.
01:09:19Is this gets dispersed over
01:09:21a much larger population,
01:09:23we're going to learn a lot,
01:09:26alot more about that were.
01:09:28Yeah, we've been doing our long-term.
01:09:31Follow up now and our depression study
01:09:34and just try looking as best we can
01:09:38for predictors of of non response
01:09:40and so far nothing is showing up.
01:09:44I mean you could make the guess that.
01:09:49A number of the kinds of people
01:09:51that we would have screened out.
01:09:53Under concern about our inability to
01:09:57develop significant trust and report with.
01:10:01Then you know said borderline
01:10:06personality types,
01:10:08for instance,
01:10:10or people who hold incredibly
01:10:16rigid worldviews.
01:10:18You know those people would would
01:10:21likely be screened out because
01:10:23we would feel like we couldn't
01:10:25couldn't work with them and so
01:10:27it may very well be that you know
01:10:30populations of that type are going to.
01:10:34Are going to have more difficult times
01:10:36or or be less responsive to treatment?
01:10:40And there was actually the
01:10:42next question in the chat.
01:10:43Was about borderline personality
01:10:45and whether you or anyone
01:10:46has done work in that area.
01:10:48And I hear what you say about it may
01:10:50be difficult to form the bond and
01:10:52that maybe maybe have a qualitatively
01:10:54different experience because of that.
01:10:56On the other hand,
01:10:57your theory about rewriting the
01:10:59self narrative being the core
01:11:00therapeutic component that might
01:11:01be exactly what people with
01:11:03borderline personality needs.
01:11:04And so I wonder if you have any
01:11:07comments on that.
01:11:10Let's see well.
01:11:12Yeah, I think that's exactly right.
01:11:15It's it's unknown and God bless
01:11:18you if you want to undertake that.
01:11:23Big big big because yeah,
01:11:26we you know we have had a
01:11:30Kate occasional volunteers
01:11:32who we subsequently recognize
01:11:35have strong tendency toward
01:11:39borderline personalities and and.
01:11:42And you can imagine that they are.
01:11:47Can be very difficult to deal
01:11:49with and particularly under
01:11:51these conditions where you've
01:11:53given them something very.
01:11:55You know? Very potent,
01:11:56and if they interpreted as
01:11:59not having been helpful,
01:12:01you have your hands full.
01:12:06Want to come back to the
01:12:08raised hands? Colin LK.
01:12:11Thank you so wonderful talk in
01:12:13thinking about kind of relating
01:12:15to psychological mechanisms of
01:12:16the mystical experience
01:12:17that you talked
01:12:19about to biological mechanisms.
01:12:20I was thinking about the study from
01:12:23the Kobayakawa Group in Osaka,
01:12:24where they show that.
01:12:26Serotonin 2A receptor effects
01:12:28should decrease innate fear
01:12:30behavior but not learn fear.
01:12:32Through this central amygdala.
01:12:35Subpopulation of neurons.
01:12:37And I was wondering to what extent
01:12:40you could speculate on the relationship
01:12:42between a kind of suppression of
01:12:44innate fear or innate fear responses
01:12:46and that kind of ontological
01:12:47shock that you were describing.
01:12:52That's an interesting question.
01:12:57So you know we have not looked for
01:13:01instance at psilocybin and for treatment
01:13:04of PTSD not that's an innate fear,
01:13:07but it's an acquired very significant fear.
01:13:12Until we suspect when we have some
01:13:16funding to look at at PTS di,
01:13:19we suspect it might be,
01:13:22you know, quite quite helpful.
01:13:26But 111 concern is that is it possible
01:13:30that these kinds of experiences
01:13:33could actually re traumatized people,
01:13:36and so it's it's unknown.
01:13:42I don't think I don't think I
01:13:44have any particular thoughts
01:13:45about innate innate fears.
01:13:47What? What would an example
01:13:49of that innate fear be?
01:13:51So in this study they used kind
01:13:54of predator odorant. And what
01:13:55they show basically is that.
01:13:59That kind of fear would be suppressed
01:14:02by the serotonin 2A agonism,
01:14:04whereas learn fear would be
01:14:06the opposite, yeah?
01:14:10Interesting question.
01:14:12I don't have any. Any thoughts?
01:14:16I wonder how if innate fears were some.
01:14:21Somehow suppressed in during Lee what?
01:14:23How would that show up clinically?
01:14:26I mean, these individuals are.
01:14:29You know who report positive experiences?
01:14:34Appear to be well adjusted in engaged and.
01:14:42And and not.
01:14:46And not compromised in any sense.
01:14:50But we could be missing something.
01:14:56I have several questions in
01:14:57the chat that are speaking to
01:14:59the demographics of the samples in
01:15:01your study, which you acknowledged
01:15:03are large majority white and large
01:15:05majority highly educated. And as I said,
01:15:08there are several questions on this,
01:15:10but if you could speak to the gender,
01:15:12how that may limit the
01:15:13generalizability of this,
01:15:14what you are doing practically,
01:15:16and what other groups can do practically
01:15:18to try to mitigate it going forward
01:15:20and what you see the role of these.
01:15:23These approaches being to address
01:15:26difficulties that may be specific
01:15:28to other groups.
01:15:30For example,
01:15:31the experience of racial trauma and
01:15:33chronic stress source associated with
01:15:36minority status, yeah, well.
01:15:38Let's say it's it's unknown,
01:15:41so it's a you know a significant
01:15:44limitation of what we have
01:15:46done to date and and you know,
01:15:48I've wondered a lot about that.
01:15:52Peter Hendricks is doing this work.
01:15:55The time that I referenced
01:15:58in burning Birmingham, AL.
01:16:00On cocaine dependence.
01:16:02And Interestingly,
01:16:04the demographics of the
01:16:05group that he's looking at,
01:16:08and it's just been a small number,
01:16:10but it's it's mostly.
01:16:15Very underprivileged minority communities.
01:16:18Large, largely black.
01:16:22And and yet his reports to date have
01:16:26been that the intervention with
01:16:29psilocybin has been hugely effective.
01:16:35His his group, it actually gets to
01:16:39the expectancy question. Curious too.
01:16:44His group is such that he claims a
01:16:47number of the individuals who have
01:16:51enrolled in treatment haven't had
01:16:54no idea what a psychedelic even is,
01:16:58and so somewhere there they're coming in
01:17:02with zero expectancies in that score.
01:17:06Yet they feel.
01:17:07Are there yet the results appear
01:17:10to be very positive,
01:17:12so I so I simply don't know I I
01:17:15actually was astonished when Peter
01:17:17initially told me of those results,
01:17:20'cause I I think I would have predicted
01:17:23that so much of this is about cut
01:17:26cognitive meaning and interpretation,
01:17:28and that that's less likely
01:17:31going to be the case.
01:17:34In underprivileged population,
01:17:37you know, and then in terms of,
01:17:40you know, racial trauma.
01:17:42You know of some type.
01:17:44I mean that that kind of fits with,
01:17:47you know, perhaps the PTSD question.
01:17:50I think it just remains to be to be examined.
01:17:57Thanks. I'm gonna go back to the
01:18:01raised hand Zoncolan and reading.
01:18:04Hi, thanks for your work,
01:18:06Doctor Griffiths.
01:18:07I remember reading some of it in
01:18:09College in 2007 and never thinking
01:18:12that this could ever be related to
01:18:15my career and as a resident now.
01:18:18It's amazing to see the
01:18:20possibilities that exist.
01:18:21So my question was you mentioned the
01:18:24overlapping perspectives fostered
01:18:25by psilocybin and those of major
01:18:27religious and spiritual traditions? To
01:18:29what degree has I guess
01:18:31spiritually or emergently
01:18:33oriented thinking?
01:18:34Kind of driven your.
01:18:35Hard science, so to speak,
01:18:38hypothesis generation.
01:18:42Yeah, I don't think I'm quite
01:18:47catching what. Restate the question to
01:18:50what extent, to
01:18:52what extent has like I guess more
01:18:55spiritually oriented thinking?
01:18:58As a lot of this kind of reminds me of kind
01:19:03of Eastern spiritual constructs driven,
01:19:05your creation of hypothesis within a
01:19:08more kind of Western hard science system.
01:19:13Well, let's say so my my personal story
01:19:17is that I was doing psychopharmacology
01:19:21for decades at Johns Hopkins.
01:19:24Mostly on mood altering drugs.
01:19:27Most of my research is funded by Hnyda,
01:19:30so I was really interested in mood altering
01:19:34drugs and measurement of subjective
01:19:36effects and then about 25 years ago I
01:19:40started a meditation practice that was.
01:19:43Pivotal to me it just got me
01:19:46asking questions about changes and
01:19:48worldview with nature of meditation.
01:19:50What you know? What is this?
01:19:53How does this fit in with spirituality?
01:19:56You know more broadly and I I had no.
01:20:03Particular religious affiliation,
01:20:04or even grounding in spirituality.
01:20:08So so so I got it intellectually
01:20:12interested in that question,
01:20:15and that actually prompted me to start
01:20:18reading the older literature on psychedelics.
01:20:23An an you know,
01:20:26eventually proposing to do.
01:20:28A study with psilocybin.
01:20:30So I was I was moved to to initiate this
01:20:34research because I was deeply curious
01:20:37about transformative experiences.
01:20:40And that and that continues to be the case.
01:20:44I mean, I'm I'm I'm very interested
01:20:46in my own exploration of the
01:20:49nature of experiences and then and
01:20:52then nature of what is true at
01:20:55the deepest level and and how to.
01:20:57How do I interpret that?
01:20:59And so that has led us to this
01:21:02series of studies that I didn't
01:21:05talk about an beginning,
01:21:07meditators and long term
01:21:09meditators in the study were just.
01:21:11Concluding in religious clergy.
01:21:15Because I'm really interested in
01:21:19the interplay between those things.
01:21:24But so I guess the answer to
01:21:27the question is that that.
01:21:29I'm interested in that, but I don't.
01:21:33I don't think that has.
01:21:37Impacted this in.
01:21:38The the core of a science that
01:21:42I want to do and how I want to
01:21:45understand the mechanisms that
01:21:48whether the reason I ask is because
01:21:51it seems like the cross disease
01:21:54or the fact that it affects a
01:21:57variety of diseases that might
01:21:59not from a more reductionist
01:22:02perspective seem to be linked.
01:22:04It makes much more, so to speak,
01:22:07common sense from a more
01:22:09like spirituals psycho.
01:22:11Dynamic respective issues like
01:22:12personal narrative and spirituality
01:22:14with regard to like addiction
01:22:16and depression and so forth.
01:22:17Yeah, I mean,
01:22:19but you wouldn't. You wouldn't need
01:22:21to bring spirituality into it.
01:22:23I mean, it could be.
01:22:25Yeah, it could be changed
01:22:27in narrative structure,
01:22:28and in that sort of thing,
01:22:31but I am interested in that.
01:22:33I just want to comment on the
01:22:36your initial comment about you.
01:22:38Having read about this in 2007 and thought
01:22:42there's no way that you would touch it.
01:22:46We have a couple of postdocs who
01:22:48are in our who were residents
01:22:51in psychiatry at Johns Hopkins,
01:22:53and now have gotten very involved
01:22:55in our work and are doing some
01:22:58some really interesting things.
01:23:00An just earlier this week they gave a
01:23:04presentation to GW medical students and
01:23:06I asked him what was that like and they said,
01:23:10you know there were.
01:23:12They have 40 students on the line and I said,
01:23:16well. Was there skepticism because I
01:23:18haven't gotten into this work initially?
01:23:21There was plenty of skepticism
01:23:23within the psychiatric community,
01:23:25and they said no, not at all.
01:23:28There's a lot of enthusiasm,
01:23:30and then one of them reflected that
01:23:33when when she was in medical school.
01:23:36Like you, she actually had this
01:23:38curiosity about psychedelics,
01:23:40but she felt like she needed
01:23:42to keep it a secret,
01:23:44and so she should go out.
01:23:47On the Internet and kind of
01:23:49explore this kind of stuff,
01:23:51but it was not a topic that she was even
01:23:55willing to broach with her mentors at
01:23:58the time because it was it was considered.
01:24:02Ascentia a taboo subject,
01:24:04so so the that the shift within psychiatry
01:24:07and the culture is just been profound.
01:24:10In that sense,
01:24:11I felt that way.
01:24:13So thank you for making that
01:24:15less of a concern.
01:24:20I think we're going to have to
01:24:21make this next. The last question
01:24:23I want to call Angela Heating.
01:24:29Oh yes, well you kind of
01:24:30asked my question earlier,
01:24:32but I was just wondering if you
01:24:33could talk a little bit about the
01:24:35roots of psychedelic treatment.
01:24:37An traditional healing practices
01:24:38in communities of color and one
01:24:40of your colleagues, Alan Davis,
01:24:41just recently published a paper in
01:24:43collaboration with Doctor Monica Williams.
01:24:45Um on a secondary or data collection.
01:24:48Looking at the effects of racial
01:24:50trauma and reduce the effects
01:24:51of psychedelic use in reducing
01:24:53racial trauma among black,
01:24:55indigenous and other people of color.
01:25:00Yeah, let's see.
01:25:01So I yeah, I think that's it.
01:25:04Certainly open area investigation.
01:25:06There's a lot that can be done with that.
01:25:10You know in terms of where how this
01:25:13interfaces with Indigenous use.
01:25:17I I kind of deeply conflicted
01:25:21feelings about that.
01:25:23I mean, there's there's a lot
01:25:28of wisdom that's come out of.
01:25:32Indigenous communities that
01:25:34have used these sorts of.
01:25:37Substance I'm sure but.
01:25:41But we we get into, you know very.
01:25:45Tricky an as yet unresolved.
01:25:49No set of ethical questions about how.
01:25:56What is the world view that the
01:25:59therapist holds an an and what is
01:26:03the world view that we're going to
01:26:06structure these experiences around?
01:26:10And I did and I have and I
01:26:13have concern because of the.
01:26:16Ontological shock characteristics of
01:26:19these kinds of experiences that under.
01:26:24Set and setting conditions you know
01:26:27that would encourage a very radically
01:26:30different and alternative worldview that
01:26:33you might open people up to that Ann.
01:26:37And I'm not wise enough to
01:26:40understand what the consequences are,
01:26:42but, but to the extent that.
01:26:47It disconnected from some of the
01:26:50understandings that we hold in
01:26:53our current culture that I see
01:26:55that as as deeply problematic.
01:26:58So I think there are some really
01:27:01interesting questions to be asked there,
01:27:02but to get to get back to your point yet,
01:27:05yes, certainly there are going
01:27:08to be opportunities for.
01:27:10To address.
01:27:12Psychological problems that
01:27:15come out of trauma.
01:27:19Do too.
01:27:20Minority status in the line.
01:27:25Alright. So we do have questions
01:27:27continuing to come in in the chat,
01:27:29but I think we're at
01:27:30where it's time boundary.
01:27:31I haven't managed to convey every
01:27:32single question in the chat,
01:27:34but I think we've hit on
01:27:35the majority of the themes.
01:27:37And this has been a wonderful
01:27:39rich discussion.
01:27:40I want to thank you again,
01:27:42rolling for coming.
01:27:43Being with us today in our last
01:27:45grand rounds of this remarkable
01:27:47year and ending it on such a
01:27:50high note with this beautiful
01:27:51talk and rich discussions.